Abstract
Aims/hypothesisThe molecular basis for the pathological impact of specific HLA molecules on autoimmune diseases such as type 1 diabetes remains unclear. Recent natural history studies in children have indicated a link between specific HLA genotypes and the first antigenic target against which immune responses develop. We set out to examine this link in vivo by exploring the diabetogenicity of islet antigens on the background of a common diabetes-associated HLA haplotype.MethodsWe generated a novel HLA-transgenic mouse model that expresses high-risk genes for type 1 diabetes (DRB1*03:01-DQA1*05:01-DQB1*02:01) as well as human CD80 under the rat insulin promoter and human CD4, on a C57BL/6 background. Adjuvanted antigen priming was used to reveal the diabetogenicity of candidate antigens and peptides.ResultsHLA-DR3-DQ2+huCD4+IA/IE−/−RIP.B7.1+ mice spontaneously developed autoimmune diabetes (incidence 46% by 35 weeks of age), accompanied by numerous hallmarks of human type 1 diabetes (autoantibodies against GAD65 and proinsulin; pancreatic islet infiltration by CD4+, CD8+ B220+, CD11b+ and CD11c+ immune cells). Disease was markedly accelerated and had deeper penetrance after adjuvanted antigen priming with proinsulin (mean onset 11 weeks and incidence 100% by 20 weeks post challenge). Moreover, the diabetogenic effect of proinsulin located to the 15-residue B29-C11 region.Conclusions/interpretationOur study identifies a proinsulin-derived peptide region that is highly diabetogenic on the HLA-DR3-DQ2 background using an in vivo model. This approach and the peptide region identified may have wider implications for future studies of human type 1 diabetes.
Highlights
Type 1 diabetes, like all autoimmune diseases, results from the inappropriate activation of the immune system in response to autoantigen encounter
Given the antigen-presenting properties of HLA molecules, it is assumed that the diabetes risk associated with HLA-DR3-DQ2 relates to the selective presentation of peptide epitopes of potentially diabetogenic autoantigens
A specific region of proinsulin is responsible for diabetes induction in this model We examined whether there is a dominant region of proinsulin that interacts in DR3DQ2×RIPB7.1 mice to promote diabetes by repeating these adjuvanted priming experiments with each of the four proinsulin-2 peptides individually (Fig. 3a–e)
Summary
Type 1 diabetes, like all autoimmune diseases, results from the inappropriate activation of the immune system in response to autoantigen encounter. The reasons for the loss of selftolerance in type 1 diabetes remain debated but it is well established that the HLA system constitutes a major genetic risk factor. HLA-DR3-DQ2 (DRB1*03:01-DQA1*05:01DQB1*02:01) is the most common haplotype found in individuals with type 1 diabetes, at a frequency of around 34% [3], and Diabetologia (2019) 62:2252–2261 delineates a major, identifiable disease cohort. Given the antigen-presenting properties of HLA molecules, it is assumed that the diabetes risk associated with HLA-DR3-DQ2 relates to the selective presentation of peptide epitopes of potentially diabetogenic autoantigens. Identification of these autoantigens and specific disease-determining regions is an important step towards understanding disease aetiology
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