Category: Autoimmune rheumatologic diseases
Major histocompatibility complex (MHC) is the strongest genetic risk factor for many immune diseases. Disease modulating amino acid (AA) polymorphisms are often localized in the antigen binding pocket of MHC, and affect epitope bindings. To understand their impact on immune systems, we need to understand how such MHC-epitope complexes influence the repertoire of T cell receptors (TCRs). We assessed TCR frequencies using RNA-seq data of CD4+ T cells from BLUEPRINT consortium (n=169). After extracting reads from TCR regions, we identified the AAs of complementary determining region 3 (CDR3), and quantified them in each position of CDR3 (275 AAs in total). We imputed AA polymorphisms for HLA-A, B, C, DPA1, DPB1, DQA1, DQB1 and DRB1 using SNP2HLA and the reference panel from Type 1 Diabetes Genetics Consortium (n=5,225). We analyzed the associations between MHC AA polymorphisms and the AA usage in each CDR3 position. Consistent with the MHC class II restriction of CD4+ T cells, most associations were observed within MHC class II regions, prominently in DRB1 loci: six out of eight significant associations were led by AAs of DRB1 (Bonferroni corrected P value < 0.05). One such example includes the association between the 4-th AA of CDR3 of beta chain and AA position 11 of DRB1 (P value = 7.7 x 10-13), which is also a reported risk AA position of rheumatoid arthritis (RA) and type I diabetes. Our study showed novel associations of MHC-epitope-CDR3 interactions, and may help to further decipher the pathogenesis of RA and other autoimmune diseases.