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1
Ludewig, Burkhard, Philippe Krebs, Helen Metters, Jutta Tatzel, Özlem Türeci, and Ugur Sahin. "Molecular Characterization of Virus-induced Autoantibody Responses." Journal of Experimental Medicine 200, no. 5 (September 6, 2004): 637–46. http://dx.doi.org/10.1084/jem.20040358.
Повний текст джерелаАнотація:
Here we present a comprehensive molecular mapping of virus-induced autoimmune B cell responses obtained by serological identification of antigens by recombinant expression cloning analysis. Immunoscreening of cDNA expression libraries of various organs (lung, liver, and spleen) using sera from mice infected with cytopathic (vaccinia virus [VV]) or noncytopathic (lymphocytic choriomeningitis virus [LCMV]) viruses revealed a broad specificity of the elicited autoantibody response. Interestingly, the majority of the identified autoantigens have been previously described as autoantigens in humans. We found that induction of virus-induced autoantibodies of the immunoglobulin G class largely depends on the CD40–CD40L-mediated interaction between T and B cells. Furthermore, antibody titers against a number of autoantigens were comparable to the concomitantly induced antiviral antibody response. Comparison of serum reactivity against a selected panel of autoantigens after infection with VV, LCMV, or vesicular stomatitis virus showed that the different virus infections triggered distinct autoantibody responses, suggesting that virus infections may leave specific “autoantibody fingerprints” in the infected host.
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Mikecz, K., T. T. Glant, E. Buzás, and A. R. Poole. "Cartilage proteoglycans as potential autoantigens in humans and in experimental animals." Agents and Actions 23, no. 1-2 (February 1988): 63–66. http://dx.doi.org/10.1007/bf01967190.
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Francoeur, A. M., C. L. Peebles, K. J. Heckman, J. C. Lee, and E. M. Tan. "Identification of ribosomal protein autoantigens." Journal of Immunology 135, no. 4 (October 1, 1985): 2378–84. http://dx.doi.org/10.4049/jimmunol.135.4.2378.
Повний текст джерелаАнотація:
Abstract Approximately 20% of patients with systemic lupus erythematosus and with anti-Sm autoantibodies synthesize autoantibodies, called anti-rRNP, to components of the ribosome. We found that anti-rRNP sera reacted predominantly with three ribosomal phosphoproteins of approximate Mr = 38,000, 16,000 and 15,000, both by immunoprecipitation and by immunoblotting. The human autoantibodies cross-reacted with similar antigens present in rodent, brine shrimp, and yeast cells but reacted weakly if at all with proteins of bacteria. Thus the human autoantibodies recognize epitopes that are widely conserved in evolution. Purified ribosomal proteins together with specific rabbit antisera were used to identify the two smaller rRNP antigens as the acidic phosphoproteins of the large ribosomal subunit, designated P1/P2(L40/L41) (rat), eL7/eL12 (Artemia, brine shrimp), and A1/A2 (yeast). These proteins function in the elongation step of protein synthesis in an analogous fashion to the L7/L12 ribosomal proteins of E. coli. The 38,000-dalton rRNP antigen corresponds to a nonacidic protein also associated with the large ribosomal subunit. The human autoantibodies appear to have a specificity similar to that of a previously described mouse monoclonal antibody obtained from mice injected with heterologous (chick) ribosomes, suggesting that both the human polyclonal autoantibodies and the mouse monoclonal recognize a class of epitope(s) that is common in all three ribosomal proteins. In addition, we found that many of the anti-ribosomal sera contained a further class of autoantibodies reactive with naked RNA. These may be similar to the anti-RNA antibodies previously described in both humans and mice with autoimmune disease.
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Harrison, Leonard C., Majella Dempsey-Collier, David R. Kramer та Kazuma Takahashi. "Aerosol Insulin Induces Regulatory CD8 γδ T Cells That Prevent Murine Insulin-dependent Diabetes". Journal of Experimental Medicine 184, № 6 (1 грудня 1996): 2167–74. http://dx.doi.org/10.1084/jem.184.6.2167.
Повний текст джерелаАнотація:
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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Vaughan, Kerrie, Yohan Kim, and Alessandro Sette. "A Comparison of Epitope Repertoires Associated with Myasthenia Gravis in Humans and Nonhuman Hosts." Autoimmune Diseases 2012 (2012): 1–16. http://dx.doi.org/10.1155/2012/403915.
Повний текст джерелаАнотація:
Here we analyzed the molecular targets associated with myasthenia gravis (MG) immune responses, enabled by an immune epitope database (IEDB) inventory of approximately 600 MG-related epitopes derived from 175 references. The vast majority of epitopes were derived from theα-subunit of human AChR suggesting that other MG-associated autoantigens should be investigated further. Humanα-AChR was mostly characterized in humans, whereas reactivity primarily toT. californicaAChR was examined in animal models. While the fine specificity of T-cell response was similar in the two systems, substantial antibody reactivity to the C-terminus was detected in the nonhuman system, but not in humans. Further analysis showed that the reactivity of nonhuman hosts to the C-terminus was eliminated when data were restricted to hosts tested in the context of autoimmune disease (spontaneous or induced), demonstrating that the epitopes recognized in humans and animals were shared when disease was present. Finally, we provided data subsets relevant to particular applications, including those associated with HLA typing or restriction, sets of epitopes recognized by monoclonal antibodies, and epitopes associated with modulation of immunity or disease. In conclusion, this analysis highlights gaps, differences, and similarities in the epitope repertoires of humans and animal models.
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Misharin, Alexander V., Yuji Nagayama, Holly A. Aliesky, Basil Rapoport, and Sandra M. McLachlan. "Studies in Mice Deficient for the Autoimmune Regulator (Aire) and Transgenic for the Thyrotropin Receptor Reveal a Role for Aire in Tolerance for Thyroid Autoantigens." Endocrinology 150, no. 6 (March 5, 2009): 2948–56. http://dx.doi.org/10.1210/en.2008-1690.
Повний текст джерелаАнотація:
The autoimmune regulator (Aire) mediates central tolerance for many autoantigens, and autoimmunity occurs spontaneously in Aire-deficient humans and mice. Using a mouse model of Graves’ disease, we investigated the role of Aire in tolerance to the TSH receptor (TSHR) in Aire-deficient and wild-type mice (hyperthyroid-susceptible BALB/c background). Mice were immunized three times with TSHR A-subunit expressing adenovirus. The lack of Aire did not influence T-cell responses to TSHR protein or TSHR peptides. However, antibody levels were higher in Aire-deficient than wild-type mice after the second (but not the third) immunization. After the third immunization, hyperthyroidism persisted in a higher proportion of Aire-deficient than wild-type mice. Aire-deficient mice were crossed with transgenic strains expressing high or low-intrathyroidal levels of human TSHR A subunits. In the low-expressor transgenics, Aire deficiency had the same effect on the pattern of the TSHR antibody response to immunization as in nontransgenics, although the amplitude of the response was lower in the transgenics. High-expressor A-subunit transgenics were unresponsive to immunization. We examined intrathymic expression of murine TSHR, thyroglobulin, and thyroid peroxidase (TPO), the latter two being the dominant autoantigens in Hashimoto’s thyroiditis (particularly TPO). Expression of the TSHR and thyroglobulin were reduced in the absence of Aire. Dramatically, thymic expression of TPO was nearly abolished. In contrast, the human A-subunit transgene, lacking a potential Aire-binding motif, was unaffected. Our findings provide insight into how varying intrathymic autoantigen expression may modulate thyroid autoimmunity and suggest that Aire deficiency may contribute more to developing Hashimoto’s thyroiditis than Graves’ disease.
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Liminet, Christelle, Julien Vouillarmet, Karim Chikh, and Emmanuel Disse. "Antibody-Mediated Insulin Resistance: When Insulin and Insulin Receptor Act as Autoantigens in Humans." Canadian Journal of Diabetes 40, no. 5 (October 2016): 462–65. http://dx.doi.org/10.1016/j.jcjd.2016.02.007.
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Härkönen, Taina, Anja Paananen, Hilkka Lankinen, Tapani Hovi, Outi Vaarala, and Merja Roivainen. "Enterovirus infection may induce humoral immune response reacting with islet cell autoantigens in humans." Journal of Medical Virology 69, no. 3 (January 13, 2003): 426–40. http://dx.doi.org/10.1002/jmv.10306.
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Chen, Xin, Venkata Mallajosyula, Mustafa Ghanizada, Elsa Sola, Lei Chen, Lilit Kamalyan, Jing Li, and Mark M. Davis. "Distinct roles of CD4 +and CD8 +Tregs in regulating human autoreactive T cells, B cells, and antibodies in genetically engineered tonsil organoid system." Journal of Immunology 210, no. 1_Supplement (May 1, 2023): 247.20. http://dx.doi.org/10.4049/jimmunol.210.supp.247.20.
Повний текст джерелаАнотація:
Abstract CD4 +and CD8 +regulatory T cells (Treg) are critical for maintaining immune tolerance, and alternations in number and function are associated with detrimental outcomes in infectious and autoimmune diseases. Despite their importance, their distinct roles and mechanisms in regulating self-tolerance need to be better characterized in humans. Here we analyzed the relative contribution of CD4 +and CD8 +Tregs to control autoreactive T cells, B cells, and antibodies in an entirely human tonsil organoid system in vitro. We disrupted their suppressive functions by knocking out FOXP3 and GZMB genes using CRISPR/Cas9 technology. Normally tonsil organoids make robust antibody and cellular responses to live attenuated flu vaccine, but not to autoantigens. In contrast, FOXP3 KO tonsil organoids produced autoantibodies when stimulated with a panel of classical autoantigens, including double-stranded DNA and others. We also detected increased CD8 +T cells specific for autoantigens, including SMCY antigen. With the GZMB KO, we found a marked increase in follicular helper T cells and autoreactive CD4 +and CD8 +T cells. Interestingly the GZMB KO tonsils showed an expansion of plasmablasts, but only a low level of autoantibodies and autoreactive B cells was detected. This indicates that CD8 +Tregs control the early T and B cell activation but not autoantibody production. Moreover, knocking out FOXP3 generated high-affinity HA-specific antibodies in tonsil organoids compared to control, indicating that CD4 +Tregs are a key checkpoint for high-affinity antibodies and the production of autoantibodies. We conclude that CD8 +and CD4 +Tregs have distinct and complementary roles in regulating cellular and humoral responses and preventing autoimmunity.
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Mamula, M. J., S. Fatenejad, and J. Craft. "B cells process and present lupus autoantigens that initiate autoimmune T cell responses." Journal of Immunology 152, no. 3 (February 1, 1994): 1453–61. http://dx.doi.org/10.4049/jimmunol.152.3.1453.
Повний текст джерелаАнотація:
Abstract Antibodies against U small nuclear ribonucleoprotein (snRNP) particles are a common finding in the sera of humans with SLE and in certain strains of mice with murine lupus. It is likely that Th cells are important in amplifying this autoantibody response. The focus of this work was to investigate events that might initiate autoimmune B and T cell response in non-autoimmune mice to native snRNP particles. Mice that were immunized and boosted with native mouse snRNPs failed to produce any detectable specific anti-snRNP antibody or T cell responses, suggesting that these autoreactive cells were deleted from the repertoire or were anergic to stimulation with this self Ag. In contrast, immunization with native foreign (human) snRNPs elicited both T cells and cross-reactive anti-snRNP antibodies; the latter predominantly were directed toward the A protein of the U1 snRNP. When mice were immunized with human and mouse snRNPs together in adjuvant, T cells specific for mouse snRNPs could be elicited. The results of these experiments suggested that the mechanism of breaking T cell tolerance to self snRNPs was dependent on the ability of cross-reactive B cells to process and present these autoantigens. To address this hypothesis, B cells purified from mice immunized with recombinant human A protein were transferred into naive mice. Upon boosting with native mouse snRNPs, autoreactive CD4+ T cells specific for mouse Ags, and not cross-reactive with human snRNPs, were observed. These studies support a model of molecular mimicry whereby autoantigen-presenting B cells are generated by foreign cross-reactive determinants that can, in turn, elicit an autoimmune T cell response.
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Zhang, Mei-Yun, Bang K. Vu, Anil Choudhary, Hong Lu, Michael Humbert, Helena Ong, Munir Alam, et al. "Cross-Reactive Human Immunodeficiency Virus Type 1-Neutralizing Human Monoclonal Antibody That Recognizes a Novel Conformational Epitope on gp41 and Lacks Reactivity against Self-Antigens." Journal of Virology 82, no. 14 (May 14, 2008): 6869–79. http://dx.doi.org/10.1128/jvi.00033-08.
Повний текст джерелаАнотація:
ABSTRACT Broadly cross-reactive human immunodeficiency virus (HIV)-neutralizing antibodies are infrequently elicited in infected humans. The two best-characterized gp41-specific cross-reactive neutralizing human monoclonal antibodies, 4E10 and 2F5, target linear epitopes in the membrane-proximal external region (MPER) and bind to cardiolipin and several other autoantigens. It has been hypothesized that, because of such reactivity to self-antigens, elicitation of 2F5 and 4E10 and similar antibodies by vaccine immunogens based on the MPER could be affected by tolerance mechanisms. Here, we report the identification and characterization of a novel anti-gp41 monoclonal antibody, designated m44, which neutralized most of the 22 HIV type 1 (HIV-1) primary isolates from different clades tested in assays based on infection of peripheral blood mononuclear cells by replication-competent virus but did not bind to cardiolipin and phosphatidylserine in an enzyme-linked immunosorbent assay and a Biacore assay nor to any protein or DNA autoantigens tested in Luminex assays. m44 bound to membrane-associated HIV-1 envelope glycoproteins (Envs), to recombinant Envs lacking the transmembrane domain and cytoplasmic tail (gp140s), and to gp41 structures containing five-helix bundles and six-helix bundles, but not to N-heptad repeat trimers, suggesting that the C-heptad repeat is involved in m44 binding. In contrast to 2F5, 4E10, and Z13, m44 did not bind to any significant degree to denatured gp140 and linear peptides derived from gp41, suggesting a conformational nature of the epitope. This is the first report of a gp41-specific cross-reactive HIV-1-neutralizing human antibody that does not have detectable reactivity to autoantigens. Its novel conserved conformational epitope on gp41 could be helpful in the design of vaccine immunogens and as a target for therapeutics.
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Zdinak, Paul, Stephanie J. Grebinoski, Jessica Torrey, Sanjay Rathod, Rashi Ranjan, Louise Hicks, and Alok V. Joglekar. "Profiling transcriptomes, TCR repertoires, and antigenic specificities of islet-infiltrating T cells in Non-Obese Diabetic mice." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 104.05. http://dx.doi.org/10.4049/jimmunol.208.supp.104.05.
Повний текст джерелаАнотація:
Abstract Type 1 Diabetes (T1D) is an autoimmune disease caused by progressive destruction of pancreatic β-cells, resulting in reduced insulin production. The role of islet-infiltrating CD4+ T cells in mediating β-cell destruction and autoantibody formation is well established. However, many of the antigen specificities of CD4+ T cells which initiate disease are undefined. In this project, we performed single cell RNA sequencing of pancreatic islet infiltrating T cells from 6-, 8- , and 10-week-old Non-Obese Diabetic (NOD) mice. NOD mice recapitulate many immunologic features of T1D and share many autoantigens with human T1D patients. Analysis of TCR repertoires revealed clonal expansion in activated and pre-exhausted effector CD4+ T cells as well as regulatory T cells. Despite subtle differences, expanded effector CD4+ T cells showed a well-defined cell state. We cloned 40 TCRs from the top expanded T cells and expressed them in Jurkat cells. We performed antigen discovery assays on these TCRs using our lab’s Signaling and Antigen-presenting Bifunctional Receptor (SABR) platform. We constructed a SABR library of 4,075 I-Ag7-restricted epitopes based on published datasets. We identified several previously reported and novel autoantigens. Surprisingly, antigenic specificities did not influence the shared phenotype dramatically. These results identify several potential autoantigens that will be valuable for diagnostic, preventative, and therapeutic purposes. Moreover, these results suggest that the islet microenvironment is a major determinant of infiltrating CD4+ T cell states. Similar studies focused on CD8+ T cells in NOD mice and CD4+ and CD8+ T cells in humans are underway. dkNET New investigator Pilot Program in Bioinformatics (PI: Joglekar) NIDDK New Investigator Gateway Award 1R03DK127447 (PI: Joglekar) PACER Innovative Discovery Award (PI: Joglekar)
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Eisenbarth, George S. "Etiology of Organ-Specific Autoimmunity: Basic Research and Clinical Implications in IBD." Canadian Journal of Gastroenterology 10, no. 2 (1996): 121–25. http://dx.doi.org/10.1155/1996/909212.
Повний текст джерелаАнотація:
Autoimmunity develops in the setting of genetic susceptibility and can be monogenic (eg, autoimmune polyendocrine syndrome type I with Addison’s disease, mucocutaneous candidiasis and hypoparathyroidism, which is autosomal recessive with the causative gene on the tip of chromosome 21) or polygenic (usually with important alleles within the major histocompatibility complex [eg, type I diabetes]). In addition to genetic susceptibility, many autoimmune disorders can be classified into etiological categories (oncogenic, drug-induced, diet-induced, infectious or idiopathic). For most autoimmune disorders there are multiple target autoantigens and, for type I diabetes, a combinatorial approach (eg, expression of at least two autoantibodies of insulin, glutamic acid decarboxylase and/or ICA512/IA-2) is the best predictor of diabetes risk. Finally, antigen-specific therapies hold promise for the prevention and therapy of autoimmunity, eg, parenteral or oral therapy with insulin delays or prevents type I diabetes in animal models, and a small pilot trial of parenteral insulin in humans suggests that such therapy may similarly prevent diabetes in humans.
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Martin, Cyrus C., Brian P. Flemming, Yingda Wang, James K. Oeser, and Richard M. O'Brien. "Foxa2 and MafA regulate islet-specific glucose-6-phosphatase catalytic subunit-related protein gene expression." Journal of Molecular Endocrinology 41, no. 5 (August 27, 2008): 315–28. http://dx.doi.org/10.1677/jme-08-0062.
Повний текст джерелаАнотація:
Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP/G6PC2) is a major autoantigen in both mouse and human type 1 diabetes. IGRP is selectively expressed in islet β cells and polymorphisms in the IGRP gene have recently been associated with variations in fasting blood glucose levels and cardiovascular-associated mortality in humans. Chromatin immunoprecipitation (ChIP) assays have shown that the IGRP promoter binds the islet-enriched transcription factors Pax-6 and BETA2. We show here, again using ChIP assays, that the IGRP promoter also binds the islet-enriched transcription factors MafA and Foxa2. Single binding sites for these factors were identified in the proximal IGRP promoter, mutation of which resulted in decreased IGRP fusion gene expression in βTC-3, Hamster insulinoma tumor (HIT), and Min6 cells. ChiP assays have shown that the islet-enriched transcription factor Pdx-1 also binds the IGRP promoter, but mutational analysis of four Pdx-1 binding sites in the proximal IGRP promoter revealed surprisingly little effect of Pdx-1 binding on IGRP fusion gene expression in βTC-3 cells. In contrast, in both HIT and Min6 cells mutation of these four Pdx-1 binding sites resulted in a ∼50% reduction in fusion gene expression. These data suggest that the same group of islet-enriched transcription factors, namely Pdx-1, Pax-6, MafA, BETA2, and Foxa2, directly or indirectly regulate expression of the two major autoantigens in type 1 diabetes.
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Marklein, B., C. Grimm, G. R. Burmester, and K. Skriner. "THU0118 Toll-Like Receptor Dependent Autoantigens in Animal Models and Humans in Use to Improve Collagen Induced Arthritis." Annals of the Rheumatic Diseases 72, Suppl 3 (June 2013): A202.2—A202. http://dx.doi.org/10.1136/annrheumdis-2013-eular.646.
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Pahor, Artur. "Autoimmune diseases: a diagnostic challenge." Acta Medico-Biotechnica 5, no. 1 (November 27, 2021): 24–31. http://dx.doi.org/10.18690/actabiomed.63.
Повний текст джерелаАнотація:
The immune system defends humans against foreign factors that could damage healthy tissue. It detects and distinguishes a wide variety of substances from the organism’s own structures. Failing to recognize the organism’s own structures as self structures causes autoimmune disorders. These self-structures are called “autoantigens”. Autoimmune disorders are divided into those directly damaging only a single organ system, and those in which many important organs are damaged (systemic). This article deals with the most important autoimmune mechanisms inducing autoimmune inflammation. It discusses the diagnoses of autoimmune disorders, which are based mainly on the clinical picture, and the most frequently used laboratory and immunological tests crucial for diagnosing particular autoimmune diseases. The purpose of this article is to emphasize the importance of the early clinical picture and laboratory testing of autoimmune diseases.
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Taylor, Philip R., Anna Carugati, Valerie A. Fadok, H. Terence Cook, Mark Andrews, Michael C. Carroll, John S. Savill, Peter M. Henson, Marina Botto, and Mark J. Walport. "A Hierarchical Role for Classical Pathway Complement Proteins in the Clearance of Apoptotic Cells in Vivo." Journal of Experimental Medicine 192, no. 3 (July 31, 2000): 359–66. http://dx.doi.org/10.1084/jem.192.3.359.
Повний текст джерелаАнотація:
The strongest susceptibility genes for the development of systemic lupus erythematosus (SLE) in humans are null mutants of classical pathway complement proteins. There is a hierarchy of disease susceptibility and severity according to the position of the missing protein in the activation pathway, with the severest disease associated with C1q deficiency. Here we demonstrate, using novel in vivo models of apoptotic cell clearance during sterile peritonitis, a similar hierarchical role for classical pathway complement proteins in vivo in the clearance of apoptotic cells by macrophages. Our results constitute the first demonstration of an impairment in the phagocytosis of apoptotic cells by macrophages in vivo in a mammalian system. Apoptotic cells are thought to be a major source of the autoantigens of SLE, and impairment of their removal by complement may explain the link between hereditary complement deficiency and the development of SLE.
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Akimoto, Hidetoshi, Emi Fukuda-Kawaguchi, Omar Duramad, Yasuyuki Ishii, and Kazunari Tanabe. "A Novel Liposome Formulation Carrying Both an Insulin Peptide and a Ligand for Invariant Natural Killer T Cells Induces Accumulation of Regulatory T Cells to Islets in Nonobese Diabetic Mice." Journal of Diabetes Research 2019 (October 23, 2019): 1–9. http://dx.doi.org/10.1155/2019/9430473.
Повний текст джерелаАнотація:
Type 1 diabetes (T1D) is an autoimmune disease caused by the destruction of pancreatic β cells by autoantigen-reactive diabetogenic cells. Antigen-specific therapies using islet autoantigens for restoring immune tolerance have emerged as promising approaches for the treatment of T1D but have been unsuccessful in humans. Herein, we report that RGI-3100-iB, a novel liposomal formulation carrying both α-galactosylceramide (α-GalCer), which is a representative ligand for invariant natural killer T (iNKT) cells, and insulin B chain 9–23 peptide, which is an epitope for CD4+ T cells, could induce the accumulation of regulatory T cells (Tregs) in islets in a peptide-dependent manner, followed by the remarkable prevention of diabetes onset in nonobese diabetic (NOD) mice. While multiple administrations of a monotherapy using either α-GalCer or insulin B peptide in a liposomal formulation was confirmed to delay/prevent T1D in NOD mice, RGI-3100-iB synergistically enhanced the prevention effect of each monotherapy and alleviated insulitis in NOD mice. Immunopathological analysis showed that Foxp3+ Tregs accumulated in the islets in RGI-3100-iB-treated mice. Cotransfer of diabetogenic T cells and splenocytes of NOD mice treated with RGI-3100-iB, but not liposomal α-GalCer encapsulating an unrelated peptide, to NOD-SCID mice resulted in the prevention of diabetes and elevation of Foxp3 mRNA expression in the islets. These data indicate that the migration of insulin B-peptide-specific Tregs to islet of NOD mice that are involved in the suppression of pathogenic T cells related to diabetes onset and progression could be enhanced by the administration of liposomes containing α-GalCer and insulin B peptide.
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Kasmar, Anne G., Ildiko van Rhijn, Tan-Yun Cheng, Marie Turner, Chetan Seshadri, Andre Schiefner, Ravi C. Kalathur та ін. "CD1b tetramers bind αβ T cell receptors to identify a mycobacterial glycolipid-reactive T cell repertoire in humans". Journal of Experimental Medicine 208, № 9 (1 серпня 2011): 1741–47. http://dx.doi.org/10.1084/jem.20110665.
Повний текст джерелаАнотація:
Microbial lipids activate T cells by binding directly to CD1 and T cell receptors (TCRs) or by indirect effects on antigen-presenting cells involving induction of lipid autoantigens, CD1 transcription, or cytokine release. To distinguish among direct and indirect mechanisms, we developed fluorescent human CD1b tetramers and measured T cell staining. CD1b tetramer staining of T cells requires glucose monomycolate (GMM) antigens, is specific for TCR structure, and is blocked by a recombinant clonotypic TCR comprised of TRAV17 and TRBV4-1, proving that CD1b–glycolipid complexes bind the TCR. GMM-loaded tetramers brightly stain a small subpopulation of blood-derived cells from humans infected with Mycobacterium tuberculosis, providing direct detection of a CD1b-reactive T cell repertoire. Polyclonal T cells from patients sorted with tetramers are activated by GMM antigens presented by CD1b. Whereas prior studies emphasized CD8+ and CD4−CD8− CD1b-restricted clones, CD1b tetramer-based studies show that nearly all cells express the CD4 co-receptor. These findings prove a cognate mechanism whereby CD1b–glycolipid complexes bind to TCRs. CD1b tetramers detect a natural CD1b-restricted T cell repertoire ex vivo with unexpected features, opening a new investigative path to study the human CD1 system.
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Binks, Sophie, Abbe H. Crawford, Mark Woodhall, Andrew Fower, Hattie Syme, Lorna J. Kennedy, Patrick Waters, Lucy Davison, Sarosh Irani, and Akos Pakozdy. "067 One Health: Clinical characteristics of spontaneously-arising feline LGI1- autoantibody limbic encephalitis in a large international cohort." Journal of Neurology, Neurosurgery & Psychiatry 93, no. 9 (August 12, 2022): e2.15. http://dx.doi.org/10.1136/jnnp-2022-abn2.111.
Повний текст джерелаАнотація:
IntroductionLeucine-rich glioma-inactivated 1 (LGI1) is one of the most common surface neuronal autoantigens associated with autoimmune limbic encephalitis (LE) in humans, with hallmarks of personality change, amnesia and seizures. Recently, these autoantibodies were described in domestic cats with LE, likewise with a distinctive phenotype of behavioural change and orofacial seizures.MethodsUsing a feline-specific cell-based assay for LGI1-autoantibodies, we tested serum from 123 cats with neurological signs, submitted by veterinary surgeons across Europe. Clinical presentation, investiga- tions, management and outcomes were captured by questionnaire and review of medical records.Results56 samples were positive for LGI1-autoantibodies. The median age was 45 months and 34/54 (63%) were female. Most (44/56, 79%) had LE but other clinical syndromes included epilepsy, encephalopathy and feline hyperesthesia syndrome. Focal seizures without generalisation were reported in 42/51 (82%) compared to 25/47 (53%) in seronegative cats (p=0.02). Among seropositive cats, MRI abnormalities were identified in 23/42 (55%), adverse drug reactions in 7/50 (14%), and 8/51 (16%) were euthanised due to refractory seizures or status epilepticus.ConclusionMany features are common to humans and cats with LGI1-autoantibodies. Feline patients represent a naturally-occurring disease model and an opportunity to benefit health in both species via a bi-directional translational model.
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Ehrenstein, Michael R., H. Terence Cook, and Michael S. Neuberger. "Deficiency in Serum Immunoglobulin (Ig)m Predisposes to Development of Igg Autoantibodies." Journal of Experimental Medicine 191, no. 7 (April 3, 2000): 1253–58. http://dx.doi.org/10.1084/jem.191.7.1253.
Повний текст джерелаАнотація:
Serum immunoglobulin (Ig)M provides the initial response to foreign antigen and plays a regulatory role in subsequent immune response development, accelerating the production of high-affinity IgG. Here we show that mice deficient in serum IgM have an increased propensity to spontaneous autoimmunity as judged by the development with age of serum IgG anti-DNA antibodies and the renal deposition of IgG and complement. They also exhibit augmented anti-DNA IgG production on exposure to lipopolysaccharide. Thus, deficiency in serum IgM leads to diminished responsiveness to foreign antigens but increased responsiveness to self—a paradoxical association reminiscent of that described in humans deficient in complement or IgA. We wondered whether serum IgM might play an analogous role with regard to the response to self-antigens. However, here—in contrast to the sluggish response to foreign antigens—we find that deficiency in serum IgM actually predisposes to the development of IgG antibodies to autoantigens.
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Samson, Sonia, Lakshmi Mundkur, and Vijay V. Kakkar. "Immune Response to Lipoproteins in Atherosclerosis." Cholesterol 2012 (August 23, 2012): 1–12. http://dx.doi.org/10.1155/2012/571846.
Повний текст джерелаАнотація:
Atherosclerosis, the underlying cause of cardiovascular disease, is characterized by chronic inflammation and altered immune response. Cholesterol is a well-known risk factor associated with the development of cardiovascular diseases. Elevated serum cholesterol is unique because it can lead to development of atherosclerosis in animals and humans even in the absence of other risk factors. Modifications of low-density lipoproteins mediated by oxidation, enzymatic degradation, and aggregation result in changes in their function and activate both innate and adaptive immune system. Oxidized low-density lipoprotein (LDL) has been identified as one of the most important autoantigens in atherosclerosis. This escape from self-tolerance is dependent on the formation of oxidized phospholipids. The emerging understanding of the importance of immune responses against oxidized LDL in atherosclerosis has focused attention on the possibility of development of novel therapy for atherosclerosis. This review provides an overview of immune response to lipoproteins and the fascinating possibility of developing an immunomodulatory therapy for atherosclerosis.
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Singh, R., E. Yen, and I. Valera. "POS0360 X-CHROMOSOME DOSAGE, RATHER THAN THE GONADAL SEX ITSELF, MAJORLY CONTRIBUTES TO SEX BIAS IN AUTOIMMUNITY IN HUMANS." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 430.2–431. http://dx.doi.org/10.1136/annrheumdis-2023-eular.683.
Повний текст джерелаАнотація:
BackgroundMost autoimmune diseases exhibit a profound female sex bias. Mechanisms underlying this sexual dimorphism remain unclear. We previously reported that the XX sex chromosome complement, as compared to XY, imparts greater susceptibility to autoimmune diseases such as lupus in experimental models (Smith-Bouvier D, et al, J Exp Med 2008). Gonadectomized XX female mice had more anti-DNA antibodies, autoimmune pathology, and mortality than XY female (Sryko) mice. Similarly, gonadectomized XX male (SryTg) mice had more severe autoimmune disease than XY male (SrykoSryTg). To begin to translate these murine findings onto humans, we asked if sex chromosome dosage plays a role in predisposition to autoimmunity.ObjectivesTo test the hypothesis that X chromosome dosage, rather than the female sex itself, imparts susceptibility to autoimmunity in humans.MethodsWe administered autoimmune disease and connective tissue disease questionnaires and analyzed serum autoantibody levels in males and females with sex chromosome aneuploidy including males with two X chromosomes (XX males, including Klinefelter’s syndrome) and females with one X chromosome (X0 females, including Turner’s syndrome) and their respective male and female controls with normal sex chromosome numbers.ResultsLevels of IgG anti-chromatin, anti-nucleosome and anti-histone (H2A, H2B and H3) autoantibodies were significantly higher in XX males (47,XXY; 48,XXYY, and mosaics) compared to 46,XY men. XX males, however, did not have non-specific B cell hyper-reactivity, as the levels of anti-thyroid peroxidase antibody that is associated with autoimmune thyroiditis were similar between the two groups and antibodies against intrinsic factor which are present in patients with autoimmune gastritis/pernicious anemia were reduced in XX males than in XY males. In contrast to the increased frequency of autoantibodies against systemic autoantigens in XX males vs. XY males, such autoantibodies were reduced in X0 females as compared to XX females. However, autoantibodies against organ-specific autoantigens such as thyroid and gliadin were higher in X0 females than in XX females. A preliminary analysis of clinical questionnaire revealed an increase in autoimmune conditions in XX males when compared with known population prevalence of these diseases. Preliminary immune phenotyping of peripheral blood cells conducted thus far show altered frequency and/or function of natural killer T-cells, CD8+ T cells or IL-4/IL-17 producing cells in individuals with sex chromosome aneuploidy compared to their respective controls.ConclusionThese data suggest that humans with two X chromosomes as compared to those with one X chromosome, regardless of their gonadal sex, exhibit increased susceptibility to systemic autoimmunity. Preliminary evidence also suggests a differential regulation of systemic versus organ-specific autoimmunity in persons with sex chromosome aneuploidy.Reference[1]Smith-Bouvier D, Divekar A, Sasidhar M, Du S, Tiwari S, King J, Arnold A, Singh RR*, Voskuhl RR*. A role for sex chromosome complement in the female bias in autoimmune disease.J Exp Med2008;205:1099-1108. *Co-corresponding author.AcknowledgementsSupported in part by NIH/ NIAMS R01 grant. Thanks to Dr. Prasanth Surampudi, Christina Wang, and Ronald Swerdloff for specimens, Rita Okorogu, Jennifer Woo and Chetachi Okereke for enrollment and sample processing, and Priti Prasad, Cynthia Tran, Miguel-Angel Gutierrez, and Ramesh Halder for technical assistance.Disclosure of InterestsNone Declared.
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Du Clos, Terry W. "Pentraxins: Structure, Function, and Role in Inflammation." ISRN Inflammation 2013 (September 14, 2013): 1–22. http://dx.doi.org/10.1155/2013/379040.
Повний текст джерелаАнотація:
The pentraxins are an ancient family of proteins with a unique architecture found as far back in evolution as the Horseshoe crab. In humans the two members of this family are C-reactive protein and serum amyloid P. Pentraxins are defined by their sequence homology, their pentameric structure and their calcium-dependent binding to their ligands. Pentraxins function as soluble pattern recognition molecules and one of the earliest and most important roles for these proteins is host defense primarily against pathogenic bacteria. They function as opsonins for pathogens through activation of the complement pathway and through binding to Fc gamma receptors. Pentraxins also recognize membrane phospholipids and nuclear components exposed on or released by damaged cells. CRP has a specific interaction with small nuclear ribonucleoproteins whereas SAP is a major recognition molecule for DNA, two nuclear autoantigens. Studies in autoimmune and inflammatory disease models suggest that pentraxins interact with macrophage Fc receptors to regulate the inflammatory response. Because CRP is a strong acute phase reactant it is widely used as a marker of inflammation and infection.
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Dhahbi, Joseph M., Stephen R. Spindler, Hani Atamna, Dario Boffelli, Patricia Mote, and David I. K. Martin. "5′-YRNA fragments derived by processing of transcripts from specific YRNA genes and pseudogenes are abundant in human serum and plasma." Physiological Genomics 45, no. 21 (November 1, 2013): 990–98. http://dx.doi.org/10.1152/physiolgenomics.00129.2013.
Повний текст джерелаАнотація:
Small noncoding RNAs carry out a variety of functions in eukaryotic cells, and in multiple species they can travel between cells, thus serving as signaling molecules. In mammals multiple small RNAs have been found to circulate in the blood, although in most cases the targets of these RNAs, and even their functions, are not well understood. YRNAs are small (84–112 nt) RNAs with poorly characterized functions, best known because they make up part of the Ro ribonucleoprotein autoantigens in connective tissue diseases. In surveying small RNAs present in the serum of healthy adult humans, we have found YRNA fragments of lengths 27 nt and 30–33 nt, derived from the 5′-ends of specific YRNAs and generated by cleavage within a predicted internal loop. Many of the YRNAs from which these fragments are derived were previously annotated only as pseudogenes, or predicted informatically. These 5′-YRNA fragments make up a large proportion of all small RNAs (including miRNAs) present in human serum. They are also present in plasma, are not present in exosomes or microvesicles, and circulate as part of a complex with a mass between 100 and 300 kDa. Mouse serum contains far fewer 5′-YRNA fragments, possibly reflecting the much greater copy number of YRNA genes and pseudogenes in humans. The function of the 5′-YRNA fragments is at present unknown, but the processing and secretion of specific YRNAs to produce 5′-end fragments that circulate in stable complexes are consistent with a signaling function.
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Haidar Ahmad, Ahmad, Dyhia Melbouci, and Patrice Decker. "Polymorphonuclear Neutrophils in Rheumatoid Arthritis and Systemic Lupus Erythematosus: More Complicated Than Anticipated." Immuno 2, no. 1 (January 7, 2022): 85–103. http://dx.doi.org/10.3390/immuno2010007.
Повний текст джерелаАнотація:
Polymorphonuclear neutrophils (PMN) are the most abundant leucocytes in the circulation in humans. They represent a heterogeneous population exerting diverse functions through several activities. Usually described as typical pro-inflammatory cells, immunomodulatory properties of PMNs have been reported. Among others, once activated and depending on the stimulus, PMNs expel neutrophil extracellular traps (NET) in the extracellular space. NETs are complexes made of DNA and granule proteins representing an innate immune mechanism fighting infections. Nevertheless, an excess of NET formation might be involved in the development of inflammatory or autoimmune responses. Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are two chronic, inflammatory, autoimmune diseases of unknown etiology and affecting mostly women. Several abnormal or non-classical functions of PMNs or PMN sub-populations have been described in SLE and RA. Particularly, NETs have been suggested to trigger pro-inflammatory responses by exposing pro-inflammatory mediators. Likewise, NETs may be the targets of autoantibodies or even might trigger the development of autoantibodies by exposing autoantigens. In the present review, we will summarize heterogeneous properties of human PMNs and we will discuss recent evidence linking PMNs and NETs to the pathogenesis of both SLE and RA.
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Chen, Xin, Mustafa Ghanizada, Elsa Sola, and Mark M. Davis. "Developing a model of autoimmune diseases with human tonsil organoids." Journal of Immunology 208, no. 1_Supplement (May 1, 2022): 44.12. http://dx.doi.org/10.4049/jimmunol.208.supp.44.12.
Повний текст джерелаАнотація:
Abstract Mouse models have contributed significantly to our knowledge of the pathogenesis of autoimmune diseases. However, differences in mouse and human immune systems limit the translation of the knowledge in mechanism and therapeutic outcomes from mouse to human. Therefore, a human model of autoimmune diseases is urgently needed. Recently, our lab has developed a functional tonsil organotypic system that can recapitulate key T cells responses and germinal center response to influenza vaccine in vitro. We now want to utilize this tonsil system to study autoimmunity. Regulatory T cells (Tregs) have been suggested to play a central role in maintaining self-tolerance. Reduced Treg cell frequencies and impaired suppressive function have been reported in a wide range of autoimmune diseases. In this study, we show that we can efficiently knock out FOXP3 in T cells from human tonsil organoids by using CRISPR technology. We also show that tonsil organoids with FOXP3 knocked-out T cells are able to induce humoral immune responses towards autoantigens stimulation and influenza vaccination. This system could be useful for studying underlying mechanisms in the functions of Tregs in the autoimmune condition in humans and provides insights into the therapeutic strategy for autoimmune diseases.
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Christensen, Sean R., Michael Kashgarian, Lena Alexopoulou, Richard A. Flavell, Shizuo Akira, and Mark J. Shlomchik. "Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus." Journal of Experimental Medicine 202, no. 2 (July 18, 2005): 321–31. http://dx.doi.org/10.1084/jem.20050338.
Повний текст джерелаАнотація:
Systemic autoimmune disease in humans and mice is characterized by loss of immunologic tolerance to a restricted set of self-nuclear antigens. Autoantigens, such as double-stranded (ds) DNA and the RNA-containing Smith antigen (Sm), may be selectively targeted in systemic lupus erythematosus because of their ability to activate a putative common receptor. Toll-like receptor 9 (TLR9), a receptor for CpG DNA, has been implicated in the activation of autoreactive B cells in vitro, but its role in promoting autoantibody production and disease in vivo has not been determined. We show that in TLR9-deficient lupus-prone mice, the generation of anti-dsDNA and antichromatin autoantibodies is specifically inhibited. Other autoantibodies, such as anti-Sm, are maintained and even increased in TLR9-deficient mice. In contrast, ablation of TLR3, a receptor for dsRNA, did not inhibit the formation of autoantibodies to either RNA- or DNA-containing antigens. Surprisingly, we found that despite the lack of anti-dsDNA autoantibodies in TLR9-deficient mice, there was no effect on the development of clinical autoimmune disease or nephritis. These results demonstrate a specific requirement for TLR9 in autoantibody formation in vivo and indicate a critical role for innate immune activation in autoimmunity.
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Saunders, Karin A., Tim Raine, Anne Cooke, and Catherine E. Lawrence. "Inhibition of Autoimmune Type 1 Diabetes by Gastrointestinal Helminth Infection." Infection and Immunity 75, no. 1 (October 16, 2006): 397–407. http://dx.doi.org/10.1128/iai.00664-06.
Повний текст джерелаАнотація:
ABSTRACT Gastrointestinal nematode infections are prevalent worldwide and are potent inducers of T helper 2 responses with the capacity to modulate the immune response to heterologous antigens. Parasitic helminth infection has even been shown to modulate the immune response associated with autoimmune diseases. Nonobese diabetic (NOD) mice provide a model for studying human autoimmune diabetes; as in humans, the development of diabetes in NOD mice has been linked to the loss of self-tolerance to beta cell autoantigens. Previous studies with the NOD mouse have shown that helminth and bacterial infection appears to inhibit type 1 diabetes by disrupting the pathways leading to the Th1-mediated destruction of insulin-producing beta cells. The aim of our study was to examine whether infection with the gastrointestinal helminths Trichinella spiralis or Heligmosomoides polygyrus could inhibit the development of autoimmune diabetes in NOD mice and to analyze the mechanisms involved in protection and the role of Th2 responses. Protection from diabetes was afforded by helminth infection, appeared to inhibit autoimmune diabetes by disrupting pathways leading to the destruction of beta cells, and was mediated by seemingly independent mechanisms depending on the parasite but which may be to be related to the capacity of the host to mount a Th2 response.
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New, James, Brian Dizon, Rodney King, and John Kearney. "Modulation of autoimmune diabetes by innate-like B cell derived antibodies specific for N-acetyl-D-glucosamine. (BA7P.148)." Journal of Immunology 194, no. 1_Supplement (May 1, 2015): 115.8. http://dx.doi.org/10.4049/jimmunol.194.supp.115.8.
Повний текст джерелаАнотація:
Abstract The immunodominant epitope of Group A Streptococcus (GAS) is the cell wall associated N-acetyl-D-Glucosamine (GlcNAc) of Group A Carbohydrate (GAC). Previous reports in humans and rodent models have suggested a link between GAS exposure and protection from T1D. Through neonatal immunization with GAS and serum-transfer experiments we find that T1D protection elicited by neonatal GAS exposure is conferred by the antibody (Ab) response to GAC, and the differentiation of unique GlcNAc-specific clonotypes into long-lived plasma cells. Glycan microarray analysis of GAC-specific antibodies indicates they recognize aberrantly truncated mammalian glycans. GlcNAc-terminating glycans exist on a subset of insulin-containing granules and are generated as neoepitpoes during beta cell apoptosis. We find GAC-specific Abs directly block recognition of GlcNAc-modified autoantigens by innate lectins, dampen inflammatory complement activation, and reduce the capacity of dendritic cells to present beta cell antigen. Importantly, T1D patients are deficient in GAS-reactive IgM antibodies. These observations suggest that early exogenous antigen exposure in crucial for developing protective GlcNAc-specific natural antibodies and validate a role for the hygiene hypothesis in T1D. Subsets of GlcNAc-specific antibodies may serve as biomarkers for identifying at-risk patients with natural antibody deficits, and boosting these clonotypes may serve to suppress T1D development
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Sugihara, S., H. Fujiwara, and G. M. Shearer. "Autoimmune thyroiditis induced in mice depleted of particular T cell subsets. Characterization of thyroiditis-inducing T cell lines and clones derived from thyroid lesions." Journal of Immunology 150, no. 2 (January 15, 1993): 683–94. http://dx.doi.org/10.4049/jimmunol.150.2.683.
Повний текст джерелаАнотація:
Abstract We have previously shown that autoimmune thyroiditis spontaneously develops in T cell-depleted (C57BL/6xC3H/He)F1 mice after adoptive transfer of syngeneic lymphoid cells that have been depleted of CD5bright T lymphocytes. This mouse model was considered to be an instructive model for Hashimoto's thyroiditis in humans, and suggested that CD5dull CD4+ autoreactive T cells are not deleted in normal lymphoid cell populations and induce thyroiditis after elimination of regulatory T cell subsets. In our study, we have established thyroid-derived T cell lines and clones by culturing thyroid-infiltrating lymphocytes with thyroid epithelial cells and syngeneic feeder cells in the presence of exogenous IL-2. Both CD4+ T cells and CD8+ T cells were identified and their CD5 expression was dull or negative. In our report, we focused on CD4+ T cells. Four CD4+ T cell lines and 19 clones were generated and characterized. CD4+ T cell clones derived from F1 hybrid (H-2b/k) mice responded to thyroid Ag in the context of not only class II MHC molecules from both parental strains (I-Ak or I-Ab), but also F1 unique MHC molecules. Thyroglobulin (Tg) was demonstrated to be a major autoantigen of the thyroid for T cell responses, and at least two epitopes of Tg were suggested to be recognized by T cell clones. An additional undefined thyroid component other than Tg was recognized by some T cell clones. Thyroid-derived T cells were all TCR-alpha beta+. Five types of V beta usage (V beta 2, 4, 8.3, 14, and an undefined V beta) were found in CD4+ T cells. Finally, the thyroid lesions could be transferred to syngeneic mice by five distinct groups of CD4+ T cell clones, which were distinguished on the basis of their Ag specificity, MHC restriction, and TCRV beta usage. The considerable heterogeneity of TCRV beta usage of thyroiditis-inducing T cell clones in this study may be attributed to the multiple patterns of their recognition of the thyroid autoantigens. These findings provide important implications for further understanding of organ-specific autoimmune processes induced by depletion of regulatory T cell subsets.
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Porst, Theresa, Jörg Johannes, Hans Gluschke, Richard Köhler, Sebastian Mehl, Peter Kühnen, Kostja Renko, Waldemar B. Minich, Susanna Wiegand, and Lutz Schomburg. "Natural Autoimmunity to the Thyroid Hormone Monocarboxylate Transporters MCT8 and MCT10." Biomedicines 9, no. 5 (April 30, 2021): 496. http://dx.doi.org/10.3390/biomedicines9050496.
Повний текст джерелаАнотація:
The monocarboxylate transporters 8 (MCT8) and 10 (MCT10) are important for thyroid hormone (TH) uptake and signaling. Reduced TH activity is associated with impaired development, weight gain and discomfort. We hypothesized that autoantibodies (aAb) to MCT8 or MCT10 are prevalent in thyroid disease and obesity. Analytical tests for MCT8-aAb and MCT10-aAb were developed and characterized with commercial antiserum. Serum samples from healthy controls, thyroid patients and young overweight subjects were analyzed, and prevalence of the aAb was compared. MCT8-aAb were additionally tested for biological effects on thyroid hormone uptake in cell culture. Positive MCT8-aAb and MCT10-aAb were detected in all three clinical cohorts analyzed. MCT8-aAb were most prevalent in thyroid patients (11.9%) as compared to healthy controls (3.8%) and overweight adolescents (4.2%). MCT8-aAb positive serum reduced T4 uptake in cell culture in comparison to MCT8-aAb negative control serum. Prevalence of MCT10-aAb was highest in the group of thyroid patients as compared to healthy subjects or overweight adolescents (9.0% versus 4.5% and 6.3%, respectively). We conclude that MCT8 and MCT10 represent autoantigens in humans, and that MCT8-aAb may interfere with regular TH uptake and signaling. The increased prevalence of MCT8-aAb and MCT10-aAb in thyroid disease suggests that their presence may be of pathophysiological relevance. This hypothesis deserves an analysis in large prospective studies.
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Ogra, Pearay L., Howard Faden, and Robert C. Welliver. "Vaccination Strategies for Mucosal Immune Responses." Clinical Microbiology Reviews 14, no. 2 (April 1, 2001): 430–45. http://dx.doi.org/10.1128/cmr.14.2.430-445.2001.
Повний текст джерелаАнотація:
SUMMARY Mucosal administration of vaccines is an important approach to the induction of appropriate immune responses to microbial and other environmental antigens in systemic sites and peripheral blood as well as in most external mucosal surfaces. The development of specific antibody- or T-cell-mediated immunologic responses and the induction of mucosally induced systemic immunologic hyporesponsiveness (oral or mucosal tolerance) depend on complex sets of immunologic events, including the nature of the antigenic stimulation of specialized lymphoid structures in the host, antigen-induced activation of different populations of regulatory T cells (Th1 versus Th2), and the expression of proinflammatory and immunoregulatory cytokines. Availability of mucosal vaccines will provide a painless approach to deliver large numbers of vaccine antigens for human immunization. Currently, an average infant will receive 20 to 25 percutaneous injections for vaccination against different childhood infections by 18 months of age. It should be possible to develop for human use effective, nonliving, recombinant, replicating, transgenic, and microbial vector- or plant-based mucosal vaccines to prevent infections. Based on the experience with many dietary antigens, it is also possible to manipulate the mucosal immune system to induce systemic tolerance against environmental, dietary, and possibly other autoantigens associated with allergic and autoimmune disorders. Mucosal immunity offers new strategies to induce protective immune responses against a variety of infectious agents. Such immunization may also provide new prophylactic or therapeutic avenues in the control of autoimmune diseases in humans.
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Bonifacio, Ezio, Miriam Scirpoli, Katharina Kredel, Martin Füchtenbusch, and Anette-G. Ziegler. "Early Autoantibody Responses in Prediabetes Are IgG1 Dominated and Suggest Antigen-Specific Regulation." Journal of Immunology 163, no. 1 (July 1, 1999): 525–32. http://dx.doi.org/10.4049/jimmunol.163.1.525.
Повний текст джерелаАнотація:
Abstract The islet autoimmunity of preclinical type 1 diabetes remains poorly characterized in humans. In this paper, the IgG subclass response to the islet autoantigens insulin, glutamic acid decarboxylase, and IA-2 was studied sequentially from birth to diabetes onset or current follow-up in 26 autoantibody positive offspring of parents with diabetes. Islet autoantibody appearance was characterized by an early IgG1 peak response to one or more Ags, most commonly to insulin, at a median age of 2.2 yr (interquartile range, 2–2.9 yr). In five offspring, an acute fulminant β-cell destruction and diabetes onset occurred during this initial Ab response. In the remainder, early Ab levels declined markedly, and Ab peaks against other β cell Ags arose sequentially over several years suggesting regulation and spreading of autoimmunity. Second peak Ab responses to the same Ag were observed in only two offspring, both developing diabetes at this time. Two others developed diabetes with declining Ab levels. Abs of IgG1 subclass dominated against each Ag, and other subclasses, were usually only detected during peak IgG1 responses. The IgG4 response to insulin was exceptional, being dominant over IgG1 in four offspring and in five others appeared and/or persisted after IgG1 levels declined. These Th2-associated IgG4 responses were not correlated with protection from diabetes. The presence of IgG1-restricted responses to DA2 were associated with diabetes development. These findings suggest that type 1 diabetes has an early acute destructive phase of β cell autoimmunity, which may be regulated and which spreads chronically until diabetes onset.
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Zhang, Xiao-Lin, Jun Peng, Shu-Qian Xu, Xin-Guang Liu, Yuan Yu, Ping Qin, Yan Shi, Lin Wang, and Ming Hou. "Cell-Based Immunotherapy with Different Subsets of Tolerogenic Dendritic Cell in Idiopathic Thrombocytopenic Purpura." Blood 112, no. 11 (November 16, 2008): 3408. http://dx.doi.org/10.1182/blood.v112.11.3408.3408.
Повний текст джерелаАнотація:
Abstract There is growing evidence that tolerogenic dendritic cells (DCs) play an important role in maintaining peripheral tolerance through the induction of anergic or regulatory T cells. However, in humans, little is known about the ability of tolerogenic DCs to induce tolerance to autoantigens in autoimmune patients. Idiopathic thrombocytopenic purpura (ITP) is an immune-mediated disease in which platelets are destroyed by antiplatelet autoantibodies. Here, we explored in vitro the ability of four subsets of tolerogenic DCs (i.e., immature DCs (imDCs), IL-10-modulated DCs (IL-10-DCs), vasoactive intestinal peptide-modulated DCs (VIP-DCs) or plasmacytoid DCs (pDCs)) derived from patients with ITP, to induce an anergic state or regulatory T cells in autologous platelet glycoprotein (GP)-specific T cells. GPIIb/IIIa-reactive T cells were preincubated with GPIIb/IIIa-loaded imDCs, IL- 10-DCs, pDCs or VIP-DCs, and then rechallenged with autologous mature DCs (mDCs) in the presence of GPIIb/IIIa. Only when T cells were cultured with GPIIb/IIIa-loaded VIP-DCs in primary incubation, inhibited proliferation of GPIIb/IIIa-reactive T cells could be observed at rechallenge with GPIIb/IIIa-loaded mDCs. The anergic state of VIPDC- primed GPIIb/IIIa-reactive T cells could be reversed when rechallenged with GPIIb/ IIIa-loaded mDCs in the presence of a high concentration of exogenous IL-2. Meanwhile, GPIIb/IIIa-reactive T cells were also cultured with VIP-DCs loaded with tetanus toxoid (TT). In contrast to T cells pretreated with GPIIb/IIIa-loaded VIP-DCs, GPIIb/IIIareactive T cells pretreated with TT-loaded VIP-DCs proliferated when rechallenged with GPIIb/IIIa-loaded mDCs, which demonstrated that the induced anergy of autoreactive T cells is antigen specific. Additionally, functional analysis showed that VIP-DC-modulated T cells could not suppress the proliferation of newly induced GPIIb/IIIa-reactive T cells when cocultured with GPIIb/IIIa-loaded mDCs. These results indicated that VIP-DCs could induce autoreactive T cells anergic but not functionally suppressive. Moreover, we found that coculture of VIP-DCs with autologous PBMCs resulted in reduced production of anti-GPIIb/IIIa antibodies, suggesting that GPIIb/IIIa-reactive T cells lost their helper function for inducing autoantibody production by B cells. In contrast, reduced antibody production could not be found when autologous PBMCs were cocultured with imDCs, IL-10-DCs or pDCs. In conclusion, our studies revealed the therapeutic potential of VIPDCs, compared with imDCs, IL-10-DCs or pDCs, to induce autoreactive T-cell anergy to GP antigens, which would in turn facilitate the reestablishment of autoantigen-specific tolerance in patients with ITP.
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Straub, Rainer H. "The Complex Role of Estrogens in Inflammation." Endocrine Reviews 28, no. 5 (August 1, 2007): 521–74. http://dx.doi.org/10.1210/er.2007-0001.
Повний текст джерелаАнотація:
There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17β-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor α and β depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.
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Ridgway, William M., Hiroaki Ito, Marcella Fassò, Chen Yu, and C. Garrison Fathman. "Analysis of the Role of Variation of Major Histocompatibility Complex Class II Expression on Nonobese Diabetic (NOD) Peripheral T Cell Response." Journal of Experimental Medicine 188, no. 12 (December 21, 1998): 2267–75. http://dx.doi.org/10.1084/jem.188.12.2267.
Повний текст джерелаАнотація:
The current paradigm of major histocompatibility complex (MHC) and disease association suggests that efficient binding of autoantigens by disease-associated MHC molecules leads to a T cell–mediated immune response and resultant autoimmune sequelae. The data presented below offer a different model for this association of MHC with autoimmune diabetes. We used several mouse lines expressing different levels of I-Ag7 and I-Ak on the nonobese diabetic (NOD) background to evaluate the role of MHC class II in the previously described NOD T cell autoproliferation. The ratio of I-Ag7 to I-Ak expression correlated with the peripheral T cell autoproliferative phenotype in the mice studied. T cells from the NOD, [NOD × NOD.I-Anull]F1, and NOD I-Ak transgenic mice demonstrated autoproliferative responses (after priming with self-peptides), whereas the NOD.H2h4 (containing I-Ak) congenic and [NOD × NOD.H2h4 congenic]F1 mice did not. Analysis of CD4+ NOD I-Ak transgenic primed lymph node cells showed that autoreactive CD4+ T cells in the NOD I-Ak transgenic mice were restricted exclusively by I-Ag7. Considered in the context of the avidity theory of T cell activation and selection, the reported poor peptide binding capacity of NOD I-Ag7 suggested a new hypothesis to explain the effects of MHC class II expression on the peripheral autoimmune repertoire in NOD mice. This new explanation suggests that the association of MHC with diabetes results from “altered” thymic selection in which high affinity self-reactive (potentially autoreactive) T cells escape negative selection. This model offers an explanation for the requirement of homozygous MHC class II expression in NOD mice (and in humans) in susceptibility to insulin-dependent diabetes mellitus.
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Gupta, Shivai, and Cuong Q. Nguyen. "Disease-specific antigen presentation on MHC class II is inhibited by a small molecule in Sjögren’s Syndrome." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 104.01. http://dx.doi.org/10.4049/jimmunol.206.supp.104.01.
Повний текст джерелаАнотація:
Abstract Sjogren’s Syndrome (SjS) is one of the more common autoimmune diseases that has a strong genetic linkage. To date, no vaccine or therapeutic exists to cure SjS, and patients must rely on lifelong therapies to treat symptoms. Class II MHC are the primary susceptibility loci that form the genetic basis for many auto-immune disorders including SjS. I-Ag7 is the MHC in NOD mice that is used for the presentation of autoantigens and plays a critical role in the adaptive immune response. HLA-DQ8 the MHC in humans, is analogous to I-Ag7, in the NOD mouse model and is an important model for the onset of SjS. Using an in-silico molecular docking program a chemical library was screened that defined small molecules that were capable of occupying specific structural pockets along the I-Ag7 binding groove, with the objective of influencing auto-antigen peptide presentation to T cells. In this study we show, that the small molecule TATD can inhibit TCR signaling based on the structural pocket targeting mechanism. TATD previously proven to inhibit the onset of diabetes by blocking the auto-antigen presentation on I-Ag7, was analyzed to observe effects of prevention of SjS by, preventing the accumulation of B and T cells within the salivary gland of NOD mice. Treated mice also showed reduction in the incidence of inflammatory cell infiltration into lacrimal and salivary glands as compared to control mice with notable reduction in of the hallmark SjS anti-nuclear antibodies of Ro52, Ro60 and La. As a result this study presents a novel method for identifying small molecules capable of inhibiting T cell responses, with potentially therapeutic applications.
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Windhagen, A., D. E. Anderson, A. Carrizosa, R. E. Williams, and D. A. Hafler. "IL-12 induces human T cells secreting IL-10 with IFN-gamma." Journal of Immunology 157, no. 3 (August 1, 1996): 1127–31. http://dx.doi.org/10.4049/jimmunol.157.3.1127.
Повний текст джерелаАнотація:
Abstract A clear differentiation of Th1 and Th2 cytokine-secreting subsets in humans has not yet been defined. To further examine cytokine-directed differentiation of human T cell responses to both exogenous and autoantigens, we generated 346 short term T cell lines at limiting dilutions from six normal individuals to tetanus toxoid and myelin basic protein in the presence of IL-2 with or without the addition of IL-12 and anti-IL-4 mAb. T cell lines were examined for [3H]thymidine incorporation and cytokine secretion of IFN-gamma, IL-4, and IL-10. After culture in the presence of IL-12 and anti-IL-4 mAb, the predominant T cell response to Ag stimulation was simultaneous secretion of IL-10 and IFN-gamma. The concomitant secretion of IL-10 and IFN-gamma by T cells was confirmed by stimulating lines in the absence of APCs with plate-bound anti-CD3 mAb after two rounds of Ag-specific stimulation. Moreover, IL-12 enhanced IL-10 and IFN-gamma production in a myelin basic protein-reactive T cell clone, demonstrating that a differentiated T cell clone could be induced to secrete both cytokines. The addition of a neutralizing anti-IFN-gamma Ab to cultures with IL-12 and anti-IL-4 mAb during the generation of tetanus toxoid-reactive lines had no effect on the induction of IL-10 and IFN-gamma secretion, indicating that IL-12 and not IFN-gamma was responsible for the induction of this subset of T cells. Thus, in human T cells, IL-12 induces concomitant secretion of IL-10 and IFN-gamma.
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Maas, Alex, Gemma M. Dingjan, Frank Grosveld, and Rudolf W. Hendriks. "Early Arrest in B Cell Development in Transgenic Mice That Express the E41K Bruton’s Tyrosine Kinase Mutant Under the Control of the CD19 Promoter Region." Journal of Immunology 162, no. 11 (June 1, 1999): 6526–33. http://dx.doi.org/10.4049/jimmunol.162.11.6526.
Повний текст джерелаАнотація:
Abstract Bruton’s tyrosine kinase (Btk) is a nonreceptor protein kinase that is defective in X-linked agammaglobulinemia in humans and in X-linked immunodeficiency in mice. To study the effect of Btk activation in early B cell development in vivo, we have created transgenic mouse strains expressing Btk under the control of the human CD19 promoter region. The transgenic expression of wild-type human Btk corrected all X-linked immunodeficiency features in mice carrying a targeted disruption of the Btk gene. In contrast, expression of an activated form of Btk, the E41K mutant, resulted in an almost complete arrest of B cell development in the immature IgM+IgD− B cell stage in the bone marrow, irrespective of the presence of the endogenous intact Btk gene. Immature B cells were arrested at the progression from IgMlow into IgMhigh cells, which reflects the first immune tolerance checkpoint at which autoreactive B cells become susceptible to apoptosis. As the constitutive activation of Btk is likely to mimic B cell receptor occupancy by autoantigens in the bone marrow, our findings are consistent with a role for Btk as a mediator of B cell receptor-induced apoptotic signals in the immature B cell stage. Whereas the peripheral mature B cell pool was reduced to <1% of the normal size, significant numbers of IgM-secreting plasma cells were present in the spleen. Serum IgM levels were substantial and increased with age, but specific Ab responses in vivo were lacking. We conclude that the residual peripheral B cells were efficiently driven into IgM+ plasma cell differentiation, apparently without functional selection.
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Meyer, Sara C., Carlo R. Largiader, Shengyu Jin, X. Long Zheng, Clemens A. Dahinden, James N. George, Bernhard Lammle, and Johanna A. Kremer Hovinga. "The ADAMTS13 Gene as the Immunological Culprit in Acute Acquired TTP - First Evidence of Genetic Out-Breeding Depression in Humans." Blood 110, no. 11 (November 16, 2007): 277. http://dx.doi.org/10.1182/blood.v110.11.277.277.
Повний текст джерелаАнотація:
Abstract Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder due to autoantibodies against ADAMTS13. The case of identical twins suffering from acute acquired TTP with severe autoantibody-mediated ADAMTS13 deficiency (Studt JD et al., Blood2004;103:4195) led us to speculate on unknown genetic determinants of acquired TTP and on the immunological basis of ADAMTS13 autoimmunity. We investigated 37 patients (pts) with acute TTP with acquired severe ADAMTS13 deficiency of <10% of the normal, as well as 60 healthy controls. We measured ADAMTS13 activity, anti-ADAMTS13 IgG by ELISA and searched for a functional ADAMTS13 inhibitor. The ADAMTS13 gene was sequenced and 15 short tandem repeats (STR) at loci not linked to the ADAMTS13 gene were analyzed. Genotypic data of 25 polymorphic markers on the ADAMTS13 gene were used for haplotype inference. Inter-allelic diversity was assessed by summing up the number of individual heterozygous base positions for the polymorphic markers on the ADAMTS13 gene and the STR loci separately. Identified ADAMTS13 mutations were expressed in COS-7 cells and their effect on biosynthesis, secretion and activity was determined. We found that 4 of 37 pts with severe acquired ADAMTS13 deficiency were heterozygous carriers of an ADAMTS13 mutation. The mutation P457L, found in two pts, is a known mutation reported in hereditary TTP. R1096H and A1145T are new mutations. Expression studies revealed that P457L and A1145T mutants were secreted normally, but showed reduced activity of 44% and 11%, respectively. Secretion of the R1096H mutant, however, was reduced. A particular ADAMTS13 haplotype (designated H6) inferred from single nucleotide polymorphism (SNP) data was significantly more frequent in pts than in controls (p<0.0001). Moreover, individual ADAMTS13 inter-allelic diversity was significantly higher in pts than in controls (p=0.012). Primarily, non-synonymous SNPs, which encode amino acid exchanges, contributed to this phenomenon (p=0.0014). The increased inter-allelic diversity in pts was found to be restricted to and specific for the ADAMTS13 gene, as individual inter-allelic diversity at 15 neutral STR markers was similar in pts and controls. In conclusion, heterozygous ADAMTS13 missense mutations are found in a high frequency in pts with acquired TTP. The mutations P457L, R1096H and A1145T, reduce baseline ADAMTS13 activity in vitro by at least 50% and may render heterozygous carriers more susceptible for TTP. In addition, ADAMTS13 mutations, such as R1096H, may promote autoantibody production due to increased intracellular degradation and MHC presentation. The ADAMTS13 haplotype H6 and particularly the increased inter-allelic diversity represent risk factors for autoimmunity towards ADAMTS13 and acute acquired TTP. ADAMTS13 autoimmunity as a result of increased inter-allelic diversity represents the first example of genetic out-breeding depression in humans. As autoantigens in general seem to have increased numbers of SNPs, increased inter-allelic diversity may represent an important pathophysiological feature in other autoimmune disorders as well.
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Logtenberg, T., P. M. Melissen, A. Kroon, F. H. Gmelig-Meyling, and R. E. Ballieux. "Autoreactive B cells in normal humans. Autoantibody production upon lymphocyte stimulation with autoantigen-xenoantigen conjugates." Journal of Immunology 140, no. 2 (January 15, 1988): 446–50. http://dx.doi.org/10.4049/jimmunol.140.2.446.
Повний текст джерелаАнотація:
Abstract Mononuclear cells (MNC) from the blood of healthy individuals cannot be stimulated in vitro with the soluble autoantigen thyroglobulin (Tg). However, when Tg or pepsin fragments of Tg were coupled with a carrier protein, tetanus toxoid (TT), MNC from four healthy TT vaccinated individuals responded to the carrier-autoantigen conjugates by generating anti-Tg antibody forming cells (AFC), as shown in a spot enzyme-linked immunosorbent assay. Generation of anti-TT and anti-Tg AFC after stimulation with the conjugates required the donors to be boostered with TT. The autoantibodies were exclusively of the IgM class, in contrast to the carrier-specific anti-TT antibodies, which were predominantly of the IgG isotype. Activation of normal B cells to anti-Tg production was dependent on the presence of T cells in the cultures and required physical linkage of carrier and autoantigen: no anti-Tg AFC could be detected when MNC were stimulated with uncoupled combinations of Tg and TT. The autoreactive and the carrier-reactive B cells exhibited almost identical conjugate dose-response profiles, which suggest that they responded in a similar way to regulatory signals. These findings indicate that normal blood B cells are competent to respond to the autoantigen Tg in conjunction with signals originating from xeno-antigen-stimulated T cells.
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Ciavatta, Dominic J., JiaJin Yang, Gloria A. Preston, Anshul K. Badhwar, Hong Xiao, Peter Hewins, Carla M. Nester, et al. "Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis." Journal of Clinical Investigation 120, no. 9 (September 1, 2010): 3209–19. http://dx.doi.org/10.1172/jci40034.
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McLachlan, Sandra M., and Basil Rapoport. "Autoimmune Response to the Thyroid in Humans: Thyroid Peroxidase-The Common Autoantigenic Denominator." International Reviews of Immunology 19, no. 6 (January 2000): 587–618. http://dx.doi.org/10.3109/08830180009088514.
Повний текст джерела
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Danner, Rebecca, Michael Pereckas, Joseph Rouse, Amanda Wahhab, and Robert Lochhead. "Immunopeptidomics analysis of Lyme arthritis: insights into infection and autoimmunity." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 93.10. http://dx.doi.org/10.4049/jimmunol.206.supp.93.10.
Повний текст джерелаАнотація:
Abstract Background: Lyme arthritis (LA) is caused by infection with the Lyme disease spirochete Borrelia burgdorferi (Bb) and in humans is often accompanied by autoimmune T and B cell responses. In this study, we used an immunopeptidomics approach to gain further insight into mechanisms of infection-induced autoimmunity. Methods: C57BL/6 (B6) mice, which develop mild, self-limiting LA, and B6 Il10−/− mice, which develop chronic, autoimmune-like LA, were inoculated with 2×104 Bb. Inguinal and popliteal lymph nodes (LN) were harvested from infected mice at 4 weeks and 16 weeks post-inoculation. MHC class II molecules were isolated by immunoaffinity capture and MHC-bound peptides were identified by LC/MS/MS. Results: Nearly 10,000 MHCII-bound peptides were identified. At 4 weeks post-inoculation, representing the peak of LA, proteins involved in leukocyte trans-endothelial migration, tissue repair, and immune activation, including a known Lyme autoantigen ApoB-100, were over-represented in both B6 and Il10−/− mice. Peptides from these proteins returned to near baseline levels in LN from B6 mice at 16 weeks post-inoculation, when arthritis resolves, but were further enriched in Il10−/− mice at 16 weeks, during the chronic, autoimmune-like phase. Surprisingly, only 27 peptides derived from Bb proteins were identified, all but one of which were from proteins found in the inner membrane, periplasm, or cytosol. Conclusions: This study identified immune-relevant proteins presented by APCs in draining LN that are associated with LA development, which included ApoB-100, a known Lyme autoantigen in humans. Further studies are underway to assess T cell responses to identified Bb and self-peptides, including ApoB-100, during Bb infection.
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Malkovics, Tamás, Anna Görög, and Miklós Sárdy. "Role of transglutaminases in dermatitis herpetiformis." Bőrgyógyászati és Venerológiai Szemle 99, no. 1 (March 14, 2023): 60–69. http://dx.doi.org/10.7188/bvsz.2023.99.1.8.
Повний текст джерелаАнотація:
In this review article, after a short introduction, the authors present the pathogenesis and pathomechanism of dermatitis herpetiformis from the perspective of the transglutaminase enzyme family. According to our current knowledge, these isoenzymes consist of nine members in humans, and four of them play a role in the development of the disease. The main autoantigen is probably epidermal transglutaminase, but the role of other isozymes cannot be neglected either. The mechanism of the development of gluten-sensitive enteropathy is presented, followed by the theory of formation of IgA-epidermal transglutaminase immune complexes. The article also briefly covers the associated disorders of the blood coagulation system and neurological conditions.
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Moslehi, Javid. "Abstract IA21: Immune Checkpoint Inhibitor-Associated Myocarditis: Learning from mice and humans." Cancer Immunology Research 10, no. 12_Supplement (December 1, 2022): IA21. http://dx.doi.org/10.1158/2326-6074.tumimm22-ia21.
Повний текст джерелаАнотація:
Abstract We and others have defined cardiovascular toxicities including myocarditis as an infrequent, but often fatal toxicity associated with immune checkpoint inhibitors (ICI).1 ICI-myocarditis is characterized by refractory electrophysiological disturbances, concomitant myositis, T-cell and macrophage infiltration into the myocardium and frequent mortality.2-4 Existing clinical practice extrapolates from general myocarditis literature for diagnosis of ICI-associated myocarditis with diagnosis being made using a combination of biomarkers (specifically troponin), cardiac imaging and biopsy.5 To better define mechanisms of ICI-associated myocarditis, our group has developed several mouse models. These include pharmacological models and genetic mouse models (where one or more immune checkpoints are genetically deleted). Specifically, monoallelic loss of Ctla4 (gene for CTLA-4) in the context of complete genetic absence of Pdcd1 (gene for PD-1) leads to premature death in approximately half of mice, resulting from myocardial infiltration by T cells and macrophages and severe electrocardiographic abnormalities, closely recapitulating the clinical and pathologic hallmarks of ICI-associated myocarditis observed in patients.6 Using this model, we show that Ctla4 and Pdcd1 functionally interact in a gene dosage–dependent manner, providing a mechanism by which myocarditis arises with increased frequency in the setting of combination ICI therapy. We demonstrate that intervention with CTLA4–Ig (abatacept) is sufficient to ameliorate disease progression and additionally provide a case series of patients in which abatacept mitigates the fulminant course of ICI myocarditis.7 More recently, we show that single cell RNA/T cell receptor (TCR) sequencing on the cardiac immune infiltrate of ICI-myocarditis mice identifies clonal effector CD8+ T cells as the dominant cell population. Treatment with anti-CD8, but not anti-CD4, depleting antibodies rescued survival myocarditis with adoptive transfer of immune cells from mice with myocarditis induced fatal myocarditis in recipients which required CD8+ T cells. Alpha-myosin, a cardiac specific protein absent from the thymus was identified as the cognate antigen source for three MHC-I restricted TCRs derived from mice with fulminant myocarditis. Peripheral blood T cells from three patients with ICI-myocarditis were expanded by alpha-myosin peptides, and these alpha-myosin expanded T cells shared TCR clonotypes with diseased heart and skeletal muscles, indicating that alpha-myosin may be a clinically important autoantigen in ICI-myocarditis. These studies underscore the critical role for cytotoxic CD8+ T cells, are the first to identify a candidate autoantigen in ICI-myocarditis and yield new insights into ICI toxicity pathogenesis. We have leveraged these mouse models and a growing population of ICI-myocarditis cases from around the world to define novel diagnostic and treatment strategies for these groups of patients. Citation Format: Javid Moslehi. Immune Checkpoint Inhibitor-Associated Myocarditis: Learning from mice and humans [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr IA21.
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Waldner, Hanspeter, Gregory Berry, Lynn Budgeon, Timothy Cooper, and Neil Christensen. "The type 1 diabetes resistance locus B10 Idd9.3 impairs B cell development and implicates microRNA-34a as a regulator of T1D pathogenesis (BA14P.200)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 178.1. http://dx.doi.org/10.4049/jimmunol.192.supp.178.1.
Повний текст джерелаАнотація:
Abstract Type 1 diabetes (T1D) is an autoimmune disease resulting from the T cell-mediated destruction of insulin-producing pancreatic beta cells. Multiple insulin-dependent diabetes (Idd) loci confer T1D susceptibility or resistance in both humans and nonobese diabetic (NOD) mice, but the genes and mechanisms by which they control disease development are largely unknown. NOD.B10 Idd9.3 mice contain the Idd9.3 locus from T1D-resistant C57BL/10 mice that encodes 19 genes, including microRNA (miR)-34a, and confers partial T1D protection. B cells have been shown to play a critical role in priming autoantigen-specific CD4+ T cells in NOD mice. We show that early B cell development is impaired in NOD.B10 Idd9.3 mice, resulting in significant reduction of splenic B cells compared to NOD mice. Molecular analysis revealed that miR-34a expression was significantly elevated in B cell progenitors and marginal zone B cells of NOD.B10 Idd9.3 mice compared to NOD mice. Furthermore, miR-34a expression inversely correlated with levels of Foxp1, an essential regulator of B cell lymphopoiesis, which is directly repressed by miR-34a. Importantly, peripheral B cell paucity in NOD.B10 Idd9.3 mice was associated with impaired proliferation of islet-antigen-specific CD4+ T cells in response to endogenous autoantigen in pancreatic lymph nodes. These data suggest that miR-34a negatively regulates B cell development in NOD.B10 Idd9.3 mice and thereby may contribute to their T1D protection.
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St Clair, E. W., D. Kenan, J. A. Burch, J. D. Keene, and D. S. Pisetsky. "The fine specificity of anti-La antibodies induced in mice by immunization with recombinant human La autoantigen." Journal of Immunology 144, no. 10 (May 15, 1990): 3868–76. http://dx.doi.org/10.4049/jimmunol.144.10.3868.
Повний текст джерелаАнотація:
Abstract Because of increasing evidence suggesting that anti-La autoantibodies are induced in humans by an Ag-specific mechanism, we investigated the antibody response of animals immunized with the human La Ag and studied its relationship to the anti-La response of autoimmune patients. Anti-La antibodies were raised in 6- to 8-wk-old male MRL(-)+/+, C57BL/6J, BALB/c, and A/J mice by immunizing with authentic human La protein obtained by recombinant expression in Escherichia coli. As we have shown previously for human autoantibodies, induced mouse anti-La antibodies reacted with recombinant fusion proteins containing nonoverlapping sequences from different portions of the La molecule. The epitope specificity of antibodies to the middle region of the La Ag was further evaluated using six synthetic La peptides predicted to be antigenic based on their hydrophilic properties. Although the induced mouse anti-La antibodies bound to five of the six synthetic La peptides, human anti-La autoantibodies failed to recognize any of the peptide homologs. These results suggest that mice respond to immunization with human La protein differently than humans who develop autoimmunity to this self Ag.
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van Sechel, Arianne C., Jeffrey J. Bajramovic̀, Marianne J. B. van Stipdonk, Carla Persoon-Deen, Sacha B. Geutskens та Johannes M. van Noort. "EBV-Induced Expression and HLA-DR-Restricted Presentation by Human B Cells of αB-Crystallin, a Candidate Autoantigen in Multiple Sclerosis". Journal of Immunology 162, № 1 (1 січня 1999): 129–35. http://dx.doi.org/10.4049/jimmunol.162.1.129.
Повний текст джерелаАнотація:
Abstract The development of multiple sclerosis is most likely influenced by autoimmune responses to central nervous system myelin proteins as well as by infections with common viruses such as EBV and human herpesvirus-6. However, much remains to be established on how these factors interact. In this study, we show that upon EBV infection, human B cells start to express αB-crystallin, a small stress protein that was identified previously as an immunodominant Ag of CNS myelin in multiple sclerosis patients. EBV-induced expression of αB-crystallin in B cells leads to HLA-DR-restricted presentation of the protein and to activation of proinflammatory αB-crystallin-specific Th cells. While αB-crystallin is present in EBV-infected human B cells, the protein is absent from human lymphoid tissues under normal conditions. This is in sharp contrast to other stress proteins such as heat-shock protein (hsp)27 and hsp60 that are ubiquitously expressed in these tissues. In addition, the absence of αB-crystallin from lymphoid tissues in humans is unique as compared with other mammals. All other species examined, including rodents, sheep, and primates, showed constitutive expression of αB-crystallin in secondary lymphoid tissues and sometimes even in the thymus. Since constitutive lymphoid expression most likely results in immunologic tolerance, such a state of tolerance to αB-crystallin can be expected for all of these species, but not for humans. When taken together, our data provide evidence for a novel mechanism by which common viral infections can trigger myelin-directed autoimmunity in a way that is unique for humans.