Journal articles on the topic 'C4 protein deficiency'
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Lokki, Marja-Liisa, Antonella Circolo, Pirkko Ahokas, Kristi L. Rupert, C. Yung Yu, and Harvey R. Colten. "Deficiency of Human Complement Protein C4 Due to Identical Frameshift Mutations in the C4A and C4B Genes." Journal of Immunology 162, no. 6 (March 15, 1999): 3687–93. http://dx.doi.org/10.4049/jimmunol.162.6.3687.
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Abstract The complement protein C4, encoded by two genes (C4A and C4B) on chromosome 6p, is the most polymorphic among the MHC III gene products. We investigated the molecular basis of C4 deficiency in a Finnish woman with systemic lupus erythematosus. C4-specific mRNA was present at low concentrations in C4-deficient (C4D) patient fibroblasts, but no pro-C4 protein was detected. This defect in C4 expression was specific in that synthesis of two other complement proteins was normal. Analysis of genomic DNA showed that the proposita had both deleted and nonexpressed C4 genes. Each of her nonexpressed genes, a C4A null gene inherited from the mother, a C4A null gene, and a C4B null gene inherited from the father, all contained an identical 2-bp insertion (TC) after nucleotide 5880 in exon 29, providing the first confirmatory proof of the C4B pseudogene. This mutation has been previously found only in C4A null genes. Although the exon 29/30 junction is spliced accurately, this frameshift mutation generates a premature stop at codon 3 in exon 30. These truncated C4A and C4B gene products were confirmed through RT-PCR and sequence analysis. Among the possible genetic mechanisms that produce identical mutations in both genes, the most likely is a mutation in C4A followed by a gene conversion to generate the mutated C4B allele.
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Yu, Chack Yung, Ji Yih Chen, Yee Ling Wu, Mo Yin Mok, Yeong-Jian Jan Wu, Katherine E. Lintner, Chin-Man Wang, et al. "Effects of Complement C4 Gene Copy-Number Variations, Gene Size Dichotomy and C4A-Deficiency on Genetic Risk and Clinical Presentation of East-Asian and European Systemic Lupus Erythematosus (SLE)." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 193.10. http://dx.doi.org/10.4049/jimmunol.196.supp.193.10.
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Abstract Human complement C4 is complex with multiple layers of diversity. This study aims to elucidate the copy-number variations (CNVs) of C4A and C4B in disease risk of SLE, and compare the basis of race-specific C4A-deficiency in East-Asians (EA) and Europeans. Our study-populations included (a) 999 EA-SLE patients and 1,347 healthy subjects; and (b) 232 European SLE patients and 500 healthy subjects. Variations in gene copy-numbers (GCNs) for total C4, C4A, C4B, long and short genes were determined and validated by independent genotyping technologies. Genomic regions with C4B96 were investigated to determine the basis of the most basic C4B protein that is concurrent with C4A-deficiency. In EA, strong protective effects for high GCNs of total C4 and C4A against SLE were notable; low and medium GCNs of total C4 and C4A, and the absence of short genes were risk factors for SLE. Homozygous C4A-deficiency was infrequent but had an odds-ratio (OR) of 12.4 (p=0.0015) in SLE. Low serum complement levels were strongly associated with low GCNs of total C4 (OR=3.27, p=7.0×10−7) and C4B (OR=2.55, p=2.5×10−5). Patients with low complement had high frequencies of anti-dsDNA (OR=4.96, p=9.7×10−17), hemolytic anemia (OR=3.89, p=3.6×10−10) and renal disease (OR=2.18, p=8.5×10−6). The monomodular-short haplotype with C4A-deficiency and in linkage-disequilibrium with HLA-DRB1*0301 prevalent in Europeans was scarce in EA. Instead, most EA-subjects with C4A-deficiency shared a recombinant haplotype with bimodular-LS encoding C4B1 and C4B96, which was linked to HLA-DRB1*1501. DNA-sequencing revealed the E920K polymorphism for C4B96. In conclusion, C4 CNVs and C4A-deficiency are important in the risk and manifestations of East-Asian and European SLE.
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Wenderfer, Scott, Boazhen Ke, Kiprito Somio, Rick Wetsel, and Michael Braun. "Mice with combined C4 binding protein and factor H deficiency develop progressive lethal renal disease." Molecular Immunology 45, no. 16 (October 2008): 4101. http://dx.doi.org/10.1016/j.molimm.2008.08.019.
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Mulvihill, Evan, Stacy Ardoin, Susan D. Thompson, Bi Zhou, Gakit Richard Yu, Emily King, Nora Singer, et al. "Elevated serum complement levels and higher gene copy number of complement C4B are associated with hypertension and effective response to statin therapy in childhood-onset systemic lupus erythematosus (SLE)." Lupus Science & Medicine 6, no. 1 (July 2019): e000333. http://dx.doi.org/10.1136/lupus-2019-000333.
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ObjectiveSystemic lupus erythematosus (SLE) features high frequency of cardiovascular disease (CVD) and fluctuating complement levels. The clinical trial Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) aimed to evaluate whether atorvastatin treatment reduced the progression of atherosclerosis in 221 patients with childhood-onset SLE (cSLE), using carotid intima media thickness (CIMT) as surrogates. We leveraged APPLE biorepository and trial data to investigate the relationship between complement and CVD in cSLE.MethodsGene copy numbers (GCNs) for total C4, C4A and C4B were measured by TaqMan-based real-time PCR and Southern blotting, and analysed with laboratory and clinical parameters through Student’s t-test and χ2 analyses. Effects of total C4, C4A and C4B GCNs on the response to placebo or atorvastatin treatment and progression of CIMT were examined by regression analyses.ResultsAt baseline, C4 protein levels strongly correlated with GCNs of total C4 (p=1.8×10−6). Each copy of C4 gene increased mean serum C4 by 3.28 mg/dL. Compared with those without hypertension (N=142), individuals with hypertension demonstrated significantly elevated serum levels for C4 and C3 at baseline and serially (C4: P=5.0×10−25; C3: P=5.84×10−20). Individuals with ≥2 C4B genes had 2.5 times the odds of having hypertension (p=0.016) and higher diastolic blood pressure (p=0.015) compared with those with C4B deficiency. At the study end, subjects with ≥2 C4B and atorvastatin treatment had significantly slower increase in CIMT compared with those treated with placebo (p=0.018).ConclusionscSLE with hypertension had elevated serum levels of C4 and C3 and higher GCN of C4B; cSLE with ≥2 C4B genes would benefit from statins therapy to prevent atherosclerosis.
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Jack, Dominic L., Alister W. Dodds, Natasha Anwar, Catherine A. Ison, Alex Law, Matthias Frosch, Malcolm W. Turner, and Nigel J. Klein. "Activation of Complement by Mannose-Binding Lectin on Isogenic Mutants of Neisseria meningitidis Serogroup B." Journal of Immunology 160, no. 3 (February 1, 1998): 1346–53. http://dx.doi.org/10.4049/jimmunol.160.3.1346.
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Abstract Mannose-binding lectin (MBL) is a serum protein that has been demonstrated to activate the classical complement pathway and to function directly as an opsonin. Although MBL deficiency is associated with a common opsonic defect and a predisposition to infection, the role of the protein in bacterial infection remains unclear. We have investigated MBL binding to Neisseria meningitidis serogroup B1940 and three isogenic mutants, and the subsequent activation of the two major isoforms of C4 (C4A and C4B) by an associated serine protease, MASP. The mutants lacked expression of the capsular polysaccharide (siaD−), the lipo-oligosaccharide (LOS) outer core that prevented LOS sialylation (cpsD−), or both capsule and LOS outer core (cps−). Using flow cytometry, it was possible to detect strong MBL binding to the cps− and cpsD− mutants over a wide range of concentrations. In contrast, minimal or no MBL binding was detected on the parent organism, with binding to siaD− only at higher MBL concentrations. C4 was activated and bound by mutants that had previously bound MBL/MASP, but there was no significant difference in the amounts of C4A and C4B bound. When sialic acid residues were removed from the parent organism by neuraminidase treatment, the binding of both MBL and C4 increased significantly. Our results suggest that MBL may bind to and activate complement on these encapsulated organisms, and the major determinants of these effects are the LOS structure and sialylation.
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Feng, Sheng, Deborah Cooper, Lu Tan, Gail Meyers, and Michael Bennett. "Medium- and Short-Chain L-3-Hydroxyl-Acetyl-Coenzyme A Deficiency: A New Identified Mutation in Four Cases." American Journal of Clinical Pathology 152, Supplement_1 (September 11, 2019): S9. http://dx.doi.org/10.1093/ajcp/aqz112.017.
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Abstract Medium- and short-chain L-3-hydroxyacyl-coenzyme A dehydrogenase (M/SCHAD, SCHAD) deficiency is a mitochondrial fatty acid oxidation disorder (FAOD). This enzyme catalyzes the penultimate step in fatty acid oxidation, the NAD+ dependent conversion of L-3-hydroxyacyl-CoA to 3-ketoacyl-CoA for medium- and short-chain acyl-CoA intermediates (C4-C12). The clinical presentations of most patients are recurrent hypoglycemia associated with hyperinsulinism. We presented four infants with C4 acyl-carnitine elevation identified by newborn screening that also showed an unusual phenotype of congenital hypotonia and gross developmental delay. Enzymatic studies confirmed the disease. Sequencing analysis of all the HADH coding exons on the four patients revealed a homozygous variant of a novel change (c.908G>T, p.Gly303Val). Western blot analysis subsequently confirmed the lack of the SCHAD protein. In addition, there is another previously reported benign variant (c.257T>C) identified in three infants. Therefore, we postulate that the HADH variant (c.908G>T) is indeed pathogenic and associated with a severe phenotype as evidenced by the cases described herein. Population screening for the c.908G>T mutation suggests this mutation to be common among Puerto Ricans. We recommend that SCHAD deficiency is included as part of the differential diagnosis of all infants with congenital hypotonia.
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CHOU, Susan S., Michael S. CLEGG, Tony Y. MOMMA, Brad J. NILES, Jodie Y. DUFFY, George P. DASTON, and Carl L. KEEN. "Alterations in protein kinase C activity and processing during zinc-deficiency-induced cell death." Biochemical Journal 383, no. 1 (September 24, 2004): 63–71. http://dx.doi.org/10.1042/bj20040074.
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Protein kinases C (PKCs) are a family of serine/threonine kinases that are critical for signal transduction pathways involved in growth, differentiation and cell death. All PKC isoforms have four conserved domains, C1–C4. The C1 domain contains cysteine-rich finger-like motifs, which bind two zinc atoms. The zinc-finger motifs modulate diacylglycerol binding; thus, intracellular zinc concentrations could influence the activity and localization of PKC family members. 3T3 cells were cultured in zinc-deficient or zinc-supplemented medium for up to 32 h. Cells cultured in zinc-deficient medium had decreased zinc content, lowered cytosolic classical PKC activity, increased caspase-3 processing and activity, and reduced cell number. Zinc-deficient cytosols had decreased activity and expression levels of PKC-α, whereas PKC-α phosphorylation was not altered. Inhibition of PKC-α with Gö6976 had no effect on cell number in the zinc-deficient group. Proteolysis of the novel PKC family member, PKC-δ, to its 40-kDa catalytic fragment occurred in cells cultured in the zinc-deficient medium. Occurrence of the PKC-δ fragment in mitochondria was co-incident with caspase-3 activation. Addition of the PKC-δ inhibitor, rottlerin, or zinc to deficient medium reduced or eliminated proteolysis of PKC-δ, activated caspase-3 and restored cell number. Inhibition of caspase-3 processing by Z-DQMD-FMK (Z-Asp-Gln-Met-Asp-fluoromethylketone) did not restore cell number in the zinc-deficient group, but resulted in processing of full-length PKC-δ to a 56-kDa fragment. These results support the concept that intracellular zinc concentrations influence PKC activity and processing, and that zinc-deficiency-induced apoptosis occurs in part through PKC-dependent pathways.
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Ohsawa, Isao, Masaya Ishii, Hiroyuki Ohi, and Yasuhiko Tomino. "Pathological Scenario with the Mannose-Binding Lectin in Patients with IgA Nephropathy." Journal of Biomedicine and Biotechnology 2012 (2012): 1–5. http://dx.doi.org/10.1155/2012/476739.
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A deeper understanding of the mechanism of complement activation may help to elucidate the pathogenesis of IgA nephropathy (IgAN). Traditionally, the activation of an alternative pathway (AP) has been recognized as an enhancer mechanism of glomerular damage. This paper documents contemporary information concerning the possible pathological mechanisms of the lectin pathway (LP) in the circulation and in the glomerulus. The circulating initiator of LP activation is not fully understood. However, ligands for mannose-binding lectin (MBL) which are among the starter molecules of the LP are aberrant glycosylated molecules-containing immune complex. Recent reports have focused onN-glycans on secretory IgA as a candidate ligand. Mesangial deposits of MBL are seen in 25% of patients with IgAN. Mesangial deposits of MBL and C4 and/or C4 breakdown products are implicated as markers for disease progression of IgAN. On the other hand, patients with MBL deficiency tend to show better clinical presentation and lower levels of urinary protein and serum creatinine than MBL-sufficient patients. It is now recognized that involvement of AP and LP constitutes an additional mechanism for explaining the progression of IgAN.
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Yuasa, Miori, Ikue Hata, Keiichi Sugihara, Yuko Isozaki, Yusei Ohshima, Keiichi Hara, Go Tajima, and Yosuke Shigematsu. "Evaluation of Metabolic Defects in Fatty Acid Oxidation Using Peripheral Blood Mononuclear Cells Loaded with Deuterium-Labeled Fatty Acids." Disease Markers 2019 (February 7, 2019): 1–11. http://dx.doi.org/10.1155/2019/2984747.
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Because tandem mass spectrometry- (MS/MS-) based newborn screening identifies many suspicious cases of fatty acid oxidation and carnitine cycle disorders, a simple, noninvasive test is required to confirm the diagnosis. We have developed a novel method to evaluate the metabolic defects in peripheral blood mononuclear cells loaded with deuterium-labeled fatty acids directly using the ratios of acylcarnitines determined by flow injection MS/MS. We have identified diagnostic indices for the disorders as follows: decreased ratios of d27-C14-acylcarnitine/d31-C16-acylcarnitine and d23-C12-acylcarnitine/d31-C16-acylcarnitine for carnitine palmitoyltransferase-II (CPT-II) deficiency, decreased ratios of d23-C12-acylcarnitine/d27-C14-acylcarnitine for very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency, and increased ratios of d29-C16-OH-acylcarnitine/d31-C16-acylcarnitine for trifunctional protein (TFP) deficiency, together with increased ratios of d7-C4-acylcarnitine/d31-C16-acylcarnitine for carnitine palmitoyltransferase-I deficiency. The decreased ratios of d1-acetylcarnitine/d31-C16-acylcarnitine could be indicative of β-oxidation ability in patients with CPT-II, VLCAD, and TFP deficiencies. Overall, our data showed that the present method was valuable for establishing a rapid diagnosis of fatty acid oxidation disorders and carnitine cycle disorders and for complementing gene analysis because our diagnostic indices may overcome the weaknesses of conventional enzyme activity measurements using fibroblasts or mononuclear cells with assumedly uncertain viability.
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Bennett, Michael J., Sheila D. Spotswood, Karen F. Ross, Susan Comfort, Robert Koonce, Richard L. Boriack, Lodewijk Ijlst, and Ronald J. A. Wanders. "Fatal Hepatic Short-Chain l-3-Hydroxyacyl-Coenzyme a Dehydrogenase Deficiency: Clinical, Biochemical, and Pathological Studies on Three Subjects with This Recently Identified Disorder of Mitochondrial β-Oxidation." Pediatric and Developmental Pathology 2, no. 4 (July 1999): 337–45. http://dx.doi.org/10.1007/s100249900132.
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This report describes the clinical, biochemical, and pathological findings in three infants with hepatic short-chain l-3-hydroxyacyl-coenzyme A dehydrogenase (SCHAD) deficiency, a recently recognized disorder of the mitochondrial oxidation of straight-chain fatty acids. Candidate subjects were identified from an ongoing study of infant deaths. SCHAD analysis was performed on previously frozen liver and skeletal muscle on subjects with a characteristic urine organic acid profile. Autopsy findings were correlated with the biochemical abnormalities. Enzyme analysis in liver revealed marked deficiency in SCHAD with residual activities of 3–11%. All subjects had normal activity in skeletal muscle. However, Western blot analysis of SCHAD revealed an identical truncated protein in both liver and muscle from one patient, suggesting that SCHAD is similar in liver and muscle and that the normal activity in muscle may be due to other enzymes with C4 activity. Autopsy findings revealed marked steatosis and a muscle pattern consistent with spinal muscular atrophy in one patient. Lipid storage was less pronounced in one patient and not detected in the third patient who had a well-documented history of recurrent hypoglycemia. This is the initial pathological characterization of this enzyme defect, and our observations suggest that SCHAD deficiency is a very severe disorder contributing to early infant death.
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Zhou, Danlei, Michalea Lai, Aiqin Luo, and Chack-Yung Yu. "An RNA Metabolism and Surveillance Quartet in the Major Histocompatibility Complex." Cells 8, no. 9 (August 30, 2019): 1008. http://dx.doi.org/10.3390/cells8091008.
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At the central region of the mammalian major histocompatibility complex (MHC) is a complement gene cluster that codes for constituents of complement C3 convertases (C2, factor B and C4). Complement activation drives the humoral effector functions for immune response. Sandwiched between the genes for serine proteinase factor B and anchor protein C4 are four less known but critically important genes coding for essential functions related to metabolism and surveillance of RNA during the transcriptional and translational processes of gene expression. These four genes are NELF-E (RD), SKIV2L (SKI2W), DXO (DOM3Z) and STK19 (RP1 or G11) and dubbed as NSDK. NELF-E is the subunit E of negative elongation factor responsible for promoter proximal pause of transcription. SKIV2L is the RNA helicase for cytoplasmic exosomes responsible for degradation of de-polyadenylated mRNA and viral RNA. DXO is a powerful enzyme with pyro-phosphohydrolase activity towards 5′ triphosphorylated RNA, decapping and exoribonuclease activities of faulty nuclear RNA molecules. STK19 is a nuclear kinase that phosphorylates RNA-binding proteins during transcription. STK19 is also involved in DNA repair during active transcription and in nuclear signal transduction. The genetic, biochemical and functional properties for NSDK in the MHC largely stay as a secret for many immunologists. Here we briefly review the roles of (a) NELF-E on transcriptional pausing; (b) SKIV2L on turnover of deadenylated or expired RNA 3′→5′ through the Ski-exosome complex, and modulation of inflammatory response initiated by retinoic acid-inducible gene 1-like receptor (RLR) sensing of viral infections; (c) DXO on quality control of RNA integrity through recognition of 5′ caps and destruction of faulty adducts in 5′→3′ fashion; and (d) STK19 on nuclear protein phosphorylations. There is compelling evidence that a dysregulation or a deficiency of a NSDK gene would cause a malignant, immunologic or digestive disease.
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Presanis, J. S., M. Kojima, and R. B. Sim. "Biochemistry and genetics of mannan-binding lectin (MBL)." Biochemical Society Transactions 31, no. 4 (August 1, 2003): 748–52. http://dx.doi.org/10.1042/bst0310748.
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Mannose- or mannan-binding lectin (MBL) is a member of the collectin protein family, which includes lung surfactant proteins SP-A and SP-D. Each member consists of similar or identical polypeptide chains with a region of collagen-like sequence followed by a C-type lectin domain. The polypeptides associate in threes to form a subunit containing a collagen-like helix, with three clustered lectin domains. These subunits associate into larger structures, usually with 12–18 polypeptides. The collectins bind to patterns of neutral sugars on surfaces (e.g. of micro-organisms) and mediate effector functions associated with killing/phagocytosis. MBL is the only collectin which activates complement. It resembles in quaternary structure the complement protein C1q, which recognizes targets via charge clusters. Binding of MBL to a surface activates MBL-associated serine proteases (MASPs) attached to MBL, and MASP-2 activates complement proteins C4 and C2. The MASPs are homologous to the C1q-associated proteases, C1r and C1s. MBL therefore activates complement by a mechanism very similar to C1q, and engages the opsonic activity of complement to clear micro-organisms. The serum concentration of MBL is very variable in humans. The variability is largely associated with mutations leading to amino acid substitutions in the collagen-like region which decrease MBL assembly and stability. Many studies demonstrate that MBL deficiency is associated with susceptibility to a range of infectious and inflammatory diseases.
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Li, Z. Y., J. Saleh, S. Huang, M. Elhassan, and C. Yuvienco. "AB1247 ELEVATED SERUM COMPLEMENT (C3/C4) LEVEL AS AN INFLAMMATORY MARKER FOR INFECTION IN PATIENTS WITH FEVER: A RETROSPECTIVE STUDY." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1915.2–1915. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1922.
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Background:The functions of the complement system are to protect the host against infection, clearance of immune complexes, and regulate adaptive immunity after activation by C-reactive protein (CRP) or foreign cells.1C3 and C4 may increase up to 50 percent of baseline values as part of the acute-phase response, which is an expected host response for infection and injury.2Objectives:We aimed to examine the correlation between elevated C3/C4 levels and the underlying causes (infectious vs. non-infectious) of fever (subjective and/or objective) in adults admitted to Community Regional Medical Center (CRMC).Methods:This is a retrospective study of C3/C4 level that was ordered in adult patients who were admitted to CRMC in April 1st, 2018 to September 30th, 2018 with fever. This was also analyzed in comparison to elevated lactic acid, erythrocyte sedimentation rate (ESR), and CRP level.Results:Complement levels were ordered in 210 patients admitted to CRMC medicine or intensive care units. Among these patients, 28.09% (59/210) were diagnosed with various infectious diseases confirmed by gold standard methods (cultures, serology tests, computerized tomography, or magnetic resonance imaging), regardless of fever status during admission.About 26.6% (56/210) had subjective or objective (temperature greater than100.4 F or above), and52of them had complement levels (C3/C4) ordered with resulted in either normal or elevated. Within these52patients, lactic acid, ESR, and CRP were ordered in33,28,25of them respectively.Table 1.Elevated C3/C4 level vs. normal C3/C4 level in detecting infection in fever patients when tested against gold standards.Patients with infectious disease diagnosisPatients without infectious disease diagnosisElevated C3 or C4 or both (screen test +)137Positive predictive value (PPV)=13/20=65%Both normal C3 and C4 (screen test -)824Negative predictive value (NPV)=15/32=48.9%Sensitivity=13/21=61.9%Specificity=24/31=77.4%Table 2.Sensitivity, specificity, PPV, NPV, likelihood ratio positive (LR+), and likelihood ratio negative (LR-) among C3/C4, lactic acid, ESR, CRPI/CRPH in detecting infection in patient with feverC3/C4 (N=52)Lactic Acid(N=33)ESR(N=28)CRPI/CRPH(N=25)Sensitivity61.9%50%90%100%Specificity77.4%91.3%11.1%11.8%PPV65%71.4%36%34.8%NPV48.9%80.8%66.6%100%LR+2.75.71.01.1LR -0.490.550.90Conclusion:Complement levels can be used as a rapid screening test to guide infection consideration as it correctly identified 61.9 % of febrile patients with infection, and 77.4% who didn’t have an infection. A positive screening test in itself still requires further investigation in the causes of fever to confirm the diagnosis since the PPV is 65%. With the NPV of 48.9%, a negative screening test is still not reassuring that the febrile patient doesn’t have an infection. Our study demonstrated the potential utilization of the elevated complement level as an inflammatory marker for infectious etiology of fever, as it has better LR+ when compares to ESR and CRP with similar turnaround time.This study helps educate providers to acknowledge the fact that complement level does not have to be limited to be used on autoimmune related disorders only. Further large pool studies will be necessary to further investigate the role of complement levels as part of the screening test in a patient with fever.References:[1]Walport. MJ. Complement. Second of two parts. N Engl J Med.2001 Apr 12; 344(15):1140-4. DOI: 10.1056/NEJM200104123441506[2]Wen L, Atkinson JP, Giclas PC. Clinical and laboratory evaluation of complement deficiency. J Allergy Clin Immunol. 2004;113(4):585. DOI: 10.1016/j.jaci.2004.02.003Characters from table content:731Disclosure of Interests:None declared
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Dong, Yu-Wen, Wei-Dan Jiang, Yang Liu, Pei Wu, Jun Jiang, Sheng-Yao Kuang, Ling Tang, et al. "Threonine deficiency decreased intestinal immunity and aggravated inflammation associated withNF-κBandtarget of rapamycinsignalling pathways in juvenile grass carp (Ctenopharyngodon idella) after infection withAeromonas hydrophila." British Journal of Nutrition 118, no. 2 (July 28, 2017): 92–108. http://dx.doi.org/10.1017/s0007114517001830.
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AbstractThis study aimed to investigate the impacts of dietary threonine on intestinal immunity and inflammation in juvenile grass carp. Six iso-nitrogenous semi-purified diets containing graded levels of threonine (3·99–21·66 g threonine/kg) were formulated and fed to fishes for 8 weeks, and then challenged withAeromonas hydrophilafor 14 d. Results showed that, compared with optimum threonine supplementation, threonine deficiency (1) decreased the ability of fish against enteritis, intestinal lysozyme activities (except in the distal intestine), acid phosphatase activities, complement 3 (C3) and C4 contents and IgM contents (except in the proximal intestine (PI)), and it down-regulated the transcript abundances ofliver-expressed antimicrobial peptide(LEAP)-2A,LEAP-2B,hepcidin, IgZ, IgMandβ-defensin1(except in the PI) (P<0·05); (2) could up-regulate intestinal pro-inflammatory cytokinesTNF-α,IL-1β,IL-6, IL-8andIL-17DmRNA levels partly related toNF-κBsignalling; (3) could down-regulate intestinal anti-inflammatory cytokinetransforming growth factor(TGF)-β1,TGF-β2,IL-4/13A(notIL-4/13B) andIL-10mRNA levels partly by target of rapamycin signalling. Finally, on the basis of the specific growth rate, against the enteritis morbidity and IgM contents, the optimum threonine requirements were estimated to be 14·53 g threonine/kg diet (4·48 g threonine/100 g protein), 15.05 g threonine/kg diet (4·64 g threonine/100 g protein) and 15·17 g threonine/kg diet (4·68 g threonine/100 g protein), respectively.
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Ospina-Caicedo, Ana Isabel, Alex Darío Cardona-Rincón, Juan Manuel Bello-Gualtero, Rafael Valle-Oñate, Consuelo Romero-Sánchez, Philippe Chalem-Choueka, and Gloria Vásquez Duque. "Lower Levels of Vitamin D Associated with Disease Activity in Colombian Patients with Systemic Lupus Erythematosus." Current Rheumatology Reviews 15, no. 2 (April 5, 2019): 146–53. http://dx.doi.org/10.2174/1573397114666181015161547.
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Background: Systemic Lupus Erythematosus (SLE) involves genetic, environmental, and hormonal alterations, including Vitamin D deficiency. Objective: To evaluate the association between vitamin D levels with anti-dsDNA, complement proteins, immunoglobulins levels and disease activity scores. Methods: : A cross-sectional study was performed. The levels of 25-OH vitamin D were measured in patients older than 18 years with SLE according to ACR/97 [American College of Rheumatology 1997] from 2013 to 2015. The association was assessed by Mann-Whitney U and Kruskal Wallis tests for continuous variables, and by the Chi or Fisher exact test for the nominal variables. Results: Sixty-nine patients were included; 82% were women; the mean age was 38.5 years; 36.2% had low levels of vitamin D with higher consumption [p=0.006] of C4 and C3 complement proteins, plus higher levels of anti-dsDNA. Lower values of vitamin D were observed in patients with moderate to severe activity [p=0.0001] by SLEDAI [Systemic Lupus Erythematosus Activity Index] and general domain [p=0.039] and renal domain [p=0.009] by BILAG [British Isles Lupus Assessment Group] 2004. The mean vitamin D levels were higher in the group not receiving steroids when compared to those groups with dosages of 0.5-1mg/kg/d [p=0.048]. Conclusion: Lower levels of vitamin D are associated with greater complement protein consumption and higher disease activity rates. Therefore, it is important to evaluate vitamin D supplementation in patients with SLE as part of the treatment, especially when it includes the use of steroids.</P>
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Enwemnwa, Nneamaka N., Abhinav B. Chandra, Porselvi Chockalingam, and Jack Burton. "Waldenstrom's Microglobulinemia Presenting with Recurrent Angioedema Secondary to C1q Esterase Inhibitor (C1 INH) Deficiency." Blood 116, no. 21 (November 19, 2010): 5009. http://dx.doi.org/10.1182/blood.v116.21.5009.5009.
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Abstract Abstract 5009 Description: A 57 year-old Bangladeshi man presented to the emergency room with a 4-day history of shortness of breath, productive cough and sensation of choking. He had a history of recurrent dyspnea, chest pain and chronic bilateral pedal edema. He had recent admissions for similar complaints at different hospitals where he was diagnosed with low grade non-Hodgkin lymphoma not requiring treatment and was discharged with bronchodilators and anti-tussives. He was symptom-free between episodes. There was no fever, night sweats or weight loss and there was no history of asthma. Physical exam revealed moderate dyspnea with some stridor, cervical lymphadenopathy with many firm and mobile small lymph nodes. There was no hepato-splenomegaly, urticaria or rashes. Results of routine blood tests including CBC and C-reactive protein were normal. Chest X-ray showed mild pulmonary congestion and CT images of the chest and abdomen showed multiple lymph nodes of about 1–1.5 cm in size. X-rays of the hands showed multiple small lytic lesions. Laryngoscopy showed laryngeal edema. Bone marrow biopsy showed a few paratrabecular areas with increased numbers of small lymphocytes and a lymph node biopsy revealed low grade B-cell lymphoma with plasmacytic differentiation, which was positive for CD19, 20, 22, 38, and CD44. Serum viscosity was 1.6. Immunological studies showed a low C4 at 4 mg/dl (normal range 10–40 mg/dl), low C1q at <3.6 (normal range 5–8.6), C1 esterase inhibitor low-normal at 16 (normal range 11–26). Serum immunoglobulins showed IgM gammopathy with low IgA and normal IgG levels. Beta-2 microglubulin was also elevated at 4.93 mg/dl (normal range < 2.51). Serum protein electrophoresis showed a monoclonal IgM spike measuring 1.5 g/dl with immunofixation positive for a IgM kappa band. Total protein, alpha2- and beta-globulins were elevated and urine electrophoresis was positive for kappa light chains. A diagnosis of Waldenström's macroglobulinemia with angioneurotic edema was made. He was treated with 4 cycles of bortezomib (Velcade®), dexamethasone and rituximab. The patient's angioedema and respiratory symptoms improved dramatically. Follow-up serum electrophoresis showed a very good response to treatment, with a major decrease in total protein and the M-spike. Complement levels returned to normal. Discussion: C1 is the first protein of the classical and kinin pathways which is an arm of the innate immune system. Triggering factors activate the complement cascade and lead to activation of C1 which in turn cleaves C2, the product of which is an inflammatory mediator responsible for angioedema by causing increased capillary permeability and extravasations. In C1INH deficiency, this process occurs uninhibited, triggered by minimal stimulation. C1q esterase inhibitor deficiency is a rare manifestation of Waldenström's macroglobulinemia with very few reported cases in literature. Symptoms are non-allergic, non-pruritic and clinical presentation depends on parts of the anatomy affected and may be as mild as inconvenient skin blotching up to life-threatening laryngeal edema or shock. They vary widely, often self limiting and recurrent. Angioedema, acquired or inherited, is complement mediated, characterized by low levels of complement proteins during attacks. C1INH deficiency can be acquired due to increased consumption or/and inactivation by circulating autoantibodies or secondary to lymphoproliferative diseases that lead to increased catabolism. These are often associated with B-cell disorders but may be associated with other disease patterns. Symptomatology is variable and periods of remission and recurrence lead to easy misdiagnosis and incomplete treatment. Proper diagnosis is dependent on awareness and knowledge of the various clinical presentations, adequate and focused use of laboratory analyses and immunopathology studies. The key to treatment is first therapy of the acute stage (in our patient with the use of intravenous steroids) and then more specific treatment of the underlying disease entity (in our patient with bortezomib, dexamethasone and rituximab). Conclusion: Waldenstrom's macroglobulinemia presenting with angioedema is rare, often misdiagnosed and acquired C1 esterase inhibitor deficiency should be at least ruled out, as presentation is varied and could be potentially life-threatening. Disclosures: No relevant conflicts of interest to declare.
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Gábos, Gabriella, Dumitru Moldovan, Daniela Dobru, Enikő Mihály, Noémi Bara, Valentin Nădășan, Adina Hutanu, and Katalin Csép. "Mutational spectrum and genotype-phenotype relationships in a cohort of Romanian hereditary angioedema patients caused by C1 inhibitor deficiency." Revista Romana de Medicina de Laborator 27, no. 3 (July 1, 2019): 255–67. http://dx.doi.org/10.2478/rrlm-2019-0029.
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Abstract Background: Hereditary angioedema due to C1 inhibitor deficiency (C1-INH-HAE) caused by SERPING1 mutations is a rare monogenic disorder characterized by a high frequency of de novo mutations, allelic heterogeneity and populational differences. Geno- and phenotype correlation data are limited. Addressing the pathogenic complexity, we proposed to analyze the clinical and genetic characteristics in a set of Romanian patients. Material and Methods: 49 patients from 22 unrelated families with C1-INH-HAE were investigated, by calculating clinical severity score (CSS), C1-INH and C4 level assessment by nephelometric assays, C1-INH function study by functional enzyme-linked immunosorbent assay, and mutation analysis by sequencing and MLPA. Clinical manifestations by missense vs other mutation mechanisms were compared. Results: The mean age at diagnosis and onset was 28.8±14.7 and 15.1±15.2 years, while the diagnostic delay 13.1±10.1 years. CSS ranged from 2 to 9, with a mean of 5.4±1.8. The frequency of missense and nonsense mutations, splice defects, frameshift mutations and large gene rearrangements was 61.22, 6.12, 22.4, 6.12 and 4.08%; in the regulatory sequence no mutation was described. In type II, only missense mutations were noted. Lower levels of C1-INH characterized index cases caused by mechanisms other than missense mutation, with more severe consequences on protein synthesis (p=0.017). 53% of the cases were identified by familial screening. Conclusion: A later onset of disease manifestations and a higher frequency of missense mutations characterize HAE in Romanian patients with SERPING1 mutation. Genetic analysis improves the management of affected families, and may inform about disease severity.
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Castelli, Roberto, Davide Rossi, Arquati Massimo, Suffritti Chiara, Andrea Zanichelli, Wu Maddalena, and Cicardi Marco. "High Prevalence of Marginal ZONE Lymphoma Among Patients with Acquired C1- Inhibtor Deficiency." Blood 126, no. 23 (December 3, 2015): 1444. http://dx.doi.org/10.1182/blood.v126.23.1444.1444.
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Abstract Background: Lymphoma of the marginal zone, represent less than 10% of al non Hodgkin lymphoma (NHL). Nevertheless, they are the predominant form of lymphoma associated with angioedema due to acquired C1-inhibitor deficiency (C1-INH-AAE). In this rare condition C1-INH is consumed mainly due to the presence of neutralizing autoantibodies to this protein. Interestingly, 30% of patients with C1-INH-AAE have or develop NHL, which in the large majority derives from the marginal zone. The clinical features of C1-INH deficiency, which more commonly is of genetic origin (hereditary angioedema HAE), include recurrent, self-limiting local swellings involving the upper respiratory tract and the gastrointestinal tract. Swelling is due to local accumulation of bradykinin released from high molecular weight kininogen upon uncontrolled activation of plasma kallikrein. The etiology of acquired C1-INH deficiency remains undefined, but the majority of patients carry an underlying B-cell disorders. These B-cell disorders range from production of anti-C1-INH autoantibodies to monoclonal gammopathies of uncertain significance (MGUS) to Non Hodgkin Lymphomas (NLHs) Growing experimental evidence suggests that microenvironmental interactions driven by inflammatory and infectious conditions favor development or promotion of specific subtypes of indolent non-follicular NHL (marginal zone lymphomas, MZLs; lymphoplasmatycic lymphomas, LPLs ;small lymphocytic lymphomas, SLLs). This evidence suggests a role for chronic immune stimulation, either from persistent microbial infections or to autoantigens, in B cell transformation. Here we report data from 72 C1-INH-AAE patients associated to NHL in 24. Most NHL are indolent non follicular B cells lymphoproliferative disease (INFBCLs,) suggesting a likely antigen-driven pathogenetic mechanism. Patients and Methods: Seventy-two AAE patients were included.The diagnosis was based on a history of recurrent angioedema , which began during or after the fourth decade of life, absence of family history of angioedema, and detection of C1-INH functional levels below 50% of normal. Serum or plasma samples were stored at -80°C until tested. C1-INH, C4, C3, and C1q antigens were measured by radial immunodiffusion. C1-INH antigenic and C4 were quantified using radial immunodiffusion or nephelometry; C1-INH function was measured using an immunoenzimatic assay. Autoantibodies to C1-INH in serum were measured by enzyme-linked immunosorbent assay Hematoxyllin-eosin stained slides were reviewed. Lymphoprolipherative disorders were classified according to the WHO classification. Results: Overall, 33.3% (24/72) of AAE patients had an underlying B-cell NHL. Most NHL (62,5%, 15/24) were diagnosed at onset of AAE or thereafter (3 months to 7 years), while in the remaining cases were diagnosed before the onset of AEE symptoms. According to the WHO classification, 29% (21/72) patients had indolent NHL and 4% (3/72) aggressive NHL (1 diffuse large B-cell lymphoma and 2 mantle cell lymphoma). Among patients with indolent NHL, most had splenic MZL (71%, 15/21), while the remaining had had LPL (n=3), SLL (n=2), or follicular lymphoma (n=1). Serological evidence of hepatitis C virus infection was reported in 1 of 24 patients. Autoantibodies to C1-INH were detected in 54% (13/24) patients, including 12/15 ( 80%) of cases with a diagnosis of SMZL.Of the 20 patients with indolent B cell lymphoprolipherative disease 13/20 received systemic therapy. Chemotherapy was performed in 13/24 patients (2 R-CHOP,1 Rituximab -fludarabine,1 Chlorambucil, 5 Bendamustine R, 2 R-CVP, 2 CFX/Prednisone). Splenectomy without chemotherapy was performed in 3; 2 patients were treated with Rituximab alone. Thirteen patients experienced complement improvement or reduction in AAE symptoms after chemotherapy. Four patients received no therapy. Conclusions: Our series is the largest reported to date and confirms that SMZL represents the most common histotype among AAE patients, with a frequency of 75% of INFBCL (15/20 indolent lymphoprolipherative disease) and of 62.5% of all lymphoprolipherative diseases identified.The post-germinal center origin of most of NHLs suggests that immune stimulation may contribute to lymphomagenesis. Disclosures No relevant conflicts of interest to declare.
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Barbosa, Edna J. L., Camilla A. M. Glad, Anna G. Nilsson, Helena Filipsson Nyström, Galina Götherström, Per-Arne Svensson, Isabela Vinotti, et al. "Genotypes associated with lipid metabolism contribute to differences in serum lipid profile of GH-deficient adults before and after GH replacement therapy." European Journal of Endocrinology 167, no. 3 (September 2012): 353–62. http://dx.doi.org/10.1530/eje-12-0263.
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ObjectiveGH deficiency (GHD) in adults is associated with an altered serum lipid profile that responds to GH replacement therapy (GHRT). This study evaluated the influence of polymorphisms in genes related to lipid metabolism on serum lipid profile before and after 1 year of GHRT in adults.Design and methodsIn 318 GHD patients, total cholesterol (TC) serum concentrations, LDL-C, HDL-C, and triglycerides (TG) were assessed. Using a candidate gene approach, 20 single nucleotide polymorphisms (SNPs) were genotyped. GH dose was individually titrated to obtain normal serum IGF1 concentrations.ResultsAt baseline, the minor alleles of cholesteryl ester transfer protein (CETP) gene SNPs rs708272 and rs1800775 were associated with higher serum TC and apolipoprotein E (APOE) gene SNP rs7412 with lower TC concentrations;CETPSNPs rs708272, rs1800775, and rs3764261 and apolipoprotein B (APOB) gene SNP rs693 with higher serum HDL-C;APOESNP rs7412, peroxisome proliferator-activated receptor gamma (PPARG) gene SNP rs10865710 with lower LDL-C, andCETPSNP rs1800775 with higher LDL-C; andAPOE/C1/C4/C2cluster SNP rs35136575 with lower serum TG. After treatment,APOBSNP rs676210 GG genotype was associated with larger reductions in TC and LDL-C andPPARGSNP rs10865710 CC genotype with greater TC reduction. All associations remained significant when adjusted for age, sex, and BMI.ConclusionsIn GHD adults, multiple SNPs in genes related to lipid metabolism contributed to individual differences in baseline serum lipid profile. The GH treatment response in TC and LDL-C was influenced by polymorphisms in theAPOBandPPARGgenes.
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Patel, Gayatri, and Jacqueline A. Pongracic. "Hereditary and acquired angioedema." Allergy and Asthma Proceedings 40, no. 6 (November 1, 2019): 441–45. http://dx.doi.org/10.2500/aap.2019.40.4267.
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Hereditary angioedema (HAE) is an autosomal dominant disorder defined by a deficiency of functional C1 esterase inhibitor (C1-INH). Acquired angioedema is due to either consumption (type 1) or inactivation (type 2) of CI-INH. Both HAE and acquired angioedema can be life-threatening. Of the three types of HAE, type 1 is most common, occurring in approximately 85% of patients and characterized by decreased production of C1-INH, which results in reduced functional activity to 5‐40% of normal. Type 2 occurs in 15% of cases; C1-INH is detectable in normal or elevated quantities but is dysfunctional. Also, HAE with normal CI-INH (previously called type 3 HAE) is rare and characterized by normal complement studies. Specific genetic mutations have been linked to factor XII, angiopoietin-1, and plasminogen gene. Patients with unknown mutations are classified as unknown. The screening test for types 1 and 2 is complement component C4, which is low to absent at times of angioedema and during quiescent periods. A useful test to differentiate HAE from acquired angioedema is C1q protein, which is normal in HAE and low in acquired angioedema. The management of HAE has been transformed with the advent of disease-specific therapies. On-demand therapy options include plasma and recombinant C1-INH for intravenous infusion; ecallantide, an inhibitor of kallikrein; and icatibant, a bradykinin β2 receptor antagonist, both administered subcutaneously. For long-term prophylaxis, intravenous or subcutaneous C1-INH enzyme replacement and lanadelumab, a monoclonal antibody against kallikrein that is administered subcutaneously, are effective agents.
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Ray, Arghya, Ting DU, Krishan Chauhan, Yan Song, Dharminder Chauhan, and Kenneth Anderson. "Analysis of Sars-Cov-2-Associated Proteins Identify Tank-Binding Kinase-1 As an Immunotherapeutic Target in Multiple Myeloma." Blood 136, Supplement 1 (November 5, 2020): 29–30. http://dx.doi.org/10.1182/blood-2020-143393.
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Background and Rationale Patients with multiple myeloma (MM) are at a higher risk of viral infection due to immune deficiency. Importantly, recent studies highlighted the severity of COVID-19 in MM. To date, however, the mechanism(s) underlying the lack of anti-viral immune response in MM are unclear. Plasmacytoid dendritic cells (pDCs) play a key role in both recognition of viral nucleic acid and initiating anti-viral activity via type 1 interferon (IFN) response signaling. We showed that interactions of dysfunctional pDCs with MM cells, T cells, and NK cells confer immune suppression in the host-MM bone marrow (BM) microenvironment (Chauhan et al, Cancer Cell 2009; 16: p309;Ray et al, Leukemia 2015; 29: p1441). Here, we analyzed the immune-pathway proteins implicated in Covid-19-host interactions [Gordon et al, Nature 2020; 583, p459] to assess whether pDC-MM interactions modulate these pathways to confer immune suppression and susceptibility to COVID-19. We identified the TLR pathway serine/threonine kinase TBK1 (TANK-binding kinase 1), involved in type I IFN induction, as a potential immunotherapeutic target in MM. Moreover, Covid-19 relies on host-Ubiquitin-proteasome-system for propagation, and we found that targeting ubiquitin receptor Rpn13 with a specific inhibitor RA190 restores TBK1 expression in MM. Methods For our studies, we examined SARS-CoV-2-human protein-protein interactions (PPIs) maps (Gordon et al, 2020). pDC-MM co-cultures, and RNAseq using next- generation sequencing (NGS): Purified MM patient pDCs were cocultured with autologous MM cells (1pDC/5MM) for 48h, followed by separation of MM cells from pDCs using FACS. Total RNA from MM cells was subjected to RNAseq analysis using Illumina NGS. Raw sequence data were analyzed to generate differential expression (DEseq2). Linear model (Limma) and its GUI (Glimma) were also used. Statistical significance: log2FC (fold change) values in coculture vs control, with a False Discovery Rate value of <0.05, was considered significant (CI > 95). The heatmap analysis was done using Morpheus software (Broad Institute, MIT). MM patient and pDCs data used for bioinformatics were from the NCBI GEO. Results A total of 41 genes involved in the Covid-19 host-pathogen immune interactions are also differentially expressed in MM after coculture with pDCs. (log2Fold change: ± 3.5-fold; p < 0.00001; pDC-MM vs MM alone). The gene expression widely varies in pDC-MM vs MM [Median (log10): -0.13 to 4.5; adj p < 0.001]. We identified 3 specific innate immunity-linked genes TBK1, IRF3 (Interferon regulatory factor 3), and RAE1 (interferon-inducible mRNA nuclear export factor) which are essential for IFN production in MM. Importantly, pDCs decrease TBK1 (Log2FC: -0.5) and RAE1 (Log2FC: -0.3) as well as induce IRF3 (Log2FC: 1.5) in MM (p < 0.0001). Analysis of publicly available gene profiling datasets on relapsed MM patient showed low levels of TBK1 and RAE1 and higher IRF3 (n = 50) [Log2FC: TBK1: -0.208; RAE1: -0.286; IRF3: 0.273; vs normal; p < 0.05). Of note, low TBK1 expression correlates with poor survival in MM patients (n = 350) and elevated TBK1 correlates with a better prognosis (p = 0.026). Similar analysis showed that most of 41 genes involved in the Covid-19 host-pathogen immune interactions are expressed in pDCs. In unstimulated pDCs, TBK1 expression is significantly lower than IRF3 and RAE1 (2-3-fold, p < 0.05). In functional studies, treatment of pDCs with IFN-α activating CpG-ODN type-A increases both TBK1 (adj P = 0.004) and RAE1 (adj P = 0.043), without significantly altering IRF3 expression. Taken together, we show that TBK1 is downregulated in pDCs, and pDCs-MM interactions further decreases TBK1 in MM, thereby attenuating IFN-mediated anti-viral immune response signaling in MM. Finally, we found that blockade of proteasome-mediated protein degradation via inhibition of Ubiquitin receptor Rpn13 upregulates TBK-1 expression, indicating potential clinical use of targeting Rpn13 in restoring anti-viral immune responses in MM. Conclusion We found that pDC-MM interactions downregulate TBK1, which in turn reduces IFN response signaling essential to generate an effective anti-viral immune response in the MM BM microenvironment. Our findings suggest that: 1) low levels of TBK1 may confer increased susceptibility of MM patients to COVID-19; and 2) targeting TBK1 may restore anti-viral immune response and reduce COVID-19 severity in MM. Disclosures Chauhan: consultant to Stemline Therapeutics, Inc., and Equity owner in C4 Therapeutics.: Consultancy, Other: Equity owner in C4 Therapeutics.; Oncopeptide AB: Consultancy. Anderson:Janssen: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees.
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Feola, Maria, Daniel Moskop, Nada Terra, Young C. Park, Andrew Dunbar, Ross L. Levine, Ronald Hoffman, and Yelena Ginzburg. "Aberrant Responsiveness of Erythropoiesis to Iron Deficiency in Polycythemia Vera." Blood 134, Supplement_1 (November 13, 2019): 429. http://dx.doi.org/10.1182/blood-2019-131095.
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Polycythemia vera (PV) presents with iron deficiency at diagnosis, and the mainstay of treatment, i.e. therapeutic phlebotomy, worsens iron deficiency. Iron deficiency is associated with anemia and symptoms of cognitive impairment and fatigue even in the absence of anemia, and patients with low risk PV often suffer from iron deficiency related symptoms How iron deficiency develops in PV patients prior to phlebotomy is not well understood. We previously demonstrated that PV patients exhibit a greater extent of iron deficiency relative to wild type JAK2 patients with other causes of erythrocytosis [Ginzburg Leuk 2018]. We hypothesize that mutated JAK2 leads to aberrant insensitivity of erythropoiesis to iron deficiency. To explore this hypothesis, we first analyzed serum data from iron deficient PV patients (n=14) and blood donors (n=15), normalized for age (51 vs. 42 years, P=0.12) and serum ferritin concentration (22 vs. 22 ng/ml, P=0.95); our data demonstrate that PV patients have significantly lower hepcidin, transferrin saturation, MCV, a higher HCT, and a trend toward higher erythroferrone (ERFE) relative to controls (Fig 1a-1e). Secondly, CD34+ cells were isolated from mononuclear cells and plated with erythropoietin and either 100% or 10% transferrin saturation to mimic iron replete and iron deficient conditions, respectively; differentiation and proliferation were analyzed using flow cytometry. These experiments revealed that although glycophorin A (GPA) and CD36+ cells were decreased in iron deficient relative to iron replete control cells, PV cells continue to proliferate irrespective of iron status (Fig 1f). In addition, only iron deficient control, not PV, cells demonstrated an erythroid lineage specific decrease in proliferation relative to iron replete cells (Fig 1g), demonstrating that iron restriction in PV does not limit erythroid differentiation or proliferation in vitro. Thirdly, we transplanted JAK2 V617F (PV) and wild type (WT) cells into recipient females and placed mice on 35ppm (iron replete (IR)) or 2.5ppm (iron deficient (ID)) diets. IR PV mice exhibited the expected erythrocytosis and decrease in MCV and MCH relative to WT controls (Fig 2a-2d). WT mice on an ID diet exhibited decreased MCV, MCH, and RET-He while PV mice had decreased RBC counts with an increased MCHC (Fig 2a, 2c-2f). These findings demonstrate altered iron regulation in PV erythroblasts with a preference for decreasing RBC count, rather than cellular Hb production, in iron deficiency in vivo. No differences were found in the total number of bone marrow erythroblasts in PV mice relative to WT mice on IR or ID diets. IR and ID PV mice demonstrated splenomegaly relative to WT controls. In addition, IR PV erythroblasts expressed significantly more ERFE relative to WT controls with decreased ERFE expression in ID PV erythroblasts (Fig 2g). Similarly, liver hepcidin expression was lower in IR PV relative to WT controls, but was restored in ID PV mice (Fig 2h), the later likely a response to decreased ERFE expression (Fig 2g); no changes are observed in liver iron concentration in IR relative to ID PV mice. Furthermore, the expected decrease in pSTAT is observed only in ID WT (Fig 2i), not ID PV (Fig 2j) erythroblasts. Lastly, TfR2 protein expression was increased in IR PV relative to WT controls (Fig 2k) and decreased only in ID WT (Fig 2l) but not ID PV (Fig 2m) erythroblasts. Since TfR2 degradation is enhanced during iron deficiency [Khalil JEM 2018] and TfR2 enables iron delivery for mitochondrial heme synthesis [Khalil Blood Adv 2017], persistently increased TfR2 in PV erythroblasts may explain why cellular Hb synthesis (i.e. MCH and RET-He) remains unaffected by iron deficiency in PV mice. Taken together, these findings demonstrate that in vitro iron deficiency fails to limit differentiation and proliferation in PV erythroblasts and enhances STAT5 signaling in ID PV erythroblasts in vivo but results in decreased circulating RBCs in PV mice. In addition, decreased erythroblast ERFE expression in ID PV mice results in increased hepcidin to limit erythroblast iron availability, but persistently increased TfR2 concentration enables mitochondrial iron delivery for Hb synthesis despite cellular iron deficiency. Our studies provide novel mechanistic insights into the dysregulation of iron utilization for erythropoiesis in PV. Disclosures Levine: Prelude Therapeutics: Research Funding; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Research Funding; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Novartis: Consultancy; Gilead: Consultancy; Lilly: Honoraria; Loxo: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Isoplexis: Membership on an entity's Board of Directors or advisory committees. Hoffman:Merus: Research Funding. Ginzburg:La Jolla Pharma: Membership on an entity's Board of Directors or advisory committees.
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Kaur, Harjot, Appalanaidu Sasapu, Michele H. Fox, and Pooja Motwani. "Successful Eculizumab Therapy in Thrombotic Thrombocytopenic Purpura (TTP) Refractory to Plasma Exchange, Steroids and Rituximab." Blood 124, no. 21 (December 6, 2014): 2794. http://dx.doi.org/10.1182/blood.v124.21.2794.2794.
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Abstract Introduction We present a case of TTP refractory to usual therapies treated successfully with eculizumab. Case presentation A 64 year-old African American female with history of diabetes and hypertension presented with left sided weakness and seizure-like activity preceded by 2 days of headaches and 2 weeks of easy bruising. On admission her vital signs and physical exam were unremarkable. Her basic metabolic panel, ANA panel, hepatitis panel, HIV, and anti-phospholipid panel was negative. Her hemoglobin was 9.0 g/dL, platelets were 13K/uL, LDH was 954IU/L, haptoglobin <30 mg/dL, eGFR was 50, and blood smear showed 4-5 schistocytes/high power field. ADAMTS13 activity was <5% and there was an inhibitor level of 1.1BU. C3 level was 75.3 (normal range 90-180mg/dL), C4 was <10 mg/dL (normal range 15-45 mg/dL). On day 1, she was started on oral prednisone (1mg/kg/day) and daily plasma exchange (TPE). changes. After 6 days of TPE without signs of improvement, the first dose of rituximab 375 mg/msq/dose was given on day 7. During the second week of hospitalization, patient also developed delirium and mental status changes. Vincristine 2 mg was given on day 13 for refractory TTP. Due to clinical worsening of microangiopathy and mental status, a decision was made to administer eculizumab 900 mg on day 17. Within a few hours of eculizumab administration, her platelets improved from 8k/uL to 21k/uL and to 47k/uL 12 hours later. After the second dose of eculizumab on day 24, platelets improved to 117k/uL and continued to rise. Eculizumab 900 mg was given weekly for 4 weeks, at which time ADAMTS13 activity was 75% and ADAMTS13 inhibitor was undetectable. Eculizumab 1200 mg was then given every two weeks, for a total of 3 more doses, during which the CBC, LDH, and haptoglobin remained in the normal range. Eculizumab was stopped, and after four months of close follow up, platelets, LDH, renal function and mental status were still normal range. C3 level was 203 (normal range 90-180 mg/dl), C4 was 35 mg/dl (normal range 15-45 mg/dl), ADAMTS 13 activity assay is >100% and there is no inhibitor. Discussion TTP and aHUS are both thrombotic microangiopathies (TMA). TTP is caused by acquired or inherited deficiency of the ADAMTS 13 protein or due the formation of an inhibitor to the ADAMTS13 protein. aHUS results, in most cases, from a genetic mutation in complement factor H in the alternative pathway of the complement cascade. Recent studies have described the importance of the complement system in all forms of TMA (Update on the role of the complement system in the pathogenesis of thrombotic microangiopathies. Prilozi. 2014;35(1):115-22). While plasma exchange is the cornerstone of TTP treatment, complement inhibition with drugs such as eculizumab is the treatment of choice for aHUS. The use of complement inhibiting drugs has not yet been studied in TTP. We report an unusual case of TTP, with confirmed ADAMTS 13 inhibitor and low activity, which did not respond to conventional treatment for TTP. Theorizing that this patient either had concurrent aHUS or had TTP with a dysregulated alternate complement pathway, we used eculizumab, to which the patient had a remarkable and persistent response. There are other reports in literature of patients with aHUS having reduced levels of ADAMTS13 protein; however, these patients did not have an inhibitor as was seen in our patient (Partial ADAMTS13 deficiency in atypical hemolytic uremic syndrome. Blood. 2013 Aug 22;122(8):1487-93). There is one other case in the literature where TTP was treated successfully with eculizumab. In that case, discontinuation of eculizumab was associated with a relapse of TTP and so had to be continued (Eculizumab in the treatment of refractory idiopathic thrombocytopenic purpura. Br J Haematology. 2012 June;157 (6):772-4). To our knowledge, we report the first case of a confirmed diagnosis of TTP treated successfully with eculizumab with remission continuing 3 months after discontinuation of the drug. The use of eculizumab and the role of the complement pathway in TTP deserves further study. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures No relevant conflicts of interest to declare.
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van Mens, Thijs E., Helena Liang, Irene Hernandez, Mark Zogg, Jennifer May, Sreemanti Basu, Berend H. Isermann, and Hartmut Weiler. "Protein C Activation Is the Critical Thrombomodulin Function in Embryonic and Adult Survival in Mice." Blood 128, no. 22 (December 2, 2016): 14. http://dx.doi.org/10.1182/blood.v128.22.14.14.
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Abstract BACKGROUND AND APPROACH: Thrombomodulin (Thbd) is a multifunctional transmembrane molecule expressed on endothelial, hematopoietic, placental trophoblast, and various other cells. Thbd facilitates protein C and TAFI activation by thrombin, but also exerts thrombin- and protein C-independent functions to regulate complement activity and inflammatory signaling. Complete Thbd deficiency causes embryonic death through as yet unclear mechanisms, while ablation of the lectin-like Thbd domain, reduction of Thbd cofactor activity for protein C (pC) activation, or truncation of the cytoplasmic domain do not impair embryonic development1-3. Here we applied in vivo structure-function and genetic complementation analyses to differentiate between pC-dependent and -independent Thbd functions. RESULTS: Three mouse strains with various function-selective Thbd mutations were generated, i.e. ThbdPro/ΔCS, ThbdEGF4-6, and ThbdLT (Table 1). Of these, only the latter mutant with defective thrombin-binding reproduced the embryonic lethal phenotype of complete Thbd deficiency. To examine the developmental role of Thbd expression in cell types other than placental trophoblast, Thbd LoxP mice carrying a conditional Thbd allele were crossed with mice expressing Cre recombinase under control of the endogenous Meox2 gene promotor, resulting in selective ablation of Thbd in the embryo proper, but preservation in extra-embryonic placental tissue. This yielded a normal number of Thbd-deficient embryos at term pregnancy. Preservation of Thbd function in the embryonic placenta therefore was sufficient to prevent intrauterine lethality until birth. Immunohistochemistry of term embryos and adult mice (week 10-16) confirmed persistent absence of Thbd expression. Half of Thbd-null mice were lost prior to weaning (3 weeks). Surviving mice were smaller, yet exhibited normal weight gain thereafter. By 4 weeks of age, 19 of 28 Thbd-deficient animals developed grossly observable lesions, i.e. purple discoloration and swelling of tail segments, followed by, edematic swelling and discoloration of the tail and hind limb digits, distal tail necrosis and/or uni- or bilateral eye degeneration. More than half of the Thbd-null mice expired within the first 10 weeks of life, and only 2 of 28 mice survived to week 40. Neither gross anatomical inspection nor histological surveys of internal organs revealed evidence of severe thrombotic organ damage, and except for elevated IL-6, cytokine plasma levels were normal. Tamoxifen-induced Thbd LoxP gene ablation in adult mice (10-12 week old) reproduced the phenotype of Meox2Cre-Thbd-null mice. Genetic supplementation of activated PC by transgenic expression of a partially Thbd-independent murine pC zymogen variant (“hyperactivatable” protein C4), prevented perinatal lethality, partially restored normal birth weight, and largely prevented the phenotype of Thbd-null mice. However, Thbd-null females expressing the pC transgene exhibited pregnancy-induced morbidity and mortality with complete penetrance. When mated to wild type males (embryonic placenta expresses Thbd), 8 of 8 pregnancies ended in death or severe distress during gestation or postpartum. CONCLUSIONS: These findings indicate that the lack of protein C activation by Thbd-bound thrombin is the sole cause of lethality of embryonic and adult Thbd-null mice; and that Thbd expression in extra-embryonic placental tissue is sufficient to prevent intra-uterine lethality. The mortality of pregnant Thbd-null females expressing the protein C transgene constitutes a novel model for pregnancy-specific complications associated with defects in the function of natural anticoagulant pathways. REFERENCES: 1. Isermann B et al. Nat Med. 2003;9(3):331-337. 2. Conway EM et al. Blood. 1999;93(10):3442-3450. 3. Conway EM et al. J Exp Med. 2002;196(5):565-577. 4. Isermann B et al. Nat Med. 2007;13(11):1349-1358. Figure. Survival of Thbd-null mice with and without the hyperactivatable PC transgene (hmPC). Figure. Survival of Thbd-null mice with and without the hyperactivatable PC transgene (hmPC). Disclosures No relevant conflicts of interest to declare.
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Salib, Mary, Anne-Sophie Lemay, Megan Buchholz, and Katerina Pavenski. "Thrombocytopenia and Microangiopathic Hemolytic Anemia Precipitated By Acute Pancreatitis: A Single Center Experience of Five Cases." Blood 128, no. 22 (December 2, 2016): 1377. http://dx.doi.org/10.1182/blood.v128.22.1377.1377.
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Abstract Introduction Thrombotic thrombocytopenic purpura (TTP) is a prothrombotic disorder characterized by microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. It has been associated with a deficiency or dysfunction of ADAMTS13, an enzyme responsible for cleaving ultra-large von Willebrand factor multimers, thus preventing spontaneous platelet adhesion and aggregation. In its absence, platelet aggregates accumulate in the microvasculature causing neurological symptoms, cardiac ischemia and renal dysfunction. Most cases in adults are idiopathic, and associated with severe ADAMTS13 deficiency (<10%) and anti-ADAMTS13 antibodies. Acquired TTP due to various conditions, such as HIV, drugs, malignancy, collagen disease, bone marrow transplant and acute pancreatitis (AP), have also been described. Some cases of these secondary TTP may be associated with no to moderate ADAMTS13 deficiency and are referred to as thrombotic microangiopathies (TMAs). If plasma exchange (PLEX) has been the treatment of choice for acquired TTP, it has not been shown to be very effective for TMAs. AP-associated MAHA and thrombocytopenia (MAHA-T) might be one exception. Methods To better understand the relationship between AP and MAHA-T and to evaluate its response to PLEX, we retrospectively reviewed all cases of suspected TTP/ MAHA-T treated by PLEX in the context of AP in our institution from 2005 to 2015. For the purpose of this report, we preferred to use the term MAHA-T to describe this phenomenon since TMA usually refers to a pathologic diagnosis. Finally, a literature review of published cases was also performed. Results Five patients were treated with PLEX for suspicion of TTP in the context of AP between January 1st, 2005 and December 31st, 2015 at our centre. Median age was 36 (31-60). Etiologies for pancreatitis were alcohol (3/5) or idiopathic (2/5). Peak lipase level ranged between 426 and 5853 U/L. One patient had 3 episodes of MAHA-T following AP, always in the context of alcohol abuse. Two patients had evidence of MAHA-T on admission, while the remaining 3 patients had an unremarkable CBC at presentation followed by an abrupt drop in platelet count (nadir, 9-23 x 109/L). All patients showed simultaneously signs of MAHA (Hb nadir between 47 and 93 g/L) with fragmentation on the blood smear and abnormal hemolytic parameters: LD level 1104-8097 U/L, bilirubin 36-176 umol/L, reticulocyte count 130-541 x109/L and undetectable haptoglobin. The median time from AP presentation to the development of laboratory or clinical features of MAHA-T in these cases was 2 days (1-3). Acute kidney injury was present in all cases with creatinine levels ranging between 118-906 umol/L. One patient required hemodialysis. Other observed end organ damage included neurologic symptoms (3/5 patients), elevated troponin (5/5 patients) and transaminitis (4/5). One patient experienced a cardiac arrest. All patients had ADAMTS13 activity measured. One patient had severe deficiency on two separate episodes (ADAMTS13 was <1% and 6% respectively). Three other patients had normal ADAMTS13 activity (average 69%) and one had a moderate deficiency by a qualitative assay. In 4 patients, where tests were performed, there was significant heterogeneity in complement protein and function studies between patients ranging from normal to depressed C3 and C4 and normal to elevated CH50. Complement genetics screen was performed in 3 cases and was normal in all 3 cases. PLEX was initiated in all patients and remission (platelet count over 150 x 109/L) was seen for all after a median of 10 daily treatments (2-12). High dose steroids were used in 4 patients. All patients survived to discharge and completely recovered their kidney function. Conclusion TTP/MAHA-T precipitated by AP is increasingly recognized and more than 40 cases have been described in the literature. Similar to our findings, time to MAHA-T occurrence is generally reported within the first 4 days after admission for AP, often when markers for pancreatitis are improving, and most patients do not have severe ADAMTS13 deficiency. While many have looked at ADAMTS13 level, to our knowledge, none have yet reported thorough complement studies and genetics. The 3 cases described herein are then the first cases suggesting this is not a complement mediated disorder. Finally, our review and cases confirm that PLEX is effective and prognosis is good in almost all cases. Disclosures Pavenski: Alexion Pharmaceuticals Inc.: Honoraria, Other: attended an entity's advisory boards.
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Taskinen, Mervi H., Satu Mustjoki, Kirsi Jahnukainen, Luca Trotta, Timo Siitonen, Timo Hautala, Andrey Zavialov, et al. "Large Granular Lymphocyte Infiltration in the Bone Marrow in Children and Young Adults May Suggest Primary Immune Deficiency." Blood 126, no. 23 (December 3, 2015): 1024. http://dx.doi.org/10.1182/blood.v126.23.1024.1024.
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Abstract Large granular lymphocyte (LGL) leukemia is a group of rare lymphoproliferative disorders which involve inappropriate clonal expansion of either cytotoxic T-lymphocytes (CTLs) or natural killer cells (NK). The usual age at onset is between 40 to 60 years. We here describe four very young patients showing LGL infiltration in the bone marrow (BM) and all diagnosed with primary immune deficiency. Patient 1 is a 13-year old male who presented with gingivostomatitis, but no severe infections, autoimmune disease or allergies. He had persistent leukopenia (1.9x109/L), neutropenia (<0.05x109/L), thrombocytopenia (60-80x109/L) and mild anemia. The BM showed myeloid maturation arrest and infiltration of LGL cells with NK cell phenotype (CD3-, CD2+, CD16+, CD56-/+, CD57-, CD4-, CD8-) at 50% of the BM cellularity. In peripheral blood (PB) T, B and NK cell counts were normal. However, low levels of monocytes (0.09x109/L), normal levels of monocytoid (2.7x106/L) and low levels of plasmacytoid (0.1x106/L) dendritic cells (DC) were detected. While germline whole exome sequencing (WES) did not identify mutations likely to cause the disease, targeted sequencing of GATA2 mRNA showed uniallelic GATA2 expression, confirming haploinsufficiency. Patient 2 is a 15-year old female who has neonatal diabetes, autoimmune desquamative interstitial pulmonary disease, autoimmune enteropathy, exocrine pancreatic insufficiency and delayed growth. She developed transfusion-dependent, Coombs-negative anemia at age of 15. In the PB, 50% of the lymphocytes were LGLs. BM showed pure red cell aplasia plus LGL infiltration of TCRgd positive T cells (CD3+, CD2+, CD5+, CD8-/+, CD4-/+, CD57+) at 43% of BM cellularity. Clonal TCRg rearrangement was detected. Hypogammaglobulinemia presented at age of 7. T, B and NK cell counts were low normal, but DCs were non-existent. WES and functional studies revealed a germline gain-of-function mutation of STAT3 gene. Patient 3 is 42-year old female who has had severe infections (bacterial, viral and protozoan) starting at the age of 4 months. From age of 9, autoimmune manifestations occurred with immune thrombocytopenia, neutropenia and anemia, and intensively positive rheumatoid factor. Since age of 17, CD8+ LGLs were detected in PB reaching level of 50% of lymphocytes. In the BM, CD3+CD5-CD56- T -lymphocyte infiltration with clonal TCRd rearrangement was detected. In her 30ies she developed pulmonal arterial hypertension and hypogammaglobulinemia (0.8 g/L). She has low counts of B cells (0.02x109/L), and monocytoid (1.9x106/L) and plasmacytoid (0) DCs. WES identified a homozygous germline missense mutation in CECR1 gene, leading to total loss-of-function of the encoded adenosine deaminase 2 (ADA2) protein. Patient 4 presented with waxing and waning skin nodules from age of 10 years, but no severe infections or allergies. At age of 26, she was diagnosed with hemolytic anemia with spherocytosis, splenomegaly and cholelithiasis. Five years later remarkable hepatomegaly, and clinical autoimmune manifestations with SLE-type skin lesions, autoimmune hemolytic anemia and iritis were observed. Complement C3 (0.17 g/l) and C4 (<0.02 g/L) and NK cell (0.081) levels were low, but CD3, CD8 and CD4 counts and IgM and IgG levels were increased. T-cell infiltration was shown in the skin nodules and liver. BM showed mildly decreased myelo- and erythropoiesis and T cell infiltration (CD3+, CD8+, CD7+, CD45RO+, BCL2+, CD56-) up to 70% of the BM cellularity consistent with LGL infiltration. WES identified the same germline missense mutation in CECR1 gene as seen in patient 3, and a functional analysis showed no ADA2 activity. We conclude that LGL lymphoproliferation in young patients is often a sign of underlying primary immunodeficiency, highlighting the need for detailed genetic studies in these cases. Table 1. Patient Age at LGL LGL in PB(109/L) LGL immune-phenotype Clonality BM LGL infiltration Clinical PID 1 13 0.38 NK NA 40% N,THepatomegaly GATA2 deficiency 2 15 1.79 CTL TCRg 43% AutoimmunityAHepatosplenomegaly STAT3 hyperactivation 3 17 1,49 CTL TCRd NA N,T, AAutoimmunityPulmonary arterial hypertension ADA2 deficiency 4 31 NA CTL TCRg weak 40% AutoimmunityHepatosplenomegalyHepatopulmonal syndrome ADA2 deficiency A, anemia; N, neutropenia, CTL, cytotoxic T cell; LGL, large granular lymphocyte; NK, natural killer cell; PID, primary immune deficiency; TCR, T cell receptor; T, thrombocytopenia Disclosures Mustjoki: Signe and Ane Gyllenberg Foundation: Research Funding; Finnish Cancer Institute: Research Funding; Sigrid Juselius Foundation: Research Funding; Academy of Finland: Research Funding; the Finnish Cancer Societies: Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Siitonen:Pzizer: Other: charges of EAHAD congress 2015; Novartis: Other: charges of EHA congress 2015. Saarela:Roche: Honoraria.
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Shurko, N. "Von Willebrand factor: structure, properties and role in the process of hemostasis." Visnyk of Lviv University. Biological series, no. 83 (December 25, 2020): 3–13. http://dx.doi.org/10.30970/vlubs.2020.83.01.
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The article reviews the scientific papars on the structure, function and biological role of von Willebrand factor (vWF). The vWF mainly was considered as the main factor in the development of bleeding disorders (von Willebrand’s disease). On the other hand, it can be able the cause thrombotic complications through to the functional ability of the factor to stimulate platelet adhesion. The aim of this work was to conduct an analysis of the structure of the factor, its role in the process of hemostasis to determine a border between two opposing processes. Von Willebrand factor is a hemostatic, multimeric glycoprotein, one of the key components of the hemostasis system, taking an active part at startup mechanisms of platelet adhesion at the site of vesselendothelial damage. On the other hand, another important function of vWF is co-factor activity related to coagulation factor VIII (FVIII), which is to stabilize its activity, promoting thrombin activation and preventing the cleavage of the molecule by blood plasma proteinases. The human gene of vWF is localized on the short arm of the 12 chromosome, contains 52 exons and covers approximately 180 kb. VWF is made by endothelial cells and by bone marrow megakaryocytes. The factor is preserved in the Weibel-Palade bodies of endotolial cells and α-granules of platelets. The primary pro-polypeptide consists of 2813 amino acid, of which 2050 form the mature peptide. The molecular weight of vWF is 220 kDa. In bloodstreamv WF circulates as a multimeric protein with a molecular weight from 400 to 20,000 kDa. The synthesized molecule has the next domain structure: D1-D2-D’-D3-A1-A2-A3-D4-C1-C2-C3-C4-C5-C6-CK. Domains are responsible for binding various proteins, including FVIII, fibrin, collagen, heparin, complement components etcetra. Von Willebrand disease (vWD) is the most common autosomal inherited disorder of the hemostasis system (from 0.6 to 2.0% of the population) and the cause is a genetic deficiency of quantitative and/or qualitative abnormal multimeric structure of the vWF molecule. There are three main subtypes of vWD. Quite often in such patients there is a decrease in FVIII activity, as an indirect consequence of changes in vWF. The basic principle of vWD treatment is based on the normalization of vWF and/or FVIII levels by increasing the level of external vWF under the action of desmopressin or the introduction of factor concentrates. In contrast to hereditary vWD, acquired von Willebrand syndrome is a relatively rare acquired bleeding of the blood coagulation system (incidence from 0.04 to 0.13 %) associated with various underlying diseases. For today a significant amount of research devoted to the relationship between vWF and thrombotic complications, that is due functional ability of the factor stimulate platelet adhesion. In particular, there are reports of the following complications in: pneumonia caused by Streptococcus pneumoniae; COVID-19; polycythemia vera; chronic kidney disease etcetra.
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Naqvi, Syed Mujtaba, Carrisa Schwartz, Rachel Whittaker, Ghayth Hammad, and Rishi Agarwal. "A Rare Case of Mild COVID-19 Disease Associated with Type 1 Cryoglobulinemia and Thrombotic Thrombocytopenic Purpura." Blood 138, Supplement 1 (November 5, 2021): 4253. http://dx.doi.org/10.1182/blood-2021-146288.
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Abstract Introduction: Type I cryoglobulinemia (Type I CG) usually develops in the setting of protein-secreting monoclonal gammopathies [1,2]. The estimated frequency of renal involvement is 30% in Type 1 CG. Thrombotic Thrombocytopenic Purpura (TTP) is a life-threatening disease in which there is a deficiency in ADAMTS13, a protease which normally functions to cleave von Willebrand factor (vWF). A deficiency leads to persistence of large vWF multimers and the formation of platelet-rich thrombi in the microvasculature. We present a case of 52 years old female with Type 1 CG and acquired autoimmune TTP secondary to mild Covid-19 disease. Case Report: A 52-year-old woman with medical history significant for CKD stage 2, with baseline creatinine (Cr) of 2.5, Diffuse Large B-Cell Gastric Lymphoma (DLBCL), in complete remission, and recent diagnosis with COVID-19 presented to the ED for evaluation of three days of a petechial rash on her bilateral extremities. Significant labs on arrival included hemoglobin (Hgb) 8.9, platelet count 65, Cr of 3.65, and K+ 6.6, meeting criteria for acute kidney injury (AKI). Peripheral blood smear showed thrombocytopenia and normochromic normocytic anemia with no schistocytes or microangiopathic changes. ADAMTS13 was 43% and there was no clinical suspicion for TTP. The patient's Cr continued to worsen up to 8.1 during admission, prompting renal biopsy. Renal biopsy showed Type 1 cryoglobulinemic glomerulonephritis with vasculitis and 30 to 40% fibrosis of glomeruli. The patient was started on systemic steroids, plasma exchange every 2-3 day (completed 6 sessions) and hemodialysis. Her platelet counts steadily increased to 212 but had a significant drop to 32 when rechecked seven days later, prompting further investigation. ADAMTS13 was rechecked and found to be 5% with presence of inhibitor, Hgb was 7.7, haptoglobin was <20, and a diagnosis of TTP was made. The patient was started on daily plasmapheresis, rituximab, Caplacizumab and high dose systemic steroid therapy. Our patient had prior history of DLBCL and was treated with radiation therapy. Restaging PET/CT and EGD with biopsy showed no evidence of recurrence. Bone marrow biopsy was negative for evidence of lymphoma. Several serologic tests were used to rule out other etiologies of Type I CG and came back negative including: SLE, HIV, hepatitis C, multiple myeloma, and Waldenstrom's macroglobulinemia. The patient had elevations in multiple immune markers including IgG, IgM, free kappa light chains, and free lambda light chains. She also had hypocomplementemia of both C3 and C4. Discussion: The relationship of Type I CG and COVID-19 is unclear, though viral infections can trigger autoimmune diseases [3]. Previously, all patients with Type I CG had either a hematologic malignancy, solid-organ malignancy, infection, or autoimmune syndromes. Interestingly, in our patient, several serologic tests were performed and negative, which ruled out these etiologies of Type I CG. Our patient's manifestation of Type I CG was petechial rash on extremities and acute on chronic renal disease. Specific treatment of CG can include plasma exchange, corticosteroids, rituximab, and hemodialysis, depending on underlying cause. Our patient was started on systemic steroids, plasma exchange every 2-3 days, and hemodialysis due to worsening renal functions. Despite cases of covid-19 and TTP being reported, the relationship between the disease processes remains unclear. COVID-19 infection can cause disproportionate activation of the complement system and lead to excessive coagulation and thrombotic events. Systemic infection can decrease ADAMTS-13 activity, and this has also been noted in COVID studies. ADAMTS-13 deficiency has no pathophysiologic relevance specific to Type 1 CG. Our patient developed anemia and thrombocytopenia, and ADAMTS13 activity testing was found to be 5% with presence of an inhibitor. Considered as high-risk disease, our patient was started on steroids, rituximab, Caplacizumab and daily plasmapheresis. Repeated weekly ADAMTS13 level was 26% and platelets were stabilized at 69k/microL. Conclusion: Suggests that Covid-19 virus has the capability to induce cryoglobulinemia through an unknown mechanism • There are two other case reports of an association between Covid-19 and TTP. • May be the first case indicating a possible association of Covid-19 with cryoglobulinemia. Disclosures No relevant conflicts of interest to declare.
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Knutzen Steuer, K. L., L. B. Sloan, T. J. Oglesby, T. C. Farries, M. W. Nickells, P. Densen, J. B. Harley, and J. P. Atkinson. "Lysis of sensitized sheep erythrocytes in human sera deficient in the second component of complement." Journal of Immunology 143, no. 7 (October 1, 1989): 2256–61. http://dx.doi.org/10.4049/jimmunol.143.7.2256.
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Abstract Analysis of C-dependent lysis of sensitized SRBC by C2-deficient sera (C2D) led to the characterization of a C2 bypass pathway. Lysis in the total hemolytic C assay by C2D sera was Ca2+-dependent and required a high concentration of hemolysin to sensitize E. Selective component depletion indicated a requirement for C1 and C4 of the classical pathway (CP) and proteins B, P, and probably D of the alternative pathway (AP). Total hemolytic C could be restored to normal in these C2D sera by utilizing heavily sensitized E or by the addition of a supranormal concentration of B. This system most closely resembles a pathway described by J. E. May and M. M. Frank which requires antibody, C1, and the AP but not C4 or C2. It differs in its requirement for C4. We hypothesize that this pathway represents vestiges of a more primitive C pathway. It becomes evident and possibly clinically important in the setting of C2 deficiency, by allowing C activation, other than the AP, and perhaps in normal individuals, by damaging microorganisms that have evolved means to inhibit early components of the CP.
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Fleming, Patrick, Maggie Cheung, and David Sokol. "Complement-Mediated Thrombotic Microangiopathy: A Murky Presentation of a Rare Disease Entity." Blood 132, Supplement 1 (November 29, 2018): 5005. http://dx.doi.org/10.1182/blood-2018-99-119893.
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Abstract Complement-mediated thrombotic microangiopathy (TMA), also known as atypical hemolytic uremic syndrome (aHUS) is a rare, hereditary, progressive, life-threatening disorder caused by a disruption in regulation of the alternative pathway of the complement system. Eculizumab, a terminal complement inhibitor, has emerged as a first-line therapy, however data are limited to small case series (Brocklebank et al., 2017). Here, we present a diagnostically challenging case of complement-mediated TMA, who received eculizumab therapy with excellent hematologic response. A 68-year-old female with history of possible Sjogren's syndrome, migraine disorder, chronic fatigue syndrome, inflammatory colitis, hypertension, and poor medical follow up presented with 6-day history of severe fatigue, hematochezia, decreased urine output, dyspnea with exertion and anginal chest pain. 2 weeks prior, patient endorsed "flu-like" illness and had diffuse myalgias without fevers. Further history revealed ibuprofen usage of 800-1200 mg/day for several years. Shortly after admission, patient became severely agitated and confused with an attempt to elope from hospital. During diagnostic workup, labs were significant for hemoglobin 5.6 g/dL, platelets 57,000/uL, serum creatinine 6.6 mg/dL, BUN 101 mg/dL. Peripheral smear showed schistocytes and tear drop cells, low platelets without clumping, and hypochromic normocytic red cells. LDH of 2152 U/L, haptoglobin <34 mg/dL, and GI PCR was panel negative for E. coli O157 and Shiga-like toxin producing E. coli. She was presumed to have thrombotic thrombocytopenic purpura (TTP) as she presented with 4 of the 5 characteristic pentad, including microangiopathic hemolytic anemia, acute renal failure, thrombocytopenia, and severe neurologic findings. Patient received several PRBC transfusions, five plasma exchange treatments, hemodialysis and corticosteroids. She had initial improvement in platelet count and decrease in LDH with plasma exchange, however plateaued by day 5. Further testing revealed low complement C3 level of 51 mg/dL, low complement C4 level of 22.7 mg/dL, and pre-PLEX ADAMSTS13 level of 93%, suggesting complement-mediated TMA as the correct diagnosis. Patient was subsequently transferred to tertiary care center for initiation of eculizumab. Genetic testing was completed, notable for decreased Factor H and a heterozygous missense mutation in complement factor H of uncertain significance, only having been previously reported in a single patient with aHUS (Fremeaux-Bacci et al., 2013). She achieved excellent hematologic response with eculizumab evidenced by improved platelet count, haptoglobin, decreased LDH, however she unfortunately remained dialysis-dependent. Thrombotic microangiopathy (TMA) syndromes are overlapping entities which can be categorized by primary vs secondary etiology. Primary syndromes include TTP (hereditary or acquired), Shiga-toxin mediated HUS, drug-induced TMA and complement mediated TMA. Secondary causes include pregnancy-associated (pre-eclampsia/HEELP syndrome), malignancy, systemic infection, severe hypertension, autoimmune disorders like SLE, and complications from organ transplantation. When evaluating a patient with suspected TMA, it is important to correctly categorize their disease to guide appropriate treatment. Complement-mediated TMA results from a hereditary deficiency of regulatory proteins that restrict activation of alternative complement pathway. These proteins include complement factor H (CFG) and its related proteins (CFHRs), membrane cofactor protein (MCP), CFI. Instead, it may result from an autoantibody inhibiting CFH of CFI. The consequence of this up-regulation is uncontrolled damage to vascular endothelium and renal cells, which manifests as a characteristic pentad. In our case, a CFH gene mutation was identified and history revealed a flu-like illness preceding her hospitalization. It is plausible that this illness may have served as a "second-hit" via complement-amplification. (Asif et al., 2017). Alternatively, in this patient with history of inflammatory colitis and reported Sjogren's syndrome, subclinical autoimmune disorder may also have served as a trigger. This case presentation serves as a reminder to not overlook the "zebra" that is complement-mediated TMA, to allow for prompt initiation of eculizumab therapy. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Atrash, Shebli, David Kent McKelvey, Appalanaidu Sasapu, Muthu Veeraputhiran, Soumya Pandey, Michele H. Cottler-Fox, and Pooja Motwani. "Three Cases of Patients with Complement Regulatory Factor Genetic Mutations and Acquired Thrombotic Thrombocytopenic Purpura (TTP)." Blood 128, no. 22 (December 2, 2016): 1362. http://dx.doi.org/10.1182/blood.v128.22.1362.1362.
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Abstract Acquired TTP is a thrombotic microangiopathy (TMA) associated with deficiency of the vonWillebrandfactor cleaving protein ADAMTS13. Atypical hemolytic uremic syndrome (aHUS) is a TMA with a genetic predisposition todysregulationin the alternative complement pathway. Causes ofaHUSinclude mutations in CD46, complement factor I (CFI), complement factor B, complement component 3 (C3), complement factor H-related 5 (CFHR5), andthrombomodulin(THBD) or secondary to Complement factor H (CFH) autoantibodies. Treatment of these two TMAs differs. Whereas therapeutic plasma exchange (TPE), steroids, rituximab, cyclophosphamide and/or vincristine are used in TTP,aHUSrequires controlling unrestrained complement activation with eculizumab, an antibody preventing cleavage of C5. Testing for genetic predisposition to complementdysregulationis not commonly considered in TTP. To our knowledge, only one case report has described such a genetic association (Ref: PMID# 22409250). Here we describe 3 new cases with concurrent TTP,aHUSand genetic changes in complement genes. Case 1: 24y.o. African American (AA) man with XXY syndrome presented with bloody diarrhea, diffuse abdominal pain and renal dysfunction and a presumptive diagnosis ofaHUS. He was treated with eculizumab prior to transfer to our institution. On arrival to us, ADAMTS13 was low and inhibitor elevated. He initially responded to TPE but renal failure progressed andaHUS gene testing was ordered revealing a CFHR1-CFHR3 homologous deletion. Eculizumab was restarted but increased ADAMTS13 inhibitor required continued TPE, rituximab and vincristine; eculizumab was held until ADAMTS13 inhibitor was no longer detectable. At 8 months he continues on eculizumab with undetectable ADAMTS13 inhibitor and normal renal function, platelets and LDH (Figure). Case 2: 35y.o. AA woman presented with complaints of slurred speech, left-sided numbness, and thrombocytopenia, but normal renal function. Testing revealed ADAMTS13 <5%, presence of inhibitor (2.2 BU; normal <0.4 BU) and normal complement levels. TPE and steroids were initiated, with rituximab and vincristine added due to inhibitor boosting after initial response. Despite continued treatment, clinical/laboratory parameters did not improve, C3 and C4 levels declined, andaHUS genetic mutation analysis was ordered. This revealed heterozygous missense variants in exon 11 (c.1246A>C, plle416Leu) and exon 7 (c.1135G>C,p.Val379Leu). Once platelets recovered, we treated her with one dose of eculizumab; however, subsequently her plateletsdropped as she had not yet cleared the inhibitor. We then resumed plasma exchange and added eculizumab to her treatment at a later point (figure). Her laboratory parameters have normalized and she is on eculizumab maintenance. Case 3: 67y.o. AA woman presented with thrombocytopenia, microangiopathic hemolytic anemia, and left arm weakness. Renal function was mildly affected, with GFR ~ 30 mL/min/1.73m2. ADAMTS13 was <5% and inhibitor titer was 1.1 BU. TPE and steroids were initiated on admission, followed by rituximab, but due to lack of response after 14 days, she was given eculizumab. She had an immediate rise in platelet count after one dose and a sustained rise after the second dose. Her CBC and hemolysis parameters normalized after 4 doses. She continued treatment with eculizumab for a total of 6 months after which she opted to stop the drug. Within a month of discontinuing treatment, she developed a deep venous thrombosis and received anticoagulation for 6 months. She is now 2 years out of stopping eculizumab and has a normal CBC and LDH. Subsequent gene testing revealed the same CFHR1-CFHR3 homologous deletion identified in case 1. (Figure) Conclusion: We found treatment of TTP first allowed control of complementdysregulation, while treatment ofaHUSfirst did not allow control of TTP. This suggests that low ADAMTS13 levels may be the initiating factor in uncontrolled complement activation inaHUS. These cases suggest the need to test forgermlinemutations leading to abnormal complement activation in patients with refractory TTP, as they may have a dual diagnosis of both TTP andaHUSas our patients did. We therefore suggest treating the underlying TTP first, monitoring the ADAMTS13 activity and inhibitor levels to assess the clearance of the inhibitor, and initiating treatment with eculizumab once the inhibitor has cleared. Figure Figure. Disclosures No relevant conflicts of interest to declare.
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Tabra, Samar abd Alhamed, Hend Hassan Abdelnabi, Nivine Fathi Mahmoud Darwish, Amal Mohammed El-Barbary, Muhammad Tarek AbdelGhafar, and Mohammed Hassan Abu-Zaid. "Juvenile lupus and serum vitamin D levels: A cross-sectional study." Lupus 29, no. 13 (September 13, 2020): 1752–58. http://dx.doi.org/10.1177/0961203320957721.
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Background Juvenile systemic lupus erythematosus (JSLE) is usually associated with vitamin D deficiency and low bone mineral density. Objectives To evaluate serum levels of 25-OH vitamin D in JSLE patients and to correlate these findings with disease activity and bone density. Methods This study was conducted on 100 patients with JSLE and 100 healthy children as controls. Disease duration and SLEDAI for disease activity were evaluated. CBC, anti-dsDNA, C3,C4,24hr urinary proteins, creatinine, estimated glomerular filtration rate(e-GFR),Ca,P,PTH, 25 (OH) D levels, and bone mineral density(BMD)Z score were measured. Results There were significant differences in mean 25(OH)D concentration between patients group (19.37 ± 9.72 ng/ml) and controls 35.90 ± 9.66 ng/ml(p < 0.05), with significant difference between active and inactive patients (p < 0.05).There were significant negative correlations between serum 25(OH)D and SLEDAI (r-0.545, p 0.001), steroid dose (r-0.561, p 0.001), anti-dsDNA (r-0.685, p 0.006), 24 hr-proteinuria (r-0.738, p 0.001) and PTH (r-0.335, p 0.001), significant positive correlations between 25(OH)D and C3 (r0.617, p 0.001),C4 (r0.544, p 0.001) serum Ca (r0.424, p 0.001) and Z score (r0.561, p 0.001),with non-significant correlations between 25(OH)D and serum P and both disease & steroid duration, (p > 0.05). Conclusion Vitamin D deficiency is common in JSLE, it’s correlated significantly with disease activity and bone mineral density.
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Kosturkova, M., T. Shivacheva, G. Mihaylova, V. Vasilev, and M. Radanova. "AB0007 ASSOCIATION OF rs172378 VARIANT IN C1q GENE CLUSTER WITH SOME CLINICAL AND IMMUNOLOGICAL ASPECTS OF SYSTEMIC LUPUS ERYTHEMATOSUS IN BULGARIAN PATIENTS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1139.1–1139. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2540.
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BackgroundSingle nucleotide polymorphisms (SNPs) in complement C1q component are found to be linked with systemic lupus erythematosus (SLE), but less is known about their association with the clinical and immunological aspects of the disease.ObjectivesThe aim of the study was to examine five SNPs – rs665691, rs682658, rs172378, rs294179, rs292001 in C1q gene cluster for association with some clinical (age at disease onset, organ involvement, BILAG score, SLICC/ACR DI) and immunological (ANA, anti-dsDNA, complement factors C3 and C4) aspects of SLE.Methods53 SLE patients were enrolled in this cross-sectional study and relevant clinical information was collected. SNP genotyping was performed on extracted DNAs from patients using a TaqMan allelic discrimination assay. ANA, anti-dsDNA and complement proteins C3 and C4 were measured by IIF, ELISA and radial immunodiffusion resp.ResultsG-allele and GG-genotype of rs172378 were overrepresented among patients with LN compared to the other SLE patients – 64% vs 31% for G-allele and 48% vs 7.7% and were associated with renal involvement – OR=3.96 (95%CI: 1.53 – 10.23), р=0.005 for G-allele and OR=10.86 (95%CI: 1.29 – 91.58), р=0.028 for GG-genotype.G-allele and GG-genotype were also associated with increased levels of anti-dsDNA antibodies – OR=2.95 (95%CI: 1.21 – 7.18), p=0.017 and OR=6.33 (95%CI: 1.41 – 28.39), р=0.016, resp.G-allele showed weak correlation with earlier age at disease onset (point biserial r=-0.22, p=0.03) and patients, carrying it (GG- and AG-genotypes) were younger at disease onset then those with AA-genotype (p=0.05 and p=0.02 resp.).Conclusionrs172378 associates with some clinical and immunological parameters of SLE, traditionally linked to disease severity, therefore it may possibly play a role in disease pathogenesis.References[1]Guo J, G. Y. (2018). Investigation of C1-complex regions reveals new C1Q variants associated with protection from systemic lupus erythematosus, and affect its transcript abundance. Sci Rep., 8048. doi:10.1038/s41598-018-26380-x[2]Martens HA, Z. M. (2009). Analysis of C1q polymorphisms suggests association with systemic lupus erythematosus, serum C1q and CH50 levels and disease severity. Ann Rheum Dis. 2009 May;68(5):715-20. doi:, 715-20.[3]Mosaad YM, H. A.-R. (2015). C1q rs292001 polymorphism and C1q antibodies in juvenile lupus and their relation to lupus nephritis. Clin Exp Immunol., 23-34. doi:10.1111/cei.12666[4]Namjou B, K. M. (2012). Identification of novel coding mutation in C1qA gene in an African-American pedigree with lupus and C1q deficiency. Lupus., 1113-8. doi:10.1177/0961203312443993[5]Petry F, L. M. (2005). Common silent mutations in all types of hereditary complement C1q deficiencies. Immunogenetics, 566-71.[6]Racila DM, S. C. (2003). Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus. Lupus, 124-32.[7]Radanova M, V. V. (2015, Mar). Association of rs172378 C1q gene cluster polymorphism with lupus nephritis in Bulgarian patients. Lupus, 280-9. doi:10.1177/0961203314555173[8]Rafiq S, F. T. (2010, Aug). Assessing association of common variation in the C1Q gene cluster with systemic lupus erythematosus. Clin Exp Immunol., 284-9. doi:10.1111/j.1365-2249.2010.04185.xDisclosure of InterestsNone declared
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Sharma, Vasundhara, Lanzhu Yue, Nathan P. Horvat, Agni Christodoulidou, Afua Adutwumwa Akuffo, Mathew Beatty, Cem Murdun, et al. "Selective Targeting of Histone Deacetylase 11 Disables Metabolism of Myeloproliferative Neoplasms." Blood 134, Supplement_1 (November 13, 2019): 474. http://dx.doi.org/10.1182/blood-2019-127235.
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Introduction: Acetylated histone and non-histone proteins are pharmacologic targets for both solid and hematological cancers including myeloproliferative neoplasms (MPNs), a group of clonal hematological malignancies driven by aberrant JAK2/STAT signaling. MPNs are characterized by epigenetic alterations, including aberrant acetylation, which makes this disease particularly interesting for targeting with HDAC inhibitors. Four classes of histone deacetylases (Class I-IV HDACs) regulate gene transcription and modulate cellular processes that drive the initiation and progression of cancer. Pan-HDAC and class I-selective HDAC inhibitors have gained traction in clinical settings, yet we reasoned that specific targeting of the 18 distinct HDAC proteins may establish roles for select HDACs as therapeutic vulnerabilities in MPNs. Methods: To explore the roles of individual HDACs in MPN, we first conducted an inhibitor screen of compounds having distinct HDAC selectivity based on electrophoretic mobility shift assays with full-length human HDAC proteins expressed in baculovirus and unique peptide substrates. Ultra-specific HDAC6 compounds were initially targeted for analysis based on its previously defined role in HSP90-mediated JAK2 stabilization and translation. Survival of MPN cell line models, MPN patient samples, leukemia cell lines, and MPN disease progression in mice transplanted with Hdac6-/-, and Hdac11-/- hematopoietic stem cells (HSCs) transduced with the MPLW515L oncogene, as well as Tg-Hdac11-eGfp mice were used to show the role of HDAC6 and HDAC11 in oncogene-driven and homeostatic hematopoiesis. As further proof of specificity, HDAC6 and HDAC11 were genetically ablated in MPN model cell lines using either RNA interference or inducible shRNA. For HDAC11 substrate identification, a combination of RNA-seq, acetylated proteome (SILAC), global metabolomics (LC-MS), Seahorse metabolic assays (Agilent Technologies), enzymatic assays, and acetylation-specific immunoblotting and mutation profiling were performed (Fig. 1). Results: Despite the established interplay between HDAC6, HSP90 and JAK2, neither a highly selective HDAC6 inhibitor, HDAC6 silencing, nor the Hdac6 deficiency suppressed MPN pathogenesis, although there were clear effects on the acetylation of α-tubulin, a well characterized HDAC6-selective substrate. Intriguingly, both inhibition of HDAC11 activity with highly-specific HDAC11 inhibitors and silencing HDAC11 using an inducible validated shRNA, identified HDAC11 as a therapeutic vulnerability for multiple human MPN cell lines. The Tg-Hdac11-eGFP reporter mice showed that HDAC11 is expressed in several hematopoietic cell types, including myeloid cells, erythroblasts, and megakaryocytes. Thus, Hdac11-/- and Hdac11+/+MPLWT bone marrow were examined for steady-state hematopoiesis and transplantation chimerism. These studies demonstrated that HDAC11 does not contribute to homeostatic or transplantated bone marrow reconstitution. However, in the oncogenic MPL model, recipient mice transplanted withoncogenic MPLW515L-expressing Hdac11-deficient HSCs displayed markedly impaired cytokine-independent colony-formation, had less fibrosis, and displayed improved survival in primary and secondary MPN hematopoietic stem cell transplantation; thus HDAC11 contributes to MPN pathogenesis (Fig. 1). Studies in additional leukemia cell lines, including THP-1, HL-60, and mantle lymphoma cell lines, but not in Ramos or K562 cells, established that HDAC11 contributes to oncogene-driven events in other cell types. Mechanistically, RNA-seq, SILAC proteomics, and metabolic profiling revealed that HDAC11 controls aerobic glycolysis by deacetylating Lys343 of the glycolytic enzyme enolase-1 (ENO1), functionally inactivating ENO1. Finally, the effects of targeting HDAC11 on metabolism were augmented by blocking compensatory pathways of oxidative phosphorylation that are induced via JAK2V617Fand MPLW515L oncogenic signaling. Conclusions: Our comprehensive screens of HDAC inhibitors, coupled with our biological, in vivo and molecular studies, indicate that HDAC11 is an attractive and potent target for disabling MPN metabolism and pathogenesis. These finding support the rationale for further development of clinical HDAC11 inhibitors for the treatment of metabolically-active cancers such as MPNs. Disclosures Pinilla Ibarz: Teva: Consultancy; TG Therapeutics: Consultancy; Sanofi: Speakers Bureau; Bayer: Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Reuther:Incyte Corporation: Research Funding. Levine:Loxo: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Research Funding; Lilly: Honoraria; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Gilead: Consultancy; Celgene: Consultancy, Research Funding; Qiagen: Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Amgen: Honoraria. Verma:BMS: Research Funding; Janssen: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria. Epling-Burnette:Incyte Corporation: Research Funding; Celgene Corporation: Patents & Royalties, Research Funding; Forma Therapeutics: Research Funding.
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Wang, Hongbin, and Mengyao Liu. "Complement C4, Infections, and Autoimmune Diseases." Frontiers in Immunology 12 (July 14, 2021). http://dx.doi.org/10.3389/fimmu.2021.694928.
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Complement C4, a key molecule in the complement system that is one of chief constituents of innate immunity for immediate recognition and elimination of invading microbes, plays an essential role for the functions of both classical (CP) and lectin (LP) complement pathways. Complement C4 is the most polymorphic protein in complement system. A plethora of research data demonstrated that individuals with C4 deficiency are prone to microbial infections and autoimmune disorders. In this review, we will discuss the diversity of complement C4 proteins and its genetic structures. In addition, the current development of the regulation of complement C4 activation and its activation derivatives will be reviewed. Moreover, the review will provide the updates on the molecule interactions of complement C4 under the circumstances of bacterial and viral infections, as well as autoimmune diseases. Lastly, more evidence will be presented to support the paradigm that links microbial infections and autoimmune disorders under the condition of the deficiency of complement C4. We provide such an updated overview that would shed light on current research of complement C4. The newly identified targets of molecular interaction will not only lead to novel hypotheses on the study of complement C4 but also assist to propose new strategies for targeting microbial infections, as well as autoimmune disorders.
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Zhou, Danlei, Emily H. King, Simon Rothwell, Olga Krystufkova, Antonella Notarnicola, Samantha Coss, Rabheh Abdul-Aziz, et al. "Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies." Annals of the Rheumatic Diseases, September 28, 2022, ard—2022–222935. http://dx.doi.org/10.1136/ard-2022-222935.
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BackgroundIdiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement C4 in IIM pathology was unknown.MethodsWe elucidated the gene copy number (GCN) variations of total C4, C4A and C4B, long and short genes in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion.ResultsThe large study populations helped establish the distribution patterns of various C4 GCN groups. Low GCNs of C4T (C4T=2+3) and C4A deficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28–2.91), p=5.0×10−53 for C4T, and 2.82 (2.48–3.21), p=7.0×10−57 for C4A deficiency. Contingency and regression analyses showed that among patients with C4A deficiency, the presence of HLA-DR3 became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had HLA-DR3 with an OR of 11.02 (1.44–84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies.ConclusionsC4A deficiency is relevant in dermatomyositis, HLA-DRB1*03 is important in IBM and both C4A deficiency and HLA-DRB1*03 contribute interactively to risk of polymyositis.
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Zhou, Danlei, Michael Rudnicki, Gilbert T. Chua, Simon K. Lawrance, Bi Zhou, Joanne L. Drew, Fatima Barbar-Smiley, et al. "Human Complement C4B Allotypes and Deficiencies in Selected Cases With Autoimmune Diseases." Frontiers in Immunology 12 (October 26, 2021). http://dx.doi.org/10.3389/fimmu.2021.739430.
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Human complement C4 is one of the most diverse but heritable effectors for humoral immunity. To help understand the roles of C4 in the defense and pathogenesis of autoimmune and inflammatory diseases, we determined the bases of polymorphisms including the frequent genetic deficiency of C4A and/or C4B isotypes. We demonstrated the diversities of C4A and C4B proteins and their gene copy number variations (CNVs) in healthy subjects and patients with autoimmune disease, such as type 1 diabetes, systemic lupus erythematosus (SLE) and encephalitis. We identified subjects with (a) the fastest migrating C4B allotype, B7, or (b) a deficiency of C4B protein caused by genetic mutation in addition to gene copy-number variation. Those variants and mutants were characterized, sequenced and specific techniques for detection developed. Novel findings were made in four case series. First, the amino acid sequence determinant for C4B7 was likely the R729Q variation at the anaphylatoxin-like region. Second, in healthy White subject MS630, a C-nucleotide deletion at codon-755 led to frameshift mutations in his single C4B gene, which was a private mutation. Third, in European family E94 with multiplex lupus-related mortality and low serum C4 levels, the culprit was a recurrent haplotype with HLA-A30, B18 and DR7 that segregated with two defective C4B genes and identical mutations at the donor splice site of intron-28. Fourth, in East-Asian subject E133P with anti-NMDA receptor encephalitis, the C4B gene had a mutation that changed tryptophan-660 to a stop-codon (W660x), which was present in a haplotype with HLA-DRB1*04:06 and B*15:27. The W660x mutation is recurrent among East-Asians with a frequency of 1.5% but not detectable among patients with SLE. A meticulous annotation of C4 sequences revealed clusters of variations proximal to sites for protein processing, activation and inactivation, and binding of interacting molecules.
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Zecevic, Milica, Aleksandra Minic, Srdjan Pasic, Vladimir Perovic, and Zoltán Prohászka. "Case Report: Early Onset Systemic Lupus Erythematosus Due to Hereditary C1q Deficiency Treated With Fresh Frozen Plasma." Frontiers in Pediatrics 9 (December 21, 2021). http://dx.doi.org/10.3389/fped.2021.756387.
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Background: Hereditary C1q deficiency is associated with early-onset autoimmunity causing SLE or SLE-like disease as well as increased risk for infections with encapsulated bacteria. It is a rare genetic condition inherited in an autosomal recessive manner, caused by mutations in C1q genes. Treatment and management of this rare disease are very complex and include prophylactic vaccination, antibiotics, and immunosuppressive drugs. There are two possible modalities for the replacement of the missing protein: regular fresh frozen plasma (FFP) administration and allogeneic hematopoietic stem cell transplant because the protein is derived from monocytes. Replacing C1q with FFP is being attempted in some patients with success in controlling the disease and in avoiding flare.Case Report: We report a case of sixteen-month-old girl with ulcerations in her mouth, skin erythema, and elevated liver enzymes. ANAs were positive, antibodies against dsDNA were negative, but she had positive anti-Smith antibodies. Complement complements C3 and C4 levels were normal. Total complement activity, classical pathway (hemolytic test) was deficient and C1q antigen was below the detection limit supporting the presence of C1q deficiency. The girl has pathogenic homozygous nonsense mutation in C1qC gene, Arg69Ter (c205>T). The initial response to corticosteroid therapy was good. Regular fresh frozen plasma infusions keep her disease under control, and we were able to reduce the dose of corticosteroids.Conclusion: Young patients with cutaneous lesions resembling SLE, early onset of autoimmunity, with normal C3, C4, elevated ANAs, and negative anti-dsDNA, C1q deficiency should be suspected and complement screening tests should be done. It is important to exclude secondary C1q deficiency. FFP in our patient seems to be well tolerated, without any side effects, able to control the disease.
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Moin, Abu Saleh Md, Thozhukat Sathyapalan, Alexandra E. Butler, and Stephen L. Atkin. "Classical and alternate complement factor overexpression in non-obese weight matched women with polycystic ovary syndrome does not correlate with vitamin D." Frontiers in Endocrinology 13 (December 21, 2022). http://dx.doi.org/10.3389/fendo.2022.935750.
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IntroductionWomen with polycystic ovary syndrome (PCOS) exhibit complement factor expression changes that may be obesity-driven rather than an intrinsic facet of PCOS; furthermore, complement changes have been associated with vitamin D deficiency, a common feature of PCOS. Therefore, complement pathway proteins and vitamin D levels may be linked in PCOS.MethodsWe measured plasma levels of complement pathway proteins by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement for the classical (C4, C4a, and C4b) and alternative pathways (C3, C3b, iC3b, properdin, and factors B, D, and H) in weight and age-matched non-obese non-insulin resistant women with PCOS (n = 24) and control women (n = 24). Proteins that differed between groups were correlated with 25-hydroxyvitamin D3 (25(OH)D3) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), measured by isotope-dilution liquid chromatography tandem mass spectrometry.ResultsWomen with PCOS had a higher free androgen index and anti-Mullerian hormone, though insulin resistance was comparable to controls; likewise, C-reactive protein, a marker of inflammation, was comparable between cohorts. In the alternative complement pathway, C3, iC3b, and properdin were increased in PCOS (p <0.05), while C4 in the classical pathway was increased (p <0.05). 25(OH)D3 levels positively correlated with C3b only in control subjects, with no correlation of 1,25(OH)2D3 with any of the proteins.ConclusionIn a non-obese PCOS population matched for age, insulin resistance and inflammation, initiating proteins of the classical and alternate complement cascades were increased. However, a positive correlation with 25(OH)D3 was only seen for C3b in control subjects, with no correlation to 1,25(OH)2D3, suggesting that the increase in complement proteins in PCOS is vitamin D-independent.
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Ohtani, Katsuki. "Complement-Related Proteins and Their Measurements: The Current Status of Clinical Investigation." Nephron, November 24, 2020, 1–6. http://dx.doi.org/10.1159/000512494.
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Complement has been considered to be a factor that protects the host against invading microorganisms during infection. However, in recent years, complement-related protein deficiency has been found to be involved in the onset of various diseases, such as autoimmune and inflammatory diseases. In Japan, C3, C4, and CH50 tests were generally performed only when a complement system examination was necessary and there were not enough examinations for other complement factors. Since the complement system has a very complicated activation pathway, at present, it is not well known which molecule must be measured to understand the pathological condition or pathogenesis in complement-related diseases. Furthermore, since the frequency of complement factor gene alleles also differs depending on race, data from foreign countries cannot be directly applied to Japanese populations. Under these circumstances, the Japanese Association for Complement Research (JACR) has prepared approximately 20 items for complement-related examinations, including the 5 categories of functional analysis, complement factors, complement regulators, activation products, and autoantibodies.
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Nabavi, Mohammad, Sima Bahrami, Saba Arshi, Afshin Rezaeifar, Mohammad Hassan Bemanian, Morteza Fallahpour, Sima Shokri, and Homan Tehrani. "Periodic Severe Angioedema without Exogenous Hormone Exposure." Iranian Journal of Allergy, Asthma and Immunology, February 14, 2021. http://dx.doi.org/10.18502/ijaai.v20i1.5419.
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Hereditary angioedema (HAE) is characterized by recurrent attacks of skin and mucosal swelling in any part of the body including the digestive and respiratory tract which generally improve spontaneously within 12-72 hours. The underlying mechanism in HAE is related to bradykinin dysregulation which causes these attacks not to respond to common treatment strategies including epinephrine or corticosteroid. There are several types of HAE with different etiology but with the same clinical picture. Type 1 is due to the deficiency of C1 Inhibitor (C1- INH) protein and type 2 is related to dysfunctional C1-INH protein. The third type of HAE which comprises the minority of cases is associated with the normal amount and function of C1- INH protein. The presented case in this report was a 15-years old girl with a history of spontaneous angioedema attacks from the age of 14. The frequency of attacks was initially every two months but consequently increased to every two weeks after using some hormonal medications for ovarian cyst. Each episode has lasted around 10 days without any symptoms in between. Complement studies including C4, C1q, and C1-INH protein, both quantitative and qualitative, were reported as normal. A genetic assessment revealed a mutation in the exon 9 on the gene related to factor XII, hence the diagnosis of HAE type 3 was confirmed. This was a rare type of angioedema with normal amount and function of C1-INH protein which is predominantly seen in women during periods of imbalanced estrogen increments like pregnancy, lactation, and menopause, and hence it is responsive to hormonal manipulation strategies such as the use of progesterone containing medications.
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Marino, Roxana, Angélica Moresco, Natalia Perez Garrido, Pablo Ramirez, and Alicia Belgorosky. "Congenital Adrenal Hyperplasia and Ehlers-Danlos Syndrome." Frontiers in Endocrinology 13 (February 25, 2022). http://dx.doi.org/10.3389/fendo.2022.803226.
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Congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency is an autosomal recessive disorder. The 21-hydroxylase enzyme P450c21 is encoded by the CYP21A2 gene located on chromosome 6p21.33 within the HLA major histocompatibility complex. This locus also contains the CYP21A1P, a non-functional pseudogene, that is highly homologous to the CYP21A2 gene. Other duplicated genes are C4A and C4B, that encode two isoforms of complement factor C4, the RP1 gene that encodes a serine/threonine protein kinase, and the TNXB gene that, encodes the extracellular matrix glycoprotein tenascin-X (TNX). TNX plays a role in collagen deposition by dermal fibroblasts and is expressed in the dermis of the skin and the connective tissue of the heart and skeletal muscle. During meiosis, misalignment may occur producing large gene deletions or gene conversion events resulting in chimeric genes. Chimeric recombination may occur between TNXB and TNXA. Three TNXA/TNXB chimeras have been described that differ in the junction site (CH1 to CH3) and result in a contiguous CYP21A2 and TNXB gene deletion, causing CAH-X syndrome. TNXB deficiency is associated with Ehlers Danlos syndrome (EDS). EDS comprises a clinically and genetically heterogeneous group of connective tissue disorders. As molecular analysis of the TNXB gene is challenging, the TNX-deficient type EDS is probably underdiagnosed. In this minireview, we will address the different strategies of molecular analysis of the TNXB-gene, as well as copy number variations and genetic status of TNXB in different cohorts. Furthermore, clinical features of EDS and clinical recommendations for long-term follow-up are discussed.
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"Intestinal Angioedema: Case Report and Literature Review." Journal of Gastroenterology & Digestive Systems 2, no. 2 (August 18, 2018). http://dx.doi.org/10.33140/jgds/02/02/00003.
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Hereditary angioedema (HAE) is the deficiency or dysfunction of C1 esterase inhibitor (C1-INH). However, it may also occur due to either increased activity of factor XII / estrogen levels or through an unidentified cause. It manifests the attacks of swelling involving the skin and / or the mucosa / sub mucosa of different organs. The attacks may be the result of a specific trigger or occur spontaneously. The intestinal angioedema is clinically presented with moderate or severe abdominal pain, associated with nausea, vomiting, diarrhea and / or ascites, and interpreted as an “acute abdomen”. The treatment is into three distinct phases: treatment for acute attacks, short-term prevention, and long-term prophylaxis. The 26-year-old woman with food and medication allergy presents with thirteen-year history of recurrent abdominal pain diffuse and associated with diarrhea, nausea and hands, lips and eyelids swelling. During this period, she did several exams and six laparoscopies that only revealed a small amount of free intraperitoneal fluid. Biochemical testing performed at that time revealed the C1 esterase inhibitor, decreased protein level, and C4 level, and she was, then, diagnosed in adults with intestinal involvement with HAE. After the adequate treatment and prophylaxis, she evolved with reduction of the number of attacks. The late diagnosis is associated with high morbidity. Therefore, it is extremely important the recognition and investigation of HAE with involvement in intestinal patients with recurrent attacks of unexplained abdominal pain.
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Khodadadian, Mehdi, Nahid Zarezadeh, Hossein Behrouz, and Zeinab Ahsani. "Determination of rFVII concentration in cell culture supernatant using VIISelect resin and RP-HPLC-UV." Current Pharmaceutical Analysis 18 (September 1, 2022). http://dx.doi.org/10.2174/1573412918666220901155615.
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Background: Recombinant activated human coagulation factor VIIa (rFVIIa), a vitamin K-dependent serine protease, was originally developed by Novo Nordisk® for the treatment of patients with FVII deficiency as well as patients with hemophilia A and B with inhibitors against FVIII or FIX. The gene for human FVII is cloned and expressed in baby hamster kidney (BHK) cells and the protein is secreted into the culture media, which is then converted to the active form during chromatographic purification steps. When secreted into the culture media, measuring the concentration levels of FVII is needed in order to monitor, control and optimize the production processes. However, because of the high complexity of such media, reliable analytical techniques are required for this purpose. Objective: This work focuses on the analytical application of VIISelect resin (GE Healthcare) as a highly selective adsorbent for cleanup and preconcentration of rFVII in culture supernatant before analysis by reversed phase high performance liquid chromatography (RP-HPLC). Method: Empty 1 ml SPE cartridges were packed with VIISelect resin. Four types of solutions were used for the sample preparation. The RP-HPLC separation was conducted on a C4 column with UV detection. Results: The method shows recoveries greater than 97% in culture medium with relative standard deviations (RSDs) of less than 2%. The limits of detection and quantification were 0.039 mg/L and 0.12 mg/L, respectively. Conclusion: The method showed better performance in terms of precision and accuracy for rFVIIa determination in cell culture supernatant compared with other techniques like ELISA and SDS-PAGE.
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Shenavandeh, Saeedeh, and Sepideh Sefidbakht. "Amidst the chaos of late rheumatoid arthritis with no treatment." Journal of Clinical Images and Medical Case Reports 3, no. 1 (January 5, 2022). http://dx.doi.org/10.52768/2766-7820/1535.
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A 78-year-old man with 24 years history of Rheumatoid Arthritis (RA) came with neck pain. He always refused any treatment except for NSAIDs. From 2 years ago, he was bedridden. He was chronic cigarette smoker. On examination, he had rheumatoid nodules, severe both hands deformity, elbows flexion contracture and knee joints limitation of motion. His lab tests showed high titer of rheumatoid factor and anti cyclic citrullinated protein antibody, high ESR, CRP and vitamin D deficiency. Radiologic studies showed multiple vertebral osteoporotic fractures. Cervical spine CT scan (a and b) showed destruction of the odontoid process and fusion of facet joints of the C2, C3 and C4. MRI of cervical spine (c) showed destruction of odontoid process surrounding by inflammatory synovitis. CT scan of lung (e and f) showed multiple upper lobeand sub pleural nodules along fibrotic changes in base of right lobe. X-ray of knee and hip (d and g) showed severe osteoarthritis andsite of previouship nailing. The patient was diagnosed with advanced erosive nodular RA, severe secondary osteoporosis, osteoarthritis and rheumatoid lung. Standard treatment was recommended, although he again refused. RA can result in progressive joint destruction, deformity and disability [1]. In the spine, it has a predilection for the cervical area, leads to odontoid erosion, spinal instability, and subluxation. In the era of importance of early treatment, these complications are rarely seen, however despite biologic therapy, it has been shown that 15-30% of RA patients can still have preclinical cervical spine abnormalities [2]. The Osteoporosis (OP) is more frequent in patients with high disease activity, bone erosions, >10 years disease duration, and high titers of anti-CCP and RF positivity [3]. Our patient with multiple poor prognostic factors for erosive RA came with extra articular and complications of this disease due refusing treatment.
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Szabó, Edina, Dorottya Csuka, Noémi Andrási, Lilian Varga, Henriette Farkas, and Ágnes Szilágyi. "Overview of SERPING1 Variations Identified in Hungarian Patients With Hereditary Angioedema." Frontiers in Allergy 3 (March 17, 2022). http://dx.doi.org/10.3389/falgy.2022.836465.
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BackgroundHereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare autosomal dominant disorder, characterized by recurrent, unpredictable edematous symptoms involving subcutaneous, and/or submucosal tissue. C1-INH-HAE may be caused by more than 700 different mutations in the gene encoding C1-INH (SERPING1) that may lead to decreased protein synthesis or to functional deficiency.MethodsConcentrations of C1-INH, C4, C1q, and anti-C1-INH antibodies, as well as functional C1-INH activity were determined in subjects suffering from edematous symptoms and admitted to the Hungarian Angioedema Center of Reference and Excellence. In those patients, who were diagnosed with C1-INH-HAE based on the complement measurements, SERPING1 was screened by bidirectional sequencing following PCR amplification and multiplex ligation-dependent probe amplification. For detecting large deletions, long-range PCRs covering the entire SERPING1 gene by targeting 2–7 kb long regions were applied.ResultsAltogether 197 individuals with C1-INH deficiency belonging to 68 families were identified. By applying Sanger sequencing or copy number determination of SERPING1 exons, 48 different mutations were detected in 66/68 families: 5 large and 15 small insertions/deletions/delins, 16 missense, 6 nonsense, and 6 intronic splice site mutations. Two novel variations (p.Tyr199Ser [c.596A>C] and the duplication of exon 7) were shown to cosegregate with deficient C1-inhibitor level and activity, while two other variations were detected in single patients (c.797_800delinsCTTGGAGCTCAAGAACTTGGAGCT and c.812dup). A series of long PCRs was applied in the remaining 2 families without an identified mutation and a new, 2606 bp long deletion including the last 91 bp of exon 6 (c.939_1029+2515del) was identified in all affected members of one pedigree. In the remaining one family, a deep intronic SERPING1 variation (c.1029+384A>G) was detected by a targeted next-generation sequencing panel as reported previously.ConclusionsSequencing and copy number determination of SERPING1 exons uncover most pathogenic variants in C1-INH-HAE patients, and further methods are worth to be applied in cases with unrevealed genetic background. Since knowledge of the genetic background may support the establishment of the correct and early diagnosis of C1-INH-HAE, identification of causative mutations and reporting data supporting the interpretation on the pathogenicity of these variants is of utmost importance.
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Dong, Yu-Wen, Wei-Dan Jiang, Pei Wu, Yang Liu, Sheng-Yao Kuang, Ling Tang, Wu-Neng Tang, Xiao-Qiu Zhou, and Lin Feng. "Novel Insight Into Nutritional Regulation in Enhancement of Immune Status and Mediation of Inflammation Dynamics Integrated Study In Vivo and In Vitro of Teleost Grass Carp (Ctenopharyngodon idella): Administration of Threonine." Frontiers in Immunology 13 (March 14, 2022). http://dx.doi.org/10.3389/fimmu.2022.770969.
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This study aims to investigate the effects of threonine (Thr) on immunoregulation in vivo and in vitro of teleost grass carp (Ctenopharyngodon idella). Juveniles (9.53 ± 0.02 g) were reared for 8 weeks with respective Thr diet (3.99, 7.70, 10.72, 14.10, 17.96, and 21.66 g/kg) and then challenged with Aeromonas hydrophila for in vivo study. Macrophages isolated from head kidney were treated in vitro for 48 h with L-Thr (0, 0.5, 1.0, 2.0, 4.0, and 8.0 mM) after 6 h of lipopolysaccharide induction. The results showed that, compared with Thr deficiency (3.99 g/kg), the optimal dietary Thr (14.10g/kg) affected the immunocyte activation in the head kidney (HK) and spleen (SP) by downregulating the mRNA expressions of MHC-II and upregulating CD4 (not CD8), and it mediated the innate immune by enhancing the activities of lysozyme (LZ), acid phosphatase content of complement 3 (C3) and C4, increasing the mRNA abundances of hepcidin, liver expressed antimicrobial peptide-2A (LEAP-2A), LEAP-2B, β-defensin1, downregulating tumor necrosis factor α (TNF-α), IL-6, IL-1β, IL-12p35, IL-12p40, IL-17AF1, and IL-17D partly by attenuating RORγ1 transcriptional factor and nuclear factor kappa B p65 (NF-κBp65) signaling cascades [IKKβ/IκBα/NF-κBp65] and upregulating transforming growth factor β1 (TGF-β1), IL-4/13A, -4/13B, IL-10, and IL-22 partly by GATA-3. Besides these, the optimal dietary Thr regulated the adaptive immune by upregulating the mRNAs of immunoglobulin M (IgM) and IgZ (not IgD). Moreover, 2 mM Thr downregulated in vitro the mRNA abundances of colony stimulating factor-1, inducible nitric oxide synthase, mannose receptor 1, matrix metalloproteinase2 (MMP-2), and MMP-9 significantly (P < 0.05), indicating that Thr could attenuate the M1-type macrophages’ activation. Moreover, L-Thr downregulated the mRNA transcripts of TNF-α, IL-6, and IL-1β associated with impairing the SOCS1/STAT1 signaling and upregulated IL-10 and TGF-β1 partly by accentuating the SOCS3/STAT3 pathway. The above-mentioned observations suggested that Thr improved the immune status in the immune organs of fish by enhancing the immune defense and mediating the inflammation process. Finally, based on the immune indices of LZ activity in HK and C3 content in SP, the optimal Thr for immune enhancement in juvenile grass carp (9.53–53.43 g) was determined to be 15.70 g/kg diet (4.85 g/100 g protein) and 14.49 g/kg diet (4.47 g/100 g protein), respectively.
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Mudawi, Tareg, Constanta Amoasii, and Adrian Clewes. "EP10 A rare cause of lobular panniculitis." Rheumatology 59, Supplement_2 (April 1, 2020). http://dx.doi.org/10.1093/rheumatology/keaa109.009.
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Abstract Background Weber-Christian disease is a rare inflammatory disorder of the subcutaneous fatty tissue. It is characterised by painful relapsing, subcutaneous nodules occurring preferentially at the upper arm, thigh and trunk regions. The disease is often accompanied by recurrent temperatures and constitutional symptoms. Methods We aimed to increase awareness regarding clinical presentation, diagnosis, and treatment of this rare disorder. Results A 65 year old female had been investigated thoroughly within a period of 7 years by a number of dermatology and rheumatology departments of North West hospitals. Symptoms started after mastitis with skin rash in form of macular blanching on upper abdomen and episodes of fever ranging between 38 and 40 degree Celsius, fatigability and arthritis. C-reactive protein was 300 mg/l, Erythrocytes Sedimentation Rate 150 mm/H and haemoglobin 95 g/L, positive lupus anticoagulant and negative anti-nuclear antibodies as well as extractable nuclear antibodies and normal complement levels C3 and C4 . Investigations results showed no evidence of infection, malignancy, vasculitis or connective tissue disease. PET scan revealed subcutaneous fat inflammation with increased uptake in mediastinum fat, initial skin biopsy showed lobular panniculitis with mild dermatitis suggestive of lupus profundus. Symptoms and inflammatory markers responded well to steroids however all tried DMARDs (methotrexate, azathoprime, hydroxychlorquine and mycophenolate) as well as dapsone and colchicine were not successful. In addition, 2 doses of rituximab were also ineffective in controlling her disease. Following a required excessive steroid therapy she developed cataract, osteopenia, and diabetes and became cushingoid. Repeated biopsy from the skin showed mixed inflammatory lobular pannicuilitis with neutrophils, lymphocytes and histiocytic. As per Dermatology Multi-Disciplinary Team the diagnosis of Weber-Christian disease was raised. As her condition continued to be very active she was also referred to London, where treatment with anakinra was organised. Conclusion The diagnosis of Weber-Christian disease depends on the presence of relapsing fever, systemic inflammation and panniculitis and prognosis varies depending on the response to steroids or DMARDs. For diagnosis you need to exclude all likely differential diagnoses of lobular panniculitis, like infections, certain malignancies, alpha-1-antitrypsin deficiency, pancreatitis and systemic lupus erythematosus. In conclusion, the patient has symptoms and signs as well as investigation results in keeping with Weber-Christian disease. Due to the rare nature of this disease the patient went through, multiple rheumatology and dermatology reviews and investigations and treatment trials over a period of 7 years prior to the correct diagnosis being reached. We believe reporting this case would raise awareness and improve on future patients journeys and care. Disclosures T. mudawi None. C. Amoasii None. A. Clewes None.
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Sullivan, Kathleen E. "The yin and the yang of early classical pathway complement disorders." Clinical and Experimental Immunology, June 1, 2022. http://dx.doi.org/10.1093/cei/uxac056.
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Abstract The classical pathway of the complement cascade has been recognized as a key activation arm, partnering with the lectin activation arm and the alternative pathway to cleave C3 and initiate the assembly of the terminal components. While deficiencies of classical pathway components have been recognized since 1966, only recently have gain-of-function variants been described for some of these proteins. Loss-of-function variants in C1, C4, and C2 are most often associated with lupus and systemic infections with encapsulated bacteria. C3 deficiency varies slightly from this phenotypic class with membranoproliferative glomerulonephritis and infection as the dominant phenotypes. The gain-of- function variants recently described for C1r and C1s lead to periodontal Ehlers Danlos syndrome, a surprisingly structural phenotype. Gain-of-function in C3 and C2 are associated with endothelial manifestations including hemolytic uremic syndrome and vasculitis with C2 gain-of-function variants thus far having been reported in patients with a C3 glomerulopathy. This review will discuss the loss-of-function and gain-of-function phenotypes and place them within the larger context of complement deficiencies.
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Alper, Chester A. "The Path to Conserved Extended Haplotypes: Megabase-Length Haplotypes at High Population Frequency." Frontiers in Genetics 12 (August 6, 2021). http://dx.doi.org/10.3389/fgene.2021.716603.
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This minireview describes the history of the conceptual development of conserved extended haplotypes (CEHs): megabase-length haplotypes that exist at high (≥0.5%) population frequency. My career began in internal medicine, shifted to pediatrics, and clinical practice changed to research. My research interest was initially in hematology: on plasma proteins, their metabolism, synthesis, and function. This narrowed to a focus on proteins of the human complement system, their role in immunity and their genetics, beginning with polymorphism and deficiency of C3. My group identified genetic polymorphisms and/or inherited deficiencies of C2, C4, C6, and C8. After defining glycine-rich beta glycoprotein as factor B (Bf) in the properdin system, we found that the genes for Bf (CFB), C2, C4A, and C4B were inherited as a single haplotypic unit which we named the “complotype.” Complotypes are located within the major histocompatibility complex (MHC) between HLA-B and HLA-DRB1 and are designated (in arbitrary order) by their CFB, C2, C4A, and C4B types. Pedigree analysis revealed long stretches (several megabases) of apparently fixed DNA within the MHC that we referred to as “extended haplotypes” (later as “CEHs”). About 10 to 12 common CEHs constitute at least 25 – 30% of MHC haplotypes among European Caucasian populations. These CEHs contain virtually all the most common markers of MHC-associated diseases. In the case of type 1 diabetes, we have proposed a purely genetic and epigenetic model (with a small number of Mendelian recessive disease genes) that explains all the puzzling features of the disease, including its rising incidence.