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Preuss, Klaus-Dieter, Gerhard Held, Natalie Fadle, Evi Regitz, Maria Kemele, Stephan Stilgenbauer, Andreas Buehler, and Michael Pfreundschuh. "Autoantigenic Targets of B-Cell Receptors (BCR) Derived From Chronic Lymphocytic Leukemias Bind to and Induce Proliferation of Leukemic Cells." Blood 120, no. 21 (November 16, 2012): 2884. http://dx.doi.org/10.1182/blood.v120.21.2884.2884.
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Abstract Abstract 2884 Background Auto-antigenic targets of the B-cell receptor (BCR) derived from malignant cells in chronic lymphocytic leukemia (CLL) might play a role in the pathogenesis of this neoplasm. Patients and Methods In order to identify autoantigenic targets of CLL-derived BCR we screened human tissue-derived protein macroarrays with Fab fragments obtained by papain treatment of CLL cells derived from 50 consecutive cases. Antigens were biochemically and molecularly characterized and recombinantly expressed. Results An autoantigenic target was identified for 12/50 (24%) of the cases, with 3 autoantigens being the target of the BCR from two patients each. CLL-BCR derived from the same stereotype subset recognized the same antigen, but differed epitopes. By flow cytometry using flag-tagged recombinantly expressed autoantigens binding of antigen to the surface of CLL was demonstrated, which was specific for the CLL cells from which the BCR used for the identification of the respective autoantigen was derived. Moreover, binding of the autoantigen to the respective leukemic cells induced specific activation as shown by increased cytoplasmic calcium concentration, induced MYC expression and proliferation of leukemic CLL cells as demonstrated by a proliferation assay (EZ4U). Conclusions Autoantigens are frequent targets of CLL-derived BCR. Their specific binding to and induction of proliferation in respective leukemic cells, which has been demonstrated for the first time, provide the most convincing evidence to date for the long-time hypothesized role of autoantigens in the pathogenesis of chronic lymphocyte leukemia. Supported by Sander-Stiftung (Munich, Germany) Disclosures: No relevant conflicts of interest to declare.
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Sármay, Gabriella. "Biologia Futura: Emerging antigen-specific therapies for autoimmune diseases." Biologia Futura 72, no. 1 (February 4, 2021): 15–24. http://dx.doi.org/10.1007/s42977-021-00074-4.
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AbstractAutoimmune diseases are caused by breaking the central and/or peripheral tolerance against self, leading to uncontrolled immune response to autoantigens. The incidences of autoimmune diseases have increased significantly worldwide over the last decades; nearly 5% of the world's population is affected. The current treatments aim to reduce pain and inflammation to prevent organ damage and have a general immunosuppressive effect, but they cannot cure the disease. There is a huge unmet need for autoantigen-specific therapy, without affecting the immune response against pathogens. This goal can be achieved by targeting autoantigen-specific T or B cells and by restoring self-tolerance by inducing tolerogenic antigen-presenting cells (APC) and the development of regulatory T (Treg) cells, for example, by using autoantigenic peptides bound to nanoparticles. Transferring in vitro manipulated autologous tolerogenic APC or autologous autoantigen-specific Treg cells to patients is the promising approach to develop cellular therapeutics. Most recently, chimeric autoantibody receptor T cells have been designed to specifically deplete autoreactive B cells. Limitations of these novel autoantigen-specific therapies will also be discussed.
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Moritz, Christian P., Yannick Tholance, Oda Stoevesandt, Karine Ferraud, Jean-Philippe Camdessanché, and Jean-Christophe Antoine. "CIDP Antibodies Target Junction Proteins and Identify Patient Subgroups." Neurology - Neuroimmunology Neuroinflammation 8, no. 2 (January 6, 2021): e944. http://dx.doi.org/10.1212/nxi.0000000000000944.
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ObjectiveTo discover systemic characteristics in the repertoires of targeted autoantigens in chronic inflammatory demyelinating polyneuropathy (CIDP), we detected the entire autoantigen repertoire of patients and controls and analyzed them systematically.MethodsWe screened 43 human serum samples, of which 22 were from patients with CIDP, 12 from patients with other neuropathies, and 9 from healthy controls via HuProt Human Proteome microarrays testing about 16,000 distinct human bait proteins. Autoantigen repertoires were analyzed via bioinformatical autoantigenomic approaches: principal component analysis, analysis of the repertoire sizes in disease groups and clinical subgroups, and overrepresentation analyses using Gene Ontology and PantherDB.ResultsThe autoantigen repertoires enabled the identification of a subgroup of 10/22 patients with CIDP with a younger age at onset and a higher frequency of mixed motor and sensory CIDP. IV immunoglobulin therapy responders targeted 3 times more autoantigens than nonresponders. No CIDP-specific autoantibody is present in all patients; however, anchoring junction components were significantly targeted by 86.4% of patients with CIDP. There are potential novel CIDP-specific autoantigens such as the myelination- or axo-glial structure–related proteins actin-related protein 2/3 complex subunit 1B, band 4.1-like protein 2, cadherin-15, cytohesin-1, epidermal growth factor receptor, ezrin, and radixin.ConclusionsThe repertoire of targeted autoantigens of patients with CIDP differs in a systematic degree from those of controls. Systematic autoantigenomic approaches can help to understand the disease and to discover novel bioinformatical tools and novel autoantigen panels to improve diagnosis, treatment, prognosis, or patient stratification.
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Fussey, Shelley P. M., Shauna M. West, J. Gordon Lindsay, C. Ian Ragan, Oliver F. W. James, Margaret F. Bassendine, and Stephen J. Yeaman. "Clarification of the identity of the major M2 autoantigen in primary biliary cirrhosis." Clinical Science 80, no. 5 (May 1, 1991): 451–55. http://dx.doi.org/10.1042/cs0800451.
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1. In primary biliary cirrhosis, the major M2 autoantigen, reacting with antimitochondrial antibodies in sera from >90% of patients, has been identified as the E2 component of the pyruvate dehydrogenase complex. However, two recent reports suggest that alternative polypeptides may be major autoantigens. 2. The evidence that a 75 kDa subunit of complex I of the respiratory chain is a major autoantigen (Frostell, Mendel-Hartvig, Nelson, Totterman, Bjorkland & Ragan, Scand. J. Immunol. 1988; 28, 157–65) is refuted. The findings of Frostell et al. can be explained by contamination of complex I with the pyruvate dehydrogenase complex, evidence for which is presented here. 3. Inspection of the partial amino acid sequence of an unidentified mitochondrial autoantigen (Muno, Kominami, Ishii, Usui, Saituku, Sakakibara & Namihisa, Hepatology 1990; 11, 16–23) shows that it is the El β-subunit of the pyruvate dehydrogenase complex, previously identified as a major autoantigen, and not a ‘new’ alternative major autoantigen. 4. These findings substantiate previous work showing that the mitochondrial M2 autoantigens identified so far in primary biliary cirrhosis are all polypeptide components of the pyruvate dehydrogenase complex or the other related 2-oxo acid dehydrogenase complexes.
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Si, Fuchun. "Identification and expression distribution of esophageal carcinoma autoantigens." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16520-e16520. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16520.
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e16520 Background: To identify the autoantigen protein molecules with autoserum in the tissues from the esophageal carcinoma (EC) patients, analyze autoantigen expression distribution in EC tissues, so as to provide basis for the molecular pathogenesis and clinical medication of EC. Methods: 69 cases of EC patients tissues and serum and 81 cases of healthy people serum were collected, serological proteome analysis (SERPA) was modified with sequential extraction of subcellular protein fractions to identify esophageal oncopathgensis stages autoantigen with autoserum in the tissues from the EC patients. Another 93 cases of EC patients tissue were collected, immunohistochemical and western blot method were used to detect expression distribution of EC autoantigens in esophageal carcinoma tissue, para-carcinoma tissue and normal tissue. Results: Autoantigens CK13, CK16, CaD, ACTG2, tumor rejection antigen (gp96) 1 variant, heat shock protein gp96 precursor were identified, among wihich, CK16, CaD, ACTG2, tumor rejection antigen (gp96)1 variant, heat shock protein gp96 precursor were firstly reported as EC autoantigens. Expression of autoantigens CK16, CaD, ACTG2 were increased in EC carcinoma tissue than para-carcinoma tissue and normal tissue, while CK13 were decreased. Positive expression level of CK16 in normal tissue, para-carcinoma tissue and cancer tissue of EC patients was 0.0076±0.0033, 0.0158±0.0065, 0.0356±0.0165 respectively, CaD was 0.0085±0.0048, 0.0107±0.0056, 0.0177±0.0103 respectively, ACTG2 was 0.0091±0.0039, 0.0136±0.0043, 0.0214±0.0110 respectively, and CK13 was 0.2053±0.0311, 0.1633±0.0280, 0.0412±0.0239 respectively. Conclusions: 6 EC autoantigens were identified, and 5 were first reported. Autoantigens CK13, CK16, CaD and ACTG2 were expressed in EC patients carcinoma tissue, which can be the potential biomarkers of esophageal carcinoma. This study provides new basis for the EC molecular mechanism and development of molecular drugs.
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Pravda, Jay. "Systemic Lupus Erythematosus: Pathogenesis at the Functional Limit of Redox Homeostasis." Oxidative Medicine and Cellular Longevity 2019 (November 26, 2019): 1–11. http://dx.doi.org/10.1155/2019/1651724.
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Systemic lupus erythematosus (SLE) is a disease characterized by the production of autoreactive antibodies and cytokines, which are thought to have a major role in disease activity and progression. Immune system exposure to excessive amounts of autoantigens that are not efficiently removed is reported to play a significant role in the generation of autoantibodies and the pathogenesis of SLE. While several mechanisms of cell death-based autoantigenic exposure and compromised autoantigen removal have been described in relation to disease onset, a significant association with the development of SLE can be attributed to increased apoptosis and impaired phagocytosis of apoptotic cells. Both apoptosis and impaired phagocytosis can be caused by hydrogen peroxide whose cellular production is enhanced by exposure to endogenous hormones or environmental chemicals, which have been implicated in the pathogenesis of SLE. Hydrogen peroxide can cause lymphocyte apoptosis and glutathione depletion, both of which are associated with the severity of SLE. The cellular accumulation of hydrogen peroxide is facilitated by the myriad of stimuli causing increased cellular bioenergetic activity that enhances metabolic production of this toxic oxidizing agent such as emotional stress and infection, which are recognized SLE exacerbating factors. When combined with impaired cellular hydrogen peroxide removal caused by xenobiotics and genetically compromised hydrogen peroxide elimination due to enzymatic polymorphic variation, a mechanism for cellular accumulation of hydrogen peroxide emerges, leading to hydrogen peroxide-induced apoptosis and impaired phagocytosis, enhanced autoantigen exposure, formation of autoantibodies, and development of SLE.
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Tian, Jun, Yaojun Wang, Ming Ding, Yue Zhang, Jiaoni Chi, Tao Wang, Bin Jiao, et al. "The Formation of Melanocyte Apoptotic Bodies in Vitiligo and the Relocation of Vitiligo Autoantigens under Oxidative Stress." Oxidative Medicine and Cellular Longevity 2021 (October 28, 2021): 1–13. http://dx.doi.org/10.1155/2021/7617839.
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Background. Oxidative stress has a vital role in the early stages of vitiligo. Autoantigens released from apoptotic melanocytes (MC) under oxidative stress are involved in the presentation and recognition of antigens. However, the transport of autoantigens to the cell surface and their release to the extracellular environment are still unclear. Apoptotic bodies (ABs) have always been considered as a key source of immunomodulators and autoantigens. Yet, the role of ABs in the immune mechanism of vitiligo is still unknown. Purpose. To explore whether MC’s autoantigens translocate into ABs during oxidative stress-induced apoptosis and study the molecular mechanisms underlying autoantigen migration and AB formation. Methods. PIG3V (an immortalized human vitiligo melanocyte cell line) were treated with H2O2, and ABs were separated. Transmission electron microscopy, flow cytometry, Western blot, mass spectrometry, and other methods were used to determine the relocation of specific antigens in PIG3V cells to ABs. After pretreatment with specific inhibitors (Rho kinase (Y-27632), myosin light chain kinase (MLCK, ML-9), pan-caspase (zVAD-FMK), and JNK (SP600125)), the pathway of autoantigen translocation into ABs and the formation of apoptotic bodies were determined. Results. When treated with 0.8 mM H2O2, ABs were released from these cells. Autoantigens such as tyrosinase-related protein 1 (TYRP-1) and cleavage nuclear membrane antigen Lamin A/C (Asp230) were concentrated in ABs. The expression of autoantigens and the formation of ABs increased in a time- and dose-dependent manner after treatment with H2O2, while the application of specific inhibitors inhibited the formation of apoptotic bodies, i.e., the expression of antigens. Conclusion. Vitiligo autoantigens translocate into ABs in the process of apoptosis induced by oxidative stress. The cytoskeletal protein activation pathway and the JNK-related apoptosis pathway are involved in the transport of autoantigens and the formation of ABs. ABs may be the key bridge between MC cell apoptosis and cellular immunity.
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Casciola-Rosen, Livia, Kanneboyina Nagaraju, Paul Plotz, Kondi Wang, Stuart Levine, Edward Gabrielson, Andrea Corse, and Antony Rosen. "Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy." Journal of Experimental Medicine 201, no. 4 (February 21, 2005): 591–601. http://dx.doi.org/10.1084/jem.20041367.
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Unique autoantibody specificities are strongly associated with distinct clinical phenotypes, making autoantibodies useful for diagnosis and prognosis. To investigate the mechanisms underlying this striking association, we examined autoantigen expression in normal muscle and in muscle from patients with autoimmune myositis. Although myositis autoantigens are expressed at very low levels in control muscle, they are found at high levels in myositis muscle. Furthermore, increased autoantigen expression correlates with differentiation state, such that myositis autoantigen expression is increased in cells that have features of regenerating muscle cells. Consistent with this, we found that cultured myoblasts express high levels of autoantigens, which are strikingly down-regulated as cells differentiate into myotubes in vitro. These data strongly implicate regenerating muscle cells rather than mature myotubes as the source of ongoing antigen supply in autoimmune myositis. Myositis autoantigen expression is also markedly increased in several cancers known to be associated with autoimmune myositis, but not in their related normal tissues, demonstrating that tumor cells and undifferentiated myoblasts are antigenically similar. We propose that in cancer-associated myositis, an autoimmune response directed against cancer cross-reacts with regenerating muscle cells, enabling a feed-forward loop of tissue damage and antigen selection. Regulating pathways of antigen expression may provide unrecognized therapeutic opportunities in autoimmune diseases.
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Mauvais, François-Xavier, Julien Diana, and Peter van Endert. "Beta cell antigens in type 1 diabetes: triggers in pathogenesis and therapeutic targets." F1000Research 5 (April 22, 2016): 728. http://dx.doi.org/10.12688/f1000research.7411.1.
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Research focusing on type 1 diabetes (T1D) autoantigens aims to explore our understanding of these beta cell proteins in order to design assays for monitoring the pathogenic autoimmune response, as well as safe and efficient therapies preventing or stopping it. In this review, we will discuss progress made in the last 5 years with respect to mechanistic understanding, diagnostic monitoring, and therapeutic modulation of the autoantigen-specific cellular immune response in T1D. Some technical progress in monitoring tools has been made; however, the potential of recent technologies for highly multiplexed exploration of human cellular immune responses remains to be exploited in T1D research, as it may be the key to the identification of surrogate markers of disease progression that are still wanting. Detailed analysis of autoantigen recognition by T cells suggests an important role of non-conventional antigen presentation and processing in beta cell-directed autoimmunity, but the impact of this in human T1D has been little explored. Finally, therapeutic administration of autoantigens to T1D patients has produced disappointing results. The application of novel modes of autoantigen administration, careful translation of mechanistic understanding obtained in preclinical studies and in vitro with human cells, and combination therapies including CD3 antibodies may help to make autoantigen-based immunotherapy for T1D a success story in the future.
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Rosen, A., L. Casciola-Rosen, and J. Ahearn. "Novel packages of viral and self-antigens are generated during apoptosis." Journal of Experimental Medicine 181, no. 4 (April 1, 1995): 1557–61. http://dx.doi.org/10.1084/jem.181.4.1557.
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Immune context is an essential determinant of the host response to potential autoantigens. The clustering of the autoantigens targeted in systemic lupus erythematosus within surface blebs of apoptotic cells generates high concentrations of autoantigen within discrete subcellular packages. We demonstrate here that when apoptosis is induced by Sindbis virus infection, viral antigens and autoantigens cocluster exclusively in small surface blebs of apoptotic cells. The surface of these blebs is rich in viral glycoproteins, and virions can be seen blebbing from their surface. We propose that these blebs of mixed foreign and self-origin define a novel immune context that may challenge self-tolerance.
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Johnson, K., A. Berger, T. Watkins, C. Cheadle, L. Casciola-Rosen, and S. M. Levine. "Gene set enrichment analysis to evaluate expression of autoantigens in lung cancer." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e22048-e22048. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e22048.
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e22048 Background: There is a well-established association between certain autoimmune diseases and the development of specific malignancies. It has been demonstrated that myositis-specific autoantigens are expressed at higher levels in tumors associated with myositis compared to normal tissue, suggesting that immune responses to antigens expressed in nascent tumors may contribute to the autoimmune process. Whether this observation is a general feature of autoantigen expression in tumor tissue, and whether the relative expression of these antigens is enriched in relation to the rest of the tumor transcriptome is currently unknown. Methods: Tumor tissue from ten lung cancer biopsies (adenocarcinoma (4), carcinoid (4), and squamous cell carcinoma (2)) and normal lung from the same patients were obtained. Total RNA was extracted and hybridized to Illumina Sentrix BeadChips. Hiearchical clustering was used to visualize the expression levels of 146 known autoantigens. Gene Set Enrichment Analysis was performed using 20 disease-specific autoantigen gene sets and 1892 gene sets from the Molecular Signatures Database. Protein levels of selected autoantigens were assessed by immunoblotting detergent tissue lysates. Results: Single-linkage hierarchical clustering analysis reveals groups of autoantigens that are differentially expressed between normal lung tissue, carcinoid tumors, and adenocarcinomas. Adenocarcinoma tumor samples were significantly enriched for myositis (nominal p-value <0.001, false discovery rate (FDR) q-value 0.009) and SLE autoantigens (p-value 0.004, FDR 0.029). Scleroderma autoantigens were enriched in carcinoid tumors (p-value 0.003, FDR 0.053). Increased protein expression of the autoantigens Mi-2 and topoisomerase-1 in carcinoid tumors was confirmed by immunoblotting. Conclusions: This study reveals that autoantigens targeted in several autoimmune diseases are both transcribed and expressed at high levels in malignancies known to associate with those disorders. While autoantigens comprise only a small fraction of the total transcriptome, they are disproportionately expressed in tumors known to associate with autoimmunity, supporting the hyporthesis that autoimmunity to these proteins may arise via nascent anti-tumor responses. No significant financial relationships to disclose.
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Kawahata, Kimito, Yoshikata Misaki, Yoshinori Komagata, Keigo Setoguchi, Shinji Tsunekawa, Yasuji Yoshikawa, Jun-ichi Miyazaki, and Kazuhiko Yamamoto. "Altered Expression Level of a Systemic Nuclear Autoantigen Determines the Fate of Immune Response to Self." Journal of Immunology 162, no. 11 (June 1, 1999): 6482–91. http://dx.doi.org/10.4049/jimmunol.162.11.6482.
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Abstract One of the hallmarks of systemic autoimmune diseases is immune responses to systemic nuclear autoantigens. We have examined the fate of the immune response against a nuclear autoantigen using human U1 small nuclear ribonucleoprotein-A protein (HuA) transgenic (Tg) mice by adoptive transfer of autoreactive lymphocytes. We obtained two Tg lines that have different expression levels of the transgene. After spleen cells from HuA-immunized wild-type mice were transferred to Tg mice and their non-Tg littermates, these recipients were injected with HuA/IFA to induce a recall memory response. HAB69, which expressed a lower amount of HuA, exhibited a vigorous increase in the autoantibody level and glomerulonephritis. Moreover, the autoreactivity spread to 70K autoantigen. Alternatively, in HAB64, which expressed a higher amount of HuA, the production of autoantibody was markedly suppressed. The immune response to HuA autoantigen was impaired as demonstrated in a both delayed-type hypersensitivity response and proliferation assay. This inhibition was Ag-specific and was mediated by T cells. These data suggest that the expression level of systemic autoantigens influences the outcome of the immune response to self.
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Okubo, M., K. Yamamoto, T. Kato, N. Matsuura, T. Nishimaki, R. Kasukawa, K. Ito, Y. Mizushima, and K. Nishioka. "Detection and epitope analysis of autoantigen-reactive T cells to the U1-small nuclear ribonucleoprotein A protein in autoimmune disease patients." Journal of Immunology 151, no. 2 (July 15, 1993): 1108–15. http://dx.doi.org/10.4049/jimmunol.151.2.1108.
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Abstract T cells that recognize autoantigens might play an important role in autoimmune diseases. To analyze "autoantigen-reactive T cell" in patients with an autoimmune disease, a human lymphocyte proliferation assay using soluble recombinant autoantigens has been conducted. PBMC from mixed connective tissue disease and SLE patients who possessed anti-U1-small nuclear ribonucleoprotein (snRNP) A autoantibodies responded to a recombinant U1-snRNP A protein. In contrast, PBMC from healthy subjects or autoimmune disease patients not possessing anti-U1-snRNP A autoantibodies did not show such responses. In addition, this proliferative response was inhibited by anti-CD4 mAb. Limiting dilution analyses revealed that the autoantigen-reactive T cells exist in relatively high frequency (1 of 4,065 to 1 of 23,256) in the mixed connective tissue disease patients. Moreover, by T cell epitope mapping, the T cell epitope area was found to be located in the C-terminus of the U1-snRNP A protein, overlapping the B cell epitope area that has been reported. These findings suggest the presence of autoantigen-reactive T cells in such patients, and when these T cells are activated, they may play a central role in the autoantibody generation.
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Yang, Xiao-Feng, Bernard Ng, Fan Yang, David P. Huston, Leif E. Peterson, and Hong Wang. "Increased Non-Canonical Splicing of Autoantigen Transcripts Provides the Structural Basis for Expression of Untolerized Epitopes." Blood 104, no. 11 (November 16, 2004): 3232. http://dx.doi.org/10.1182/blood.v104.11.3232.3232.
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Abstract Alternative splicing is important for increasing the complexity of the human proteome from a limited genome. Previous studies have shown that for some autoantigens, there is differential immunogenicity among alternatively spliced isoforms. In this report, we tested the hypothesis that alternative splicing is a common feature for transcripts of autologous proteins that are autoantigens. The corollary hypothesis tested was that non-autoantigen transcripts have a lower frequency of alternative splicing. We compared the extent of alternative splicing within 45 randomly selected self-proteins associated with autoimmune diseases to 9554 randomly selected proteins encoded in human genome using bioinformatics analysis. Isoform specific regions that result from alternative splicing were studied for their potential to be epitopes for antibodies or T cell epitopes. Our results demonstrate for the first time that alternative splicing occurred in 100% of the autoantigen transcripts. This is significantly higher that the approximately 42% rate of alternative splicing observed in 9554 randomly selected human gene transcripts. In addition, the majority of isoform-specific regions of these autoantigens encoded MHC restricted T cell antigen epitopes and autoantibody binding epitopes. Furthermore, 80% of the autoantigen transcripts underwent non-canonical alternative splicing, which is also significantly higher than the less than 1% rate in randomly selected gene transcripts. These studies suggest that non-canonical alternative splicing may be an important mechanism for the generation of untolerized epitopes that may lead to autoimmunity. Furthermore, the product of a transcript that does not undergo alternative splicing is unlikely to be a target antigen in autoimmunity.
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Casciola-Rosen, L. A., G. Anhalt, and A. Rosen. "Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes." Journal of Experimental Medicine 179, no. 4 (April 1, 1994): 1317–30. http://dx.doi.org/10.1084/jem.179.4.1317.
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Systemic lupus erythematosus is a multisystem autoimmune disease in which the autoantibody response targets a variety of autoantigens of diverse subcellular location. We show here that these autoantigens are clustered in two distinct populations of blebs at the surface of apoptotic cells. The population of smaller blebs contains fragmented endoplasmic reticulum (ER) and ribosomes, as well as the ribonucleoprotein, Ro. The larger blebs (apoptotic bodies) contain nucleosomal DNA, Ro, La, and the small nuclear ribonucleoproteins. These autoantigen clusters have in common their proximity to the ER and nuclear membranes, sites of increased generation of reactive oxygen species in apoptotic cells. Oxidative modification at these sites may be a mechanism that unites this diverse group of molecules together as autoantigens.
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Darrah, Erika, Antony Rosen, Jon T. Giles, and Felipe Andrade. "Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substrates: novel insights into autoantigen selection in rheumatoid arthritis." Annals of the Rheumatic Diseases 71, no. 1 (August 21, 2011): 92–98. http://dx.doi.org/10.1136/ard.2011.151712.
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ObjectiveTo define the relationship between autoantigen citrullination and different peptidylarginine deiminase (PAD) enzymes in rheumatoid arthritis (RA).MethodsCitrullinated autoantigens were identified by immunoblotting control and ionomycin-activated human primary neutrophil lysate with RA sera. Autoantigen identity and citrullination sites were defined by mass spectrometry. PAD isoenzyme expression in human neutrophils was determined by immunoblotting. PAD substrate specificity was addressed in HL-60 cell lysates co-incubated with human recombinant PAD2, PAD3 and PAD4.ResultsAlthough prominent protein citrullination is observed in ionomycin-activated neutrophils, RA sera only recognised a limited number of these citrullinated molecules. Among these, the authors identified that β and γ-actins are citrullinated on at least 10 arginine residues, generating a novel 47 kDa species that is frequently recognised by RA autoantibodies. Interestingly, the authors showed that the PAD enzymes expressed in human neutrophils (ie, PAD2, PAD3 and PAD4) have unique substrate specificities, independent of their subcellular distribution. Thus, only PAD2 was able to citrullinate native β/γ-actin, while histone H3 was only citrullinated by PAD4.ConclusionThese studies identified β and γ-actins as novel citrullinated autoantigens in RA, allowing enzyme specificity against intracellular substrates to be addressed. The studies provide evidence that PAD enzymes have the intrinsic capacity to select unique protein targets. The authors propose that unique PAD specificity may play a role in autoantigen selection in RA.
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Yaglova, N. V., and V. V. Yaglov. "The effect of long-term exposure to low doses of endocrine disruptor ddt on serum levels of thyroid protein autoantigenes and antithyroid autoantibodies." Biomeditsinskaya Khimiya 62, no. 1 (January 2016): 73–78. http://dx.doi.org/10.18097/pbmc20166201073.
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Changes in secretion of thyroid autoantigenes and production of antithyroid autoantibodies after long-term exposure to low doses of DDT were studied. Changes in serum levels of antithyroid peroxidase antibodies and thyroid peroxidase, attributed to disruption of thyroxine production by DDT were found. Long-term exposure of rats to low doses of DDT revealed no specific impact on serum autoantibodies to all thyroid autoantigenes studied. The increase of the ratio of autoantibody/autoantigen for thyroid peroxidase and thyroglobulin was rather small and thus could not be considered as a significant symptom of thyroid autoimmunity.
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Kojima, K., T. Berger, H. Lassmann, D. Hinze-Selch, Y. Zhang, J. Gehrmann, K. Reske, H. Wekerle, and C. Linington. "Experimental autoimmune panencephalitis and uveoretinitis transferred to the Lewis rat by T lymphocytes specific for the S100 beta molecule, a calcium binding protein of astroglia." Journal of Experimental Medicine 180, no. 3 (September 1, 1994): 817–29. http://dx.doi.org/10.1084/jem.180.3.817.
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The pathogenic potential of autoimmune T cell responses to nonmyelin autoantigens was investigated in the Lewis rat using the astrocyte-derived calcium binding protein S100 beta, as a model nonmyelin autoantigen. The Lewis rat mounts a vigorous RT1B1 (major histocompatibility complex class II) restricted autoimmune response to an immunodominant S100 beta epitope (amino acid residues 76-91). The adoptive transfer of S100 beta-specific T cell lines induced a severe inflammatory response in the nervous system, but only minimal neurological dysfunction in naive syngeneic recipients. The inability of S100 beta-specific T cell transfer to induce severe disease was associated with a decreased recruitment of ED1+ macrophages into the central nervous system (CNS) in comparison with that seen in severe experimental autoimmune encephalomyelitis (EAE) induced by the adoptive transfer of myelin basic protein (MBP)-specific T line cells. Moreover, unlike encephalitogenic MBP-specific T cell lines, S100 beta-specific T cell lines exhibited no cytotoxic activity in vitro. Histopathological analysis also revealed striking differences in the distribution of inflammatory lesions in MBP- and S100 beta-specific T cell-mediated disease. In contrast to the MBP paradigm, S100 beta-specific T cell transfer induces intense inflammation not only in the spinal cord, but throughout the entire CNS and also in the uvea and retina of the eye. In view of the distribution of lesions throughout the grey and white matter of the CNS we propose to term this new model experimental autoimmune panencephalomyelitis (EAP) to differentiate it from EAE. These experiments demonstrate for the first time that nonmyelin CNS autoantigens can initiate a pathogenic autoimmune T cell response, although the nature of the target autoantigen profoundly influences the clinical and histopathological characteristics of the resulting autoimmune disease. This is not simply a consequence of the distribution of the autoantigen, as both MBP and S100 beta are coexpressed in many areas of the CNS, but reflects differences in the capacity of different regions of the CNS to process and present specific autoantigens. This new model of T cell-mediated autoimmune CNS disease exhibits a number of similarities to multiple sclerosis (MS), such as its mild clinical course and the involvement of areas of the brain and eye, which are absent in myelin-mediated models of EAE. Nonmyelin autoantigens may therefore play an unexpectedly important role in the immunopathogenesis of inflammatory diseases of the CNS.
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Casciola-Rosen, Livia, Fredrick Wigley, and Antony Rosen. "Scleroderma Autoantigens Are Uniquely Fragmented by Metal-catalyzed Oxidation Reactions: Implications for Pathogenesis." Journal of Experimental Medicine 185, no. 1 (January 1, 1997): 71–80. http://dx.doi.org/10.1084/jem.185.1.71.
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The observation that revelation of immunocryptic epitopes in self antigens may initiate the autoimmune response has prompted the search for processes which induce novel fragmentation of autoantigens as potential initiators of autoimmunity. The reversible ischemia reperfusion which characterizes scleroderma has focused attention on reactive oxygen species as molecules which might induce autoantigen fragmentation. We demonstrate that several of the autoantigens targeted in diffuse scleroderma are uniquely susceptible to cleavage by reactive oxygen species, in a metal-dependent manner. Multiple features of the fragmentation reaction and its inhibition indicate that these autoantigens possess metal-binding sites, which focus metal-catalyzed oxidation reactions (and consequent fragmentation) to specific regions of the antigens. These data suggest that the autoantibody response in scleroderma is the immune marker of unique protein fragmentation, induced by ischemia reperfusion in the presence of appropriate metals, and focus attention on abnormal metal status as a potential pathogenic principle in this disease.
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Wang, Julia, and Michael Roehrl. "A unifying principle for autoantigenicity: Transforming self-molecules into autoantigens by association with dermatan sulfate polysaccharide (159.25)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 159.25. http://dx.doi.org/10.4049/jimmunol.188.supp.159.25.
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Abstract Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are chronic and disabling diseases that affect hundreds of millions of people worldwide. Despite great advances in biomedical research, etiology and pathogenesis of systemic autoimmune diseases have remained mysterious. In particular, the question of why and how a small, seemingly disparate subset of self-molecules become autoantigenic holds a key to understanding the basic principles of autoimmunity. Based on our recent data, we propose a unifying principle for autoantigenicity. We discovered that dermatan sulfate (DS) is an important functional link between cell turnover, autoantigens (autoAgs), autoAbs, autoreactive B-1a cells, and autoimmunity. By selectively interacting with autoAgs released from apoptotic/dead cells, DS can tether many autoAg molecules along its polymeric chain and convert singular self-molecules into multivalent polymer-like antigens, thus changing the “self”-nature of this molecule. Polymeric DS-autoAg complexes are potent stimulators of autoreactive B-1a cells that secrete autoAbs and present autoAgs to autoreactive T cells. This principle provides a mechanistic explanation for how only certain self-molecules derived from dead cells become autoantigenic. This principle also explains how microbial pathogens may convert self-molecules to autoantigens and provides clues to how environmental factors may contribute to autoimmunity and trigger autoimmune diseases.
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Daridon, Capucine, Christoph Loddenkemper, Simone Spieckermann, Anja A. Kühl, Abdulgabar Salama, Gerd R. Burmester, Peter E. Lipsky, and Thomas Dörner. "Splenic proliferative lymphoid nodules distinct from germinal centers are sites of autoantigen stimulation in immune thrombocytopenia." Blood 120, no. 25 (December 13, 2012): 5021–31. http://dx.doi.org/10.1182/blood-2012-04-424648.
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Abstract To understand more specific abnormalities of humoral autoimmunity, we studied 31 spleens from immune thrombocytopenia (ITP) patients and 36 control spleens. Detailed analysis identified at least 2 different splenic structures accommodating proliferating B cells, classic germinal centers (GCs), and proliferative lymphoid nodules (PLNs). PLNs were characterized by proliferating Ki67+ B cells close to follicular dendritic cells (FDCs) and lacked polarization into dark and light zones. As opposed to cells in GCs, proliferating B cells in PLN lacked expression of Bcl6. In both PLNs and GCs of ITP spleens, the density of T cells was significantly reduced. Both T follicular helper cells (TFH) and regulatory T cells were reduced within PLNs of ITP spleens suggesting a defect of tolerance related to a loss of T-cell control. Within PLNs of ITP, but not controls, abundant platelet glycoprotein (GP) IIb/IIIa autoantigens was found in IgM containing immune complexes tightly bound to FDCs and closely approximated to proliferating B cells. GPIV was found less often, but not in the same PLNs as GPIIb/IIIa. Autoantigens were not found in the GCs of ITP or controls indicating that PLNs are the sites of autoantigen stimulation in ITP potentially related to a lack of control by T cells and/or the present autoantigen.
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Halouani, Aymen, Hélène Michaux, Habib Jmii, Charlotte Trussart, Ahlem Chahbi, Henri Martens, Chantal Renard, et al. "Coxsackievirus B4 Transplacental Infection Severely Disturbs Central Tolerogenic Mechanisms in the Fetal Thymus." Microorganisms 9, no. 7 (July 19, 2021): 1537. http://dx.doi.org/10.3390/microorganisms9071537.
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Thymus plays a fundamental role in central tolerance establishment, especially during fetal life, through the generation of self-tolerant T cells. This process consists in T cells education by presenting them tissue-restricted autoantigens promiscuously expressed by thymic epithelial cells (TECs), thus preventing autoimmunity. Thymus infection by Coxsackievirus B (CV-B) during fetal life is supposed to disturb thymic functions and, hence, to be an inducing or accelerating factor in the genesis of autoimmunity. To further investigate this hypothesis, in our current study, we analyzed thymic expression of autoantigens, at the transcriptional and protein level, following in utero infection by CV-B4. mRNA expression levels of Igf2 and Myo7, major autoantigens of pancreas and heart, respectively, were analyzed in whole thymus and in enriched TECs together along with both transcription factors, Aire and Fezf2, involved in autoantigens expression in the thymus. Results show that in utero infection by CV-B4 induces a significant decrease in Igf2 and Myo7 expression at both mRNA and protein level in whole thymus and in enriched TECs as well. Moreover, a correlation between viral load and autoantigens expression can be observed in the whole thymus, indicating a direct effect of in utero infection by CV-B4 on autoantigens expression. Together, these results indicate that an in utero infection of the thymus by CV-B4 may interfere with self-tolerance establishment in TECs by decreasing autoantigen expression at both mRNA and protein level and thereby increase the risk of autoimmunity onset.
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Tian, Jide, Min Song, and Daniel L. Kaufman. "Designing Personalized Antigen-Specific Immunotherapies for Autoimmune Diseases—The Case for Using Ignored Target Cell Antigen Determinants." Cells 11, no. 7 (March 23, 2022): 1081. http://dx.doi.org/10.3390/cells11071081.
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We have proposed that antigen-specific immunotherapies (ASIs) for autoimmune diseases could be enhanced by administering target cell antigen epitopes (determinants) that are immunogenic but ignored by autoreactive T cells because these determinants may have large pools of naïve cognate T cells available for priming towards regulatory responses. Here, we identified an immunogenic preproinsulin determinant (PPIL4-20) that was ignored by autoimmune responses in type 1 diabetes (T1D)-prone NOD mice. The size of the PPIL4-20-specific splenic naive T cell pool gradually increased from 2–12 weeks in age and remained stable thereafter, while that of the major target determinant insulin B-chain9-23 decreased greatly after 12 weeks in age, presumably due to recruitment into the autoimmune response. In 15–16 week old mice, insulin B-chain9-23/alum immunization induced modest-low level of splenic T cell IL-10 and IL-4 responses, little or no spreading of these responses, and boosted IFNγ responses to itself and other autoantigens. In contrast, PPIL4-20/alum treatment induced robust IL-10 and IL-4 responses, which spread to other autoantigens and increased the frequency of splenic IL-10-secreting Treg and Tr-1-like cells, without boosting IFNγ responses to ß-cell autoantigens. In newly diabetic NOD mice, PPIL4-20, but not insulin B-chain9-23 administered intraperitoneally (with alum) or intradermally (as soluble antigen) supplemented with oral GABA induced long-term disease remission. We discuss the potential of personalized ASIs that are based on an individual’s naïve autoantigen-reactive T cell pools and the use of HLA-appropriate ignored autoantigen determinants to safely enhance the efficacy of ASIs.
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Iwama, Shintaro, Yoshihisa Sugimura, Atsushi Kiyota, Takuya Kato, Atsushi Enomoto, Haruyuki Suzuki, Naoko Iwata, et al. "Rabphilin-3A as a Targeted Autoantigen in Lymphocytic Infundibulo-neurohypophysitis." Journal of Clinical Endocrinology & Metabolism 100, no. 7 (July 1, 2015): E946—E954. http://dx.doi.org/10.1210/jc.2014-4209.
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Context: Central diabetes insipidus (CDI) can be caused by several diseases, but in about half of the patients the etiological diagnosis remains unknown. Lymphocytic infundibulo-neurohypophysitis (LINH) is an increasingly recognized entity among cases of idiopathic CDI; however, the differential diagnosis from other pituitary diseases including tumors can be difficult because of similar clinical and radiological manifestations. The definite diagnosis of LINH requires invasive pituitary biopsy. Objective: The study was designed to identify the autoantigen(s) in LINH and thus develop a diagnostic test based on serum autoantibodies. Design: Rat posterior pituitary lysate was immunoprecipitated with IgGs purified from the sera of patients with LINH or control subjects. The immunoprecipitates were subjected to liquid chromatography-tandem mass spectrometry to screen for pituitary autoantigens of LINH. Subsequently, we made recombinant proteins of candidate autoantigens and analyzed autoantibodies in serum by Western blotting. Results: Rabphilin-3A proved to be the most diagnostically useful autoantigen. Anti-rabphilin-3A antibodies were detected in 22 of the 29 (76%) patients (including 4 of the 4 biopsy-proven samples) with LINH and 2 of 18 (11.1%) patients with biopsy-proven lymphocytic adeno-hypophysitis. In contrast, these antibodies were absent in patients with biopsy-proven sellar/suprasellar masses without lymphocytic hypophysitis (n = 34), including 18 patients with CDI. Rabphilin-3A was expressed in posterior pituitary and hypothalamic vasopressin neurons but not anterior pituitary. Conclusions: These results suggest that rabphilin-3A is a major autoantigen in LINH. Autoantibodies to rabphilin-3A may serve as a biomarker for the diagnosis of LINH and be useful for the differential diagnosis in patients with CDI.
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Preuss, Klaus-Dieter, Natalie Fadle, Evi Regitz, and Michael Pfreundschuh. "Sumoylated HSP-90 Is a Frequent Autosomal-Inherited Target of Paraproteins in Monoclonal Gammopathies." Blood 124, no. 21 (December 6, 2014): 26. http://dx.doi.org/10.1182/blood.v124.21.26.26.
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Abstract Background Chronic antigenic stimulation might have a role in the pathogenesis of monoclonal gammopathy of unknown significance (MGUS) and multiple myeloma. We previously identified a group of 11 autoantigenic paraprotein targets (paratargs) of which paratarg-7 is the most frequent, found in ~15 % of all MGUS/MM/Waldenstrom patients. These paratarg autoantigens all have in common to be 1) recognised by patients paraprotein with an extreme high titer (>1:1011), 2) hyperphosphorylated in patients, and 3) their phosphorylation carrier state is autosomal-dominant inherited in patients families. The finding that all these paratargs were permanently hyperphosphorylated in patients in contrast to healthy controls brought up the assumption that abnormal posttranslational modification of autoantigens might be a frequent finding in those patients. Methods A RZPD macroarray representing more than 30.000 different human proteins was subjected to in-vitro posttranslational modification using sumoylation-competent recombinant enzymes followed by screening with paraprotein-containing sera at high dilution (1:107). Immunopositive signals were identified and characterized by DNA sequencing, SDS-PAGE, isoelectric focusing, western blotting and ELISA. Findings Twenty-seven of 226 (11.9%) paraproteins from European, 9/80 (11.2%) from African-American and 9/176 (5.1%) from Japanese patients reacted specifically with the sumoylated heat shock protein-90β isoform-α (HSP90-SUMO). No reactivity was detected in >800 controls. All patients with HSP90-SUMO-binding paraproteins carried HSP90-SUMO. HSP90-SUMO carrier state is autosomal-dominantly inherited and was sown to be caused by the inability of SENP2 to desumoylate HSP90-SUMO. Five of 550 (0.9%) European, 2/100 (2%) African-American and 2/178 (0.8%) Japanese controls carried HSP90-SUMO, resulting in odds ratios of 14.8, 6.2 and 7.4, respectively, of healthy carriers for MGUS/MM/WM. Only, but all MGUS/MM/WM patients who were HSP90-SUMO carriers had HSP90-SUMO-specific paraproteins suggesting that sumoylated HSP-90 is involved in the pathogenesis of MGUS/MM/WM by chronic antigenic stimulation. Demonstration of HSP90-SUMO carriership identifies family members of HSP90-SUMO patients at risk. Interpretation A significant proportion of MGUS/MM/WM are associated with a dominant inheritance of posttranslationally modified autoantigens as shown for members of the paratarg autoantigen family and for HSP90-SUMO, enabling family members at increased risk for MGUS/MMWM to be identified by simple analysis of their peripheral blood. That only patients with MGUS/MM/WM who are carriers of such modified autoantigens have target-specific paraproteins suggests that the posttranslational modification induces auto-immunity and is involved in the pathogenesis of MGUS/MM/WM, for example, by chronic antigenic stimulation. Supported by Deutsche Forschungsgemeinschaft DFG, Deutsche José Carreras Leukämie Stiftung, Wilhelm-Sander-Stiftung, Deutsche Krebshilfe e.V. Disclosures No relevant conflicts of interest to declare.
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Smith, Casey Jo Anne, Sophie Bensing, Christine Burns, Phillip J. Robinson, Anna A. Kasperlik-Zaluska, Rodney J. Scott, Olle Kämpe, and Patricia A. Crock. "Identification of TPIT and other novel autoantigens in lymphocytic hypophysitis; immunoscreening of a pituitary cDNA library and development of immunoprecipitation assays." European Journal of Endocrinology 166, no. 3 (March 2012): 391–98. http://dx.doi.org/10.1530/eje-11-1015.
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BackgroundLymphocytic hypophysitis is an organ-specific autoimmune disease of the pituitary gland. A specific and sensitive serological test currently does not exist to aid in the diagnosis.ObjectiveTo identify target autoantigens in lymphocytic hypophysitis and develop a diagnostic assay for these proteins.Design/methodsA pituitary cDNA expression library was immunoscreened using sera from four patients with lymphocytic hypophysitis. Relevant cDNA clones from screening, along with previously identified autoantigens pituitary gland-specific factor 1a and 2 (PGSF1a and PGSF2) and neuron-specific enolase (NSE) were tested in anin vitrotranscription and translation immunoprecipitation assay. The corticotroph-specific transcription factor, TPIT, was investigated separately as a candidate autoantigen.ResultsSignificantly positive autoantibody reactivity against TPIT was found in 9/86 hypophysitis patients vs 1/90 controls (P=0.018). The reactivity against TPIT was not specific for lymphocytic hypophysitis with autoantibodies detectable in the sera from patients with other autoimmune endocrine diseases. Autoantibodies were also detected against chromodomain-helicase-DNA binding protein 8, presynaptic cytomatrix protein (piccolo), Ca2+-dependent secretion activator, PGSF2 and NSE in serum samples from patients with lymphocytic hypophysitis, but at a frequency that did not differ from healthy controls. Importantly, 8/86 patients with lymphocytic hypophysitis had autoantibodies against any two autoantigens in comparison with 0/90 controls (P=0.0093).ConclusionsTPIT, a corticotroph-specific transcription factor, was identified as a target autoantigen in 10.5% of patients with lymphocytic hypophysitis. Further autoantigens related to vesicle processing were also identified as potential autoantigens with different immunoreactivity patterns in patients and controls.
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Van de Water, J., D. Fregeau, P. Davis, A. Ansari, D. Danner, P. Leung, R. Coppel, and M. E. Gershwin. "Autoantibodies of primary biliary cirrhosis recognize dihydrolipoamide acetyltransferase and inhibit enzyme function." Journal of Immunology 141, no. 7 (October 1, 1988): 2321–24. http://dx.doi.org/10.4049/jimmunol.141.7.2321.
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Abstract Autoantibodies against mitochondria occur in the sera of patients with primary biliary cirrhosis (PBC) with characteristic reactivity to an inner membrane protein of approximately 74 kDa. To precisely define these autoantigens, we recently cloned and sequenced a rat liver cDNA (pRMIT) that encodes for all of the epitopes recognized by Ig to the 74-kDa autoantigen. In the present study we have used this recombinant probe as a tool, in addition to purified enzymes, to demonstrate by immunoblotting that the 74-kDa mitochondrial autoantigen is dihydrolipoamide acetyltransferase (EC 2.3.1.12), the core protein of the pyruvate dehydrogenase complex. Furthermore, and of particular interest, inhibition of pyruvate dehydrogenase enzyme activity was demonstrated after incubation with sera from patients with PBC but not from normal volunteers or patients with chronic active hepatitis. Such inhibition was abrogated by absorption of the PBC sera with an expressing subclone of pRMIT, designated pRMIT-603. Identification of dihydrolipoamide acetyltransferase as the target of autoimmunity in PBC provides a reagent that can be used to determine mechanisms by which this molecule is recognized. It will allow study of whether autoimmune reactivity, at the humoral or T cell level, is the basis for the pathogenesis of PBC. Additionally, such data present evidence of functional inhibition of a critical metabolic enzyme. Dihydrolipoamide acetyltransferase is well-known to mitochondrial biochemistry and, similar to identified autoantigens in other autoimmune diseases, is highly conserved in evolution.
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Tian, Jide, and Daniel L. Kaufman. "Attenuation of Inducible Th2 Immunity with Autoimmune Disease Progression." Journal of Immunology 161, no. 10 (November 15, 1998): 5399–403. http://dx.doi.org/10.4049/jimmunol.161.10.5399.
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Abstract Autoantigen-based immunotherapeutics have been shown to activate regulatory responses capable of inhibiting T cell-mediated autoimmune disease in animal models. However, their efficacy generally declines, as treatment occurs later in the disease process, and their mechanism of action is a matter of intense debate. Here, we report that the early administration of β cell autoantigens (βCAAs) to nonobese diabetic (NOD) mice broadly diverts the natural development of potentially pathogenic Th1-biased autoimmune responses toward the Th2 phenotype through Th2 spreading. With disease progression, there was a steady decline in the ability of βCAA treatment to promote Th2-type cellular and humoral autoimmunity. Late in the disease process, some βCAAs were still able to induce Th2 responses and Th2 spreading (although to a much lesser extent), while other autoantigens were not. This attenuation of inducible Th2 immunity with disease progression is likely to reflect a reduction in the availability of uncommitted autoantigen-reactive precursor T cells. These findings suggest that there are inherent differences in the frequency of βCAA-reactive T cells and that, in advanced stages of autoimmune disease, regulatory responses may be best elicited with target tissue Ags against which large uncommitted T cell pools are still available. Since individuals presenting the first signs of autoimmune disease are likely to already have an advanced disease process, these findings may be useful for the rational design of Ag-based immunotherapeutics.
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Thurner, Lorenz, Klaus-Dieter Preuss, Moritz Bewarder, Maria Kemele, Natalie Fadle, Evi Regitz, Sarah Altmeyer, et al. "Hyper-N-glycosylated SAMD14 and neurabin-I as driver autoantigens of primary central nervous system lymphoma." Blood 132, no. 26 (December 27, 2018): 2744–53. http://dx.doi.org/10.1182/blood-2018-03-836932.
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Abstract To address the role of chronic antigenic stimulation in primary central nervous system lymphoma (PCNSL), we searched for autoantigens and identified sterile α-motif domain containing protein 14 (SAMD14) and neural tissue-specific F-actin binding protein I (neurabin-I) as autoantigenic targets of the B-cell receptors (BCRs) from 8/12 PCNSLs. In the respective cases, SAMD14 and neurabin-I were atypically hyper-N-glycosylated (SAMD14 at ASN339 and neurabin-I at ASN1277), explaining their autoimmunogenicity. SAMD14 and neurabin-I induced BCR pathway activation and proliferation of aggressive lymphoma cell lines transfected with SAMD14- and neurabin-I-reactive BCRs. Moreover, the BCR binding epitope of neurabin-I conjugated to truncated Pseudomonas exotoxin-killed lymphoma cells expressing the respective BCRs. These results support the role of chronic antigenic stimulation by posttranslationally modified central nervous system (CNS) driver autoantigens in the pathogenesis of PCNSL, serve as an explanation for their CNS tropism, and provide the basis for a novel specific treatment approach.
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Bachmann, Michael P., Tabea Bartsch, Claudia C. Bippes, Dominik Bachmann, Edinson Puentes-Cala, Jennifer Bachmann, Holger Bartsch, et al. "T Cell Mediated Conversion of a Non-Anti-La Reactive B Cell to an Autoreactive Anti-La B Cell by Somatic Hypermutation." International Journal of Molecular Sciences 22, no. 3 (January 26, 2021): 1198. http://dx.doi.org/10.3390/ijms22031198.
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Since the first description of nuclear autoantigens in the late 1960s and early 1970s, researchers, including ourselves, have found it difficult to establish monoclonal antibodies (mabs) against nuclear antigens, including the La/SS-B (Sjögrens’ syndrome associated antigen B) autoantigen. To date, only a few anti-La mabs have been derived by conventional hybridoma technology; however, those anti-La mabs were not bona fide autoantibodies as they recognize either human La specific, cryptic, or post-translationally modified epitopes which are not accessible on native mouse La protein. Herein, we present a series of novel murine anti-La mabs including truly autoreactive ones. These mabs were elicited from a human La transgenic animal through adoptive transfer of T cells from non-transgenic mice immunized with human La antigen. Detailed epitope and paratope analyses experimentally confirm the hypothesis that somatic hypermutations that occur during T cell dependent maturation can lead to autoreactivity to the nuclear La/SS-B autoantigen.
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Yang, Fan, Yan Yan, Zeyu Xiong, Irene H. Chen, Hong Wang, and Xiao-Feng Yang. "Novel Model of Stimulation-Responsive Splicing for Generation of Immunogenic Isoforms of Tumor Antigens and Autoantigens." Blood 108, no. 11 (November 16, 2006): 5188. http://dx.doi.org/10.1182/blood.v108.11.5188.5188.
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Abstract Alternative splicing is a process that removes introns and alters exons to generate multiple isoforms from a single pre-mRNA transcript. Alternative splicing is the major mechanism by which a small number of human genes (6 × 104) can encode the larger complexity of the human proteome (1 × 106 proteins). Previously we demonstrated that alternative splicing of apoptosis-regulatory protein transcripts regulates immune responses by modulating lymphocyte survival (Immunity, 1997; Mol. Immunol. 2002; J Exp Med, 2002; Oncogene 2005; Biochem J, 2005). To examine the hypothesis that alternative splicing plays a role in selection of nonmutated self-protein isoforms for tumor antigens and autoantigens, recently, we showed that alternative splicing is a major mechanism in regulation of the immunogenicity of tumor antigen CML66 (J. Immunol. 2004). In addition, we found that alternative splicing occurs in 100% of the autoantigen transcripts. This is significantly higher than the approximately 42% rate of alternative splicing observed in the 10,000 randomly selected human gene transcripts (p<0.001) [J. Allergy Clin. Immunol., 2004 (cover article)]. Here, we report that essential alternative splicing factor ASF/SF2 expression in samples from patients with chronic inflammation is lower than that of the healthy controls (p<0.05). In addition, TNF-a significantly downregulates ASF/SF2 expression (7 folds) in cultured cells in comparison to the expression variations of b-actin control. These findings demonstrate that ASF/SF2, presumably affecting splicing of self-antigen transcripts, is downregulated in autoimmune inflammatory disease potentially via a TNF-a-mediated pathway. Collectively, we propose for the first time a novel model of “stimulation-responsive splicing”, which emphasizes that stimulation-responsive splicing plays a critical role in selection of nonmutated self-protein isoforms to become tumor antigens and autoantigens (Clin. Immunol. Invited Review, in press, 2006). The new model for the definition of immunogenic isoforms of tumor antigens and autoantigens is significant in facilitating the development of: immunogenic antigen isoform microarrays for disease diagnosis and prognosis; autoantigen-tolerizing therapy and splicing-redirection therapy for autoimmune diseases; and immunogenic antigen isoforms-based immunotherapy for tumors.
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Gupta, Shivai, Danmeng Li, David A. Ostrov, and Cuong Q. Nguyen. "Epitope Mapping of Pathogenic Autoantigens on Sjögren’s Syndrome-Susceptible Human Leukocyte Antigens Using In Silico Techniques." Journal of Clinical Medicine 11, no. 6 (March 18, 2022): 1690. http://dx.doi.org/10.3390/jcm11061690.
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Sjögren’s syndrome (SjS) is characterized by lymphocytic infiltration and the dysfunction of the salivary and lacrimal glands. The autoimmune response is driven by the effector T cells and their cytokines. The activation of the effector helper T cells is mediated by autoantigen presentation by human leukocyte antigen (HLA) class II molecules of antigen-presenting cells. Studies using familial aggregation, animal models, and genome-wide association demonstrate a significant genetic correlation between specific risk HLAs and SjS. One of the key HLA alleles is HLA-DRB1*0301; it is one of the most influential associations with primary SjS, having the highest odds ratio and occurrence across different ethnic groups. The specific autoantigens attributed to SjS remain elusive, especially the specific antigenic epitopes presented by HLA-DRB1*0301. This study applied a high throughput in silico mapping technique to identify antigenic epitopes of known SjS autoantigens presented by high-risk HLAs. Furthermore, we identified specific binding HLA-DRB1*0301 epitopes using structural modeling tools such as Immune Epitope Database and Analysis Resource IEDB, AutoDock Vina, and COOT. By deciphering the critical epitopes of autoantigens presented by HLA-DRB1*0301, we gain a better understanding of the origin of the antigens, determine the T cell receptor function, learn the mechanism of disease progression, and develop therapeutic applications.
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Wu, Tianfu, Yulin Yuan, and Stephen K. Tyring. "Discovery of Autoantibodies Associated with Psoriatic Arthritis." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 179.2. http://dx.doi.org/10.4049/jimmunol.202.supp.179.2.
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Abstract Objective The autoimmune etiology in psoriasis is not very clear, we aim to identify autoantigens and autoantibodies in psoriasis, which may shed light on the molecular and cellular basis of the pathogenesis of psoriasis and psoriatic arthritis. Methods In this study, we developed an autoantigen array system harboring a variety of antigens including typical autoantigens in rheumatic diseases as well as skin antigens, inflammatory mediators and putative autoantigens in psoriasis. Sera from psoriasis patients (N = 73) were used to interrogate antigens on the array. Individual ELISA was also used in validation studies. Results We found several serum autoantibodies were elevated in psoriasis patients compared to healthy controls; particularly, IgG autoantibodies against two novel antigens, LL37 and ADAMTSL5, were significantly increased in the psoriasis patients compared to healthy controls. Importantly, serum levels of IgG autoantibodies against LL37 and ADAMTSL5 were correlated with Psoriasis Area and Severity Index (PASI), and reflected disease progression in longitudinally collected samples from psoriasis patients. Importantly, we found both anti-ADAMTSL5 and anti-LL-37 autoantibodies were significantly elevated in psoriatic arthritis (PsA) compared to Non-PsA, suggesting that these molecules may be involved in the pathogenesis of psoriatic arthritis. Conclusion Our findings suggest that these autoantibodies may be useful biomarkers and indicative of therapeutic targets of psoriasis and psoriatic arthritis.
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Jasinski, J. M., and G. S. Eisenbarth. "Insulin as a Primary Autoantigen for Type 1A Diabetes." Clinical and Developmental Immunology 12, no. 3 (2005): 181–86. http://dx.doi.org/10.1080/17402520500078204.
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Type 1A diabetes mellitus is caused by specific and progressive autoimmune destruction of the beta cells in the islets of Langerhans whereas the other cell types in the islet (alpha, delta, and PP) are spared. The autoantigens of Type 1A diabetes may be divided into subgroups based on their tissue distributions: Beta-cell-specific antigens like insulin, insulin derivatives, and IGRP (Islet-specific Glucose-6-phosphatase catalytic subunit Related Peptide); neurendocrine antigens such as carboxypeptidase H, insulinoma-associated antigen (IA-2), glutamic acid decarboxylase (GAD65), and carboxypeptidase E; and those expressed ubiquitously like heat shock protein 60 (a putative autoantigen for type 1 diabetes). This review will focus specifically on insulin as a primary autoantigen, an essentia l target for disease, in type 1A diabetes mellitus. In particular, immunization with insulin peptide B:9-23 can be used to induce insulin autoantibodies and diabetes in animal models or used to prevent diabetes. Genetic manipulation of the insulin 1 and 2 genes reciprocally alters development of diabetes in the NOD mouse, and insulin gene polymorphisms are important determinants of childhood diabetes. We are pursuing the hypothesis that insulin is a primary autoantigen for type 1 diabetes, and thus the pathogenesis of the disease relates to specific recognition of one or more peptides.
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Glutting, JP, Pedro A. Reche, and Masha Fridkis-Hareli. "Bioinformatics-Based Predictions of Peptide Binding to Disease-Associated HLA Proteins Suggest Explanation for Shared Autoimmunity." Immunology and Immunogenetics Insights 3 (January 2011): III.S6558. http://dx.doi.org/10.4137/iii.s6558.
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Aim This study was designed to examine the immunogenetic basis for shared autoimmunity, resulting in autoantigen presentation that leads to the production of two or more disease-specific autoantibodies. Methods A bioinformatics approach based on peptide binding predictions to disease-associated HLA determinants has been developed and tested here using 11 disease associations between autoimmune systemic and mucocutaneous blistering disorders. Various HLAs associated with antigens within a given “disease model” (set of HLA class II and protein sequences known to be associated with a specific autoimmune disease) were tested and ranked against the antigenic proteins, first with proteins they are known to associate with and then with proteins known to be implicated in a second disease model. In every case binding predictions were compared for different proteins binding to the same HLA. Subsequently, disease-related autoantigens have been tested for their binding affinity against each disease-specific HLA class II protein. Results For a single HLA haplotype, several binders have been generated from a related autoantigen with the variable binding score. In most cases, the binding score corresponding to the interactions between the autoantigen-derived epitope and the HLA associated with one disease was similar or lower than the interactions between the epitope from proteins associated with the second disease and the same HLA. Notably, there was no compelling promiscuity in peptide binding to each of the HLA molecules, in spite of the promiscuous nature of HLA class II binding. Conclusions The data suggest that, in susceptible individuals, shared autoimmunity might be initiated by two types of HLA/peptide interaction; first between an autoantigen-derived epitope and its disease-associated HLA molecules, and second, between a different peptide of the same autoantigen and HLA proteins specific for the second disease.
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Betteridge, Zoe, Hector Chinoy, Jiri Vencovsky, John Winer, Kiran Putchakayala, Pauline Ho, Ingrid Lundberg, Katalin Danko, Robert Cooper, and Neil McHugh. "Identification of a novel autoantigen eukaryotic initiation factor 3 associated with polymyositis." Rheumatology 59, no. 5 (September 17, 2019): 1026–30. http://dx.doi.org/10.1093/rheumatology/kez406.
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Abstract Objectives To describe the prevalence and clinical associations of autoantibodies to a novel autoantigen, eukaryotic initiation factor 3 (eIF3), detected in idiopathic inflammatory myositis. Methods Sera or plasma from 678 PM patients were analysed for autoantigen specificity by radio-labelled protein immunoprecipitation (IPP). Samples immunoprecipitating the same novel autoantigens were further analysed by indirect immunofluorescence and IPP using pre-depleted cell extracts. The autoantigen was identified through a combination of IPP and MALDI-TOF mass spectrometry, and confirmed using commercial antibodies and IPP-western blots. Additional samples from patients with DM (668), DM-overlap (80), PM-overlap (191), systemic sclerosis (150), systemic lupus erythematosus (200), Sjogren’s syndrome (40), rheumatoid arthritis (50) and healthy controls (150) were serotyped by IPP as disease or healthy controls. Results IPP revealed a novel pattern in three PM patients (0.44%) that was not found in disease-specific or healthy control sera. Indirect immunofluorescence demonstrated a fine cytoplasmic speckled pattern for all positive patients. Mass spectrometry analysis of the protein complex identified the target autoantigen as eIF3, a cytoplasmic complex with a role in the initiation of translation. Findings were confirmed by IPP-Western blotting. The three anti-eIF3-positive patients had no history of malignancy or interstitial lung disease, and had a favourable response to treatment. Conclusion We report a novel autoantibody in 0.44% of PM patients directed against a cytoplasmic complex of proteins identified as eIF3. Although our findings need further confirmation, anti-eIF3 appears to correlate with a good prognosis and a favourable response to treatment.
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Meng, Zhefeng, Tohti Amet, Daniel Byrd, Jie Lan, and Qigui Yu. "Antiretrovial therapy changes circulating autoantibody profiles in patients chronically infected with human immunodeficiency virus 1 (P6197)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 118.22. http://dx.doi.org/10.4049/jimmunol.190.supp.118.22.
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Abstract The emergence of severe liver injury in some patients chronically infected with human immunodeficiency virus 1 (HIV-1) during antiretroviral therapy (ART) presents a diagnostic dilemma. It is unclear whether liver injury is a direct result of drug side effects or a consequence of HIV-1-associated autoimmune responses. To investigate the effect of ART on the pattern of autoimmune responses in HIV-1-infected patients, we used a slide-based autoantigen array to profile circulating autoantibodies against a total of 84 autoantigens in HIV-1-infected patients on ART (n=16) and ART-naïve (n=14). Serum samples from 30 uninfected individuals were also included to obtain autoantibody background information. Compared to uninfected individuals, ART-naïve patients had IgG and IgM autoantibodies increased 2 folds or greater to 13 and 8 different autoantigens, respectively. Strikingly, ART profoundly suppressed autoimmune responses in HIV-1-infected patients, as only IgG autoantibodies against 2 autoantigens increased 2 folds or greater than that in uninfected subjects, and no IgM autoantibodies were increased. In addition, the titers of these 2 IgG autoantibodies in patients on ART were significantly lower than that found in ART-naïve patients. Conclusion: HIV-1 infection enhances circulating autoantibodies that can be significantly suppresed by ART, and liver damage in patients on ART is most likely due to drug side effects rather than autoimmune responses.
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Yang, Tao, Hongtao Zeng, Jian Zhang, Curtis T. Okamoto, Dwight W. Warren, Richard L. Wood, Michael Bachmann, and Austin K. Mircheff. "MHC class II molecules, cathepsins, and La/SSB proteins in lacrimal acinar cell endomembranes." American Journal of Physiology-Cell Physiology 277, no. 5 (November 1, 1999): C994—C1007. http://dx.doi.org/10.1152/ajpcell.1999.277.5.c994.
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Sjögren's syndrome is a chronic autoimmune disease affecting the lacrimal glands and other epithelia. It has been suggested that acinar cells of the lacrimal glands provoke local autoimmune responses, leading to Sjögren's syndrome when they begin expressing major histocompatibility complex (MHC) class II molecules. We used isopycnic centrifugation and phase partitioning to resolve compartments that participate in traffic between the basolateral membranes and the endomembrane system to test the hypothesis that MHC class II molecules enter compartments that contain potential autoantigens, i.e., La/SSB, and enzymes capable of proteolytically processing autoantigen, i.e., cathepsins B and D. A series of compartments identified as secretory vesicle membranes, prelysosomes, and microdomains of the trans-Golgi network involved in traffic to the basolateral membrane, to the secretory vesicles, and to the prelysosomes were all prominent loci of MHC class II molecules, La/SSB, and cathepsins B and D. These observations support the thesis that lacrimal gland acinar cells that have been induced to express MHC class II molecules function as autoantigen processing and presenting cells.
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Kurts, Christian, Isis Ludwig-Portugall, Emma E. Hamilton-Williams, Catherine Gottschalk, and Janine Gotot. "Antigen-specific suppression of non-lymphoid tissue auto-antibody production by CD25+ FoxP3+ regulatory T cells (89.22)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 89.22. http://dx.doi.org/10.4049/jimmunol.182.supp.89.22.
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Abstract To study how peripheral B cell tolerance against non-lymphoid tissue autoantigens is maintained, we generated transgenic RIP-OVA/HEL (ROH) mice expressing the model antigens, OVA and HEL, in pancreatic islet beta cells. Immunization with OVA/HEL/aluminiumhydroxide induced IgG auto-Ab titers that were much lower than in non-transgenic controls. Depletion of CD25+ cells during immunization completely restored auto-Ab production but did not affect titers against foreign antigens, indicating regulatory tolerance. Purified CD25+ FoxP3+ CD4+ T cells from ROH mice transferred B cell suppression into non-transgenic recipients. CD25+ cells also suppressed naïve transgenic HEL-specific B cells adoptively transferred into ROH mice, confirming peripheral B cell tolerance. B cell suppression mechanistically involved inhibiting the proliferation of autoreactive B cells, inducing their apoptosis after immunization with autoantigen, suppressing antibody secretion per B cell and downregulating IgMa and MHC II B cell surface expression in the autoantigen-draining lymph node. We conclude that CD25+ FoxP3+ regulatory T cells were necessary and sufficient to specifically suppress auto-Ab production against pancreatic islet cell antigens.
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Radic, Marko, and Sylviane Muller. "Epigenetics of Autoantigens: New Opportunities for Therapy of Autoimmune Diseases." Genetics & Epigenetics 5 (January 2013): GEG.S12144. http://dx.doi.org/10.4137/geg.s12144.
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The field of epigenetics requires that traditional divisions between scientific disciplines give way to cross-fertilization of concepts and ideas from different areas of investigation. Such is the case with research in autoimmunity. Recent discoveries of stimuli that induce autoimmunity reveal that epigenetic marks of autoantigens are recognized by autoreactive B and T cell receptors. Thus, insights into the initiation of autoimmunity, its prevention and therapy will arise from understanding the biochemistry, cell biology and microbiology of autoantigen epigenetics. Here, we highlight potential benefits from the inhibition of a histone modifying enzyme and the administration of a phosphorylated, spliceosome-derived peptide, in the treatment of autoimmunity.
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Andrews, J., L. Hang, A. N. Theofilopoulos, and F. J. Dixon. "Lack of relationship between serum gp70 levels and the severity of systemic lupus erythematosus in MRL/l mice." Journal of Experimental Medicine 163, no. 2 (February 1, 1986): 458–62. http://dx.doi.org/10.1084/jem.163.2.458.
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In the MRL/l mouse, gp70 apparently plays a role as an autoantigen in the development of SLE. However, while gp70 may be an important pathogenetic element, it is not essential to MRL SLE, since elimination of most of the serum gp70 and virtually all of the immune complex gp70 from MRL/l-low gp70 congenic lines had no observable effect on the course or nature of the disease. Thus, while gp70 in the MRL/l mouse appears to be a convenient autoantigenic target when present in significant levels, in its absence the host appears capable of directing its aberrant immunologic responsiveness elsewhere with undiminished pathogenicity.
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Fernando, Roshini, Andrew Vonberg, Stephen J. Atkins, Susan Pietropaolo, Massimo Pietropaolo, and Terry J. Smith. "Human Fibrocytes Express Multiple Antigens Associated With Autoimmune Endocrine Diseases." Journal of Clinical Endocrinology & Metabolism 99, no. 5 (May 1, 2014): E796—E803. http://dx.doi.org/10.1210/jc.2013-3072.
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Context: Factors common to multiple autoimmune diseases have been sought vigorously. Graves' disease (GD) and type 1 diabetes mellitus (T1DM) involve end-organ remodeling. Fibrocytes participate in inflammatory diseases and were recently shown to express thyroid-specific proteins such as the thyrotropin receptor and thyroglobulin. Objective: The objective of the study was to determine whether a broader repertoire of autoantigen expression, such as proteins associated with T1DM, can be ascribed to fibrocytes. Design, Setting, and Participants: Fibrocytes and fibroblasts were collected and analyzed from healthy individuals and those with autoimmune diseases in an academic clinical practice. Main Outcome Measures: Real-time PCR, Western blot analysis, gene promoter analysis, cell transfections, and flow cytometric cell sorting were performed. Results: Islet cell antigen ICA512 (IA-2) and islet cell autoantigen of 69 kDa (ICA69), two islet-specific proteins implicated in T1DM, are expressed by fibrocytes from healthy donors and those with T1DM, GD, and multiple sclerosis. Both transcripts are detected by PCR, the proteins are resolved on Western blots, and both gene promoters are active in fibrocytes. Levels of ICA69 are substantially higher than those of IA-2 in fibrocytes. ICA69 localizes to CD34+ GD orbital fibroblasts putatively derived from fibrocytes, whereas higher levels of IA-2 are found in CD34− fibroblasts. Conclusions: In addition to autoantigens implicated in thyroid autoimmunity, fibrocytes and derivative fibroblasts express multiple autoantigens associated with T1DM. This expression results from active gene promoters and abundant steady-state mRNA encoding ICA69 and IA-2. These latest findings demonstrate that fibrocytes express antigens relevant to multiple forms of endocrine autoimmunity. They suggest the potential for these cells playing a direct role in immune reactivity directed at the thyroid and pancreatic islets.
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Voskuhl, R. R., E. D. Robinson, B. M. Segal, L. Tranquill, K. Camphausen, P. S. Albert, J. R. Richert, and H. F. McFarland. "HLA restriction and TCR usage of T lymphocytes specific for a novel candidate autoantigen, X2 MBP, in multiple sclerosis." Journal of Immunology 153, no. 10 (November 15, 1994): 4834–44. http://dx.doi.org/10.4049/jimmunol.153.10.4834.
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Abstract Previous investigations of the major 18.5-kDa isoform of myelin basic protein (MBP) as a target autoantigen in multiple sclerosis (MS) have failed to identify an epitope uniformly recognized with higher frequency in MS patients compared with controls. Because remyelination has been observed in MS plaques, we were prompted to investigate T cells specific for myelin protein isoforms with up-regulated expression during remyelination. We have recently described such T cells that recognize the exon 2-encoded region of MBP (X2 MBP), a sequence included in the 21.5- and 20.2-kDa isoforms of MBP. These cells were shown to be CD4+, HLA class II restricted, and cytolytic. In members of one multiplex MS family, X2 MBP-specific T lymphocytes were as prevalent as T cells specific for immunodominant regions within the major 18.5-kDa isoform of MBP. The present study characterizes X2 MBP-specific T cell responses in additional multiplex MS family members as well as in heterogeneous (non-familial) MS patients and in healthy controls. The frequencies of X2 MBP-specific T cells in each of the affected family members from two of three MS families were significantly increased as compared with both the heterogeneous MS group and the healthy control group. Also, X2 MBP-specific T cell lines from affected family members were primarily restricted to molecules encoded by the DR2/DQw1 allele. Although TCR usage was generally heterogeneous, there was evidence of intraindividual sequence identity. These data suggest that: 1) Myelin proteins with up-regulated expression during the course of disease should be considered as candidate autoantigens in MS. 2) The functional basis for the association of DR2/DQw1 inheritance with MS susceptibility may be related to presentation of autoantigens by this allele. 3) TCR therapy will need to be individually tailored to target the most prevalent autoantigen-specific response.
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Alderuccio, F., B. H. Toh, S. S. Tan, P. A. Gleeson, and I. R. van Driel. "An autoimmune disease with multiple molecular targets abrogated by the transgenic expression of a single autoantigen in the thymus." Journal of Experimental Medicine 178, no. 2 (August 1, 1993): 419–26. http://dx.doi.org/10.1084/jem.178.2.419.
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Many autoimmune diseases are characterized by autoantibody reactivities to multiple cellular antigens. Autoantigens are commonly defined as targets of the autoimmune B cell response, but the role, if any, of these autoantigens in T cell-mediated autoimmune diseases is generally unknown. Murine experimental autoimmune gastritis is a CD4+ T cell-mediated organ-specific autoimmune disease induced by neonatal thymectomy of BALB/c mice. The murine disease is similar to human autoimmune gastritis and pernicious anemia, and is characterized by parietal and chief cell loss, submucosal mononuclear cell infiltrates, and autoantibodies to the alpha and beta subunits of the gastric H/K ATPase. However, the specificity of T cells that cause the disease is not known. To examine the role of the H/K ATPase in this T cell-mediated disease, transgenic mice were generated that express the beta subunit of the H/K ATPase under the control of the major histocompatibility complex class II I-Ek alpha promoter. We show that transgenic expression of the gastric H/K ATPase beta subunit specifically prevents the onset of autoimmune gastritis after neonatal thymectomy. In addition, thymocyte transfer experiments suggest that tolerance of pathogenic autoreactive T cells is induced within the thymus of the transgenic mice. We conclude that the beta subunit of the gastric H/K ATPase is a major T cell target in autoimmune gastritis and that thymic expression of a single autoantigen can abrogate an autoimmune response to multiple autoantigens.
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Trendelenburg. "Pathogenese des Systemischen Lupus Erythematodes (SLE) – Die zentrale Rolle von Komplement." Therapeutische Umschau 62, no. 5 (May 1, 2005): 285–91. http://dx.doi.org/10.1024/0040-5930.62.5.285.
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Die traditionelle Sicht der Pathogenese des Systemischen Lupus Erythematodes (SLE) ist, dass Immunkomplexe aus Autoantigenen und Autoantikörpern Komplement aktivieren und auf diese Weise entzündliche Gewebsschädigungen entstehen. Obwohl dieses Modell plausibel erscheint, kann es nicht alle klinischen Beobachtungen, die das Komplementsystem und den SLE miteinander verbinden, erklären. Insbesondere die Beobachtung, dass Komplementdefizienzen einen Lupus hervorrufen können, ist schwerlich mit dem Konzept vereinbar, dass Komplementaktivierung die Hauptursache entzündlicher Schädigungen bei dieser Erkrankung ist. Neuere Studien weisen darauf hin, dass Komplement eher einen protektiven Charakter hat, indem es an Autoantigene, insbesondere apoptotische Zellen, bindet und dadurch deren Entsorgung fördert, bevor sie eine Immunantwort auslösen können.
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Minota, S., W. N. Jarjour, N. Suzuki, Y. Nojima, R. A. Roubey, T. Mimura, A. Yamada, T. Hosoya, F. Takaku, and J. B. Winfield. "Autoantibodies to nucleolin in systemic lupus erythematosus and other diseases." Journal of Immunology 146, no. 7 (April 1, 1991): 2249–52. http://dx.doi.org/10.4049/jimmunol.146.7.2249.
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Abstract The 110-kDa intracellular phosphoprotein (110K) described previously by this laboratory as a common IgM autoantigen in SLE and certain other systemic autoimmune disorders and viral infections is identified as nucleolin in the present investigation. Using rabbit antiserum to rat nucleolin as a probe, IgM autoantibody-reactive 110K co-migrated with human lymphocyte nucleolin in one- and two-dimensional immunoblots. Rabbit anti-nucleolin also specifically depleted autoreactive 110K from detergent lysates of human cells. Because nucleolin shares amino acid sequence similarity and/or forms dynamic particles with other prominent autoantigens, the present observation raises the possibility that the nucleolin/anti-nucleolin system may be of special significance for the development of humoral autoreactivity to nuclear Ag.
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Si, Fuchun. "Effects of removing heat and phlegm prescription on the proliferation and autoantigens expression of esophageal carcinoma cell." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16510-e16510. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16510.
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e16510 Background: o explore the effects of removing heat and phlegm prescription (RHPP) on the proliferation and autoantigens expression of esophageal carcinoma(EC) cell, so as to provide basis for the molecular pathogenesis and clinical medication of EC. Methods: RHPP was developed by us for treating EC, EC autoantigens CK13, CK16, CaD, ACTG2 were identified in our previous studies. The effects of RHPP and and its ethanol extraction on the proliferation, cell cycle and autoantigen protein expression of Eca109 cell, EC9706 cell and TE-1 cell were investigated by MTT assay, flow cytometry and western blot analysis. Results: RHPP and its removing heat (RH) and removing phlegm (RP) separated prescriptions all have inhibitory effects on the proliferation of EC9706, EC109 and TE-1 cells in dose-dependent and time-dependent manner, changed morphology of four esophageal carcinoma cells, which appeared as round with rough edges, karyopyknosis, and karyorrhexis. Ic50 values of RHPP for Ec9706, Eca109 and TE1 cell were 33.31 ug·ml−1, 20.70 ug·ml−1, 21.93 ug·ml−1 respectively, while Ic50 values of RHPP’s ethanol extraction for Ec9706, Eca109, TE1 were 0.653 ug·ml−1, 0.082 ug·ml−1, 0.172 ug·ml−1 respectively. RHPP and RP induced G2/M phase arrest in EC109 and TE-1 cells, while RH induced G0/G1 phase arrest in EC109 and TE-1 cells; RHPP and RP induced G0/G1 phase arrest in EC9706 cells, while RH induced S phase arrest in EC9706 cells. RHPP and its two separated prescription could downregulate CK16, CaD, ACTG2 expression and upregulate CK13 expression. Conclusions: Autoantigens CK13, CK16, CaD and ACTG2 were expressed in EC cell, RHPP could regulate these four autoantigens expression. This study provides new basis for the EC mlecular mechanism and development of anti-esophageal carcinoma drugs in traditional Chinese medicine.
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Jenning, Madeleine, Bianka Marklein, Jimmy Ytterberg, Roman A. Zubarev, Vijay Joshua, Dirkjan van Schaardenburg, Lotte van de Stadt, et al. "Bacterial citrullinated epitopes generated by Porphyromonas gingivalis infection—a missing link for ACPA production." Annals of the Rheumatic Diseases 79, no. 9 (June 12, 2020): 1194–202. http://dx.doi.org/10.1136/annrheumdis-2019-216919.
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ObjectivesPorphyromonas gingivalis (P.g.) is discussed to be involved in triggering self-reactive immune responses. The aim of this study was to investigate the autocitrullinated prokaryotic peptidylarginine deiminase (PPAD) from P.g. CH2007 (RACH2007-PPAD) from a rheumatoid arthritis (RA) patient and a synthetic citrullinated PPAD peptide (CPP) containing the main autocitrullination site as potential targets for antibody reactivity in RA and to analyse the possibility of citrullinating native human proteins by PPAD in the context of RA.MethodsRecombinant RACH2007-PPAD was cloned and expressed in Escherichia coli. Purified RACH2007-PPAD and its enzymatic activity was analysed using two-dimensional electrophoresis, mass spectrometry, immunoblot and ELISA. Autoantibody response to different modified proteins and peptides was recorded and bioinformatically evaluated.ResultsRACH2007-PPAD was capable to citrullinate major RA autoantigens, such as fibrinogen, vimentin, hnRNP-A2/B1, histone H1 and multiple peptides, which identify a common RG/RGG consensus motif. 33% of RA patients (n=30) revealed increased reactivity for α-cit-RACH2007-PPAD before RA onset. 77% of RA patients (n=99) presented α-cit-specific signals to CPP amino acids 57–71 which were positively correlated to α-CCP2 antibody levels. Interestingly, 48% of the α-CPP-positives were rheumatoidfactor IgM/anti-citrullinated peptide/protein antibodies (ACPA)-negative. Anti-CPP and α-RACH2007-PPAD antibody levels increase with age. Protein macroarrays that were citrullinated by RACH2007-PPAD and screened with RA patient sera (n=6) and controls (n=4) uncovered 16 RACH2007-PPAD citrullinated RA autoantigens and 9 autoantigens associated with lung diseases. We showed that the α-CPP response could be an important determinant in parenchymal changes in the lung at the time of RA diagnosis (n=106; p=0.018).ConclusionsRACH2007-PPAD induced internal citrullination of major RA autoantigens. Anti-RACH2007-PPAD correlates with ACPA levels and interstitial lung disease autoantigen reactivity, supporting an infection-based concept for induction of ACPAs via enzymatic mimicry.
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Harrison, Leonard C., Majella Dempsey-Collier, David R. Kramer, and Kazuma Takahashi. "Aerosol Insulin Induces Regulatory CD8 γδ T Cells That Prevent Murine Insulin-dependent Diabetes." Journal of Experimental Medicine 184, no. 6 (December 1, 1996): 2167–74. http://dx.doi.org/10.1084/jem.184.6.2167.
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Cellular immune hyporesponsiveness can be induced by the presentation of soluble protein antigens to mucosal surfaces. Most studies of mucosa-mediated tolerance have used the oral route of antigen delivery and few have examined autoantigens in natural models of autoimmune disease. Insulin is an autoantigen in humans and nonobese diabetic (NOD) mice with insulindependent diabetes mellitus (IDDM). When we administered insulin aerosol to NOD mice after the onset of subclinical disease, pancreatic islet pathology and diabetes incidence were both significantly reduced. Insulin-treated mice had increased circulating antibodies to insulin, absent splenocyte proliferation to the major epitope, insulin B chain amino acids 9–23, which was associated with increased IL-4 and particularly IL-10 secretion, and reduced proliferation to glutamic acid decarboxylase, another islet autoantigen. The ability of splenocytes from insulin-treated mice to suppress the adoptive transfer of diabetes to nondiabetic mice by T cells of diabetic mice was shown to be caused by small numbers of CD8 γδ T cells. These findings reveal a novel mechanism for suppressing cell-mediated autoimmune disease. Induction of regulatory CD8 γδ T cells by aerosol insulin is a therapeutic strategy with implications for the prevention of human IDDM.
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Herrera-Esparza, Rafael, Ricardo Villalobos, Juan-Jose Bollain-y-Goytia, Roxana Ramírez-Sandoval, Sergio H. Sánchez-Rodriguez, Guadalupe Pacheco-Tovar, and Esperanza Avalos-Diaz. "Apoptosis and Redistribution of the Ro Autoantigen in Balb/c Mouse Like in Subacute Cutaneous Lupus Erythematosus." Clinical and Developmental Immunology 13, no. 2-4 (2006): 163–66. http://dx.doi.org/10.1080/17402520600876796.
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In subacute cutaneous lupus eryhematosus (SCLE) the cutaneous antigens constitute the main source of Ro and La autoantigens. The aim of this investigation was to demonstrate if UV light increases the availability of Ro autoantigen in the skin, also the blocking effect of Ac-DEVD-CMK a caspase inhibitor was assessed. For this purpose newborn Balb/c mice were UVB irradiated (5–30 mJ/cm2) equivalent to a moderate to severe sunburn. Animals were injected with monoclonal anti-Ro antibodies from SCLE patients. Apoptosis was also induced by anti-Fas antibody injection. Skin samples were examined by direct immunofluoresence, by TUNEL, and the expression of caspase 3 by RT-PCR. Major findings of present studies were: 1. UVB irradiation and anti-Fas induced apoptosis of keratinocytes. 2. Apoptosis redistribute the Ro antigen on cell surface and is better triggered by Ro antibody. 3. The caspase 3 inhibitor Ac-DEVD-CMK decreases the availability of Ro autoantigen in epidermis and prevents deposition of anti-Ro. In conclusion, the caspase pathway would be blocked to avoid anti-Ro deposition along skin; this finding would be a prospect in the treatment of SCLE patients.