Journal articles on the topic 'Non auto immune'
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1
Leslie, R. D. G., and M. Hawa. "Twin Studies in Auto-immune Disease." Acta geneticae medicae et gemellologiae: twin research 43, no. 1-2 (April 1994): 71–81. http://dx.doi.org/10.1017/s000156600000297x.
Abstract:
AbstractImmune-mediated diseases affect up to 5% of the population and are a major cause of morbidity and mortality. These diseases can be organ specific, such as insulin-dependent diabetes (IDDM) and non-organ specific, such as Rheumatoid Arthritis (RA). Identical and non-identical twins have been used to establish whether these diseases are determined by genetic or environmental factors. The results of these studies have been collated in a new section of the Mendel Institute in Rome.Diseases included in these studies included IDDM, RA, Systemic Lupus Erythematosus (SLE), Multiple Sclerosis (MS) and Myasthenia. Striking differences in concordance rates between identical and non-identical twins in all these studies suggest that genetic factors are important in causing these diseases. All the diseases are known to be associated with HLA genes on chromosome 6 which may account for some or all of the genetic susceptibility. However, in the majority of pairs the affected twin has an unaffected co-twin. These observations suggest that non-genetically determined factors, probably environmental factors and not somatic mutations, are critical. The study of unaffected co-twins, who are at high disease-risk, has allowed the identification of changes which precede and predict the clinical disease. The immune-mediated destruction in many of these diseases is probably caused by T-lymphocytes. Twin studies have shown the importance of genetic factors in determining T-cell responses. Identical twins should, therefore, provide the perfect test bed to assess the role of T-cells in immune-mediated diseases.
2
GARCIA, C., L. BORDIER, F. BANAL, F. DUTASTA, J. V. MALFUSON, and O. BERETS. "Stratégie diagnostique devant une suspicion de polyendocrinopathie auto-immune." Médecine et Armées Vol. 40 No. 2, Volume 40, Numéro 2 (April 1, 2012): 129–34. http://dx.doi.org/10.17184/eac.6600.
Abstract:
Les polyendocrinopathies auto-immunes de type 2 correspondent à une association d’au moins deux affections endocriniennes liées à une perturbation de la tolérance du système immunitaire. Nous rapportons l’observation d’une patiente, âgée de 38 ans, chez qui est découverte une maladie d’Addison, deux mois après l’introduction de lévothyroxine dans le traitement d’une thyroïdite à anticorps anti-thyroperoxydase, cette association étant auparavant connue sous l’appellation de syndrome de Schmidt. Ce cas clinique illustre les difficultés diagnostiques des polyendocrinopathies auto-immunes et permet de rappeler les principales associations rencontrées dans les polyendocrinopathie auto-immune de type 2. Enfin les modalités pratiques du dépistage systématique des endocrinopathies associées, non consensuelles, sont discutées.
3
Trier, Nicole Hartwig, and Gunnar Houen. "Antibody Cross-Reactivity in Auto-Immune Diseases." International Journal of Molecular Sciences 24, no. 17 (September 2, 2023): 13609. http://dx.doi.org/10.3390/ijms241713609.
Abstract:
Autoimmunity is defined by the presence of antibodies and/or T cells directed against self-components. Although of unknown etiology, autoimmunity commonly is associated with environmental factors such as infections, which have been reported to increase the risk of developing autoimmune diseases. Occasionally, similarities between infectious non-self and self-tissue antigens may contribute to immunological cross-reactivity in autoimmune diseases. These reactions may be interpreted as molecular mimicry, which describes cross-reactivity between foreign pathogens and self-antigens that have been reported to cause tissue damage and to contribute to the development of autoimmunity. By focusing on the nature of antibodies, cross-reactivity in general, and antibody–antigen interactions, this review aims to characterize the nature of potential cross-reactive immune reactions between infectious non-self and self-tissue antigens which may be associated with autoimmunity but may not actually be the cause of disease onset.
4
Bouayad, Abdellatif, and Laila Benzekri. "Thyroïdite auto-immune et vitiligo non segmentaire : association avec DQB1 * 05." Transfusion Clinique et Biologique 24, no. 3 (September 2017): 350. http://dx.doi.org/10.1016/j.tracli.2017.06.217.
5
Takeshita, Fumihiko, Kouji Kobiyama, Atsushi Miyawaki, Nao Jounai, and Kenji Okuda. "The non-canonical role of Atg family members as suppressors of innate antiviral immune signaling." Autophagy 4, no. 1 (January 2008): 67–69. http://dx.doi.org/10.4161/auto.5055.
6
Nikolajczyk, Barbara S. "B cells as under-appreciated mediators of non-auto-immune inflammatory disease." Cytokine 50, no. 3 (June 2010): 234–42. http://dx.doi.org/10.1016/j.cyto.2010.02.022.
7
Bhargava, Amit, and Nirupma Banerjee. "Rituximab in Lymphoma Associated Auto-Immune Haemolytic Anemia." Blood 116, no. 21 (November 19, 2010): 4923. http://dx.doi.org/10.1182/blood.v116.21.4923.4923.
Abstract:
Abstract Abstract 4923 The association of Autoimmune hemolytic and Non Hodgkin's lymphoma is a known phenomenon. Cold hem agglutinin disease (CHD), is an uncommon Autoimmune hemolytic anemia, mediated by cold reactive auto antibodies that bind to erythrocyte carbohydrate antigen causing hem agglutination and complement mediated hemolysis. Cold agglutinin–mediated hemolysis occurs at low temperature which may be severe and difficult to treat. CHD may be primary when it is idiopathic or secondary as in lympho-proliferative disorder of bone marrow associated with clonal proliferation of CD20 B cells that produce monoclonal 1g M cold agglutinin (kappa /lamda). Rituximab has been used as an as a novel treatment option in Autoimmune hemolytic anemia. Rituximab is a genetically engineered chimeric monoclonal antibody that targets the CD20 antigen on B cells. Rituximab in autoimmune conditions possibly acts by destruction of CD20_clonotypic precursor B cells and/or CD20 plasma cells, thus is effective in controlling immunoglobulin-mediated diseases of B lymphocytes. We analysed four patients of lymphoma with severe CHD who were successfully treated with the chimeric anti-CD20 monoclonal Rituximab (375mg/ m2) intravenously every three weeks for four to six cycles, till the Agglutinins disappeared from the serum. Patient and method In this study patients diagnosed with lymphoma associated CHD were treated with Rituximab with a dose of 375mg/ meter square given every three weeks for four to six cycles, till the primary aim was achieved. The primary aim was correction of anemia, disappearance of cold hem-agglutinins from serum, assessed by complete blood counts and measuring cold agglutinins in serum. Four such patients were studied, all of them had NHL-DLBCL (IHC proven), with severe hemolysis and jaundice with Hemoglobin <5 gm/ dl. All had presence of cold agglutinins in the serum and were positive for direct and indirect coomb's test. Response All the patients showed significant improvement in the symptoms due to anemia and there was a rise in hemoglobin detected within the first week of Rituximab treatment. They achieved normal levels of hemoglobin with four to six weeks of treatment and in three patients cold agglutinins disappeared after completion of five cycles and the fourth patients had it after the sixth cycle. None of the patients was given any transfusion because of incompatibility issues. Conclusion Our experience with Rituximab was excellent in this indication and patients had a good overall outcome. Further trials need to be done for more evidence in this regard. Disclosures: No relevant conflicts of interest to declare.
8
Rajavel, Sowndharya, Cade E. Ito, Keith Abe, Valerie Guerrero, Gene I. Uenishi, Andrew M. Scharenberg, and Gregory J. Cost. "Chemically Controlled, Immunosuppression-Resistant, Anti-Bcma CAR-T Cells for Treatment of Antibody-Mediated Autoimmunity." Blood 132, Supplement 1 (November 29, 2018): 2203. http://dx.doi.org/10.1182/blood-2018-99-117630.
Abstract:
Abstract Auto-reactive antibody production by plasma cells is the direct cause of many auto-immune diseases. In such cases elimination of plasma cells would ameliorate the disease. Chimeric antigen receptor T (CAR-T) cells with cytotoxicity toward cells expressing B-cell maturation antigen (BCMA) have shown remarkable promise for the treatment of multiple myeloma, a plasma cell neoplasm. Elimination of non-malignant plasma cells is a side-effect of anti-BCMA CAR-T treatment of multiple myeloma, suggesting the use of these anti-BCMA CAR T cells for auto-immune indications. Unfortunately, CAR-T administration requires use of lymphodepletion to achieve efficient cell engraftment, and is often accompanied by cytokine release syndrome (CRS), a potentially life-threatening side-effect. As lymphodepletion and CRS pose morbidity/mortality risks that are unacceptable for therapy of many auto-immune diseases, we have utilized CRISPR-Cas9 gene editing to develop a controllable CAR-T cell platform that provides for (1) engraftment with non-cytotoxic transient immunosuppression; and (2) small-molecule dependent CAR T-cell expansion. We have implemented this platform using a unique dual targeting approach in which a BCMA CAR transgene is integrated into the TRAC locus, and additional payloads are integrated into a second locus, thus also enabling an allogeneic manufacturing process. Transgene integration occurred in >50% of cells individually with several percent of cells targeted at two loci. TRAC-targeted, anti-BCMA CAR T cells demonstrated CAR-dependent, target-cell-BCMA-dependent cytotoxicity towards both high-BCMA- and low-BCMA-expressing cell lines and in multiple myeloma cells xenografted into NSG mice. Drug-regulation properties and immunosuppression resistance are the subject of ongoing experiments. Anti-BCMA CAR T cells that are chemically controlled, incapable of graft-versus-host disease, and insensitive to immunosuppression may be an attractive treatment option a variety of antibody-mediated auto-immune conditions. Disclosures Rajavel: Casebia Therapeutics: Employment. Ito:Casebia Therapeutics: Employment. Abe:Casebia Therapeutics: Employment. Guerrero:Casebia Therapeutics: Employment. Uenishi:Casebia Therapeutics: Employment. Scharenberg:Casebia Therapeutics: Employment; Generation Bio: Equity Ownership; Alpine Immune Sciences: Equity Ownership. Cost:Casebia Therapeutics: Employment.
9
Khungar, Jitendra Mohan, Hara Prasad Prasad Pati, and Manoranjan Mahapatra. "Diagnosis of Auto Immune Hemolytic Anemia by Detection of RBC-Bound IgG Antibodies, Using Flow-Cytometry." Blood 120, no. 21 (November 16, 2012): 5159. http://dx.doi.org/10.1182/blood.v120.21.5159.5159.
Abstract:
Abstract Abstract 5159 Introduction: Auto Immune Hemolytic Anemia (AIHA) is one of the most common types of acquired hemolytic anaemias. Its main cause is auto antibody mediated rapid destruction of RBCs. Detection of these autoantibodies to erythrocytes is of fundamental importance for diagnosis. A number of methodologies have been tried for detection & evaluation of these autoantibodies. Demonstration of a positive Direct Antiglobulin Test (DAT) against these autoantibodies is an important serological assay in the diagnosis of auto immune hemolytic anemia (AIHA). This test is also considered as pathognomonic of immune-mediated hemolysis. This routinely used direct antiglobulin test (DAT) has the disadvantage of low sensitivity and does not detect low levels of red cell auto antibodies leading sometimes to false negative results. Flow cytometry can effectively diagnose such patients of auto immune hemolytic anemia with low levels of autoantibodies. Role of flow cytometry in the diagnosis of several non-malignant haematological disorders is being explored & present study has been conducted with the same objective. Aims & Objectives: This study was conducted with the following aims and objectives: •To assess the utility of flow-cytometry (FCM) in the diagnosis of suspected AIHA patients. •Compare the sensitivity of flow-cytometry (FCM) with Direct Antiglobulin Test (DAT) by Gel-card Test (GT). •To assess the positivity in DAT negative cases by flow-cytometry in suspected AIHA cases. Material & Methods: This was a prospective study, carried out in Haematology Deptt of All India Institute of Medical Sciences, where patients with suspected auto immune hemolytic anemia (AIHA) were studied during two years period. Blood samples of suspected patients of AIHA were tested by Gel Card Test as well as by Flow cytometry for detection of RBC bound IgG. Results: A total of 50 patients with suspected diagnosis of auto immune hemolytic anemia (AIHA) were studied by flow-cytometry as well as by Gel card test (GT) for detection of RBC bound IgG. Out of these 50 cases, 41 cases have turned out to be positive and 9 were negative by flow-cytometry. The quantification of positivity by flow-cytometry was obtained by calculating percentage fluorescence. The same 50 cases were also tested by Gel card test (GT). By Gel card test, out of 50 cases, 34 were positive & 16 were negative. Therefore, there were 7 cases which were negative for RBC bound IgG by Gel card test and these were positive by flow-cytometry. The flow cytometry figures of these cases will be shown & discussed in the presentation. Conclusions: Flow-cytometry is a reliable and sensitive method of detecting RBC-bound IgG antibodies for the diagnosis of auto immune hemolytic anemia. This can be used as a new routine diagnostic technique for auto immune hemolytic anemia. Disclosures: No relevant conflicts of interest to declare.
10
Pastva, Ondřej, and Kerstin Klein. "Long Non-Coding RNAs in Sjögren’s Disease." International Journal of Molecular Sciences 25, no. 10 (May 9, 2024): 5162. http://dx.doi.org/10.3390/ijms25105162.
Abstract:
Sjögren’s disease (SjD) is a heterogeneous autoimmune disease characterized by severe dryness of mucosal surfaces, particularly the mouth and eyes; fatigue; and chronic pain. Chronic inflammation of the salivary and lacrimal glands, auto-antibody formation, and extra-glandular manifestations occur in subsets of patients with SjD. An aberrant expression of long, non-coding RNAs (lncRNAs) has been described in many autoimmune diseases, including SjD. Here, we review the current literature on lncRNAs in SjD and their role in regulating X chromosome inactivation, immune modulatory functions, and their potential as biomarkers.
11
Armand, Marine, Myriam Boudjoghra, Aliki Xochelli, Danielle Canioni, Magali Le Garff Tavernier, Monica Colombo, Pascaline Rabiega, et al. "Auto-Immune Origin of B Cells from HCV-Associated Lymphoma." Blood 126, no. 23 (December 3, 2015): 1464. http://dx.doi.org/10.1182/blood.v126.23.1464.1464.
Abstract:
Abstract Hepatitis C virus (HCV) infection is a well-established risk factor for the development of B cell non-Hodgkin lymphoma (B-NHL). Two main pathways have been proposed to explain the role of the virus in lymphomagenesis: 1) transformation of B cells either directly by oncogenic viral proteins, or by a hit-and-run mechanism inducing a mutator phenotype, and 2) chronic antigenic stimulation through the B cell receptor (BcR) in conjunction to the binding of the viral E2 protein to its receptor CD81. There are however conflicting data regarding whether the BcR of the lymphomatous cells are capable of directly recognizing viral proteins or, rather, they possess a rheumatoid factor (RF) activity, binding instead polyclonal immunoglobulin (IG) within immune complexes trapping the virus. To further elucidate the role of antigenic stimulation in the natural history of HCV-associated B-NHL, we analyzed the IG gene repertoire of both heavy and light chains expressed by neoplastic cells in 41 cases of HCV-associated NHL, including: 29 marginal zone lymphoma (MZL); 7 diffuse large B-cell lymphoma (DLBCL) of which 3 originated from transformed MZL ; and 5 other low-grade B-cell NHL. Tumor cells were obtained from blood in 39 cases, bone marrow and a lymph node biopsy in 1 case each. Forty-three productive IGHV-IGHD-IGHJ gene rearrangements were obtained, which displayed a clear biased gene composition as 3 IGHV genes contributed to almost half of the repertoire: IGHV1-69 (11/43, 25,6%), IGHV3-7 (5/43, 11.6%), IGHV3-21 (4/43, 9.3%). This was also true for both IGHD genes (IGHD3-22: 12/43, 27.9%), and IGHJ genes (IGHJ4: 17/43, 39.5%; IGHJ3: 17/43, 25.6%). All but 3 sequences carried somatic hypermutations (SHM) in their IGHV genes with a median identity to the germline of 97.6% (range 86.5-100%). Thirty-eight productive IG light chain rearrangement sequences were obtained from 36 cases, of which 30 (78.9%) were IGK. Similarly, they exhibited strong gene usage bias with an over-representation of IGKV3-20 (9/30, 30%), as well as IGKJ1 (11/30, 33.3%) and IGKJ2 (6/30, 20%). IG light chain sequences were found to harbor similar SHM load with a 97% median identity to germline (range 91-100%). As previously described, we observed preferential pairing of heavy and light chain genes, with 6 of the 9 IGHV1-69 cases (with available light chain sequence data) being associated with IGKV3-20. Using established criteria, we found 5 cases (11.6%) carrying stereotyped BcR i.e. IGHV-IGHD-IGHJ gene rearrangements with quasi-identical amino-acid (AA) sequences, including the highly variable complementary determining region 3 (CDR3). Three cases concerned IGHV3-7/IGHD3-22/IGHJ3 rearrangements with an 18 AA-long CDR3, and 2 concerned IGHV1-69/IGHD3-22/IGHJ4 rearrangements with a 13 AA-long CDR3. Identity within the CDR3 extended to AA encoded by randomly inserted N-region nucleotides. We failed to establish correlations between histological categories and IG repertoire, probably due to the uneven distribution of lymphoma subtypes within our cohort. In contrast, most if not all sequences with biased IG gene usage, including the 5 stereotyped BcR ones, were found amongst the 28/41 cases (68.3%) with mixed cryoglobulinemia type II and/or positive for RF (MC/RF+). These two categories of patients differed also regarding the SHM load of their IGHV genes since MC/RF+ cases were signlificantly less mutated than MC/RF- cases (median identity to germline: 97.9% vs 95.9%, p= 0.048). We then searched for similar sequences in public databases and collaborative studies. Stereotyped BcR sequences similar to those of our cases were detected in HCV-associated lymphoma, but also in other HCV-negative B-cell maligancies e.g. MALT lymphoma (some associated with RF) and chronic lymphocytic leukemia, non malignant B cells with RF activity, and non malignant marginal zone splenic B cells. Sequence similarity extended to some shared AA replacements, e.g. identical AA introduced by HSM at the same positions. In conclusion we confirm the highly biased IG repertoire of HCV-associated lymphoma. However this feature seems to be linked essentially to the presence of a MC and/or RF. As quasi-identical sequences are found in HCV-negative malignant and normal B cells, our data support the hypothesis that HCV-associated lymphomatous cells originate from precursors endowed with auto-immune properties rather than B cells expressing an anti-virus BcR. Disclosures Stamatopoulos: Gilead Sciences: Research Funding; Janssen Pharmaceuticals: Research Funding.
12
Sawadogo, A., J. Boursier, P. Calès, F. Oberti, and A. Schmidt. "Lymphome malin non hodgkinien au cours d’une hépatite chronique auto-immune traitée par azathioprine." Gastroentérologie Clinique et Biologique 32, no. 2 (February 2008): 143–45. http://dx.doi.org/10.1016/j.gcb.2007.10.003.
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Lamblin, Florian, Jeroen Kerstens, Sergio Muñiz-Castrillo, Bastien Joubert, Marie Benaiteau, Maarten J. Titulaer, and Jérôme Honnorat. "Encéphalite auto-immune à anti-GABABR : étude comparative des cas paranéoplasiques et non paranéoplasiques." Revue Neurologique 179 (April 2023): S143—S144. http://dx.doi.org/10.1016/j.neurol.2023.01.653.
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Kumar, Pawan, Kong Chen, Derek Pociask, and Jay Kolls. "Hepatocytes intrinsic STAT4 regulates auto-immune liver inflammation (BA3P.209)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 44.15. http://dx.doi.org/10.4049/jimmunol.192.supp.44.15.
Abstract:
Abstract Autoimmune hepatitis is a condition where immune cells target and destroy liver cells. The role of STAT4 in autoimmune hepatitis is ill-defined. Therefore, we investigated the role of STAT4 signaling in Concanavalin A (ConA)-induced auto-immune hepatitis model. Our data indicate Stat4-/- mice but not WT, Il12p35-/- or Il12p40-/- mice were resistant to ConA-induced hepatitis as measured by liver pathology and the serum alanine aminotransferase (ALT) level. Furthermore, no significant difference in serum ALT and necrotic lesions were observed when WT or Stat4-/- spleenocytes were adoptive transfer into lymphocyte deficient Rag2gc-/- mice, suggesting that protection in Stat4-/- is independent of lymphocyte STAT4. Interestingly, serum IFNg level were significantly reduced in both Il12p35-/- and Stat4-/- mice, and injection of recombinant IFNg into Stat4-/- mice increase the serum ALT, but it does not reach the level observed in WT mice, suggesting a non-IFNg mediated protection in Stat4-/- mice. Surprisingly, there were no significant difference in FAS and FasL transcript in ConA injected liver tissue in WT and Stat4-/- mice. In addition, anti-FAS antibody injections lead to significant necrotic changes in WT, but not in Stat4-/- mice. Our data strongly indicate absence of STAT4 signaling potentially in hepatocytes regulates cell survival, which is further confirmed by significantly more pSTAT3 staining in liver tissue of Stat4-/-.
15
Wang, Li, Isabelle LeMercier, Arief Suriawinata, Wenna Chen, Jiannan Li, and Randolph Noelle. "VISTA deficiency synergizes with a non-redundant immune checkpoint pathway and leads to enhanced immune activation (IRM10P.744)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 129.11. http://dx.doi.org/10.4049/jimmunol.192.supp.129.11.
Abstract:
Abstract V-domain Ig suppressor of T cell activation (VISTA) is a novel negative checkpoint ligand that suppresses T-cell mediated immune responses. Previous studies using VISTA-neutralizing monoclonal antibody show that VISTA-blockade enhances T cell-activation in an inflammatory disease model EAE, as well as in murine tumor models. Current study describes a comprehensive characterization of VISTA knockout (KO) mice. We show that despite the apparent normal hematopoietic development in young ko mice, VISTA genetic deficiency leads to a pro-inflammatory phenotype in aged animals, as well as enhanced T-cell activation in response to acute antigen immunization. In addition, we show that VISTA deficiency significantly enhanced disease development in a spontaneous model of autoimmune disease, which is correlated with the spontaneous activation of auto-antigen specific CD4+ T cells. Lastly, when combined with the genetic deficiency of another checkpoint molecule, synergistic or additive immune activation was observed.
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Oka, Satoko, and Masaharu Nohgawa. "Autoimmune Cytopenias Occurring after Treatment with Chemoimmunotherapy for Non-Hodgkin Lymphomas." Acta Haematologica 141, no. 2 (2019): 79–83. http://dx.doi.org/10.1159/000495600.
Abstract:
Autoimmune diseases, including autoimmune hemolytic anemia and immune thrombocytopenic purpura, have been described in patients with non-Hodgkin lymphoma (NHL) after immunochemotherapy. However, the underlying pathogenesis remains unclear. We examined NHL patients with autoimmune cytopenia and all patients were treated with rituximab-containing therapy. The present results showed reversed imbalances in helper/suppressor T-cell populations, and an immune system imbalance may have contributed to immunological abnormalities. Although the relationship between imbalances in helper/suppressor T-cell populations and the development of auto-antibody production after chemotherapies currently remains unclear, the immunosuppressive effects of immunochemotherapy may be a contributing factor. The long-term monitoring of T-cell populations after immunochemotherapies is important.
17
Chiappelli, Francesco. "Permafrost viremia and immune tweening." Bioinformation 19, no. 6 (June 30, 2023): 685–91. http://dx.doi.org/10.6026/97320630019685.
Abstract:
The immune system, an exquisitely regulated physiological system, utilizes a wide spectrum of soluble factors and multiple cell populations and subpopulations at diverse states of maturation to monitor and protect the organism against foreign organisms. Immune surveillance is ensured by distinguishing self-antigens from self-associated with non-self (e.g., viral) peptides presented by major histocompatibility complexes (MHC). Pathology is often identified as unregulated inflammatory responses (e.g., cytokine storm), or recognizing self as a non-self entity (i.e., auto-immunity). Artificial intelligence (AI), and in particular specific machine learning (ML) paradigms (e.g., Deep Learning [DL]) proffer powerful algorithms to better understand and more accurately predict immune responses, immune regulation and homeostasis, and immune reactivity to challenges (i.e., immune allostasis) by their intrinsic ability to interpret immune parameters, pathways and events by analyzing large amounts of complex data and drawing predictive inferences (i.e., immune tweening). We propose here that DL models play an increasingly significant role in better defining and characterizing immunological surveillance to ancient and novel virus species released by thawing permafrost.
18
Lane, H. C., and A. S. Fauci. "Immunologic Approaches to the Therapy of Auto-Immune Salivary Gland Disease." Journal of Dental Research 66, no. 1_suppl (February 1987): 703–8. http://dx.doi.org/10.1177/00220345870660s117.
Abstract:
A variety of immunologic mechanisms may theoretically give rise to disease in the salivary glands. Among them are abnormal antibody production, hyper-reactive T-lymphocytes, and mono- or oligoclonal expansions of B-lymphocytes, While it is not clear which, if any, of these mechanisms are of prime importance in the immunopathology of salivary gland disease, they provide a framework, within which to discuss theoretical approaches to the treatment of auto-immune salivary gland disease. Among the techniques used to decrease antibody-induced damage are non-steroidal anti-inflammatory agents, plasmapheresis, and corticosteroids. Cyclosporin, monoclonal antibodies, and biologic response-modifiers may be used to modulate T-cell function, and anti-idiotype antibodies or immunosuppressive agents may be used to treat malignant expansions of B-cells. Although the generally benign nature of auto-immune salivary gland disease precludes the use of many of the potentially toxic treatment regimens discussed here, the appreciation of these approaches to immunomodulation provides a basis upon which to develop new and innovative therapeutic strategies.
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Lv, Juan, Chunlei Xing, Yuhong Chen, Huihui Bian, Nanning Lv, Zhibin Wang, Mingming Liu, and Li Su. "The STING in Non-Alcoholic Fatty Liver Diseases: Potential Therapeutic Targets in Inflammation-Carcinogenesis Pathway." Pharmaceuticals 15, no. 10 (October 9, 2022): 1241. http://dx.doi.org/10.3390/ph15101241.
Abstract:
Non-alcoholic fatty liver disease (NAFLD), an important chronic disease, is one of the major causes of high mortality and creates a substantial financial burden worldwide. The various immune cells in the liver, including macrophages, NK cells, dendritic cells, and the neutrophils involved in the innate immune response, trigger inflammation after recognizing the damage signaled from infection or injured cells and tissues. The stimulator of interferon genes (STING) is a critical molecule that binds to the cyclic dinucleotides (CDNs) generated by the cyclic GMP-AMP synthase (cGAS) to initiate the innate immune response against infection. Previous studies have demonstrated that the cGAS-STING pathway plays a critical role in inflammatory, auto-immune, and anti-viral immune responses. Recently, studies have focused on the role of STING in liver diseases, the results implying that alterations in its activity may be involved in the pathogenesis of liver disorders. Here, we summarize the function of STING in the development of NAFLD and present the current inhibitors and agonists targeting STING.
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Ayub, Fatima, Romeeza Tahir, Muhammad Kashif Muhammad Kashif, Khursheed Javaid, Faheem Shahzad Faheem Shahzad, Shah Jahan Shah Jahan, and Nadeem Afzal Nadeem Afzal. "Determination of Non-Organ Specific Autoantibodies in Patients with Chronic Hepatitis C and Association with HLA DRΒ1 (*04) Allele." Sains Malaysiana 51, no. 11 (November 30, 2021): 3731–39. http://dx.doi.org/10.17576/jsm-2022-5111-17.
Abstract:
The regulation of immune mechanisms is controlled by major histocompatibility complex/human leukocyte antigen (MHC/HLA). Polymorphisms of the HLA region have an impact on susceptibility to complex infectious and autoimmune diseases. The present study was carried out to determine the frequencies of ASMA, AMA, ANA, dsDNA, and anti-LKM-1 auto-antibodies in hepatitis C patients and to determine their association with the HLA DRβ1 (*04) locus. It was a cross-sectional, analytical study, and 86 patients with chronic HCV were recruited. The presence of auto-antibodies (ASMA, AMA, ANA, dsDNA, and anti-LKM-1) was determined by indirect immunofluorescence and ELISA, while the HLA DRβ1 (*04) allele was assessed by sequence-specific conventional PCR. ANA was detected in 41%, ASMA in 17.4%, AMA in 7%, LKM-1 in 5.8% dsDNA in 4.6% of CHC patients while HLA-DRβ1 (*04) was present in 3.5% of patients, but this was not significantly associated with these auto-antibodies.
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S. Nussbaum, Eric. "Peripheral Sensory Stimulation for Neurological Disorders. A Novel, Non-invasive Therapeutic Option. Review Article." Neuroscience and Neurological Surgery 13, no. 3 (August 31, 2023): 01–04. http://dx.doi.org/10.31579/2578-8868/267.
Abstract:
Peripheral sensory stimulation (PSS) represents a new area of therapy for patients with neurological disorders. Grounded in strong basic science research, PSS carries potential promise in the management of multiple diseases. We reviewed the literature regarding those conditions that represent reasonable targets for treatment with PSS including stroke, Parkinson’s disease, traumatic brain injury, and auto-immune, inflammatory illness. Potential mechanisms of action are discussed, and future avenues of investigation are described.
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Taillan, B., F. J. Pedinielli, J. P. Routy, and A. P. Blanc. "Lymphome malin non hodgkinien et anémie auto-immune au cours de l'évolution de la sarcoïdose." La Revue de Médecine Interne 6, no. 5 (December 1985): 573–75. http://dx.doi.org/10.1016/s0248-8663(85)80040-0.
23
Valery, Marine, Emilie Vallet, Donia Lassoued, Philippe Maingon, Patrick Tilleul, Jean-Philippe Spano, Agnes Bellanger, and Aurelien Gobert. "Immunotherapy: Auto-immune toxicity as a predictive factor of response." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e14086-e14086. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e14086.
Abstract:
e14086 Background: PD-1 and PD-L1 inhibitors have now demonstrated their efficacy. Finding predictive or pre-emptive response factors is crucial and the role of immune-related adverse events (irAEs) is widely debated. The aim of our study was to evaluate the correlation between the occurrence of irAEs and overall survival, according to the time of onset. Methods: We retrospectively collected efficacy and safety data from patients treated with nivolumab, pembrolizumab and atezolizumab for metastatic cancer between July 2015 and January 2019 at the Pitié-Salpêtrière Hospital. Progression-free survival (PFS) and overall survival (OS) were analyzed for the global population, for patients who had an irAES, according to the time of onset (before or after 12 weeks). Results: 158 patients were treated with anti-PD1/PD-L1: 125 patients for NSCLC, 12 for melanoma, 11 for clear cell renal cancer, 5 for bladder cancer, 3 for digestive adenocarcinoma and 2 for mesothelioma. At the cut-off analysis, with a median follow-up of 8.6 months, 63 (40%) patients died, 30(19%) had a progressive disease, 31 (20%) were still receiving an immunotherapy. 25(18%) patients developed irAEs, 18(72%) before 12 weeks of treatment and 7(28%) after. 6 patients had to stop the treatment because of irAEs and 3 of them were still on immunotherapy at the cut-off analysis. Progression disease occurred in 7 patients and 9 died under treatment. Only a trend of efficacy was found between patients with irAEs and those without, with a median PFS of 13.2 vs 9.8 months (HR 1.3; p = 0,4) and a median OS of 28 vs 20 months (HR 1.4; p = 0,4). This statistically non-significant trend was found for OS between patients with an early irAEs and those without any toxicity with a median OS of 28 vs 20 months (HR 1.4; p = 0,8). No statistically difference was found between patients with early irAEs and late irAEs. Conclusions: In our study, 18% of the patients had irAEs. Patients with irAEs seemed to have better OS and PFS but no statistically difference was found. This trend is probably related to patients with late toxicity, which reflects the time of treatment and the increasing probability to develop an irAEs. In our study, early irAEs could not be considered as a reliable preemptive factor of response to immunotherapy.
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Kruse, M., R. Steffen, R. Batel, I. M. Muller, and W. E. Muller. "Differential expression of allograft inflammatory factor 1 and of glutathione peroxidase during auto- and allograft response in marine sponges." Journal of Cell Science 112, no. 23 (December 1, 1999): 4305–13. http://dx.doi.org/10.1242/jcs.112.23.4305.
Abstract:
Very recently, Porifera (sponges) have been proven to be suitable model systems to study auto- and allograft recognition at the molecular level. Several potential immune molecules have been isolated from the marine sponges Suberites domuncula and Geodia cydonium, among them those which comprise Ig-like domains in their extracellular part. Here we report on the isolation of two cDNAs from S. domuncula that code for molecules involved in mammals in cytokine-mediated graft response; a putative allograft inflammatory factor 1 (AIF-1) and a non-selenium glutathione peroxidase (GPX). Both polypeptides share high similarity with the corresponding mammalian proteins. The expression of the two genes during auto- and allograft recognition in S. domuncula and G. cydonium was determined. It is shown that the expression of the AIF-1-related gene is upregulated only in allografts, while the GPX-related gene is expressed in the fusion zones formed between auto- as well as allografts. Taken together, these findings suggest that besides cell-mediated defense reactions a cytokine-dependent immune response is also elicited during graft recognition in sponges.
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Ostrom, Quinn, Jacob Edelson, Jinyoung Byun, Younghun Han, Kyle Walsh, Christopher Amos, and Melissa Bondy. "GENE-11. LDSCORE REGRESSION IDENTIFIES NOVEL ASSOCIATIONS BETWEEN GLIOMA AND AUTO-IMMUNE CONDITIONS." Neuro-Oncology 21, Supplement_6 (November 2019): vi99—vi100. http://dx.doi.org/10.1093/neuonc/noz175.413.
Abstract:
Abstract BACKGROUND Prior epidemiological studies in glioma have identified 25 germline risk variants, as well as risk associations with exposure to ionizing radiation (which increases risk) and history of allergies and aspirin use (which decrease risk). In this analysis we LDscore regression, which leverages single SNP associations and known patterns of linkage disequilibrium (LD) to estimate the genetic correlation between phenotypes, to confirm prior associations as well as attempt to identify novel phenotype associations for traits not previously assessed that may improve genetic prediction for glioma. METHODS Summary statistics for all glioma, GBM, and non-GBM were obtained from a prior meta-analysis conducted by Melin, et al. Summary statistics for 13 immune- and atopy-related traits were obtained from the prior case-control studies and the UK biobank. Data were filtered to include only SNPs with imputation INFO value >0.7, and minor allele frequency >0.01, excluding SNPs within the HLA region. Pairwise genetic correlation between these traits was generated using LDSC. Associations were considered significant at p< 0.05 RESULTS Significant negative correlations were identified between glioma and ulcerative colitis (rg= -0.4039, p=4.91x10-10), celiac disease (rg= -0.2028, p=1.18x10-4), lupus (rg= -0.0956, p=0.0083), and multiple sclerosis (rg= -0.5755, p=4.46x10-9). These associations were generally consistent in both GBM and non-GBM. There was a significant correlation between both self-reported (rg= -0.102, p=0.0233) and doctor diagnosed (rg= -0.116, p=0.0305) hayfever/allergic rhinitis and GBM only. CONCLUSIONS This analysis demonstrates a genetic basis for previously identified protective effect of allergic rhinitis on GBM, and identifies novel associations between multiple auto-immune traits and glioma. Further studies are necessary in order to confirm these associations and identify the mechanism through which increased immune activity may lower risk of glioma.
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Henkel, A. W., P. S. Dittrich, T. W. Groemer, E. A. Lemke, J. Klingauf, H. W. Klafki, P. Lewczuk, et al. "Immune complexes of auto-antibodies against Aβ1-42 peptides patrol cerebrospinal fluid of non-Alzheimer's patients." Molecular Psychiatry 12, no. 6 (February 6, 2007): 601–10. http://dx.doi.org/10.1038/sj.mp.4001947.
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Arndtz, Katherine, and Gideon M. Hirschfield. "The Pathogenesis of Autoimmune Liver Disease." Digestive Diseases 34, no. 4 (2016): 327–33. http://dx.doi.org/10.1159/000444471.
Abstract:
Background: Autoimmune liver disease (AILD) encompasses 3 main distinct clinical diseases: autoimmune hepatitis, primary biliary cholangitis (formally known as cirrhosis, PBC) and primary sclerosing cholangitis (PSC). These conditions are an important, yet under-appreciated cause of patient morbidity and mortality with ongoing unmet needs for further research and clinical advances. Key Messages: There is observational evidence for genetic predisposition, with all 3 conditions being more common in first degree relatives. AILD is associated with the presence of auto-antibodies and higher risks of other non-hepatic auto-immune conditions. Genetic risk association studies have identified HLA and non-HLA risk loci for the development of disease, with some HLA loci providing prognostic information. This re-enforces the concept that genetic predisposition to autoimmunity is important, likely in the context of environmental exposures. Such environmental triggers are unclear but relevant risks include smoking, drug and xenobiotic exposure as well as the complexities of the microbiome. There is evidence for a loss of immune tolerance to self-antigens playing a part in the development of these conditions. In particular the IL-2 and IL-12 regulatory pathways have been implicated in pre-disposing to an unopposed inflammatory response within the liver. Main immunological themes revolve around loss of immune tolerance leading to T-cell mediated injury, imbalance in the regulation of immune cells and defective immune response to foreign antigens. For PBC and PSC, there is then the added complexity of the consequences of cholestasis on hepato-biliary injury, immune regulation and liver fibrosis. Conclusions: Whilst specific disease causes and triggers are still lacking, AILD arises on the background of collective genetic and environmental risk, leading to chronic and abnormal hepato-biliary immune responses. Effective and more rational therapy will ultimately be developed when the multiple pathways to liver injury are better understood.
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Hirschenberger, Maximilian, Victoria Hunszinger, and Konstantin Maria Johannes Sparrer. "Implications of Innate Immunity in Post-Acute Sequelae of Non-Persistent Viral Infections." Cells 10, no. 8 (August 19, 2021): 2134. http://dx.doi.org/10.3390/cells10082134.
Abstract:
Non-persistent viruses classically cause transient, acute infections triggering immune responses aimed at the elimination of the pathogen. Successful viruses evolved strategies to manipulate and evade these anti-viral defenses. Symptoms during the acute phase are often linked to dysregulated immune responses that disappear once the patient recovers. In some patients, however, symptoms persist or new symptoms emerge beyond the acute phase. Conditions resulting from previous transient infection are termed post-acute sequelae (PAS) and were reported for a wide range of non-persistent viruses such as rota-, influenza- or polioviruses. Here we provide an overview of non-persistent viral pathogens reported to be associated with diverse PAS, among them chronic fatigue, auto-immune disorders, or neurological complications and highlight known mechanistic details. Recently, the emergence of post-acute sequelae of COVID-19 (PASC) or long COVID highlighted the impact of PAS. Notably, PAS of non-persistent infections often resemble symptoms of persistent viral infections, defined by chronic inflammation. Inflammation maintained after the acute phase may be a key driver of PAS of non-persistent viruses. Therefore, we explore current insights into aberrant activation of innate immune signaling pathways in the post-acute phase of non-persistent viruses. Finally, conclusions are drawn and future perspectives for treatment and prevention of PAS are discussed.
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Harryvan, Tom J., Sabine de Lange, Lukas J. A. C. Hawinkels, and Els M. E. Verdegaal. "The ABCs of Antigen Presentation by Stromal Non-Professional Antigen-Presenting Cells." International Journal of Molecular Sciences 23, no. 1 (December 23, 2021): 137. http://dx.doi.org/10.3390/ijms23010137.
Abstract:
Professional antigen-presenting cells (APCs), such as dendritic cells and macrophages, are known for their ability to present exogenous antigens to T cells. However, many other cell types, including endothelial cells, fibroblasts, and lymph node stromal cells, are also capable of presenting exogenous antigens to either CD8+ or CD4+ T cells via cross-presentation or major histocompatibility complex (MHC) class II-mediated presentation, respectively. Antigen presentation by these stromal nonprofessional APCs differentially affect T cell function, depending on the type of cells that present the antigen, as well as the local (inflammatory) micro-environment. It has been recently appreciated that nonprofessional APCs can, as such, orchestrate immunity against pathogens, tumor survival, or rejection, and aid in the progression of various auto-immune pathologies. Therefore, the interest for these nonprofessional APCs is growing as they might be an important target for enhancing various immunotherapies. In this review, the different nonprofessional APCs are discussed, as well as their functional consequences on the T cell response, with a focus on immuno-oncology.
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Çetin, Gonca, Sandro Klafack, Maja Studencka-Turski, Elke Krüger, and Frédéric Ebstein. "The Ubiquitin–Proteasome System in Immune Cells." Biomolecules 11, no. 1 (January 5, 2021): 60. http://dx.doi.org/10.3390/biom11010060.
Abstract:
The ubiquitin–proteasome system (UPS) is the major intracellular and non-lysosomal protein degradation system. Thanks to its unique capacity of eliminating old, damaged, misfolded, and/or regulatory proteins in a highly specific manner, the UPS is virtually involved in almost all aspects of eukaryotic life. The critical importance of the UPS is particularly visible in immune cells which undergo a rapid and profound functional remodelling upon pathogen recognition. Innate and/or adaptive immune activation is indeed characterized by a number of substantial changes impacting various cellular processes including protein homeostasis, signal transduction, cell proliferation, and antigen processing which are all tightly regulated by the UPS. In this review, we summarize and discuss recent progress in our understanding of the molecular mechanisms by which the UPS contributes to the generation of an adequate immune response. In this regard, we also discuss the consequences of UPS dysfunction and its role in the pathogenesis of recently described immune disorders including cancer and auto-inflammatory diseases.
31
Oza, Harshal B., Sarah K. Spurgeon, and Najl V. Valeyev. "Non-Lipschitz Growth Functions as a Natural Way of Modelling Finite Time Behaviour in Auto-immune Dynamics." IFAC Proceedings Volumes 47, no. 3 (2014): 11611–16. http://dx.doi.org/10.3182/20140824-6-za-1003.01032.
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Abdel-Maksoud, Mostafa A., Ajarem Jamaan, Ebaid Hossam, Wahidah H. Al-Qahtani, and Saleh N. Maodaa. "Whey Protein-Induced Amelioration of Liver Functions in Auto-Immune Diabetic Rats is Interferon-γ Mediated." Current Topics in Nutraceutical Research 17, no. 3 (November 12, 2018): 266–70. http://dx.doi.org/10.37290/ctnr2641-452x.17:266-270.
Abstract:
The aim of this study was to determine whether dietary supplementation with WP could enhance the liver functions of diabetic rats. A total of 45 male rats were assigned into a control group (C), a diabetic group (DM) and a diabetic group orally supplemented with WP (DMWP) at a dose of 100 mg/kg body weight. WP was found to decrease the expression levels of Flavin monooxygenase 2 gene in the WP supplemented group of rats in comparison to the non-supplemented ones. A significant restoration of the expression level of interferon-γ was observed in DMWP rats in comparison to the control ones. Additionally, WP supplementation was found to significantly restore the levels of both Akt1 and Fas in the WP supplemented group in comparison to both the control group and the non-supplemented diabetic group. In conclusion, dietary supplementation with WP enhances the liver functions in the diabetic rats.
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Vargas, Salvador, and Jossue Calvo. "Sistema Nefelometrico Auto-referenciado Inmune a Fuentes de Luz Externas." KnE Engineering 3, no. 1 (February 11, 2018): 111. http://dx.doi.org/10.18502/keg.v3i1.1418.
Abstract:
This paper describes the concepts and procedures for the design and implementation of a water turbidity sensor. It is designed with the purpose of offering us water turbidity readings. The sensor is designed according to the standard ISO 7027 "The water quality, determination of turbidity", which specifies four methods for the determination of the turbidity of the water. The light source is an infrared led to 850 nm which is modulated in frequency to prevent external light interference, so that the sensor receiver is immune to external sources of light. The calibration of this sensor gets a sensitivity of 0.0014 V/NTU and a non-linear error less than 10%, for a range between 0.1 NTU to 600 NTU.Keywords: Turbidity, Nephelometer, Turbidimeter, Sensor, Calibration Curve
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Hellmuth, Joanna, T. Allen Barnett, Breton M. Asken, J. Daniel Kelly, Leonel Torres, Melanie L. Stephens, Bryan Greenhouse, et al. "Persistent COVID-19-associated neurocognitive symptoms in non-hospitalized patients." Journal of NeuroVirology 27, no. 1 (February 2021): 191–95. http://dx.doi.org/10.1007/s13365-021-00954-4.
Abstract:
AbstractAs cases of coronavirus disease 2019 (COVID-19) mount worldwide, attention is needed on potential long-term neurologic impacts for the majority of patients who experience mild to moderate illness managed as outpatients. To date, there has not been discussion of persistent neurocognitive deficits in patients with milder COVID-19. We present two cases of non-hospitalized patients recovering from COVID-19 with persistent neurocognitive symptoms. Commonly used cognitive screens were normal, while more detailed testing revealed working memory and executive functioning deficits. An observational cohort study of individuals recovering from COVID-19 (14 or more days following symptom onset) identified that among the first 100 individuals enrolled, 14 were non-hospitalized patients reporting persistent cognitive issues. These 14 participants had a median age of 39 years (interquartile range: 35–56), and cognitive symptoms were present for at least a median of 98 days (interquartile range: 71–120 following acute COVID-19 symptoms); no participants with follow-up evaluation reported symptom resolution. We discuss potential mechanisms to be explored in future studies, including direct viral effects, indirect consequences of immune activation, and immune dysregulation causing auto-antibody production.
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Thai, Lan-Huong, Ailsa Robbins, Simon Le Gallou, Nicolas Cagnard, Jean-Claude Weill, Claude-Agnès Reynaud, and Matthieu Mahevas. "BAFF and CD4 T-Cells Are Major Survival Factors for Splenic Plasma Cells in B Cell Depletion Context: Implications for Autoimmune Diseases." Blood 128, no. 22 (December 2, 2016): 129. http://dx.doi.org/10.1182/blood.v128.22.129.129.
Abstract:
Abstract The use of monoclonal anti-CD20 antibody (Rituximab) has greatly improved the treatment of B-cell mediated autoimmune diseases, albeit with variable outcomes. Our previous data in humans suggested that Rituximab induced paradoxically the settlement of splenic long-lived plasma cells (LLPC) in the context of 2 autoimmune cytopenia, immune thrombocytopenia and warm autoimmune hemolytic anemia (1) (2). The presence of splenic autoreactive LLPC explained the failure of Rituximab treatment. To investigate whether this mechanism could have a general relevance and decipher the cellular and molecular mechanism of this process, we used both non auto-immune and auto-immune mouse models. We have taken advantage of the knock-in transgenic mouse model AID-CreERT2-EYFP, which allows the irreversible expression of EYFP in B cells engaged in a germinal center-dependent immune response after tamoxifen regimen, to follow plasma cells (PC) at different times of immunization by sheep red blood cells, and upon anti-CD20 regimen (clone 18B12, Biogen Idec), in the spleen and bone marrow (3). By using a set of diagnostic genes that allowed us to distinguish short-lived and long-lived plasma cells, we compared the transcriptional program by multiplex PCR of EYFP+ B220- PC from controls and anti-CD20 treated mice, immunized and analyzed at the same time, corresponding to the nadir of B-cell depletion. While splenic PC of untreated mice displayed an intermediate profile between short-lived and long-lived plasma cells, splenic PC from anti-CD20 treated mice composed a homogeneous population that displayed a more mature program, similar to the one of natural long-lived bone marrow PC. The absolute number of splenic EYFP+ B220- did not change upon anti-CD20 treatment indicating that B-cell depletion promoted PC differentiation rather than a long-lived PC selection. We identified BAFF (B-cell activating factor) as a major player of this process. Indeed, as described in human spleens, we observed that BAFF level was increased in the supernatants of splenocytes after B-cell depletion. Above all, combination of anti-CD20 and anti-BAFF (clone 10F4, GSK) antibodies dramatically reduced the number of splenic EYFP+B220- LLPC (decrease >5 fold compared with anti-CD20 and control groups, P < 0.001). Targeting BAFF had no major impact on protective long-lived bone marrow PC as IgG1 level in the sera remained unchanged after combination therapy. We identified neutrophils as the main source of BAFF production in the spleen. Finally, CD4+ T-cells also appeared to play a key role in context of B-cell depletion for supporting plasma cell survival in the spleen as they appeared to closely interact with EYFP+ plasma cells by confocal microscopy. Moreover, their depletion (clones YTS 191.1 or GK 1.5, Bioxcell) in vivo induced a significant decrease in the number of splenic LLPCs (decrease > 2 fold compared with anti-CD20 group, P < 0.05). To assess whether B-cell depletion could also modify the splenic plasma cell program in an auto-immune context characterized by an ongoing immune response, we used NZB/NZW mice that spontaneously develop a disease closely resembling human systemic lupus. In line with our previous findings, anti-CD20 treatment also promoted the differentiation of LLPC in the spleen of the NZB/NZW model, while a treatment combining anti-CD20 with anti-BAFF induced a marked reduction in total PC numbers(decrease > 3 fold compared with anti-CD20 group, P < 0.05). In conclusion, the process of PC maturation upon anti-CD20 treatment appeared to be a general mechanism, both in non auto-immune and auto-immune models. We identified BAFF and CD4+ T-cells as key factors in the splenic environment responsible for the emergence of such LLPC. Finally, our results suggest that interfering with the plasma cell survival niche with monoclonal anti-BAFF antibody at the time of B-cell depletion might greatly improve the response rate in B-cell mediated auto-immune cytopenia. (1) Mahevas M, et al, Journal of Clinical Investigation , 2013 (2) Mahevas M, et al, Journal of Autoimmunity, 2015 (3) Dogan I, et al, Nature Immunology, 2009 Disclosures No relevant conflicts of interest to declare.
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Moturi, Krishna, Harsh Sharma, and Neda Hashemi-Sadraei. "Nephrotoxicity in the Age of Immune Checkpoint Inhibitors: Mechanisms, Diagnosis, and Management." International Journal of Molecular Sciences 25, no. 1 (December 28, 2023): 414. http://dx.doi.org/10.3390/ijms25010414.
Abstract:
Immune checkpoint inhibitors (ICI) revolutionized cancer therapy by augmenting anti-tumor immunity via cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1/programmed death-ligand 1 (PD-1/PD-L1). However, this breakthrough is accompanied by immune-related adverse effects (irAEs), including renal complications. ICI-related nephritis involves complex mechanisms like auto-reactive T cells, auto-antibodies, reactivation of drug-specific T cells, and cytokine-driven inflammation culminating in AKI. ICI-AKI typically manifests weeks to months into treatment, often with other irAEs. Timely detection relies on monitoring creatinine levels and urine characteristics. Biomarkers, like soluble interleukin-2 receptor (sIL-2R) and urine cytokine levels, provide non-invasive insights, while renal biopsy remains the gold standard for confirmation. Management of ICI-AKI requires a balance between discontinuing ICI therapy and prompt immunosuppressive intervention, typically with corticosteroids. Some cases permit ICI therapy resumption, but varying renal recovery rates highlight the importance of vigilant monitoring and effective therapy. Beyond its clinical implications, the potential of irAEs to predict positive treatment responses in certain cancers raises intriguing questions. Data on nephritis–treatment response links are limited, and ongoing research explores this complex interaction. In summary, ICI therapy’s transformative impact on cancer treatment is counterbalanced by irAEs, including nephritis. Early recognition and management are vital, with ongoing research refining diagnostic and treatment strategies.
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Ross, Connie, Amy H. Chan, Jessica Von Pein, Dave Boucher, and Kate Schroder. "Dimerization and auto-processing induce caspase-11 protease activation within the non-canonical inflammasome." Life Science Alliance 1, no. 6 (December 2018): e201800237. http://dx.doi.org/10.26508/lsa.201800237.
Abstract:
Caspase-11 is a cytosolic sensor and protease that drives innate immune responses to the bacterial cell wall component, LPS. Caspase-11 provides defence against cytosolic Gram-negative bacteria; however, excessive caspase-11 responses contribute to murine endotoxic shock. Upon sensing LPS, caspase-11 assembles a higher order structure called the non-canonical inflammasome that enables the activation of caspase-11 protease function, leading to gasdermin D cleavage and cell death. The mechanism by which caspase-11 acquires protease function is, however, poorly defined. Here, we show that caspase-11 dimerization is necessary and sufficient for eliciting basal caspase-11 protease function, such as the ability to auto-cleave. We further show that during non-canonical inflammasome signalling, caspase-11 self-cleaves at site (D285) within the linker connecting the large and small enzymatic subunits. Self-cleavage at the D285 site is required to generate the fully active caspase-11 protease (proposed here to be p32/p10) that mediates gasdermin D cleavage, macrophage death, and NLRP3-dependent IL-1β production. This study provides a detailed molecular mechanism by which LPS induces caspase-11–driven inflammation and cell death to provide host defence against cytosolic bacterial infection.
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Madaio, M. P., J. Carlson, J. Cataldo, A. Ucci, P. Migliorini, and O. Pankewycz. "Murine monoclonal anti-DNA antibodies bind directly to glomerular antigens and form immune deposits." Journal of Immunology 138, no. 9 (May 1, 1987): 2883–89. http://dx.doi.org/10.4049/jimmunol.138.9.2883.
Abstract:
Abstract The capacity of monoclonal anti-DNA antibodies, derived spontaneously from MRL-lpr/lpr mice, to bind directly to intrinsic glomerular antigens and form immune deposits was evaluated. Two antibodies, H130 (IgM-kappa) and H241 (IgG2a-kappa), bound to normal glomeruli in vitro. This binding was not inhibited by DNAase, but it was, in the case of H130, inhibited by the anti-idiotype anti-H130. Both antibodies also bound to glomerular digests on nitrocellulose. After i.v. injection, however, H241 bound to glomeruli and formed glomerular immune deposits, whereas H130 did not. Similarly, after i.p. injection of H241 hybridomas to normal mice, all mice developed glomerular immune deposits. In contrast, administration of H130 hybridomas, other anti-DNA-producing hybridomas, and other unrelated hybridomas did not lead to glomerular immune deposit formation. We conclude that certain lupus auto-antibodies can form glomerular immune deposits by binding directly to non-DNA antigenic structures that are normally present in extracellular locations within normal glomeruli.
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Shindiapina, Polina, Maciej Pietrzak, Michal Seweryn, Eric McLaughlin, Xiaoli Zhang, Mateusz Makowski, Justin Lyberger, et al. "Comparative Analysis of Immune Reconstitution in HIV-Positive Recipients of Allogeneic and Autologous Stem Cell Transplant on the BMT CTN 0903/AMC-080 and BMT CTN 0803/AMC-071 Trials." Blood 134, Supplement_1 (November 13, 2019): 4525. http://dx.doi.org/10.1182/blood-2019-129488.
Abstract:
Introduction. Our previous flow cytometry-based comparison of HIV(+) and HIV(-) autologous hematopoietic stem cell transplant (auto-HSCT) recipient immunomes at 56, 180 and 365 days post-transplant to each other and to healthy controls (HCs) showed that both sets of auto-HSCT recipient immunomes approached HCs over time, but retained significant differences. HIV(+), but not HIV(-), auto-AHCT recipients retained pro-inflammatory features consistent with chronic HIV infection. Here, we report the results of a quantitative and functional analysis of immune reconstitution in HIV(+) patients treated with allogeneic hematopoietic stem cell transplant (allo-HSCT), in comparison with HIV(+) auto-HSCT recipients and HCs. Methods. Blood samples were collected for analysis at days 56, 180 and 365 post-transplant from HIV(+) transplant recipients and at 1 time point from HCs. Whole blood analysis was performed by five-color flow cytometry across 100 immune marker combinations. Comparisons were made between HIV(+) allo-HSCT recipients (n=17, acute myeloid leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, Hodgkin and non-Hodgkin lymphoma that received myeloablative or reduced intensity conditioning on the BMT-CTN-0903/AMC-080 trial), HIV(+) auto-HSCT recipients (n=36, aggressive B cell non-Hodgkin lymphoma or Hodgkin lymphoma that received myeloablative conditioning on the BMT-CTN-0803/AMC-071 trial) and 71 HCs. Unsupervised principal component analysis (PCA) examined differences in immune cell proportions, identified by flow cytometry across 100 cell subsets at each time point. Wilcoxon rank-sum tests compared median absolute counts and median proportions of cell subsets. An independent feature importance score analysis (FIS) identified contributions of immune cell populations expressing specific immune marker combinations to the differences between HIV(+) auto-HSCT recipients, HIV(+) allo-HSCT recipients and HCs. Functional responsiveness of HIV(+) allo-HSCT recipients' T cells to stimulation with CD3- and CD28-directed antibodies, NK cells to stimulation with IL-12 and IL-18 and monocytes to stimulation with lipopolysaccharide (LPS) was assessed in a preliminary mass cytometry on peripheral blood mononuclear cells isolated at the same time points (n=2) and compared to HCs (n=2). Results. PCA showed that immunomes of HIV(+) allo-HSCT recipients and HIV(+) auto-HSCT recipients clustered together with each other, but away from HCs at all time points throughout the post-transplant year. FIS identified: 1) 13 cell subsets that defined the difference between HIV(+) allo-HSCT recipients (all visits) and HCs, and 2) 11 immune cell subsets that defined the difference between HIV(+) auto-HSCT recipients (all visits) and HCs; in both of these comparisons, activated CD3+/HLA-DR+ T cells had the greatest impact on the difference between HIV(+) and HC immunomes. At 1 year, both HIV(+) transplant recipient cohorts had higher absolute numbers of activated T cells, effector T cells and CD8+ T cells than HCs (Wilcoxon rank-sum test, p<0.0031). HIV(+) autologous and allogeneic HSCT recipients also had lower numbers of CD4+ T cells, naïve T cells and activated NK cells compared to HCs (p<0.0031). FIS also identified 20 immune cell subsets that defined the difference between HIV(+) autologous and allogeneic HSCT recipients immunomes at 1 year, with CD8+/CD27- effector T cell subset exerting the highest impact on the difference. Preliminary functional mass cytometry analysis of 2 HIV(+) allo-HSCT recipients and 2 HCs showed that: 1) IFNʏ production by CD8+ T cells was increased above that of HCs at all time points. 2) Expanded populations of CD4+/T-bet+ cytotoxic cells expressing granzyme B and perforin, and CD8+ cytotoxic T cells expressing granzyme B and perforin, persisted in HIV(+) allo-HSCT recipients at all time points, but not in HCs. 3) NK cells retained an ability to produce IFNʏ in response to stimulation with IL-12 and IL-18 in HIV(+) allo-SCT recipients. 4) Monocytes showed an enhanced production of TNFα in response to stimulation with LPS in HIV(+) allo-HSCT recipients compared to HCs at 1 year post-HSCT. Conclusion. Chronic HIV infection confers the pro-inflammatory immune features on the phenotypic and functional profiling of the T lymphocyte immunome of stem cell transplant recipients, irrespective of allogeneic or autologous stem cell donor source. Disclosures Devine: Bristol Myers: Other: Grant for monitoring support & travel support; Kiadis Pharma: Other: Protocol development (via institution); Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Noy:Janssen: Consultancy; Medscape: Honoraria; Prime Oncology: Honoraria; NIH: Research Funding; Pharamcyclics: Research Funding; Raphael Pharma: Research Funding. Popat:Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Hofmeister:Celgene: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Nektar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imbrium: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees. Navarro:Atara Biotherapeutics: Employment, Equity Ownership. Behbehani:Fluidigm corporation: Other: Travel funding. Lozanski:Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding; Stemline Therapeutics Inc.: Research Funding; Genentec: Research Funding. Baiocchi:Prelude: Consultancy.
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Pandey, Asim, Samriddhi Parajuli, Alok Dhungel, Rahul Devkota, and Angel Dongol. "Etoricoxib Induced Toxic Epidermal Necrolysis in a case of Systemic Lupus Erythematosus: A Case Report." Journal of Nepal Medical Association 60, no. 253 (August 31, 2022): 811–14. http://dx.doi.org/10.31729/jnma.7665.
Abstract:
Toxic epidermal necrolysis is a potentially life-threatening dermatological condition whose pathogenesis and exact treatment are not yet known. Drugs like anticonvulsants, allopurinol and non-steroidal anti-inflammatory drugs like etoricoxib, a selective cyclo-oxygenase-2 inhibitor prescribed for pain management are associated with a high risk of toxic epidermal necrolysis. It is also associated with immunodeficiency and dysregulated immune reactions like systemic lupus erythematosus, an autoimmune disease in which organs and cells undergo damage initially mediated by tissue binding auto-antibodies and immune complexes. Here, a 34 year old lady was presented in emergency with multiple maculopapular rashes over the neck and trunk region after treatment with etoricoxib for osteoarthritis of the left foot.
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Cassaday, Ryan D., and Ajay K. Gopal. "What Is the Role of Transplantation for Indolent Lymphoma?" American Society of Clinical Oncology Educational Book, no. 32 (June 2012): 494–500. http://dx.doi.org/10.14694/edbook_am.2012.32.238.
Abstract:
Overview: Despite advances in chemoimmunotherapy, indolent B-cell non-Hodgkin lymphomas (B-NHLs) are generally not considered curable with this approach. Much attention has been paid to the prospect of hematopoietic cell transplantation (HCT) as a way to improve long-term outcomes for this group of diseases. Autologous (auto) HCT provides intensive conditioning therapy followed by rescue of hematopoiesis, and this has been shown in randomized studies to prolong survival compared with more standard chemotherapy, albeit with increased short-term toxicity and the potential for higher rates of secondary malignancies. Allogeneic (allo) HCT can provide anticancer effects beyond the conditioning therapy through the immune-mediated graft-versus-lymphoma (GVL) effect. It can be administered following myeloablative (MA) conditioning or reduced-intensity (RI) regimens aimed at sufficiently suppressing the patient's immune system to allow engraftment of donor hematopoiesis. However, this same potentially curative alloreactivity of the engrafted immune system can lead to graft-versus-host disease (GVHD), a significant cause of morbidity and mortality following allo HCT. This article will discuss the current role of both auto HCT and allo HCT in the management of indolent lymphoma as well as the relative risks and benefits of each approach such that the reader can place this in context of the multitude of options available for patients with indolent B-NHL.
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Lee, Ferrol, and F. N. U. Manas. "PMON21 Autoimmune Polyglandular Syndrome, Type 1: A Rare Condition Manifested by Multiple Endocrine and Non-Endocrine Disorders." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A458. http://dx.doi.org/10.1210/jendso/bvac150.953.
Abstract:
Abstract Introduction Autoimmune Polyglandular Syndrome Type 1 (APS-1) is a rare autoimmune disorder with a prevalence of 1 in 2-3 million births. It is an autosomal recessive disorder caused by loss of function mutation of the Auto- Immune REgulator gene (AIRE gene) on chromosome 21. It leads to formation of autoantibodies to various hormonal, connective tissue, and protein antigens. It is characterized by the presence of two of the following three cardinal features: chronic muco-cutaneous candidiasis, hypoparathyroidism, and Addison's disease (primary adrenal insufficiency). Recently AIRE gene mutations have been seen in patients who have one of the three classic findings, but have other less commonly associated autoimmune disorders. The other auto-immune conditions associated with APS-1 are: type 1 diabetes mellitus, vitiligo, pernicious anemia, primary hypothyroidism, primary hypogonadism, pituitary failure, autoimmune hepatitis, and interstitial nephritis. The diagnosis is based on the history suggestive of endocrine and autoimmune disorders and the biochemical testing for endocrinopathies. The definitive diagnosis is made by genetic testing for AIRE gene mutation. Treatment is identical as for each isolated condition, i.e., hormone replacement, electrolyte correction and antifungals. Case Presentation A 19-year-old patient with a past medical history of congenital single kidney, oral thrush and vaginal candidiasis, hypothyroidism, intellectual disabilities, seizure disorder (onset two years earlier) and depression, was referred to the Endocrinology clinic for the evaluation of hypocalcemia. Her serum calcium was 7.9 mg/dl (normal: 8.5-10.0 mg/dl). She complained of fatigue, and constipation, but denied carpopedal spasms or perioral paresthesia. She has a family history of thyroid dysfunction and diabetes (mother). Initial workup for hypocalcemia revealed low serum calcium with low ionized calcium. Normal magnesium, creatinine, vitamin D-1,25 dihydroxy and 25-hydroxy vitamin D, and TSH (patient on levothyroxine for hypothyroidism). The parathyroid hormone level was low at 6.4 pg/ml (normal 8.0 to 65.0 pg/ml). She was diagnosed with hypoparathyroidism of unknown etiology. She was started on vitamin D and calcium supplementation. The biochemical testing for adrenal insufficiency was negative. The anti-adrenal and thyroid antibody panel was negative. She had a hormone-releasing birth control implant so ovarian function could not be assessed. Given the history of candidiasis and hypothyroidism with the new diagnosis of hypoparathyroidism, she was diagnosed with autoimmune polyglandular syndrome type 1. Conclusion Autoimmune Polyglandular Syndrome, type 1 is a rare autoimmune disorder and needs a high level of suspicion for diagnosis. The syndromic nature of this rare disorder should be recognized to facilitate early detection of other possible auto-immune conditions which can be associated with it. A history of more than one endocrine disorder and the presence of autoimmune conditions should prompt the physician to consider APS-1 as one of the possible diagnoses. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
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Van Hoef, Marlies E. H. M. "Risk Reduction of Chronic Graft Versus Host Disease by Anti-CD20 Treatment (Rituximab)." Blood 106, no. 11 (November 16, 2005): 5567. http://dx.doi.org/10.1182/blood.v106.11.5567.5567.
Abstract:
Abstract Introduction: Chronic graft versus host disease (cGVHD) occurs in 30–50% of adults transplanted by non-myeloablative (reduced intensity conditioning) allogeneic transplant, whereas it is rare in children. The syndrome complex manifests itselves as auto-immune disease. Dysregulation of B-cell function has also been reported in auto-immune diseases. This is a rationale for B-cell depletion. We considered that B-cell depletion might have a therapeutic effect in cGVHD and reduce the risks associated with cGVHD. Based on these assumptions we applied risk reduction principles and defined a plan for cure of cGVHD. Methods: To identify the risks associated with B-cell depletion in cGVHD we performed a medline search on anti-CD20 or B-cell depletion or rituximab and cGVHD. The publications were analyzed and those applicable to the topic evaluated. Clinical research methods were applied to define a plan for risk reduction of cGVHD. Results: The medline search revealed that rituximab was used for B-cell depletion in cGVHD and in auto-immune diseases. In advanced cGVHD complete and partial remissions of a variety of manifestations of cGVHD were reported. Complete remissions could also be induced early during the disease course of single manifestations of cGVHD not responsive to immune suppressive treatment or as initial treatment. The dose of rituximab varied from 1 to 4 weekly courses of rituximab 375 mg/m2, with repetitions of this schedule in advanced disease to induce complete response. During reported follow-up responding manifestations did not recur. Rituximab treatment was well tolerated with appropriate anti-allergic prophylaxis. The results support the concept that anti-CD20 treatment might cure cGVHD manifestations at first diagnosis; it is too early to define whether it also serves as prophylactic for development of new manifestations. The observations were discussed with the company marketing rituximab and a study plan was designed. This study plan is being discussed with study centers for risk reduction of cGVHD by rituximab. The risk reduction plan will be presented
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Wick, G. "Concept of a multigenic basis for the pathogenesis of spontaneous autoimmune thyroiditis." Acta Endocrinologica 116, no. 1_Suppl (August 1987): S63—S69. http://dx.doi.org/10.1530/acta.0.114s063.
Abstract:
Abstract. The review presents a concept for the pathogenesis of spontaneous, organ-specific autoimmune diseases that take into account an altered immune regulation, modulating hormonal influences and a genetically determined primary susceptibility of the target organ for the autoimmune attack. The concept is exemplified by means of the Obese strain (OS) chicken model which develops a spontaneous hereditary auto-immune thyroiditis. In repect to the the altered function of the immune system both, MHC associated (Ir) and non-MHC associated genes are involved. The MHC, i.e. a certain haplotype, only plays a modulatory role in determining the frequency and severity of spontaneous autoimmune thyroiditis, while the presence of certain non-MHC associated genes is a absolute prerequisite for the emergence of the disease. The latter is also true for the genetically determined target organ susce ptibility, while hormonal factors, notably sex-steroids and glucocorticoids, again only have a facultative, modulatory effect. Only if an appropriate genetic constellation concerning the non-MHC encoded aberrant immunological function and genes coding for the susceptibility of the thyroid gland for the autoimmune proces is present, severe autoimmune thyroids develops.
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Hong, Lih En, Deepak Singhal, Amilia Wee, Rakchha Chhetri, Mihir D. Wechalekar, Susanna Proudman, and Devendra K. Hiwase. "The Mutation Profile of Myelodysplastic Syndrome Associated with Auto-Immune Rheumatological Disorders." Blood 132, Supplement 1 (November 29, 2018): 3081. http://dx.doi.org/10.1182/blood-2018-99-119965.
Abstract:
Abstract Introduction: A subset of patients with MDS and related myeloid disorders present with concomitant autoimmune rheumatological diseases (AIRD); however the prevalence ranges from 10-48% based on limited literature. Further, use of immunosuppressive agents in AIRD patients could confound the secondary diagnosis of MDS and in some cases cause it (therapy-related myeloid neoplasm; t-MN). The prevalence of cytopenia in AIRD patients is unknown and the genetic characteristics of MDS patients with concomitant AIRD have not been described. Hence, we interrogated two large multi-institutional databases -Royal Adelaide Hospital Rheumatology Database (RAH-RD) and South-Australian MDS (SA-MDS) registry in this study. Methods: Demographic, clinical, laboratory and treatment data of 2663 AIRD and 1157 MDS patients were analysed. In AIRD patients (autoimmune inflammatory arthritis, spondyloarthritis, vasculitis and connective tissue diseases), cytopenia (persisting >6 months) were defined as follows: hemoglobin <100g/dL, absolute neutrophil <1800/mm3 and platelet <100,000/mm3. Targeted massively parallel sequencing of a custom panel of 43 myeloid neoplasms associated genes and 20 Fanconi (FA) DNA repair pathway genes (all coding regions) was performed on diagnosis bone marrow samples (n=237). An in-house well established filtering pipeline was used for identification of somatic mutations. Matched germline material was available for 62/194 (32%) patients. Only variants with Genome Aggregation Database minor allele frequency of ≤0.01% and variant allele frequency of ≥35% were selected for further analysis of germline variants. Results: During follow up of 2663 AIRD patients, 36 (1.3%) patients satisfied the criteria for at least one cytopenia. Anemia (19/36, 53%) was most common followed by neutropenia (8/36, 22%), thrombocytopenia (4/36, 11%) and bi-cytopenia (5/36, 14%). Twenty-two patients had bone marrow examination which was non-diagnostic in 16 patients, while 7/2663 (0.3%) patients were diagnosed with MDS. Importantly, 5 patients with MDS and 11 patients with cytopenia did not receive any cytotoxic agents. In the MDS database, 69(5.4%) were diagnosed with AIRD, with rheumatoid arthritis (n=20, 29%) being the most common AIRD. Among these 69 patients, 24 (34.8%) had low risk MDS and 15 (21.7%) had higher risk MDS. The remaining 30 patients had t-MN (n=19, 27.5%), MDS/MPN (n=8, 11.6%) and AML (n=3, 4.3%). Overall, in a combined population of 2663 RAH-RD and 1157 SA-MDS, 76(2%) had concomitant MDS and AIRD. Genetic profile of patients with MDS and AIRD: The cytogenetic and mutational profile of MDS patients with (n=20) or without (n=217) AIRD were compared. No significant difference was seen in the cytogenetic profile (normal, complex or monosomal karyotype, chr. 5 or 7 abnormalities) between the two groups but in mutational analysis, 56 mutations were seen in 20 MDS patients with AIRD (Fig1). In these patients, mutations in epigenetic pathways were most common (23/56, 41%) followed by transcription pathway (10/56, 18%). Splicing mutations were seen in 5 patients, with SRSF2 mutations being more common than SF3B1. Mutations in TP53 were present in 4 (24%) patients; 3/4 patients developed MDS following therapy for AIRD (t-MDS). IDH1 mutations were found in significantly higher frequency in MDS patients with AIRD compared to MDS without AIRD (30% vs 3%, p=0.04). There was no significant difference in the frequency of other mutations or overall mutation frequency between the two groups. Interestingly, 2 (10%) patients with MDS and AIRD also had rare, deleterious germline mutations in FA pathway genes (BRCA2 V2601M and L2512F) which could suggest either genetic predisposition to both these conditions or compromised DNA repair capability increasing susceptibility to t-MN. Conclusions: In a large multi-institutional cohort of autoimmune rheumatological disorders, 1.3% patients developed persistent cytopenia with 0.3% diagnosed with MDS. This is significantly higher than incidence of MDS in the general population (30-50/100,000). Similarly, 5% MDS patients had AIRD. The mutation profile of MDS patients with AIRD shows higher frequency of IDH1 and SRSF2 mutations. A small proportion of cases also had deleterious rare germline mutations in the DNA repair pathway. Our findings warrant further study and have potential implications for selection of immunosupressive agents for AIRD. Disclosures Hiwase: Novartis: Research Funding; Celgene: Research Funding.
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Minev, Boris, Antonio F. Santidrian, Ivelina Minev, Duong Nguyen, Dmitriy Zamarin, Francesco Marincola, and Dobrin Draganov Draganov. "Enhancement of the therapeutic effects of oncolytic vaccinia virus by using autologous and allogeneic cell-based delivery platforms." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e15271-e15271. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e15271.
Abstract:
e15271 Background: Clinical trials with oncolytic viruses for cancer treatment have shown limited efficacy due to viruses’ rapid clearance by patients’ innate and adaptive immune systems. In a recent first-in-human clinical trial, we confirmed the safety and feasibility of our approach to enhance oncolytic vaccinia virus (OVV) delivery and improve tumor targeting by utilizing an autologous cell-based cell delivery system (auto-OVV). We also developed an allogeneic cell-based platform (SuperNova1c - SNV1c) aiming to protect and potentiate OVV’s antitumor effects in large patient populations. Methods: We evaluated the immunomodulatory potential of auto-OVV by an extensive time-course analysis of cytokines in patients’ plasma (Luminex profiling) and peripheral blood immune cells (flow cytometry). We also analyzed the ability of SNV1c to protect the OVV from antibody/complement inactivation in vitro and in vivo following intratumoral injection in various mouse tumors. The immune cell infiltrations of the injected tumors were also analyzed. Results: Therapy with auto-OVV induced a coordinated activation of cytokine, T cell and NK responses in patients as early as 1 day, peaking around 1-week and lasting for up to 1-month post treatment. Effective OVV amplification in cancer patients correlated with significant changes of multiple innate and adaptive immune parameters. Patient stratification into groups with transient versus persistent viral DNA was linked to opposing and mutually exclusive patterns of robust activation of NK versus T cell responses, respectively. SNV1c showed significantly enhanced protection of OVV in vitro and led to statistically significant tumor growth inhibition as compared to control non-treated tumors or to naked OVV-treated tumors. Importantly, local administration of SNV1c induced systemic therapeutic effects. Five days after SNV1c administration, tumor infiltrating lymphocytes from both treated and untreated tumors showed increased CD4 and CD8 T-cell infiltrations, decreased Tregs, and improved effector to Treg ratios, associated with tumor growth inhibition at both treated and untreated tumor sites. Conclusions: This study establishes the timeline of treatment-related immunological changes and identifies potential immunological correlates associated with the OVV persistence in vivo. We also demonstrate the ability of our cell-based platforms to protect and potentiate OVV by circumventing innate and adaptive immune barriers, resulting in enhanced oncolytic virotherapy.
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Porcelijn, Leendert, Elly Huiskes, Gonda Oldert, Rob Fijnheer, Martin R. Schipperus, Jaap Jan Zwaginga, and Masja De Haas. "Detection of Platelet Autoantibodies Revisited to Identify Immune Thrombocytopenia." Blood 126, no. 23 (December 3, 2015): 1142. http://dx.doi.org/10.1182/blood.v126.23.1142.1142.
Abstract:
Abstract Introduction: Immune Thrombocytopenia (ITP) is still diagnosed by exclusion of many other causes for thrombocytopenia. In order to prevent misdiagnosis, an ITP-specific diagnostic test would be very helpful. In addition, characterization of glycoprotein specificity of platelet autoantibodies may explain (the severity of) bleeding symptoms and response to therapy. In this regard, we optimized the cut-off value of the direct monoclonal antibody immobilization of platelet antigens (MAIPA) assay for detection of platelet glycoprotein directed autoantibodies and re-evaluated its sensitivity and specificity for the diagnosis of ITP. Materials and Methods: The MAIPA was performed as part of our routine protocol, described by Kiefel et al. (1985). For the determination of a new cut-off value, and to calculate the sensitivity and specificity, blood samples were tested from 462 healthy blood donors and 43 non-immune-mediated thrombocytopenic patients, suffering from either hematological malignancies or aplastic anemia (n=20), hepato-splenomegalic pooling (n=3), drug-induced thrombocytopenias (n=4), viral infections (n=6), pregnancy related thrombocytopenia (n=7), pseudothrombocytopenias (n=2) and microangiopathy (n=1) and from 60 known ITP patients. We then have tested 120 prospectively collected samples from thrombocytopenic patients, sent for diagnostic tests to our laboratory, and categorized these samples based on subsequently obtained clinical evaluation into 'most likely ITP' (n=64) or 'most likely non-ITP' (n=56). Results: The calculated direct MAIPA sensitivity and specificity, using a cut-off value of E=0.130, in the ITP and non-ITP control groups (n=103) were 85% (95% CI, 73-93%) and 100% (95% CI, 92-100%), respectively (see Figure). The platelet auto-antibodies in the ITP control group (n=60) were directed against glycoprotein (GP)IIb/IIIa (66.7%), GPIb/IX (60%), GPV (51.7%), GPIa/IIa (40.6%) and/or GPIV (26.9%). The calculated sensitivity and specificity for detection of platelet auto-antibodies in the prospective diagnosed ITP and non-ITP patient control groups (n=120) were 75% (95% CI, 63-85%) and 96% (95% CI, 88-100%), respectively (see Figure). For this group of patients, the direct MAIPA showed, for diagnosis of ITP, a negative predictive value (NPV) of 77% (95% CI, 66-86%) and a positive predictive value (PPV) of 96% (95% CI, 86-100%). Furthermore, in 23 ITP patients the sequential sampling in a rituximab-treatment protocol showed platelet counts that were significantly and inversely correlated with the direct-MAIPA extinctions (p=0.006). In this respect, we excluded that higher platelet counts impaired the detection of platelet autoantibodies - e.g. by diluting them over an higher platelet mass-since autoantibodies were successfully detected in samples from ITP patients (n=4) with, as a result of splenectomy, platelet counts above 100 x 109/L and in untreated ITP patients with platelet counts between 75 and 100 x 109/L. These findings may implicate that response to rituximab as reflected by a rise in platelet counts is dependent on antibody presence, but the mechanism of effective lowering of platelet autoantibody levels by rituximab is still unclear. In conclusion, the revisited direct MAIPA showed to be a valuable technique for the detection of platelet autoantibodies both at diagnosis and during treatment and can possibly become a guide for optimizing therapy towards a more personalized treatment of ITP. Direct MAIPA O.D. above 0.13 is considered positive. Control samples: historically well characterized ITP patients. Prospective study: requests for serological ITP diagnostics, after final clinical evaluation classified as ITP or non-ITP. Figure 1. Figure 1. Disclosures Schipperus: Novartis: Consultancy.
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Williams, D. M. "Non-Infectious Diseases of the Oral Soft Tissue: a New Approach." Advances in Dental Research 7, no. 2 (August 1993): 213–19. http://dx.doi.org/10.1177/08959374930070021401.
Abstract:
A significant proportion of the non-infectious diseases of oral mucosa are either auto-immune in nature or have lesions which are the result of immunologically-mediated events. These include pemphigus, benign mucous membrane pemphigoid, linear IgA bullous dermatosis, dermatitis herpetiformis, epidermolysis bullosa acquisita, erythema multiforme, and lichen planus. Although each of these has certain specific characteristics, all may produce bullae, erosions, and ulcers on the oral mucosa, resulting in confusingly similar clinical presentations. With careful clinical, histological, and immunofluorescence examination, it is possible to establish a definitive diagnosis in a high proportion of cases. However, one of the most exciting developments which has emerged from recent research into these diseases is their precise molecular characterization. This raises the prospect of accurate, highly specific diagnostic tests which would provide the basis for sound clinical management, with original approaches replacing the somewhat unsatisfactory symptomatic treatment which is often all that is available.
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Alawadhi, A., N. Wilson, R. Alizadehfar, and G. Sebire. "GP.03 Immune deficiencies/dysregulations underpinning childhood limbic encephalitis: a case series and literature review." Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 45, s2 (June 2018): S8. http://dx.doi.org/10.1017/cjn.2018.79.
Abstract:
Background: Limbic encephalitis (LE) is a rare autoimmune syndrome affecting limbic system structures and causing variety of manifestations including memory changes, temporal epilepsies, and psychiatric symptoms. It is a rare disease in children but with a well-recognizable combination of clinical, neuroimaging and/or histological signature. Beyond the association with anti-neuronal auto-antibodies, no clear immune system phenotype has been associated with limbic encephalitis. Our aim is to characterize the clinical and paraclinical features of non-paraneoplasic limbic encephalitis and to correlate them with potential underlying immune deficiencies. Methods: Retrospective case series of seven patients with limbic encephalitis recruited at the Montreal Children’s Hospital (MCH) with a focus on the immune- and neuro-phenotypes, including anti-neuronal antibodies, lymphocyte sub-typing, key markers of immunoglobulin and complement systems. Literature review showed 77 cases of non-paraneoplastic non-NMDA limbic encephalitis. Results: Symptoms included temporal epilepsy (n=5), psychiatric symptoms such as ADHD or autistic symptoms (n=2), and memory changes (n=3). One patient was positive for both voltage gated potassium channel antibodies (VGKC) and anti-thyroid peroxidase antibodies (TPO) and two were positive only for anti TPO antibodies. One patient showed low CD19, and immunoglobulins. Three patients showed chronic low CD56 cell count. Conclusions: The study is still ongoing, but at least 3 patients already display some traits of immune dysregulation.
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Ribonnet, C., V. Saey, R. Ducatelle, and K. Palmers. "Immune-mediated hemolytic anemia associated with chronic fibrosing mediastinitis in an Arabo-Friesian horse." Vlaams Diergeneeskundig Tijdschrift 88, no. 5 (October 31, 2019): 278–86. http://dx.doi.org/10.21825/vdt.v88i5.16000.
Abstract:
In this report, a ten-year-old gelding with immune-mediated hemolytic anemia associated with chronic fibrosing mediastinitis of unknown origin is described. The patient suffered from chronic weight loss and intermittent diarrhea for already several months. He was presented with severe anemia, anorexia and fever of a 24-hour onset. A direct Coombs test was highly positive for IgG auto-agglutination. No evidence of an underlying process was found on clinical examination. Post-mortem examination revealed green liquid material containing food particles in the cranial mediastinum and histology suggested chronic fibrosing mediastinitis. Even though perforation of the esophagus is a plausible cause, no signs of esophageal rupture were noted on macroscopic examination. This case shows that non-responsive, immune-mediated hemolytic anemia can be due to an undetected underlying disease, such as chronic mediastinitis.