Differences in self-peptide binding between T1D-related susceptible and protective DR4 subtypes

Abstract

HLA-DR0401, 0403 and 0405 are associated with variable T1D susceptibilities when linked with a common HLA-DQ8 (DQA1*0301/DQB1*0302). It is unknown how the modest differences within the peptide binding regions of DR4 subtypes lead to distinct autoimmune risks. Since all Class II HLA molecules share the same intracellular compartments during biosynthesis, it is possible that DQ and DR compete with one another to bind and present antigenic peptides. As such, it is reasonable to hypothesize that a strong DR4 self-peptide binder down-modulates DQ8 epitope presentation more than a weak one. In this study, we first examined the binding of the peptides derived from two putative beta-cell autoantigens – GAD65 and insulin. Protective DR0403 bound similar number of self-peptides as susceptible DR0401 while highly susceptible DR0405 bound substantially less self-peptides than rest two molecules. Kinetic assays were used to further compare the stability of peptide:DR complexes formed between DR0401, 0403 and selected GAD65 peptides, which also bound DQ8. Two peptides with naturally processed DQ8 epitopes bound protective DR0403 with longer half-life and lower dissociation rate than susceptible DR0401, confirming DR0403 as a better peptide competitor than DR0401. The distinguishing peptide binding features of DR0401, DR0403, and DR0405 highlighted in this study help to explain the hierarchy of genetic associations between T1D and these DR4 subtypes. The enhanced peptide competition of DR0403 leads to a down-modulation of DQ8 epitope presentation, as compared to weak competitors such as DR0401 and DR0405, and therefore contributes to disease protection.

Human leukocyte antigen class II and type 1 diabetes in Latin America: A combined meta-analysis of association and family-based studies

“…Alleles such as DRB1*0404 that confers a lower risk than DRB1*0405 and DRB1*0401 could compete with the DQA1-DQB1 component, thus lowering the peptide presentation and the generation of auto-reactive T-cells. DRB1*0404 had a predictive behavior that was similar to DRB1*0403 (Table S6), an allele, which, in the case of GAD, has led to down-modulation of DQ8 presentation of epitopes through an enhanced peptide competition as compared to weak competitors, such as DR0401 and DR0405 [28].…”

“…There were some peptides in our prediction approach which could help to improve our understanding about how T1D associated haplotypes work. 250 PGGAISNMY 258 and 566 FRMVISNPA 574 from GAD have demonstrated in vitro that they can bind some DRB1*04 molecules [28]. FALTAVAEE, a peptide from IA2 and ICCA, is also a known inducer of T-cell response in DQ8 transgenic mice [29].…”

Genetics of Autoimmune Thyroiditis in Type 1 Diabetes Reveals a Novel Association With DPB1*0201: Data From the Type 1 Diabetes Genetics Consortium

“…The major antigen in thyroid autoimmunity is TPO ( 29 ). Whether TPO epitopes engage in a specific interaction with the HLA-DR and/or HLA-DP peptide binding pocket in a similar manner as it has been presumed for GAD65, the major T1D antigen, is unknown ( 8 , 30 , 31 ). As the T1DGC recruited affected sibling pairs and only few simplex cases (as trios), we cannot assess whether the prevalence of AITD in multiplex T1D sibling relationships is higher than in simplex (i.e., sporadic) cases.…”

MHC Class II Polymorphisms, Autoreactive T-Cells, and Autoimmunity

“…The contribution of disease-protective class II in the periphery, however, is less clear. Certain studies implicated protective class II molecules in mechanisms such as “determinant capture” that would interfere with or compete against self-antigen presentation by disease-predisposing MHCs (51–53). These mechanisms, although plausible, were countered by other reports (54–56).…”