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[PMID]: 28468970
[Au] Autor:Chowdhary VR; Krogman A; Tilahun AY; Alexander MP; David CS; Rajagopalan G
[Ad] Address:Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, MN 55905.
[Ti] Title:Concomitant Disruption of and Genes Facilitates the Development of Double Negative αß TCR Peripheral T Cells That Respond Robustly to Staphylococcal Superantigen.
[So] Source:J Immunol;198(11):4413-4424, 2017 06 01.
[Is] ISSN:1550-6606
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Mature peripheral double negative T (DNT) cells expressing αß TCR but lacking CD4/CD8 coreceptors play protective as well as pathogenic roles. To better understand their development and functioning in vivo, we concomitantly inactivated and genes in mice with intact MHC class I and class II molecules with the hypothesis that this would enable the development of DNT cells. We also envisaged that these DNT cells could be activated by bacterial superantigens in vivo as activation of T cells by superantigens does not require CD4 and CD8 coreceptors. Because HLA class II molecules present superantigens more efficiently than murine MHC class II molecules, CD4 CD8 double knockout (DKO) mice transgenically expressing HLA-DR3 or HLA-DQ8 molecules were generated. Although thymic cellularity was comparable between wild type (WT) and DKO mice, CD3 αß TCR thymocytes were significantly reduced in DKO mice, implying defects in thymic-positive selection. Splenic CD3 αß TCR cells and Foxp3 T regulatory cells were present in DKO mice but significantly reduced. However, the in vivo inflammatory responses and immunopathology elicited by acute challenge with the staphylococcal superantigen enterotoxin B were comparable between WT and DKO mice. Choric exposure to staphylococcal enterotoxin B precipitated a lupus-like inflammatory disease with characteristic lympho-monocytic infiltration in lungs, livers, and kidneys, along with production of anti-nuclear Abs in DKO mice as in WT mice. Overall, our results suggest that DNT cells can develop efficiently in vivo and chronic exposure to bacterial superantigens may precipitate a lupus-like autoimmune disease through activation of DNT cells.
[Mh] MeSH terms primary: CD4 Antigens/genetics
CD4 Antigens/immunology
CD8 Antigens/genetics
CD8 Antigens/immunology
Enterotoxins/immunology
Superantigens/immunology
T-Lymphocyte Subsets/immunology
[Mh] MeSH terms secundary: Animals
HLA-DQ Antigens/genetics
HLA-DQ Antigens/immunology
HLA-DR3 Antigen/genetics
HLA-DR3 Antigen/immunology
Histocompatibility Antigens Class II/immunology
Mice
Mice, Knockout
Mice, Transgenic
Receptors, Antigen, T-Cell, alpha-beta/genetics
Receptors, Antigen, T-Cell, alpha-beta/immunology
Spleen/cytology
Spleen/immunology
Thymus Gland/cytology
Thymus Gland/immunology
[Pt] Publication type:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL
[Nm] Name of substance:0 (CD4 Antigens); 0 (CD8 Antigens); 0 (Enterotoxins); 0 (HLA-DQ Antigens); 0 (HLA-DQ8 antigen); 0 (HLA-DR3 Antigen); 0 (Histocompatibility Antigens Class II); 0 (Receptors, Antigen, T-Cell, alpha-beta); 0 (Superantigens); 39424-53-8 (enterotoxin B, staphylococcal)
[Em] Entry month:1709
[Cu] Class update date: 180127
[Lr] Last revision date:180127
[Js] Journal subset:AIM; IM
[Da] Date of entry for processing:170505
[St] Status:MEDLINE
[do] DOI:10.4049/jimmunol.1601991

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[PMID]: 29126273
[Au] Autor:Gupta S; Köttgen A; Hoxha E; Brenchley P; Bockenhauer D; Stanescu HC; Kleta R
[Ad] Address:University College London-Centre for Nephrology, London, UK.
[Ti] Title:Genetics of membranous nephropathy.
[So] Source:Nephrol Dial Transplant;, 2017 Nov 06.
[Is] ISSN:1460-2385
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:An HLA-DR3 association with membranous nephropathy (MN) was described in 1979 and additional evidence for a genetic component to MN was suggested in 1984 in reports of familial MN. In 2009, a pathogenic autoantibody was identified against the phospholipase A2 receptor 1 (PLA2R1). Here we discuss the genetic studies that have proven the association of human leucocyte antigen class II and PLA2R1 variants and disease in MN. The common variants in PLA2R1 form a haplotype that is associated with disease incidence. The combination of the variants in both genes significantly increases the risk of disease by 78.5-fold. There are important genetic ethnic differences in MN. Disease outcome is difficult to predict and attempts to correlate the genetic association to outcome have so far not been helpful in a reproducible manner. The role of genetic variants may not only extend beyond the risk of disease development, but can also help us understand the underlying molecular biology of the PLA2R1 and its resultant pathogenicity. The genetic variants identified thus far have an association with disease and could therefore become useful biomarkers to stratify disease risk, as well as possibly identifying novel drug targets in the near future.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1711
[Cu] Class update date: 171110
[Lr] Last revision date:171110
[St] Status:Publisher
[do] DOI:10.1093/ndt/gfx296

  3 / 1364 MEDLINE  
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[PMID]: 28628857
[Au] Autor:Mahdavi M; Moreau V; Kheirollahi M
[Ad] Address:Genetic and Molecular biology Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address: mahdavi@pharm.mui.ac.ir.
[Ti] Title:Identification of B and T cell epitope based peptide vaccine from IGF-1 receptor in breast cancer.
[So] Source:J Mol Graph Model;75:316-321, 2017 Aug.
[Is] ISSN:1873-4243
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The insulin-like growth factor-1 receptor (IGF-1R) plays a key role in proliferation, growth, differentiation, and development of several human malignancies including breast and pancreatic adenocarcinoma. IGF-1R targeted immunotherapeutic approaches are particularly attractive, as they may potentially elicit even stronger antitumor responses than traditional targeted approaches. Cancer peptide vaccines can produce immunologic responses against cancer cells by triggering helper T cell (Th) or cytotoxic T cells (CTL) in association with Major Histocompatibility Complex (MHC) class I or II molecules on the cell surface of antigen presenting cells. In our previous study, we set a technique based on molecular docking in order to find the best MHC class I and II binder peptides using GOLD. In the present work, molecular docking analyses on a library consisting of 30 peptides mimicking discontinuous epitopes from IGF-1R extracellular domain identified peptides 249 and 86, as the best MHC binder peptides to both MHC class I and II molecules. The receptors most often targeted by peptide 249 are HLA-DR4, HLA-DR3 and HLA-DR2 and those most often targeted by peptide 86 are HLA-DR4, HLA-DP2 and HLA-DR3. These findings, based on bioinformatics analyses, can be conducted in further experimental analyses in cancer therapy and vaccine design.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1706
[Cu] Class update date: 170718
[Lr] Last revision date:170718
[St] Status:In-Process

  4 / 1364 MEDLINE  
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[PMID]: 28575582
[Au] Autor:Bounds CE; Terry FE; Moise L; Hannaman D; Martin WD; De Groot AS; Suschak JJ; Dupuy LC; Schmaljohn CS
[Ad] Address:a United States Army Medical Research Institute of Infectious Diseases , Fort Detrick , MD , USA.
[Ti] Title:An immunoinformatics-derived DNA vaccine encoding human class II T cell epitopes of Ebola virus, Sudan virus, and Venezuelan equine encephalitis virus is immunogenic in HLA transgenic mice.
[So] Source:Hum Vaccin Immunother;:1-13, 2017 Jun 02.
[Is] ISSN:2164-554X
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:Immunoinformatics tools were used to predict human leukocyte antigen (HLA) class II-restricted T cell epitopes within the envelope glycoproteins and nucleocapsid proteins of Ebola virus (EBOV) and Sudan virus (SUDV) and the structural proteins of Venezuelan equine encephalitis virus (VEEV). Selected epitopes were tested for binding to soluble HLA molecules representing 5 class II alleles (DRB1*0101, DRB1*0301, DRB1*0401, DRB1*0701, and DRB1*1501). All but one of the 25 tested peptides bound to at least one of the DRB1 alleles, and 4 of the peptides bound at least moderately or weakly to all 5 DRB1 alleles. Additional algorithms were used to design a single "string-of-beads" expression construct with 44 selected epitopes arranged to avoid creation of spurious junctional epitopes. Seventeen of these 44 predicted epitopes were conserved between the major histocompatibility complex (MHC) of humans and mice, allowing initial testing in mice. BALB/c mice vaccinated with the multi-epitope construct developed statistically significant cellular immune responses to EBOV, SUDV, and VEEV peptides as measured by interferon (IFN)-γ ELISpot assays. Significant levels of antibodies to VEEV, but not EBOV, were also detected in vaccinated BALB/c mice. To assess immunogenicity in the context of a human MHC, HLA-DR3 transgenic mice were vaccinated with the multi-epitope construct and boosted with a mixture of the 25 peptides used in the binding assays. The vaccinated HLA-DR3 mice developed significant cellular immune responses to 4 of the 25 (16%) tested individual class II peptides as measured by IFN-γ ELISpot assays. In addition, these mice developed antibodies against EBOV and VEEV as measured by ELISA. While a low but significant level of protection was observed in vaccinated transgenic mice after aerosol exposure to VEEV, no protection was observed after intraperitoneal challenge with mouse-adapted EBOV. These studies provide proof of concept for the use of an informatics approach to design a multi-agent, multi-epitope immunogen and provide a basis for further testing aimed at focusing immune responses toward desired protective T cell epitopes.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1706
[Cu] Class update date: 171101
[Lr] Last revision date:171101
[St] Status:Publisher
[do] DOI:10.1080/21645515.2017.1329788

  5 / 1364 MEDLINE  
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[PMID]: 28512681
[Au] Autor:Lipinska-Opalka A; Wawrzyniak A; Lewicki S; Zdanowski R; Kalicki B
[Ad] Address:Pediatric, Nephrology and Allergology Clinic, Military Institute of Medicine, Warsaw, Poland. lipinska.ag@gmail.com.
[Ti] Title:Evaluation of Immune Indices and Serum Vitamin D Content in Children with Atopic Dermatitis.
[So] Source:Adv Exp Med Biol;1020:81-89, 2017.
[Is] ISSN:0065-2598
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:The influence of vitamin D on allergic diseases, including atopic dermatitis, is linked to the presence of vitamin D nuclear receptors in immune cells. The present study seeks to determine the possible relationship between serum vitamin D content and immune indices in children with atopic dermatitis. The study was conducted in 19 children with atopic dermatitis. The control consisted of 17 age-matched healthy children. A single significant finding was a distinctly lower number of serum regulatory T cells in atopic dermatitis compared with controls (p < 0.00001). There were no appreciable differences between the two groups concerning the immunological indices such as the phenotypes: CD3, CD4, CD8, CD4/CD8, CD19, CD16/56, natural killer T cells, and anti-CD3 human leukocyte antigen - antigen D related cell surface receptor (HLA-DR3), or the percentage of lymphocytes, eosinophils, and the IgE level. We also revealed an inverse association between the serum vitamin D and the percentage of CD8+ cells (p < 0.05; r = 0.62) in atopic dermatitis. In conclusion, the results point to a regulatory role of T cells in the pathogenesis of atopic dermatitis, but fail to substantiate the influence of vitamin D on the course of the disease.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1705
[Cu] Class update date: 170820
[Lr] Last revision date:170820
[St] Status:In-Data-Review
[do] DOI:10.1007/5584_2017_20

  6 / 1364 MEDLINE  
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[PMID]: 27670087
[Au] Autor:Li CW; Osman R; Menconi F; Concepcion ES; Tomer Y
[Ad] Address:Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
[Ti] Title:Flexible peptide recognition by HLA-DR triggers specific autoimmune T-cell responses in autoimmune thyroiditis and diabetes.
[So] Source:J Autoimmun;76:1-9, 2017 Jan.
[Is] ISSN:1095-9157
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Autoimmune polyglandular syndrome 3 variant (APS3v) refers to the co-occurrence of autoimmune thyroiditis (AITD) and type 1 diabetes (T1D) within the same individual. HLA class II confers the strongest susceptibility to APS3v. We previously identified a unique amino acid signature of the HLA-DR pocket (designated APS3v HLA-DR pocket) that predisposes to APS3v. We hypothesized that both thyroid and islet peptides can be presented by the unique APS3v HLA-DR pocket, triggering AITD + T1D together. To test this hypothesis we screened islet and thyroid peptides for their ability to bind to the APS3v HLA-DR pocket. Virtual screen of all possible thyroglobulin (Tg), thyroid-stimulating hormone receptor (TSHR), thyroid peroxidase (TPO), insulin (Ins), and glutamic acid decarboxylase 65 (GAD65) peptides identified 36 peptides that bound to this unique pocket. In vitro binding assays using baculovirus-produced recombinant APS3v HLA-DR identified 11 thyroid/islet peptides (of the 36 predicted binders) that bound with high affinity. By immunizing humanized HLA-DR3 mice carrying the APS3v HLA-DR pocket we identified 4 peptides (Tg.1571, GAD.492, TPO.758, TPO.338) that were presented by antigen presenting cells and elicited T-cell response. We conclude that both thyroid and islet peptides can bind to this flexible APS3v HLA-DR pocket and induce thyroid and islet specific T-cell responses. These findings set the stage to developing specific inhibitors of the APS3v HLA-DR pocket as a precision medicine approach to treating or preventing APS3v in patients that carry this genetic HLA-DR pocket variant.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1609
[Cu] Class update date: 170220
[Lr] Last revision date:170220
[St] Status:In-Process

  7 / 1364 MEDLINE  
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[PMID]: 27602020
[Au] Autor:Inaba H; De Groot LJ; Akamizu T
[Ad] Address:The First Department of Medicine, Wakayama Medical University , Wakayama , Japan.
[Ti] Title:Thyrotropin Receptor Epitope and Human Leukocyte Antigen in Graves' Disease.
[So] Source:Front Endocrinol (Lausanne);7:120, 2016.
[Is] ISSN:1664-2392
[Cp] Country of publication:Switzerland
[La] Language:eng
[Ab] Abstract:Graves' disease (GD) is an organ-specific autoimmune disease, and thyrotropin (TSH) receptor (TSHR) is a major autoantigen in this condition. Since the extracellular domain of human TSHR (TSHR-ECD) is shed into the circulation, TSHR-ECD is a preferentially immunogenic portion of TSHR. Both genetic factors and environmental factors contribute to development of GD. Inheritance of human leukocyte antigen (HLA) genes, especially HLA-DR3, is associated with GD. TSHR-ECD protein is endocytosed into antigen-presenting cells (APCs), and processed to TSHR-ECD peptides. These peptide epitopes bind to HLA-class II molecules, and subsequently the complex of HLA-class II and TSHR-ECD epitope is presented to CD4+ T cells. The activated CD4+ T cells secrete cytokines/chemokines that stimulate B-cells to produce TSAb, and in turn hyperthyroidism occurs. Numerous studies have been done to identify T- and B-cell epitopes in TSHR-ECD, including (1) in silico, (2) in vitro, (3) in vivo, and (4) clinical experiments. Murine models of GD and HLA-transgenic mice have played a pivotal role in elucidating the immunological mechanisms. To date, linear or conformational epitopes of TSHR-ECD, as well as the molecular structure of the epitope-binding groove in HLA-DR, were reported to be related to the pathogenesis in GD. Dysfunction of central tolerance in the thymus, or in peripheral tolerance, such as regulatory T cells, could allow development of GD. Novel treatments using TSHR antagonists or mutated TSHR peptides have been reported to be effective. We review and update the role of immunogenic TSHR epitopes and HLA in GD, and offer perspectives on TSHR epitope specific treatments.
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Em] Entry month:1609
[Cu] Class update date: 170220
[Lr] Last revision date:170220
[Da] Date of entry for processing:160908
[St] Status:PubMed-not-MEDLINE
[do] DOI:10.3389/fendo.2016.00120

  8 / 1364 MEDLINE  
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[PMID]: 27506953
[Au] Autor:Sheen YH; Rajagopalan G; Snapper CM; Kita H; Wi CI; Umaretiya PJ; Juhn YJ
[Ad] Address:Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
[Ti] Title:Influence of HLA-DR polymorphism and allergic sensitization on humoral immune responses to intact pneumococcus in a transgenic mouse model.
[So] Source:HLA;88(1-2):25-34, 2016 Jul.
[Is] ISSN:2059-2310
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Asthma is independently associated with HLA-DR3 and increased risks of pneumococcal diseases. We aimed to determine whether HLA-DR polymorphism (HLA-DRB1*03), sensitization to house dust mite (HDM), or their interaction affects humoral immune responses to pneumococcal polysaccharide and protein antigens of intact pneumococci. Induction of serum titers of anti-pneumococcal polysaccharide and anti-surface protein IgM and IgG in response to immunization with intact pneumococci (Pn) serotype 14 was determined using humanized HLA-DR3 and DR2 transgenic mice. Transgenic mice were sensitized by injecting HDM and challenged with intranasal HDM. Mice were subsequently immunized with heat-killed Pn14 at day 24. Serum titers of anti-phosphorylcholine (PC) IgM and IgG, anti-pneumococcal polysaccharide, capsular type 14 (PPS14) IgM and IgG, and anti-pneumococcal surface protein A (PspA) IgG were measured. We included a total of 44 mice (22 DR3 and 22 DR2 mice) and half of mice in each group were sensitized with HDM (i.e. 22 HDM-sensitized and 22 control mice). HDM-sensitized mice, irrespective of HLA-DR polymorphism, had significantly lower humoral immune responses. HLA-DR3 mice, irrespective of HDM sensitization, elicited a significantly lower anti-PC IgG response. In contrast, the anti-PspA IgG response was higher in DR3 relative to DR2 mice. The effect of HDM sensitization on lowering humoral immune responses to Pn14 was observed in DR3 mice regardless of the nature of the antigen, whereas such decreases were observed only for the anti-PPS14 IgG and anti-PC IgM responses in DR2 mice. HDM sensitization lowered humoral immune responses to intact pneumococcus and this effect was significantly modified by the HLA-DR polymorphism.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1608
[Cu] Class update date: 171016
[Lr] Last revision date:171016
[Js] Journal subset:IM
[St] Status:In-Process
[do] DOI:10.1111/tan.12851

  9 / 1364 MEDLINE  
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[PMID]: 27314557
[Au] Autor:De Santis M; Ceribelli A; Cavaciocchi F; Generali E; Massarotti M; Isailovic N; Crotti C; Scherer HU; Montecucco C; Selmi C
[Ad] Address:Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Italy.
[Ti] Title:Effects of type II collagen epitope carbamylation and citrullination in human leucocyte antigen (HLA)-DR4(+) monozygotic twins discordant for rheumatoid arthritis.
[So] Source:Clin Exp Immunol;185(3):309-19, 2016 Sep.
[Is] ISSN:1365-2249
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:The aim of this study is to investigate the effect of the native, citrullinated or carbamylated type II human collagen T cell- and B cell-epitopes on the adaptive immune response in rheumatoid arthritis (RA). Peripheral blood T and B cells obtained from a human leucocyte D4-related (antigen DR4(-) HLA-DR4)(+) woman with early RA, her healthy monozygotic twin and an unrelated HLA-DR3(+) woman with early RA were analysed for activation (CD154/CD69), apoptosis (annexin/7-aminoactinomycin), cytokine production [interferon (IFN)γ/interleukin (IL)-17/IL-4/IL-10/IL-6] and functional phenotype (CD45Ra/CCR7) after stimulation with the collagen native T cell epitope (T261-273), the K264 carbamylated T cell epitope (carT261-273), the native B cell epitope (B359-369) or the R360 citrullinated B cell epitope (citB359-369), and the combinations of these. The T cell memory compartment was activated by T cell epitopes in both discordant DR4(+) twins, but not in the DR3(+) RA. The collagen-specific activation of CD4(+) T cells was induced with both the native and carbamylated T cell epitopes only in the RA twin. Both T cell epitopes also induced IL-17 production in the RA twin, but a greater IL-4 and IL-10 response in the healthy twin. The citrullinated B cell epitope, particularly when combined with the carbamylated T cell epitope, induced B cell activation and an increased IL-6/IL-10 ratio in the RA twin compared to a greater IL-10 production in the healthy twin. Our data suggest that circulating collagen-specific T and B cells are found in HLA-DR4(+) subjects, but only RA activated cells express co-stimulatory molecules and produce proinflammatory cytokines. Carbamylation and citrullination further modulate the activation and cytokine polarization of T and B cells.
[Mh] MeSH terms primary: Arthritis, Rheumatoid/immunology
Carbamates/metabolism
Collagen Type II/chemistry
Cytokines/blood
Epitopes, B-Lymphocyte/immunology
Epitopes, T-Lymphocyte/immunology
HLA-DR4 Antigen/immunology
[Mh] MeSH terms secundary: Adaptive Immunity
Adult
Carbamates/immunology
Collagen Type II/immunology
Epitopes, B-Lymphocyte/chemistry
Epitopes, T-Lymphocyte/chemistry
Female
HLA-DR4 Antigen/chemistry
Humans
Immunologic Memory
Interleukin-10/blood
Interleukin-17/blood
Interleukin-4/blood
Lymphocyte Activation
Phenotype
Protein Processing, Post-Translational
Twins, Monozygotic
[Pt] Publication type:JOURNAL ARTICLE
[Nm] Name of substance:0 (Carbamates); 0 (Collagen Type II); 0 (Cytokines); 0 (Epitopes, B-Lymphocyte); 0 (Epitopes, T-Lymphocyte); 0 (HLA-DR4 Antigen); 0 (IL10 protein, human); 0 (IL4 protein, human); 0 (Interleukin-17); 130068-27-8 (Interleukin-10); 207137-56-2 (Interleukin-4)
[Em] Entry month:1705
[Cu] Class update date: 170902
[Lr] Last revision date:170902
[Js] Journal subset:IM
[Da] Date of entry for processing:160618
[St] Status:MEDLINE
[do] DOI:10.1111/cei.12825

  10 / 1364 MEDLINE  
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[PMID]: 27271348
[Au] Autor:Wagner DH
[Ad] Address:Department of Medicine, Department of Neurology, Webb-Waring Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
[Ti] Title:Of the multiple mechanisms leading to type 1 diabetes, T cell receptor revision may play a prominent role (is type 1 diabetes more than a single disease?).
[So] Source:Clin Exp Immunol;185(3):271-80, 2016 Sep.
[Is] ISSN:1365-2249
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:A single determinant factor for autoimmunity does not exist; disease development probably involves contributions from genetics, the environment and immune dysfunction. Type 1 diabetes is no exception. Genomewide-associated studies (GWAS) analysis in T1D has proved disappointing in revealing contributors to disease prediction; the only reliable marker has been human leucocyte antigen (HLA). Specific HLAs include DR3/DR4/DQ2/DQ8, for example. Because HLA molecules present antigen to T cells, it is reasonable that certain HLA molecules have a higher affinity to present self-antigen. Recent studies have shown that additional polymorphisms in HLA that are restricted to autoimmune conditions are further contributory. A caveat is that not all individuals with the appropriate 'pro-autoimmune' HLA develop an autoimmune disease. Another crucial component is autoaggressive T cells. Finding a biomarker to discriminate autoaggressive T cells has been elusive. However, a subset of CD4 helper cells that express the CD40 receptor have been described as becoming pathogenic. An interesting function of CD40 on T cells is to induce the recombination-activating gene (RAG)1/RAG2 T cell receptor recombination machinery. This observation is contrary to immunology paradigms that changes in TCR molecules cannot take place outside the thymic microenvironment. Alteration in TCR, called TCR revision, not only occurs, but may help to account for the development of autoaggressive T cells. Another interesting facet is that type 1 diabetes (T1D) may be more than a single disease; that is, multiple cellular components contribute uniquely, but result ultimately in the same clinical outcome, T1D. This review considers the process of T cell maturation and how that could favor auto-aggressive T cell development in T1D. The potential contribution of TCR revision to autoimmunity is also considered.
[Mh] MeSH terms primary: Diabetes Mellitus, Type 1/immunology
Receptors, Antigen, T-Cell/physiology
T-Lymphocytes/metabolism
[Mh] MeSH terms secundary: Autoantigens/immunology
Autoimmunity/genetics
Autoimmunity/immunology
CD40 Antigens/immunology
Diabetes Mellitus, Type 1/genetics
Genes, RAG-1/genetics
HLA-DQ Antigens/genetics
HLA-DR3 Antigen/genetics
HLA-DR4 Antigen/genetics
Humans
Polymorphism, Genetic
Receptors, Antigen, T-Cell/immunology
T-Lymphocytes/immunology
T-Lymphocytes/pathology
[Pt] Publication type:JOURNAL ARTICLE; REVIEW
[Nm] Name of substance:0 (Autoantigens); 0 (CD40 Antigens); 0 (HLA-DQ Antigens); 0 (HLA-DR3 Antigen); 0 (HLA-DR4 Antigen); 0 (Receptors, Antigen, T-Cell)
[Em] Entry month:1705
[Cu] Class update date: 171116
[Lr] Last revision date:171116
[Js] Journal subset:IM
[Da] Date of entry for processing:160609
[St] Status:MEDLINE
[do] DOI:10.1111/cei.12819


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