HLA-dependent autoantibodies against post-translationally modified collagen type II in type 1 diabetes mellitus

Abstract

Aims/hypothesis In this study the involvement of oxidative stress in type 1 diabetes mellitus autoimmunity and the possible association with rheumatoid arthritis (RA) was investigated. We tested the hypothesis that oxidative stress induced by chronic hyperglycaemia triggers post-translational modifications and thus the formation of neo-antigens in type 1 diabetes, similar to the ones found in RA. Methods Collagen type II (CII), a known autoantigen in RA, was treated with ribose and various reactive oxygen species (ROS). Levels of antibodies specific to native and ROS-modified CII (ROS-CII) were compared in type 1 diabetes, type 2 diabetes and healthy controls, and related to the HLA genotype. Results Significantly higher binding to ROS-CII vs native CII was observed in type 1 diabetic patients possessing the HLA-DRB1*04 allele irrespective of variables of glucose control (blood glucose or HbA 1c ). Type 1 diabetic patients carrying a DRB1*04 allele with the shared epitope showed the highest risk for ROS-CII autoimmunity, while the DRB1*0301 allele was protective. Conversely, native CII autoimmunity was not associated with any specific DRB1 allele. Positive and inverse seroconversion rates of response to ROS-CII were high in DRB1*04-positive type 1 diabetic patients. Conclusion Hyperglycaemia and oxidative stress may trigger genetically controlled autoimmunity to ROS-CII and may explain the association between type 1 diabetes mellitus and RA.Keywords Collagen type II . Post-translational modification . Reactive oxygen species . Rheumatoid arthritis Abbreviations ACPA Anti-citrullinated peptide antibodies P. Pozzilli and A. Nissim contributed equally to this work.

Antibodies to post-translationally modified insulin in type 1 diabetes

“…Interestingly, we did not observe increased reactivity to glycated insulin in our study. This is in contrast to the increased autoreactivity to glycated collagen type II that we have previously observed [7,13]. Although this might imply that imbalance of the redox state and hence ROS production is more In this study, we developed an ELISA for detecting autoreactivity to oxPTM-INS.…”

“…It is interesting to note that one of the observed modifications involving chlorination of Tyr16 of chain B (Tyr B16) is within the region 9-23 of chain B (B:9-23), a known dominant epitope in autoimmune diabetes [21], with Tyr16 being crucial in immunoreactivity. Substitution of Tyr in position 16 to Ala (Tyr B16:Ala) has been shown to abrogate T cell reactivity [22,23], and administration of a modified B:9-23 (Tyr B16:Ala) peptide has been reported to suppress expression of IAA and prevent diabetes in the NOD mouse [24]; conversely, it is possible that Tyr16 modification by HOCl oxPTM by ROS appears to play a key role in the pathogenesis of several human autoimmune diseases [13,[25][26][27]. This is of particular relevance to type 1 diabetes, where islet inflammation and the ensuing hyperglycaemia are substantial sources of ROS production [2,5].…”

“…We have previously shown that patients with type 1 diabetes had increased levels of autoantibodies against collagen type II modified by ROS, and that this response was under the genetic control of the HLA-DRB1*04 shared epitope alleles [13]. Although the effect of ROS in inducing autoimmunity towards beta-cell-specific antigens remains largely unknown, this role for ROS is supported by the evidence that antibodies against oxidised GAD are present in diabetes [11].…”

Do post-translational beta cell protein modifications trigger type 1 diabetes?

“…Patients carrying the HLA-DRB1*04 allele showed the highest risk for autoimmunity against modified collagen, while carrying a DRB1*0301 allele was protective. Autoimmunity to native collagen type II was not associated with any DRB1 alleles [44]. This study therefore highlights that, in addition to the importance of formation of PTMs for creating neo-epitopes, specific HLA genotypes can be important for the presentation of these neoepitopes to the immune system.…”

Oxidative post-translational modifications and their involvement in the pathogenesis of autoimmune diseases

“…Recently, we [84] demonstrated that oxidative modification significantly increased the antigenicity of CII in type-I diabetes patients that carried the HLA-DRB1*4 allele associated with increased RA prevalence, but to a lesser extent in patients without the RA associated HLA-DRB1*4. These data indicate a role of oxidative PTMs in autoimmunity in type-I diabetes patients.…”