Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health

Arif, Sefina; Tree, Timothy; Astill, Thomas P.; Tremble, Jennifer; Bishop, Amanda J.; Dayan, Colin; Roep, Bart O.; Peakman, Mark

doi:10.1172/jci200419585

Cited by 237 publications

(333 citation statements)

References 36 publications

(14 reference statements)

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“…Indeed, T-cell autoreactivity has been described against DR4-(0401), DR16-and DQ8-restricted insulin B-chain epitopes. 18,22,38,39 Recent studies in NOD mice showed that the InsB12-20 and InsB13-21 peptides are the core nonamers for IA g7 binding and induced T-cell reactivity in the NOD mouse. 40,41 Within InsB12-23 four binding registers exist capable of binding this molecule.…”

Section: Discussionmentioning

confidence: 99%

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

et al. 2011

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Human leukocyte antigen (HLA) class II haplotypes are established risk factors in type 1 diabetes (T1D). The heterozygous DQ2/8 genotype confers the highest risk, whereas the DQ6/8 genotype is protective. We hypothesized that DQ2/8 transmolecules composed of a and b chains from DQ2 and DQ8 express unique b-cell epitopes, whereas DQ6 may interfere with peptide binding to DQ8. Here we show that a single insulin epitope (InsB13-21) within the T1D prototype antigenic InsB6-22 peptide can bind to both cis-and trans-dimers, although these molecules display different peptide binding patterns. DQ6 binds a distinct insulin epitope (InsB6-14). The phenotype of DQ8-restricted T cells from a T1D patient changed from proinflammatory to anti-inflammatory in the presence of DQ6. Our data provide new insights into both susceptible and protective mechanism of DQ, where protecting HLA molecules bind autoantigens in a different (competing) binding register leading to 'epitope stealing', thereby inducing a regulatory, rather than a pathogenic immune response.

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Section: Discussionmentioning

confidence: 99%

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

et al. 2011

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“…This suggests that diet has a major effect on the development of diabetes in BBdp rats. The inflammation in the pancreas that destroys islet beta cells is predominantly a Th1 process, which is characterised by the production of IFN-γ in BBdp rats [25][26][27][28] and in humans [32]. However, the origin of these Th1 cells, the stimulatory antigens, and the timing and circumstances under which the cells become activated remain unclear.…”

Section: Discussionmentioning

confidence: 99%

Wheat protein-induced proinflammatory T helper 1 bias in mesenteric lymph nodes of young diabetes-prone rats

Chakir¹,

Lefebvre

Wang³

et al. 2005

Diabetologia

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Aims/hypothesis: Type 1 diabetes is the result of an inflammatory T helper 1 (Th1) lymphocyte-mediated beta cell destructive process. The majority of diabetesprone BioBreeding (BBdp) rats fed wheat protein-based diets, such as NTP-2000, develop type 1 diabetes and display a mild coeliac-like enteropathy. Mesenteric lymph nodes (MLNs), which drain the gut, are the major inductive site where dietary antigens are recognised in the gut-associated lymphoid tissue (GALT). We hypothesised that this compartment could be a site of abnormal wheat proteininduced Th1 cell activation. Methods: MLN cells were isolated from BBdp and BB control (BBc) rats that were fed NTP-2000 or a hydrolysed casein (HC)-based diet at ages that pre-date classic insulitis. The inflammatory status, phenotype and proliferation of these cells in response to wheat protein were determined. Results: The expression ratio of T-bet : Gata3, master transcription factors for Th1 and Th2 cytokines, was increased in the MLN from NTP-2000-fed BBdp rats compared with that from BBc rats, mainly due to decreased Gata3 expression. CD3 + CD4 + IFN-γ + T cells were more prevalent in the MLN of wheatfed BBdp rats, but remained at control levels in BBdp rats fed a diabetes-retardant HC diet. BBdp MLN cells proliferated in response to wheat protein antigens in a specific, dose-dependent manner, and >93% of cells were CD3 + CD4 + T cells. This proliferation was associated with a low proportion of CD4 + CD25 + T cells and a high proportion of dendritic cells in the MLN of BBdp rats. Conclusions/ interpretation: Before insulitis is established, the MLNs of wheat-fed BBdp rats contain an unusually high proportion of Th1 cells that proliferate specifically in response to wheat protein antigens.

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“…16 In T1D patients, β-cell autoantigen-specific CD4 + T cells show a more proinflammatory phenotype with concomitant secretion of IFN-γ. 14,18 Conversely, CD4 + T cells from healthy individuals seem to have similar β-cell specificity but exhibit higher IL-10-secreting activity, and the phenotypes and functions of these cells are more regulatory. 14,18 The transfer of Th1 cells into neonatal non-obese diabetic (NOD) mice, which is an animal model of spontaneous T1D, leads to T1D onset.…”

Section: Mirnas: Regulators Of Immune Pathogenesis In T1dmentioning

confidence: 99%

miRNAs: novel regulators of autoimmunity-mediated pancreatic β-cell destruction in type 1 diabetes

2017

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MicroRNAs (miRNAs) are a series of conserved, short, non-coding RNAs that modulate gene expression in a posttranscriptional manner. miRNAs are involved in almost every physiological and pathological process. Type 1 diabetes (T1D) is an autoimmune disease that is the result of selective destruction of pancreatic β-cells driven by the immune system. miRNAs are also important participants in T1D pathogenesis. Herein, we review the most recent data on the potential involvement of miRNAs in T1D. Specifically, we focus on two aspects: the roles of miRNAs in maintaining immune homeostasis and regulating β-cell survival and/or functions in T1D. We also discuss circulating miRNAs as potent biomarkers for the diagnosis and prediction of T1D and investigate potential therapeutic approaches for this disease.

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Autoreactive T cell responses show proinflammatory polarization in diabetes but a regulatory phenotype in health

Cited by 237 publications

References 36 publications

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes

Wheat protein-induced proinflammatory T helper 1 bias in mesenteric lymph nodes of young diabetes-prone rats

miRNAs: novel regulators of autoimmunity-mediated pancreatic β-cell destruction in type 1 diabetes

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