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1
Repac, Jelena, Marija Mandić, Tanja Lunić, Bojan Božić, and Biljana Božić Nedeljković. "Mining the capacity of human-associated microorganisms to trigger rheumatoid arthritis—A systematic immunoinformatics analysis of T cell epitopes." PLOS ONE 16, no. 6 (June 29, 2021): e0253918. http://dx.doi.org/10.1371/journal.pone.0253918.
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Autoimmune diseases, often triggered by infection, affect ~5% of the worldwide population. Rheumatoid Arthritis (RA)–a painful condition characterized by the chronic inflammation of joints—comprises up to 20% of known autoimmune pathologies, with the tendency of increasing prevalence. Molecular mimicry is recognized as the leading mechanism underlying infection-mediated autoimmunity, which assumes sequence similarity between microbial and self-peptides driving the activation of autoreactive lymphocytes. T lymphocytes are leading immune cells in the RA-development. Therefore, deeper understanding of the capacity of microorganisms (both pathogens and commensals) to trigger autoreactive T cells is needed, calling for more systematic approaches. In the present study, we address this problem through a comprehensive immunoinformatics analysis of experimentally determined RA-related T cell epitopes against the proteomes of Bacteria, Fungi, and Viruses, to identify the scope of organisms providing homologous antigenic peptide determinants. By this, initial homology screening was complemented with de novo T cell epitope prediction and another round of homology search, to enable: i) the confirmation of homologous microbial peptides as T cell epitopes based on the predicted binding affinity to RA-related HLA polymorphisms; ii) sequence similarity inference for top de novo T cell epitope predictions to the RA-related autoantigens to reveal the robustness of RA-triggering capacity for identified (micro/myco)organisms. Our study reveals a much larger repertoire of candidate RA-triggering organisms, than previously recognized, providing insights into the underestimated role of Fungi in autoimmunity and the possibility of a more direct involvement of bacterial commensals in RA-pathology. Finally, our study pinpoints Endoplasmic reticulum chaperone BiP as the most potent (most likely mimicked) RA-related autoantigen, opening an avenue for identifying the most potent autoantigens in a variety of different autoimmune pathologies, with possible implications in the design of next-generation therapeutics aiming to induce self-tolerance by affecting highly reactive autoantigens.
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Zhou, Jie-Sen, Zhou-Yang Li, Xu-Chen Xu, Yun Zhao, Yong Wang, Hai-Pin Chen, Min Zhang, et al. "Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice." European Respiratory Journal 56, no. 3 (May 4, 2020): 2000404. http://dx.doi.org/10.1183/13993003.00404-2020.
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It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2 weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3 days or 1 month. Rag1−/−, Mmp12−/−, and Il17a−/− mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2 weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adoptive T cell transfer and studies in T cells deficient Rag1−/−mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.
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Maldonado-Ruiz, Roger, Lizeth Fuentes-Mera, and Alberto Camacho. "Central Modulation of Neuroinflammation by Neuropeptides and Energy-Sensing Hormones during Obesity." BioMed Research International 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/7949582.
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Central nervous system (CNS) senses energy homeostasis by integrating both peripheral and autonomic signals and responding to them by neurotransmitters and neuropeptides release. Although it is previously considered an immunologically privileged organ, we now know that this is not so. Cells belonging to the immune system, such as B and T lymphocytes, can be recruited into the CNS to face damage or infection, in addition to possessing resident immunological cells, called microglia. In this way, positive energy balance during obesity promotes an inflammatory state in the CNS. Saturated fatty acids from the diet have been pointed out as powerful candidates to trigger immune response in peripheral system and in the CNS. However, how central immunity communicates to peripheral immune response remains to be clarified. Recently there has been a great interest in the neuropeptides, POMC derived peptides, ghrelin, and leptin, due to their capacity to suppress or induce inflammatory responses in the brain, respectively. These may be potential candidates to treat different pathologies associated with autoimmunity and inflammation. In this review, we will discuss the role of lipotoxicity associated with positive energy balance during obesity in proinflammatory response in microglia, B and T lymphocytes, and its modulation by neuropeptides.
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Di Domizio, Jeremy, Ran Zhang, Ming Zhuo, Loren Stagg, John Ladbury, Michel Gilliet, and Wei Cao. "A novel class of host-derived etiological agent for autoimmunity: oligomers of endogenous proteins bind to self-nucleic acids and trigger type I IFN production by plasmacytoid dendritic cells (44.2)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 44.2. http://dx.doi.org/10.4049/jimmunol.186.supp.44.2.
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Abstract Under certain conditions, some soluble endogenous proteins can form ordered oligomeric structures leading to the assembly of stable insoluble amyloids, a process that increases with age. The presence of such structures is associated with cellular toxicity and diseases development, e.g. Alzheimer disease, type II diabetes. Recent studies clearly show that the primary toxic species in such pathologies is the soluble oligomers of proteins, precursors of amyloids. Yet, it is unknown if such aberrant forms of proteins would elicit any immune reaction. Here we obtained oligomers derived from several human endogenous proteins and characterized their biochemical and immunological functions. The oligomeric proteins preferentially bind to both DNA and RNA and can be effectively internalized by cells. Surprisingly, the soluble protein oligomers enable prominent IFNα production by PBMCs to self-DNA, self-RNA and necrotic cell debris in a pDC-dependent manner. Consistently, peptides from amyloid β and prion protein, two known etiological agents associated with amyloid diseases, display similar innate immune functions by complexing with nucleic acids and inducing IFN production by pDCs. Therefore, oligomers of endogenous proteins formed during the aging process may strongly promote the host’s type I IFN response to self-nucleic acids, a reaction likely favoring the development of autoimmunity, such as SLE where strong type I IFN presence correlates with disease pathology.
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Faccinetti, Natalia I., Luciano L. Guerra, Alberto Penas Steinhardt, Ruben F. Iacono, Gustavo D. Frechtel, Liliana Trifone, Edgardo Poskus, Aldana Trabucchi, and Silvina N. Valdez. "Characterization of zinc transporter 8 (ZnT8) antibodies in autoimmune diabetic patients from Argentinian population using monomeric, homodimeric, and heterodimeric ZnT8 antigen variants." European Journal of Endocrinology 174, no. 2 (February 2016): 157–65. http://dx.doi.org/10.1530/eje-15-0681.
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ObjectiveIn order to gain further knowledge of the structure of zinc transporter 8 (ZnT8) epitopes, we studied the role of the amino acid at position 325 in the antigen and its dimeric conformation for autoantibodies to ZnT8 (ZnT8A) recognition.MethodsFor this purpose, several ZnT8 C-terminal domain variants were designed: monomer carrying Arg325 or Trp325, homo-dimers ZnT8-Arg–Arg325 and ZnT8-Trp–Trp325, and hetero-dimer ZnT8-Arg–Trp325. Two groups of Argentinian diabetic patients were subjected to analysis using [35S]-ZnT8 variants by radioligand binding assay (RBA): i) 100 new-onset, insulin-dependent, type 1 diabetic patients and ii) 282 slowly progressing to insulin requirement, non-obese adult-onset diabetic patients. In addition, 50 type 1 diabetic patients and 100 normal control sera provided by the American Diabetes Association (ADA) were evaluated in order to calculate the sensitivity and specificity of ZnT8A assays for each antigenic variant. Other routine β-cell autoantibodies were also tested by RBA.ResultsOf the 100 Argentinian type 1 diabetic patients, 65 were ZnT8A+. Out of them, 8 patients recognized all recombinant forms of ZnT8 and most patients (56) reacted against the heterodimer. Additionally, out of 282 non-obese adult-onset diabetic patients 46 were ZnT8A+, whereas 29 patients recognized only dimers. Besides, exclusive reactivity against ZnT8A was found in 9.0% for type 1 diabetes mellitus and 10.3% for non-obese adult-onset diabetic patients.ConclusionsSignificantly higher signal values in RBA were obtained with the heterodimeric variant. An increased detection of humoral autoimmunity was found in both groups when ZnT8A was employed in combination with the other β-cell autoantibodies. The inclusion of homodimeric immunoreactive peptides revealed the existence of quaternary structure-defined epitopes probably resembling the actual state of the autoantigenin vivo. Finally, the differential profiles of ZnT8A exhibited by type 1 and non-obese adult-onset diabetic patients suggest the different nature of autoimmune processes underlying both pathologies.
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Kanduc, Darja. "The comparative biochemistry of viruses and humans: an evolutionary path towards autoimmunity." Biological Chemistry 400, no. 5 (May 27, 2019): 629–38. http://dx.doi.org/10.1515/hsz-2018-0271.
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Abstract Analyses of the peptide sharing between five common human viruses (Borna disease virus, influenza A virus, measles virus, mumps virus and rubella virus) and the human proteome highlight a massive viral vs. human peptide overlap that is mathematically unexpected. Evolutionarily, the data underscore a strict relationship between viruses and the origin of eukaryotic cells. Indeed, according to the viral eukaryogenesis hypothesis and in light of the endosymbiotic theory, the first eukaryotic cell (our lineage) originated as a consortium consisting of an archaeal ancestor of the eukaryotic cytoplasm, a bacterial ancestor of the mitochondria and a viral ancestor of the nucleus. From a pathologic point of view, the peptide sequence similarity between viruses and humans may provide a molecular platform for autoimmune crossreactions during immune responses following viral infections/immunizations.
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Lam, Brandon, Tenisha Wilson, Simone Bedoya, Cristina Armbruster, Howard Johnson, and Joseph Larkin. "Dysregulated cytokine production by leukocytes, mediated by SOCS1 deficiency, is correlated to skin pathology: implications for therapeutic targeting. (THER6P.851)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 201.7. http://dx.doi.org/10.4049/jimmunol.192.supp.201.7.
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Abstract Dysregulated leukocyte activation and cytokine signaling are known to contribute to autoimmunity. Notably, although Suppressor of Cytokine Signaling-1(SOCS1) is important in the regulation of both leukocyte activation and cytokine signaling, how deficiencies in SOCS1 relate to autoimmunity is not well understood. Therefore we analyzed leukocytes from mice bearing heterozygous expression of SOCS1 (SOCS1+/-) for dysregulated immune function. LPS stimulated SOCS1+/- leukocytes exhibited enhanced production of IL6, and IL12. Notably we observed that SOCS1+/-IFNγ-/- mice, but not IFNγ-/-, SOCS1+/-, or wild-type mice exhibited significant skin pathology on the back and ears. The observed skin pathology in SOCS1-/-IFNγ-/- mice was correlated to leukocyte accumulation within draining lymph nodes and spleen. In vitro, SOCS1+/-IFNγ-/- leukocytes activated with αCD3/αCD28 were hyper-proliferative and produced higher levels of IL17 when compared SOCS1+/+ littermates. Finally, a peptide capable of partially mimicking SOCS1 (SOCS1-KIR) was sufficient to reduce excessive proliferation, and aberrant IL12 and IL6 production of SOCS1+/- leukocytes in vitro. Together these results implicate an important role of SOCS1 in the regulation of immune responses. Moreover these results suggest that targeting SOCS1 deficiency, by a mimetic of SOCS1, may have implications in the regulation of skin pathologies mediated by immune dysregulation.
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Kanduc, Darja. "From Anti-SARS-CoV-2 Immune Responses to COVID-19 via Molecular Mimicry." Antibodies 9, no. 3 (July 16, 2020): 33. http://dx.doi.org/10.3390/antib9030033.
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Aim: To define the autoimmune potential of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Methods: Experimentally validated epitopes cataloged at the Immune Epitope DataBase (IEDB) and present in SARS-CoV-2 were analyzed for peptide sharing with the human proteome. Results: Immunoreactive epitopes present in SARS-CoV-2 were mostly composed of peptide sequences present in human proteins that—when altered, mutated, deficient or, however, improperly functioning—may associate with a wide range of disorders, from respiratory distress to multiple organ failure. Conclusions: This study represents a starting point or hint for future scientific–clinical investigations and suggests a range of possible protein targets of autoimmunity in SARS-CoV-2 infection. From an experimental perspective, the results warrant the testing of patients’ sera for autoantibodies against these protein targets. Clinically, the results warrant a stringent surveillance on the future pathologic sequelae of the current SARS-CoV-2 pandemic.
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Cassaday, R., P. Sondel, D. King, T. Warner, A. Bridges, J. Gan, H. Schalch, J. Hank, D. Mahvi, and M. Albertini. "Clinical and immunological analysis of melanoma patients receiving immunization using particle-mediated gene transfer of genes for gp100 and GM-CSF into uninvolved skin." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 13033. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.13033.
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13033 Background: To investigate a new method of activating melanoma-specific immune responses, we examined in vivo particle-mediated gene transfer (PMGT) of cDNAs for gp100 and GM-CSF into uninvolved skin of melanoma patients (pts). We now report the analysis of a completed Phase I clinical study. Methods: Two treatment groups of 6 pts each were evaluated. Group I received PMGT with cDNA for gp100 during each 3 week cycle; Group II received PMGT with cDNA for GM-CSF followed 3 days later by PMGT for gp100 at the same site. PMGT used 0.25 ug DNA and 250 ug gold/treatment. Endpoints included vaccine toxicity, transgene expression, immunological activation, and antitumor effects. Results: No systemic toxicity could be attributed to the vaccines, while local toxicity in both groups included mild erythema and induration which resolved within 2 weeks. Monitoring for autoimmunity showed no induction of pathologic autoantibodies. Biopsies of vaccine sites obtained 2 days after the gp100 PMGT showed 16% of gold beads to be in the dermis in Group I vs 3% in Group II, suggesting the prior GM-CSF PMGT inhibited bead penetration (p < 0.001 by chi-square; each bead penetration was analyzed as an independent event). Biopsies in Group I obtained 2 days after vaccination showed 16% of beads in the dermis vs 22% after 4 days (p < 0.001 by chi-square; each bead penetration was analyzed as an independent event). Transgene expression in vaccinated skin sites was detected by ELISA (GM-CSF) and IHC (gp100). One of 4 HLA-A2+ subjects showed a 5 × 5-mm DTH response to gp100 peptide 210M after Cycle 1. Preliminary in vitro studies suggest minimal immunological activation. Of 4 pts who enrolled with no evidence of disease, 2 remain disease-free after 61–73 months of follow-up. Conclusions: PMGT with cDNA for gp100 and GM-CSF yields transgene expression in normal human skin with minimal local or systemic toxicity. Pathologic autoimmunity was not demonstrated. Bead concentration in the dermis increases over time, suggesting persistence of beads in this skin level. Conclusions related to melanoma-specific immune induction await T-cell and antibody studies. Supported in part by the UW General Clinical Research Center (M01 RR03186). No significant financial relationships to disclose.
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Benedek, Gil, Mahmoud Abed El Latif, Keren Miller, Mila Rivkin, Ally Ahmed Ramadhan Lasu, Lul P. Riek, Richard Lako, et al. "Macrophage migration inhibitory factor in Nodding syndrome." PLOS Neglected Tropical Diseases 15, no. 10 (October 18, 2021): e0009821. http://dx.doi.org/10.1371/journal.pntd.0009821.
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Nodding syndrome (NS) is a catastrophic and enigmatic childhood epilepsy, accompanied by multiple neurological impairments and neuroinflammation. Of all the infectious, environmental and psychological factors associated with NS, the major culprit is Onchocerca Volvulus (Ov)–a parasitic worm transmitted to human by blackflies. NS seems to be an ’Autoimmune Epilepsy’ in light of the recent findings of deleterious autoimmune antibodies to Glutamate receptors and to Leiomodin-I in NS patients. Moreover, we recently found immunogenetic fingerprints in HLA peptide-binding grooves associate with protection or susceptibility to NS. Macrophage migration inhibitory factor (MIF) is an immune-regulatory cytokine playing a central role in modulating innate and adaptive immunity. MIF is also involved in various pathologies: infectious, autoimmune and neurodegenerative diseases, epilepsy and others. Herein, two functional polymorphisms in the MIF gene, a −794 CATT5–8 microsatellite repeat and a −173 G/C single-nucleotide polymorphism, were assessed in 49 NS patients and 51 healthy controls from South Sudan. We also measured MIF plasma levels in established NS patients and healthy controls. We discovered that the frequency of the high-expression MIF -173C containing genotype was significantly lower in NS patients compared to healthy controls. Interestingly however, MIF plasma levels were significantly elevated in NS patients than in healthy controls. We further demonstrated that the HLA protective and susceptibility associations are dominant over the MIF association with NS. Our findings suggest that MIF might have a dual role in NS. Genetically controlled high-expression MIF genotype is associated with disease protection. However, elevated MIF in the plasma may contribute to the detrimental autoimmunity, neuroinflammation and epilepsy.
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Polinski, K., E. Bemis, K. Demoruelle, J. Seifert, T. Crume, F. Yang, W. Robinson, et al. "SAT0596 ASSOCIATIONS BETWEEN CIRCULATING LIPID MEDIATORS AND INCIDENT INFLAMMATORY ARTHRITIS IN AN ANTI-CITRULLINATED PROTEIN ANTIBODY POSITIVE POPULATION." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1256.1–1256. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1884.
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Background:Lipid mediators are endogenously derived from the metabolism of omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) and have important roles in promoting and resolving inflammation in the body (1). Epidemiological studies have shown higher omega-3 PUFA status to be associated with a lower risk of both autoimmunity and progression to inflammatory arthritis (IA) (2,3).Objectives:To determine the association of lipid mediators with progression from rheumatoid arthritis (RA)-related autoimmunity to inflammatory arthritis (IA).Methods:We conducted a prospective cohort study using data from the Studies of the Etiologies of Rheumatoid Arthritis (SERA). SERA enrolled first-degree relatives (FDRs) of individuals with RA (FDR cohort) and individuals who screened positive for RA-related autoantibodies at health fairs (screened cohort). We followed 133 anti-CCP3.1 positive participants, of which 29 developed IA (22 classified as RA by 2010 ACR/EULAR criteria). We quantified lipid mediators from stored plasma samples via liquid chromatography tandem mass spectrometry methods validated against the collection and storage methods used in the study. A priori, we selected 5S-HETE, 15S-HETE and 17S-HDHA because they are precursors to leukotrienes, Lipoxin A4 and Resolvin D series lipid mediators, respectively. We fit Cox proportional hazard models for each lipid mediator as a time-varying covariate. For lipid mediators significantly associated with progression to IA we then examined IL-1β, IL-6, IL-8 and TNF-α (Bio-Plex Pro™ assay) as potential mediators of this relationship.Results:Higher plasma 5S-HETE levels were associated with an increased risk of incident IA after adjusting for age at baseline, cohort (FDR or screened), and shared epitope (SE) status (Table 1). The models examining 15S-HETE and 17S-HDHA had the same trend but did not reach statistical significance. We did not find evidence that the association between 5S-HETE and IA risk was mediated by the tested pro-inflammatory cytokines, suggesting a direct role for this lipid mediator in conversion to IA.Table 1.Hazard ratios and 95% confidence intervals of lipid mediator concentrations associated with IA, n=29 IA casesLipid mediatorCrudeAdjustedb5S-HETE2.10 (1.12, 3.92)2.41 (1.43, 4.07)15S-HETE1.61 (0.88, 2.93)1.52 (0.87, 2.65)17-HDHAa1.59 (0.68, 3.74)1.61 (0.72, 3.56)adichotomized as <limit of detection (reference) or detectedbAdjusted for SE, age at baseline and cohortConclusion:In a prospective cohort of anti-CCP positive individuals, higher circulating levels of 5S-HETE, an important precursor to pro-inflammatory leukotrienes, was associated with subsequent IA. Our findings highlight the potential pathologic and prognostic significance of these PUFA metabolites in inflammatory processes in pre-RA populations.References:[1]Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92-101.[2]Gan RW, Bemis EA, Demoruelle MK, Striebich CC, Brake S, Feser ML, et al. The association between omega-3 fatty acid biomarkers and inflammatory arthritis in an anti-citrullinated protein antibody positive population. Rheumatology. 2017.[3]Gan RW, Young KA, Zerbe GO, Demoruelle MK, Weisman MH, Buckner JH, et al. Lower omega-3 fatty acids are associated with the presence of anti-cyclic citrullinated peptide autoantibodies in a population at risk for future rheumatoid arthritis: a nested case-control study. Rheumatology. 2016;55(2):367-76.Disclosure of Interests:Kristen Polinski: None declared, Elizabeth Bemis: None declared, Kristen Demoruelle Grant/research support from: Pfizer, Jennifer Seifert: None declared, Tessa Crume: None declared, Fan Yang: None declared, William Robinson: None declared, Michael Clare-Salzler: None declared, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, Michael Holers Shareholder of: AdMIRx, Grant/research support from: AdMIRx, Pfizer, Janssen R&D, Consultant of: AdMIRx, Janssen R&D, Celgene, Bristol-Myers Squibb, Jill Norris Grant/research support from: Janssen R&D, Pfizer, Consultant of: Celgene, BMS
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Henson, David, and Vincent J. Venditto. "Abstract 416: Evaluation of Antibody Responses Toward Post-Translationally Modified and Unmodified Peptide Epitopes of Apolipoprotein A-I." Arteriosclerosis, Thrombosis, and Vascular Biology 36, suppl_1 (May 2016). http://dx.doi.org/10.1161/atvb.36.suppl_1.416.
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Antibody responses targeting ApoA-I have been documented in patients suffering from chronic inflammation associated with obesity, autoimmunity and cardiovascular disease (CVD) and correlate with a poor prognosis. Patients presenting with an acute myocardial infarction (AMI) have measurable IgG targeting the lecithin:cholesterol acyltransferase (LCAT) domain of ApoA-I and are shown to bind an epitope containing an oxidized methionine (Met-148(O)). Antibodies targeting ApoA-I are thought to be serum markers for CVD and not responsible for disease progression, but their exact role is poorly understood. We hypothesize that the B cell response to ApoA-I is nuanced with different isotypes of both protective and pathologic antibodies induced during the course of disease. To investigate this hypothesis, we synthesized a series of unmodified and modified peptides corresponding to the LCAT domain of mouse, monkey and human ApoA-I for ELISA and immunization studies. ELISA with commercially available goat polyclonal antibodies induced by immunization with human ApoA-I suggest that the LCAT domain possesses immunogenic properties and the antibodies are capable of binding to the unmodified and Met-148(O) peptides. Although affinity to the unmodified peptide appears to be higher by ELISA, pre-incubating the polyclonal antibodies with a solution of the Met-148(O) peptide significantly inhibits binding to the unmodified peptide. These data suggest that the oxidized peptide in solution may undergo a structural change that increases antibody affinity. Structural analysis of the peptides are ongoing. Serum analysis from patients presenting with an AMI and 30 days after cardiac event show a decline in IgG responses toward the Met-148(O)-modified peptide during that period. Analysis of monkey serum provides a unique comparison. Monkeys have a methionine to valine mutation at position 148, which results in a non-oxidizable residue, and instead show a decrease in IgG toward the unmodified sequence when on an atherogenic diet for 12 weeks. Correlating these ELISA assays with atherosclerosis observed in the patients and macaques along with ongoing in vivo immunization studies in mice will generate insight into the nuanced B cell response toward ApoA-I during CVD.
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Kline, Robert H., David Henson, and Vincent J. Venditto. "Abstract 395: Evaluation of Antibody Responses in Mice Toward Apolipoprotein A-I." Arteriosclerosis, Thrombosis, and Vascular Biology 37, suppl_1 (May 2017). http://dx.doi.org/10.1161/atvb.37.suppl_1.395.
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Antibodies targeting apolipoprotein A-I (ApoA-I) have been documented in patients suffering from chronic inflammation associated with obesity, autoimmunity and cardiovascular disease (CVD). Anti-ApoA-I antibodies are thought to be serum markers for CVD and not responsible for disease progression, but their exact role is poorly understood. We hypothesize that the antibody response to ApoA-I is highly nuanced with both protective and pathologic antibodies targeting modified or unmodified epitopes. We sought to induce ApoA-I specific autoantibodies in mice targeting specific modified and unmodified epitopes to study their nuanced role in disease progression. To achieve this goal we immunized mice with an immunogenic liposomal formulation containing modified or unmodified peptides derived from ApoA-I. The epitope-specific antibody response toward each epitope and the full length protein were quantified by ELISA. Mice immunized with formulations containing peptide were compared to control mice receiving either peptide or adjuvant alone. Furthermore, antibody responses toward ApoA-I from mice fed normal chow were compared to mice fed a western diet. Our vaccine strategy induced a robust immune response toward the peptide epitopes along with the full length protein. The oxidized peptide also appeared to be more immunogenic than the unmodified, but the mechanism of this observation is unclear. Antibody responses toward ApoA-I were observed after immunization with adjuvant alone suggesting that acute inflammation induces a response to ApoA-I. Studies are currently underway to evaluate the affinity of the anti-ApoA-I antibodies for HDL along with their role in cholesterol efflux and atherosclerosis progression. Correlating these findings with studies in human patients will generate insight into the nuanced antibody responses toward ApoA-I in CVD.
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Vasudevan, Vishnupreetha, Prachi Agnihotri, and Sagarika Biswas. "Post Translational Modification and its pathologic association in Rheumatoid Arthritis: A brief perspective." Current Protein & Peptide Science 22 (February 15, 2021). http://dx.doi.org/10.2174/1389203722666210215152433.
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: Post Translational Modification (PTM) is the process in which covalent addition of functional groups on protein happens to maintain their structure, function and stability. Every PTM process in our living system happens to increase the functional diversity of protein. But sometimes it happens without any regulation and occurrence of this specific change in proteins are leading to autoimmunity. Rheumatoid arthritis (RA) is one such chronic, inflammatory, autoimmune disease that affects joints. Proper treatment can be manageable for RA, but it is not completely curable. Delayed diagnosis of RA can cause severe bone pain, stiffness, inflammation, redness in joints and affect other parts of the body such as liver, kidney etc. Early diagnosis of disease is preferable to cure it effectively. Currently, Rheumatoid factor (RF) and anti-citrullinated cyclic peptide (Anti-CCP) are considered as biomarkers to diagnose RA. Other than citrullination several other PTM’s are also involved in generation of autoantibodies such as, carbamylation, glycosylation, glycation, acetylation, ubiquitination, proteolysis, phosphorylation, lipidation. Aim of this review is to elucidate several considerable changes in form, nature and function of above PTMs in RA, affecting joints and day to day life. This review will give a recent overview on the role of PTMs in the pathogenesis of RA, focusing on the modifications.
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Stachowicz, Aneta, Chunhong Mao, James Hixson, Fannie R. Jackson, Richard Vander Heide, Jennifer E. Van Eyk, David M. Herrington, and Justyna P. Fert-Bober. "Abstract 11607: Protein Citrullination Landscape of Human Coronary Atherosclerosis." Circulation 144, Suppl_1 (November 16, 2021). http://dx.doi.org/10.1161/circ.144.suppl_1.11607.
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Introduction: Recently, an irreversible enzymatic post-translational modification, citrullination, has been shown to be present in the cardiovascular system (e.g. aorta). Citrullination, in which arginine is converted to citrulline, can alter protein structure and function, and produce autoantigens Hypothesis: Emerging evidence suggest a potential role for autoimmunity in the pathogenesis of atherosclerosis. However, it remains unknown whether of post-translational citrullination of arterial proteins contributes to local inflammatory processes that initiate or accelerate the atherosclerotic process. The aim of this study was to investigate changes in protein citrullination in human left anterior descending (LAD) coronary artery specimens with and without early atherosclerosis obtained from autopsied young adults with no clinical manifestations of coronary disease. Methods: Segments of the mid-LAD from 74 autopsied individuals (age range:15-55 yrs., 75% male, 67% White) were graded by a pathologist for percent of surface area involved with fatty streaks (FS) or fibrous plaque (FP). The frozen samples were homogenized and digested with Lys-C for subsequent proteomic mass-spectrometry using a data-independent acquisition (DIA) proteomic strategy with a hyper-citrullinated spectral library approach and our published CitFinder software. Results: We found 133 differentially expressed proteins (FDR<0.05) between control, FS and FP groups. Among them, 19 citrullinated proteins with 26 modified amino acid residues were identified. Citrullinated peptides from fibrinogen alpha chain (R84) and transgelin (R146) were upregulated in FP samples in comparison to FS and normal samples. Similarly, the citrullination site (R269) on alpha-enolase was significantly increased in the FP samples compared to normal. Interestingly, citrullination (R110) on myosin light polypeptide 6 was downregulated in FP samples. Conclusions: These data represent the most comprehensive interrogation of citrullinated proteins in human arterial samples to-date and suggest a possible association between this modification of several key proteins involved in tight junction, vascular smooth muscle contraction and inflammation and early atherosclerosis.