Flexible peptide recognition by HLA-DR triggers specific autoimmune T-cell responses in autoimmune thyroiditis and diabetes

Abstract

Autoimmune polyglandular syndrome 3 variant (APS3v) refers to the co-occurrence of autoimmune thyroiditis (AITD) and type 1 diabetes (T1D) within the same individual. HLA class II confers the strongest susceptibility to APS3v. We previously identified a unique amino acid signature of the HLA-DR pocket (designated APS3v HLA-DR pocket) that predisposes to APS3v. We hypothesized that both thyroid and islet peptides can be presented by the unique APS3v HLA-DR pocket, triggering AITD+T1D together. To test this hypothesis we screened islet and thyroid peptides for their ability to bind to the APS3v HLA-DR pocket. Virtual screen of all possible thyroglobulin (Tg), thyroid-stimulating hormone receptor (TSHR), thyroid peroxidase (TPO), insulin (Ins), and glutamic acid decarboxylase 65 (GAD65) peptides identified 36 peptides that bound to this unique pocket. In vitro binding assays using baculovirus-produced recombinant APS3v HLA-DR identified 11 thyroid/islet peptides (of the 36 predicted binders) that bound with high affinity. By immunizing humanized HLA-DR3 mice carrying the APS3v HLA-DR pocket we identified 4 peptides (Tg.1571, GAD.492, TPO.758, TPO.338) that were presented by antigen presenting cells and elicited T-cell response. We conclude that both thyroid and islet peptides can bind to this flexible APS3v HLA-DR pocket and induce thyroid and islet specific T-cell responses. These findings set the stage to developing specific inhibitors of the APS3v HLA-DR pocket as a precision medicine approach to treating or preventing APS3v in patients that carry this genetic HLA-DR pocket variant.

Bioinformatics analysis of key genes and pathways in Hashimoto thyroiditis tissues

“…Human leukocyte antigen (HLA) class II genes and their alleles are considered as the pivotal factors of HT. HLA and its alleles may confer the strongest susceptibility to autoimmune poly-glandular syndrome 3 variant (APS3v), which is associated with the occurrence of HT [24,25]. In the present study, we identified not only classic HT susceptibility genes, but also several novel unreported gene markers, thereby supporting the credibility of our bioinformatics analysis.…”

Type 1 Diabetes and Autoimmune Thyroid Disease—The Genetic Link

“…Four islet and thyroid peptides (Tg.1571, GAD.492, TPO.758, and TPO.338) were identified with the ability to bind to the HLA-DR binding pocket, being presented by antigen-presenting cells and elicited a T cell response. Both thyroid and islet peptides can bind to this flexible binding pocket and induce thyroid and islet specific T cell responses, thus triggering T1D and AITD in the same individual ( 78 ). Potential mechanisms how HLA genes activate endocrine autoimmunity and predispose to both T1D and AITD, even if the autoantigenic peptides are distinct, are shown in Figure 2 .…”

Autoimmune thyroid disease and type 1 diabetes mellitus: same pathogenesis; new perspective?

“… 37 , 38 HLA genes are strongly linked with thyroid autoimmunity in patients with T1DM, demonstrating that some genetic determinants within the HLA region are involved in both T1DM and AITD. 35 , 36 , 39 , 40 The HLA DRB1*0405/DQA1*0301/DQB1*0401 haplotype confers susceptibility in patients with T1DM and GADAb-positive AITD, whereas individuals with the HLA DRB1*0803/DQB1*0601 haplotype are more susceptible to AITD but not to anti-islet autoimmunity. 5 , 41 In addition to high-risk HLA DR-DQ haplotypes, HLA class I A and C alleles also appear to be associated with T1DM in Filipino patients.…”