ABSTRACT
AIMS/HYPOTHESIS: Among white European children developing type 1 diabetes, the otherwise common HLA haplotype DR15-DQ6 is rare, and highly protective. Adult-onset type 1 diabetes is now known to represent more overall cases than childhood onset, but it is not known whether DR15-DQ6 is protective in older-adult-onset type 1 diabetes. We sought to quantify DR15-DQ6 protection against type 1 diabetes as age of onset increased. METHODS: In two independent cohorts we assessed the proportion of type 1 diabetes cases presenting through the first 50 years of life with DR15-DQ6, compared with population controls. In the After Diabetes Diagnosis Research Support System-2 (ADDRESS-2) cohort (n = 1458) clinician-diagnosed type 1 diabetes was confirmed by positivity for one or more islet-specific autoantibodies. In UK Biobank (n = 2502), we estimated type 1 diabetes incidence rates relative to baseline HLA risk for each HLA group using Poisson regression. Analyses were restricted to white Europeans and were performed in three groups according to age at type 1 diabetes onset: 0-18 years, 19-30 years and 31-50 years. RESULTS: DR15-DQ6 was protective against type 1 diabetes through to age 50 years (OR < 1 for each age group, all p < 0.001). The following ORs for type 1 diabetes, relative to a neutral HLA genotype, were observed in ADDRESS-2: age 5-18 years OR 0.16 (95% CI 0.08, 0.31); age 19-30 years OR 0.10 (0.04, 0.23); and age 31-50 years OR 0.37 (0.21, 0.68). DR15-DQ6 also remained highly protective at all ages in UK Biobank. Without DR15-DQ6, the presence of major type 1 diabetes high-risk haplotype (either DR3-DQ2 or DR4-DQ8) was associated with increased risk of type 1 diabetes. CONCLUSIONS/INTERPRETATION: HLA DR15-DQ6 confers dominant protection from type 1 diabetes across the first five decades of life.
Subject(s)
Diabetes Mellitus, Type 1/genetics , HLA-DQ Antigens/genetics , HLA-DR Serological Subtypes/genetics , Adolescent , Adult , Age of Onset , Autoantibodies/blood , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/immunology , Female , Genotype , HLA-DQ Antigens/immunology , HLA-DR Serological Subtypes/immunology , Humans , Infant , Infant, Newborn , Male , Middle Aged , Polymorphism, Genetic , Risk Factors , United Kingdom , Young AdultABSTRACT
Human leukocyte antigen (HLA)-encoded surface molecules present antigenic peptides to T lymphocytes and play a key role in adaptive immune responses. Besides their physiological role of defending the host against infectious pathogens, specific alleles serve as genetic risk factors for autoimmune diseases. For multiple sclerosis (MS), an autoimmune disease that affects the brain and spinal cord, an association with the HLA-DR15 haplotype was described in the early 1970s. This short opinion piece discusses the difficulties of disentangling the details of this association and recent observations about the functional involvement of not only one, but also the second gene of the HLA-DR15 haplotype. This information is not only important for understanding the pathomechanism of MS, but also for antigen-specific therapies.
Subject(s)
HLA Antigens/genetics , Multiple Sclerosis/genetics , Genome-Wide Association Study , HLA-DR Serological Subtypes/genetics , Haplotypes/genetics , Humans , Multiple Sclerosis/immunology , T-Lymphocytes/immunologyABSTRACT
Humanized double transgenic mice express both HLA-DR15 (the MHC gene linked to MS) and TCR.Ob1A12 from a multiple sclerosis patient (that recognizes MBP85-99 presented by HLA-DR15), yet they fail to develop autoimmune encephalomyelitis quickly, although 5-10% develop disease at 12 months. These mice were found to express large numbers of IL-10-secreting splenocytes as early as 4 weeks of age. These regulatory T cells appeared spontaneously without prior immunization with the autoantigen MBP85-99. They were of murine origin and had a cytokine secretion profile and surface phenotype similar to that reported for Tr1 cells. Notably, the frequency of disease appeared to increase at 14 months. The diseased mice had small spleens which averaged 47 mg, while the remaining non-diseased mice in our colony killed at ages 14-15 months had splenocytes that averaged 80 mg (ranging from 47-130 mg). Thus, the appearance of disease was associated with diminution in numbers of IL-10-secreting regulatory T cells with age.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental/immunology , HLA-DR Serological Subtypes/metabolism , Interleukin-10/metabolism , Multiple Sclerosis/immunology , Receptors, Antigen, T-Cell, alpha-beta/metabolism , Spleen/pathology , T-Lymphocytes, Regulatory/immunology , Animals , Cells, Cultured , Disease Models, Animal , HLA-DR Serological Subtypes/genetics , Humans , Mice , Mice, Inbred C57BL , Mice, Transgenic , Myelin Basic Protein/immunology , Peptide Fragments/immunology , Receptors, Antigen, T-Cell, alpha-beta/geneticsABSTRACT
Immune responses to Epstein-Barr virus (EBV) infection synergize with the main genetic risk factor HLA-DRB1*15:01 (HLA-DR15) to increase the likelihood to develop the autoimmune disease multiple sclerosis (MS) at least sevenfold. In order to gain insights into this synergy, we investigated HLA-DR15 positive human immune compartments after reconstitution in immune-compromised mice (humanized mice) with and without EBV infection. We detected elevated activation of both CD4+ and CD8+ T cells in HLA-DR15 donor-reconstituted humanized mice at steady state, even when compared to immune compartments carrying HLA-DRB1*04:01 (HLA-DR4), which is associated with other autoimmune diseases. Increased CD8+ T cell expansion and activation was also observed in HLA-DR15 donor-reconstituted humanized mice after EBV infection. Despite this higher immune activation, EBV viral loads were less well controlled in the context of HLA-DR15. Indeed, HLA-DR15-restricted CD4+ T cell clones recognized EBV-transformed B cell lines less efficiently and demonstrated cross-reactivity toward allogeneic target cells and one MS autoantigen. These findings suggest that EBV as one of the main environmental risk factors and HLA-DR15 as the main genetic risk factor for MS synergize by priming hyperreactive T-cell compartments, which then control the viral infection less efficiently and contain cross-reactive CD4+ T cell clones.
Subject(s)
Epstein-Barr Virus Infections/immunology , HLA-DR Serological Subtypes/immunology , Multiple Sclerosis/immunology , Adaptive Immunity , Animals , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cross Reactions , Disease Models, Animal , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/virology , Genetic Predisposition to Disease , HLA-A2 Antigen/genetics , HLA-A2 Antigen/immunology , HLA-DR Serological Subtypes/genetics , Herpesvirus 4, Human/immunology , Humans , Isoantigens , Lymphocyte Activation , Mice , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Multiple Sclerosis/etiology , Multiple Sclerosis/genetics , Myelin Sheath/immunology , Risk FactorsABSTRACT
INTRODUCTION: asthma is a complex disease caused by the interaction of several genes. Some of them have a protective effect and some others contribute to disease onset. This study focuses on a region of the short arm of chromosome 6, where the genes encoding the major histocompatibility complex called HLA are located. This short arm plays an important role in the pathogenesis of asthma. METHODS: our study included 61 subjects, 30 non-asthmatic, non-allergic subjects and 31 patients with more than a 2-year history of allergic asthma. Atopic asthma was confirmed by skin tests and HLA-typing of class II which were performed following the principle of the serological technique of separation by FluoroBeads B. RESULTS: statistical analysis showed that HLA - DR11 and DQ2 genes were significantly more frequent in the asthmatic group compared to the control. The results were as follows: HLA-DR11 with p=0.05 and HLA-DQ2 with p=0.002. Based on this results HLA markers could be associated with asthma. On the other hand HLA-DQ6 marker was substantially higher in the control group than in the asthmatic subjects with p=0.003. CONCLUSION: HLA DR11 and DQ2 markers could be potential markers of susceptibility to asthma, while HLA-DQ6 may have a protective effect.
Subject(s)
Asthma/genetics , Genes, MHC Class II/genetics , Genetic Predisposition to Disease , Adult , Algeria , Asthma/diagnosis , Asthma/epidemiology , Case-Control Studies , Female , HLA-DQ Antigens/genetics , HLA-DR Serological Subtypes/genetics , Humans , Male , Middle Aged , Skin Tests , Young AdultABSTRACT
Thirty to fifty percent of patients with acetylcholine receptor (AChR) antibody (Ab)-negative myasthenia gravis (MG) have Abs to muscle specific kinase (MuSK) and are referred to as having MuSK-MG. MuSK is a 100 kD single-pass post-synaptic transmembrane receptor tyrosine kinase crucial to the development and maintenance of the neuromuscular junction. The Abs in MuSK-MG are predominantly of the IgG4 immunoglobulin subclass. MuSK-MG differs from AChR-MG, in exhibiting more focal muscle involvement, including neck, shoulder, facial and bulbar-innervated muscles, as well as wasting of the involved muscles. MuSK-MG is highly associated with the HLA DR14-DQ5 haplotype and occurs predominantly in females with onset in the fourth decade of life. Some of the standard treatments of AChR-MG have been found to have limited effectiveness in MuSK-MG, including thymectomy and cholinesterase inhibitors. Therefore, current treatment involves immunosuppression, primarily by corticosteroids. In addition, patients respond especially well to B cell depletion agents, e.g., rituximab, with long-term remissions. Future treatments will likely derive from the ongoing analysis of the pathogenic mechanisms underlying this disease, including histologic and physiologic studies of the neuromuscular junction in patients as well as information derived from the development and study of animal models of the disease.
Subject(s)
Muscles/pathology , Myasthenia Gravis/enzymology , Myasthenia Gravis/pathology , Adrenal Cortex Hormones/therapeutic use , Animals , Female , HLA-DR Serological Subtypes/genetics , Haplotypes , Humans , Immunoglobulin G/immunology , Mice , Myasthenia Gravis/drug therapy , Myasthenia Gravis/genetics , Receptor Protein-Tyrosine Kinases/genetics , Receptors, Cholinergic/geneticsABSTRACT
BACKGROUND: Immune checkpoint inhibitors (ICPis) induce various immune-related adverse events (irAEs), despite their beneficial effects in treating various advanced cancers. ICPi-induced secondary adrenal insufficiency is described as a prevalent and serious 'pituitary irAE.' However, its precise mechanism remains unclear, and no definitive predictive markers have been reported. PATIENTS AND METHODS: We enrolled and studied 11 patients with advanced cancer (aged 39-70 years; 6 male patients) receiving nivolumab, pembrolizumab or ipilimumab who developed pituitary irAEs. Their clinical data, including endocrine functions, were retrospectively assessed and human leucocyte antigen (HLA) genotypes were determined to compare the HLA allele frequencies in these patients and healthy controls. RESULTS: Among 11 patients, 7, 3 and 1 patients exhibited malignant melanoma, non-small-cell lung cancer and gastric cancer, respectively. HLA type screening results revealed that HLA-DR15, B52 and Cw12 were observed in 9, 7, and 7 patients with pituitary irAE, respectively. DR15, B52 and Cw12 were significantly more prevalent in our group than in the healthy control group from the Japanese HLA-haplotype database (this study vs healthy control group); DR15: 81.8% vs 33.5% (n = 11, P = 0.0014), B52: 63.6% vs 21.0% (n = 11, P = 0.0026) and Cw12: 70% vs 21.3% (n = 10, P = 0.0013). CONCLUSIONS: HLA-DR15, B52 and Cw12 are possible predisposing factors for pituitary irAEs. HLA-DR15 is reportedly associated with autoimmune disease via interleukin-17 regulation, suggesting its involvement in pituitary irAE development. Using HLA haplotypes as pituitary irAE predictive markers, we could provide safe ICPi treatment and understand irAE pathogenesis.
Subject(s)
Adrenal Insufficiency/drug therapy , Antibodies, Monoclonal/therapeutic use , Biomarkers/blood , HLA-DR Serological Subtypes/genetics , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Adrenal Insufficiency/genetics , Adrenal Insufficiency/pathology , Adult , Aged , Antibodies, Monoclonal/pharmacology , Female , Humans , Male , Middle AgedABSTRACT
BACKGROUND: Immunosuppressive therapy (IST) yields durable hematologic improvement (HI) in a subset of patients with lower-risk myelodysplastic syndrome (MDS). Age, human leukocyte antigen (HLA)-DR15 positivity, and duration of transfusion dependence are putative clinical variables predictive for response. We investigated the effect of somatic gene mutations on response to IST in lower-risk MDS. PATIENTS AND METHODS: Forty of 66 patients who received antithymocyte globulin with or without cyclosporine A identified at the Moffitt Cancer Center were molecularly profiled using a 49-gene myeloid panel. All patients profiled received antithymocyte globulin, and cyclosporine A was provided to 60% of patients. RESULTS: The overall frequency of HI was 42%. Presence of a large granular lymphocytic clone, hypocellular bone marrow, HLA-DR15 positivity, trisomy 8, and age had no influence on response to IST. Among 40 patients evaluated by next-generation sequencing, the presence of an SF3B1 mutation (MT) was significantly associated with IST nonresponse (1 of 9 SF3B1 MT, 11% vs. 21 of 31 wild type, 68%; P = .002). All patients with SF3B1 MT had ring sideroblasts > 15% (RS) by morphology; the corresponding HI rate was 20% among patients with RS versus 50% for those without RS (P = .09). CONCLUSION: These findings support the clinical implementation of genomics in MDS. The presence of an SF3B1 mutation adversely influences response to IST and should be incorporated into treatment decisions upon validation of these findings.
Subject(s)
Antilymphocyte Serum/administration & dosage , Cyclosporine/administration & dosage , Immunosuppressive Agents/administration & dosage , Mutation , Myelodysplastic Syndromes , Phosphoproteins/genetics , RNA Splicing Factors/genetics , Adult , Aged , Aged, 80 and over , Female , HLA-DR Serological Subtypes/genetics , HLA-DR Serological Subtypes/metabolism , Humans , Male , Middle Aged , Myelodysplastic Syndromes/drug therapy , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/metabolism , Myelodysplastic Syndromes/mortality , Phosphoproteins/metabolism , Predictive Value of Tests , RNA Splicing Factors/metabolismABSTRACT
OBJECTIVE: To investigate molecular changes in multiple sclerosis (MS) normal-appearing cortical gray matter (NAGM). METHODS: We performed a whole-genome gene expression microarray analysis of human brain autopsy tissues from 64 MS NAGM samples and 42 control gray matter samples. We further examined our cases by HLA genotyping and performed immunohistochemical and immunofluorescent analysis of all human brain tissues. RESULTS: HLA-DRB1 is the transcript with highest expression in MS NAGM with a bimodal distribution among the examined cases. Genotyping revealed that every case with the MS-associated HLA-DR15 haplotype also shows high HLA-DRB1 expression and also of the tightly linked HLA-DRB5 allele. Quantitative immunohistochemical analysis confirmed the higher expression of HLA-DRB1 in HLA-DRB1*15:01 cases at the protein level. Analysis of gray matter lesion size revealed a significant increase of cortical lesion size in cases with high HLA-DRB1 expression. CONCLUSIONS: Our data indicate that increased HLA-DRB1 and -DRB5 expression in the brain of patients with MS may be an important factor in how the HLA-DR15 haplotype contributes to MS pathomechanisms in the target organ.
Subject(s)
Gray Matter/metabolism , Gray Matter/pathology , HLA-DR Serological Subtypes/genetics , HLA-DRB1 Chains/metabolism , HLA-DRB5 Chains/metabolism , Multiple Sclerosis/genetics , Multiple Sclerosis/metabolism , Multiple Sclerosis/pathology , Aged , Aged, 80 and over , Autopsy , Female , Gene Expression Profiling , HLA-DRB1 Chains/genetics , Haplotypes , Humans , Immunohistochemistry , Male , Middle Aged , Protein Array AnalysisABSTRACT
Goodpasture's disease manifests as rapidly progressive glomerulonephritis. Current immunosuppressive treatments do not specifically target the pathological immune response and have significant side effects. Like most autoimmune diseases, the strongest genetic association is with the HLA alleles. Inheritance of HLA-DR15 confers susceptibility, and structure-function studies have shown that HLA-DR15 plays a causative role in activating autoreactive pro-inflammatory T cells. Thus, specific inhibition of HLA-DR15 would provide a targeted therapeutic approach. We hypothesised that PV-267, an HLA-DR15-specific inhibitor, would effectively block HLA-DR15 presentation of the dominant epitope, attenuate the activation of autoreactive T cells, and limit disease. Using humanised HLA-DR15 transgenic mice, α3135-145-specific, pro-inflammatory T cell recall responses were measured using IFN-γ and IL-17A ELISPOTs and by proliferation assay. To determine if PV-267 could limit disease, experimental autoimmune anti-GBM glomerulonephritis was induced in HLA-DR15 transgenic mice (on an Fcgr2b-/- background), and functional and histological disease endpoints were measured. PV-267 effectively inhibited α3135-145-specific immune responses and disease development. Mice treated prior to immunization with α3135-145 had reduced α3135-145-specific recall responses, and limited disease by albuminuria, histological glomerular injury, IgG deposition, and inflammatory cell infiltrates. PV-267 treatment commencing after the onset of active anti-α3(IV)NC1 autoimmunity attenuated functional and histological renal injury. When treatment was administered after disease was established, PV-267 limited the severity of histological injury. In conclusion, HLA-DR15 inhibition attenuates α3(IV)NC1-specific pro-inflammatory responses and could be used as an adjunct therapy for anti-GBM disease.
Subject(s)
Anti-Glomerular Basement Membrane Disease/therapy , Autoantigens/immunology , Collagen Type IV/immunology , Glomerulonephritis/therapy , HLA-DR Serological Subtypes/metabolism , Kidney/drug effects , Peptides/therapeutic use , T-Lymphocytes/immunology , Animals , Anti-Glomerular Basement Membrane Disease/genetics , Cells, Cultured , Disease Models, Animal , Female , Genetic Predisposition to Disease , Glomerulonephritis/genetics , HLA-DR Serological Subtypes/genetics , Humans , Kidney/pathology , Lymphocyte Activation , Male , Mice , Mice, Knockout , Mice, Transgenic , Peptides/immunology , Protein Binding , Receptors, IgG/geneticsABSTRACT
BACKGROUND: The HLA-DR15 extended haplotype HLA-DRB1*15:01-DQA1*01:02-DQB1*06:02 comprises the strongest genetic risk factor for multiple sclerosis (MS). The aim of this work was to investigate whether HLA-DR15 alleles were significantly associated with the susceptibility to MS familial forms (MSf) in an admixed Brazilian population. METHODS: Association analyses between DR15 and the clinical and demographic variables were made. RESULTS: We have genotyped 25 familial cases. The DR15 was detected in 11/25 (44%) of them and in none of controls (Pâ¯<â¯.00001). DR15 was significantly associated to a foreign ancestor background (Pâ¯=â¯.029) and later age of onset (Pâ¯=â¯.018).
Subject(s)
Genetic Predisposition to Disease/epidemiology , Genetic Predisposition to Disease/genetics , HLA-DR Serological Subtypes/genetics , Multiple Sclerosis/epidemiology , Multiple Sclerosis/genetics , Adult , Brazil/epidemiology , Cross-Sectional Studies , Female , HLA-DR Serological Subtypes/blood , Humans , Male , Middle Aged , Multiple Sclerosis/bloodABSTRACT
BACKGROUND: Although HLA-B*58:01 is a well-known risk factor for the development of allopurinol-induced severe cutaneous adverse reactions (SCARs), most of the HLA-B*58:01 carriers do not suffer from SCARs despite a long-term use of allopurinol. This suggests that there are other risk factors that determine the fate of HLA-B*58:01 carriers. OBJECTIVE: The aim of this study was to investigate the additional genetic factors that increase the risk of allopurinol-induced SCARs in HLA-B*58:01 carriers. METHODS: The incidence of allopurinol-induced SCARs was investigated according to coexisting HLA alleles in all subjects with HLA-B*58:01 who took allopurinol between 2003 and 2017. The allopurinol tolerant group was defined as a group who took allopurinol for more than 60 days without developing hypersensitivity and was compared with the allopurinol-induced SCAR group. RESULTS: Among the retrospective cohort consisting of 367 HLA-B*58:01 carriers treated with allopurinol, 11 (3.0%) were diagnosed with allopurinol-induced SCARs. When HLA-B75, DR13 homozygosity, or DR14 was present, the incidence of SCARs increased up to 22.2% (odds ratio [OR], 19.568; P = .015), 20.0% (OR, 38.458; P = .001), and 10.7% (OR, 19.355; P = .004), respectively. Among the 153 HLA-B*58:01 carriers with chronic renal insufficiency (CRI), the incidence of SCARs doubled to 6.5% and further increased to 40%, 30%, and 37.5% in the presence of HLA-B75, DR13 homozygosity, or DR14, respectively. CONCLUSIONS: Secondary screening with HLA-B75, DR13 homozygosity, and DR14 in addition to primary screening with HLA-B*58:01 would enable a more accurate prediction of SCAR occurrence, especially in patients with CRI.
Subject(s)
Allopurinol/adverse effects , Drug Hypersensitivity/genetics , HLA-B Antigens/genetics , HLA-DR Serological Subtypes/genetics , Skin/pathology , Adult , Allergens/immunology , Allopurinol/immunology , Allopurinol/therapeutic use , Cohort Studies , Drug Hypersensitivity/epidemiology , Female , Homozygote , Humans , Incidence , Korea/epidemiology , Male , Middle Aged , Retrospective Studies , RiskABSTRACT
BACKGROUND: Systemic lupus erythematosus (SLE) is an autoimmune disease under genetic control. Growing evidences support the genetic predisposition of HLA-DRB1 gene polymorphisms to SLE, yet the results are not often reproducible. The purpose of this study was to assess the association of two polymorphisms of HLA-DRB1 gene (HLA-DR3 and HLA-DR15) with the risk of SLE via a comprehensive meta-analysis. METHODS: This study complied with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Case-control studies on HLA-DRB1 and SLE were searched from PubMed, Elsevier Science, Springer Link, Medline, and Cochrane Library database as of June 2018. Analysis was based on the random-effects model using STATA software version 14.0. RESULTS: A total of 23 studies were retained for analysis, including 5261 cases and 9838 controls. Overall analysis revealed that HLA-DR3 and HLA-DR15 polymorphisms were associated with the significant risk of SLE (odds ratio [OR]: 1.60, 95% confidence interval (CI): 1.316-1.934, P = 0.129 and OR: 1.68, 95% CI: 1.334-2.112, P = 0.001, respectively). Subgroup analyses demonstrated that for both HLA-DR3 and HLA-DR15 polymorphisms, ethnicity was a possible source of heterogeneity. Specifically, HLA-DR3 polymorphism was not associated with SLE in White populations (OR: 1.60, 95% CI: 1.320-1.960, P = 0.522) and HLA-DR15 polymorphism in East Asian populations (OR: 1.65, 95% CI: 1.248-2.173, P = 0.001). In addition, source of control was another possible source for both HLA-DR3 and HLA-DR15 polymorphisms, with observable significance for HLA-DR3 in only population-based studies (OR: 1.65, 95% CI: 1.370-1.990, P = 0.244) and for HLA-DR15 in both population-based and hospital-based studies (OR: 1.38, 95% CI: 1.078-1.760, P = 0.123 and OR: 2.08, 95% CI: 1.738-2.490, P = 0.881, respectively). CONCLUSIONS: HLA-DRB1 gene may be a SLE-susceptibility gene, and it shows evident ethnic heterogeneity. Further prospective validations across multiple ethnical groups are warranted.
Subject(s)
HLA-DR Serological Subtypes/genetics , HLA-DR3 Antigen/genetics , HLA-DRB1 Chains/genetics , Polymorphism, Genetic/genetics , Case-Control Studies , Gene Frequency/genetics , Genetic Predisposition to Disease/genetics , Haplotypes/genetics , Humans , Lupus Erythematosus, Systemic , Odds RatioABSTRACT
Multiple sclerosis is an autoimmune disease that is caused by the interplay of genetic, particularly the HLA-DR15 haplotype, and environmental risk factors. How these etiologic factors contribute to generating an autoreactive CD4+ T cell repertoire is not clear. Here, we demonstrate that self-reactivity, defined as "autoproliferation" of peripheral Th1 cells, is elevated in patients carrying the HLA-DR15 haplotype. Autoproliferation is mediated by memory B cells in a HLA-DR-dependent manner. Depletion of B cells in vitro and therapeutically in vivo by anti-CD20 effectively reduces T cell autoproliferation. T cell receptor deep sequencing showed that in vitro autoproliferating T cells are enriched for brain-homing T cells. Using an unbiased epitope discovery approach, we identified RASGRP2 as target autoantigen that is expressed in the brain and B cells. These findings will be instrumental to address important questions regarding pathogenic B-T cell interactions in multiple sclerosis and possibly also to develop novel therapies.
Subject(s)
B-Lymphocytes/pathology , HLA-DR Serological Subtypes/immunology , Multiple Sclerosis/immunology , Autoantigens/immunology , Autoimmune Diseases/immunology , Autoimmune Diseases/physiopathology , B-Lymphocytes/metabolism , Brain/pathology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/physiology , Guanine Nucleotide Exchange Factors/metabolism , HLA-DR Serological Subtypes/genetics , Humans , Multiple Sclerosis/genetics , Multiple Sclerosis/physiopathology , Receptors, Antigen, T-Cell , Th1 Cells/physiologyABSTRACT
Expanded polyclonal T regulatory cells (Tregs) offer great promise for the treatment of immune-mediated diseases. Inhibition by Tregs is under the control of the T-cell receptor (TCR). Therefore, we created Tregs with defined antigen specificity, using a recombinant T-cell receptor isolated from a myelin-basic protein specific T-cell clone of a multiple sclerosis (MS) patient (Ob2F3). We expressed this TCR using a retroviral expression vector in human Tregs from peripheral blood. We observed that transduced Tregs were activated in vitro in response to myelin basic protein (MBP) peptide on DR15 antigen-presenting cells (APC) and upregulated Treg markers, Foxp3, LAP and Helios. These engineered MBP-specific Tregs could suppress MBP-specific T effector cells, and were also able to suppress T cells with other specificities after Tregs had been activated through the TCR. Importantly, we showed that these engineered Tregs were able to function effectively in the presence of strong TLR-induced inflammatory signals, and that MBP-specific Tregs ameliorated EAE in myelin oligodendrocyte glycoprotein (MOG)-immunized DR15 transgenic mice. We further demonstrated in vitro that IL-2 produced by neighboring effector T cells activated MBP-specific Tregs, initiating contact-independent suppression to T effectors in local milieu. Mechanistic studies demonstrated that bystander suppression in vivo may involve transfer of soluble mediators, enhanced by cell contact between Tregs and effectors. Taken together, we show that engineered clonal MBP-specific Tregs are able to suppress autoimmune pathology in EAE. This approach may serve as a cellular therapy for MS patients with the common DR15 haplotype that is associated with disease susceptibility.
Subject(s)
Encephalomyelitis, Autoimmune, Experimental/immunology , Immunotherapy, Adoptive/methods , Multiple Sclerosis/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Autoimmunity , Bystander Effect , Cells, Cultured , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/therapy , Forkhead Transcription Factors/metabolism , Genetic Engineering , Genetic Predisposition to Disease , HLA-DR Serological Subtypes/genetics , Humans , Interleukin-2/metabolism , Lymphocyte Activation , Mice , Mice, Transgenic , Multiple Sclerosis/genetics , Multiple Sclerosis/therapy , Myelin Basic Protein/immunology , Myelin-Oligodendrocyte Glycoprotein/immunology , Polymorphism, Genetic , Receptors, Antigen, T-Cell/genetics , T-Cell Antigen Receptor SpecificityABSTRACT
INTRODUCTION: Chronic hepatitis B (CHB) is still a public health problem and its mechanism remains unclear. In this study, we detect the skewness of T cell receptor beta chain variable gene (TCR Vß) in peripheral blood lymphocytes (PBL) and the liver infiltrating lymphocytes (LIL) of patients with CHB; and hope to provide information for further research on the pathogenic mechanism of CHB. MATERIAL AND METHODS: Fifteen patients with CHB, ten healthy volunteers and three patients with liver cysts were recruited as the subjects. The usage of TCR Vß of PBL and LIL were measured and compared; the associations of the TCR Vß usage of PBL with some hematological indices, including human leukocyte antigen (HLA) alleles, percents of CD4+ and CD8+ T cells, sera levels of HBV-DNA and IFN-γ, were analyzed. RESULTS: In PBL, Vß12 and Vß13.1 were the highest predominant usage genes which usage frequencies were all 46.7%; Vß23 was the key limited usage gene (40.0%). In LIL, the mainly predominant and limited usage gene was Vß13.1 (73.3%) and Vß23 (46.7%), respectively. About half of the patients with CHB with HLA-DR9 or HLA-DR12 showed the predominant usage of Vß5.2 or Vß13.2. In patients with CHB, the percentage of CD4+ T cells was 33.41 ± 5.39 %, that of CD8+ T cells was 28.67 ± 6.77 %; the concentration of IFN-γ was 182.52 ± 44.16 pg/mL. Compared to the healthy controls, there were significant differences for these data (P < 0.05). Neither ALT nor HBV-DNA was relative to the usage of TCR Vß. CONCLUSIONS: PBL and LIL share the common sknewness of TCR Vß genes, which probably relates to some hematological indices. However, the roles of such similarities and associations in the development of CHB need further study.
Subject(s)
Genes, T-Cell Receptor beta , Hepatitis B, Chronic/genetics , Hepatitis B, Chronic/immunology , Immunoglobulin Variable Region/genetics , Liver/immunology , Lymphocytes/immunology , Receptors, Antigen, T-Cell, alpha-beta/genetics , Adult , Case-Control Studies , Complementarity Determining Regions/genetics , Complementarity Determining Regions/immunology , Female , HLA-DR Serological Subtypes/genetics , HLA-DR Serological Subtypes/immunology , Hepatitis B, Chronic/diagnosis , Hepatitis B, Chronic/virology , Host-Pathogen Interactions , Humans , Immunoglobulin Variable Region/immunology , Liver/virology , Lymphocytes/virology , Male , Middle Aged , Receptors, Antigen, T-Cell, alpha-beta/immunologyABSTRACT
INTRODUCTION: Neuromyelitis optica (NMO) and Multiple Sclerosis (MS) have been reported in different populations. NMO is more frequent in non-Caucasians, and clinical phenotype differences between populations are likely influenced by genetic susceptibility. In Brazil, it has been reported that NMO patients have a mainly European ancestry background. Like other autoimmune diseases, NMO has a multifactorial origin (i.e., genetics, environmental and infectious factors). Regarding the genetics of NMO, epidemiological findings suggest that a polygenic background has an important role in the development of this type of disease. In this context, various genes have been studied, such as those involved in the synthesis of the T cell beta chain receptor, the VH2-5 gene, myelin basic protein, the CTLA-4 gene, and the interleukin-1 gene. MATERIALS AND METHODS: We performed a study with the main objective of identifying candidate genes involved in the susceptibility to develop NMO in a Mexican population. RESULT: We included 35 patients with an NMO diagnosis according to the Wingerchuk 2006 criteria. The mean age of the patients was 43.3 years old (20-67), and 80 percent of the patients were women. The presence of HLA-DRB1*03 and HLA-DRB1*10 alleles were more frequent in NMO patients than in controls (n=198; p=0.03 and 0.005, respectively). CONCLUSION: There were no differences in the other alleles that have been described in MS subjects, such as HLA-DRB1*04, HLA-DRB1*08 and HLA-DRB1*13. These findings may support the hypothesis that implicated immune-genetics as a key factor in development of this type of disease.
Subject(s)
Genetic Predisposition to Disease/ethnology , Genetic Predisposition to Disease/genetics , Immunoglobulin G/genetics , Neuromyelitis Optica/ethnology , Neuromyelitis Optica/genetics , Adult , Aged , Ethnicity/genetics , Female , HLA-DR Serological Subtypes/blood , HLA-DR Serological Subtypes/genetics , HLA-DR3 Antigen/blood , HLA-DR3 Antigen/genetics , Humans , Immunoglobulin G/blood , Male , Mexico/ethnology , Middle Aged , Neuromyelitis Optica/blood , Young AdultABSTRACT
Reported cases of familial Antiglomerular basement membrane (anti-GBM) disease are extremely rare. The single gene mutations that may play a role in the development of familial anti-GBM disease are currently unidentified. While human leukocyte antigen (HLA)-DR15 is known to be associated with an increased risk of anti-GBM disease, HLA types in patients with familial anti-GBM disease have never been reported. We present a case of a 65-year-old woman with rapidly-progressive glomerulonephritis and pulmonary involvement, consistent with Goodpasture's syndrome. Two of her 15 siblings also had a history of anti-GBM disease during adolescence and both received a kidney transplant. Our patient and her siblings were smokers and had also had exposure to kerosene, a low-viscosity hydrocarbon. HLA testing was performed and showed identical HLA typing (0 of 6 HLA mismatch) as one of her brothers with anti-GBM disease. Interestingly, they both had HLA-DR15. Despite severe acute kidney injury requiring hemodialysis, the patient responded well to the standard therapy with cyclophosphamide, plasmapheresis, and systemic corticosteroids. At her 3-month follow-up visit, the patient's kidney functions had recovered, and hemodialysis was discontinued. Concluding, we illustrate an extremely rare familial anti-GBM disease involving 3 siblings with potential links of HLA-DR15 and environmental triggers with the development of familial anti-GBM disease.â©.
Subject(s)
Anti-Glomerular Basement Membrane Disease/genetics , HLA-DR Serological Subtypes/genetics , Histocompatibility Testing , Aged , Anti-Glomerular Basement Membrane Disease/immunology , Anti-Glomerular Basement Membrane Disease/therapy , Female , Humans , Renal Dialysis , SiblingsABSTRACT
AIMS/INTRODUCTION: To investigate the typing for human leukocyte antigen (HLA) class I in Chinese patients with type 1 diabetes as a complement screening for HLA class II. MATERIALS AND METHODS: A total of 212 type 1 diabetic patients and 200 healthy controls were enrolled. The genetic polymorphisms of HLA class I and II were examined with a high-resolution polymerase chain reaction sequence-based typing method. RESULTS: The haplotype, A*33:03-B*58:01-C*03:02(A33), was associated with type 1 diabetes (P = 1.0 × 10(-4) , odds ratio 3.2 [1.738-5.843]). The A33-DR3 and A33-DR9 haplotypes significantly enhanced the risk of type 1 diabetes (A33-DR3, odds ratio 5.1 [2.40-10.78], P = 4.0 × 10(-6) ; A33-DR9, odds ratio 13.0 [1.69-100.32], P = 0.004). In type 1 diabetic patients, compared with A33-DR3-negative carriers, A33-DR3-positive carriers had significantly lower percentages of CD3(+) CD4(+) T cells (42.5 ± 7.72 vs 37.0 ± 8.35%, P = 0.023), higher percentages of CD3(+) CD8(+) T cells (27.4 ± 7.09 vs 32.8 ± 5.98%, P = 0.005) and T-cell receptor α/ß T cells (70.0 ± 7.00 vs 73.6 ± 6.25%, P = 0.031), and lower CD4/CD8 ratios (1.71 ± 0.75 vs 1.16 ± 0.35, P = 0.003). CONCLUSIONS: It is the first time that the haplotypes A33-DR3 and A33-DR9 were found with an enhanced predisposition to type 1 diabetes in Han Chinese. A33-DR3 was associated with a reduction in the helper-to-cytotoxic cell ratio and preferential increase of T-cell receptor α/ß T cell. The typing for HLA class I and its immunogenetic effects are important for more accurate HLA class II haplotype risk prediction and etiology research in type 1 diabetic patients.
Subject(s)
Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/immunology , Genetic Predisposition to Disease , HLA Antigens/genetics , HLA-DR Serological Subtypes/genetics , HLA-DR3 Antigen/genetics , Adult , Asian People , Diabetes Mellitus, Type 1/epidemiology , Female , Gene Frequency , Haplotypes , Humans , Male , Risk Factors , Young AdultABSTRACT
AIM: We examined the combined effect of having multiple key risk factors and the interactions between the key risk factors of multiple sclerosis (MS). METHODS: We performed an incident case-control study including cases with a first clinical diagnosis of central nervous system demyelination (FCD) and population-based controls. RESULTS: Compared to those without any risk factors, those with one, two, three, and four or five risk factors had increased odds of being an FCD case of 2.12 (95% confidence interval (CI), 1.11-4.03), 4.31 (95% CI, 2.24-8.31), 7.96 (95% CI, 3.84-16.49), and 21.24 (95% CI, 5.48-82.40), respectively. Only HLA-DR15 and history of infectious mononucleosis interacted significantly on the additive scale (Synergy index, 3.78; p = 0.03). The five key risk factors jointly accounted for 63.8% (95% CI, 43.9-91.4) of FCD onset. High anti-EBNA IgG was another important contributor. CONCLUSIONS: A high proportion of FCD onset can be explained by the currently known risk factors, with HLA-DR15, ever smoking and low cumulative sun exposure explaining most. We identified a significant interaction between HLA-DR15 and history of IM in predicting an FCD of CNS demyelination, which together with previous observations suggests that this is a true interaction.