HLA-DR restrictive supertypes dominate promiscuous T cell recognition: association of multiple HLA-DR molecules with susceptibility to autoimmune diseases
Ou, D.; Mitchell, L.A.; Tingle, A.J.
Journal of Rheumatology 24(2): 253-261
1997
ISSN/ISBN: 0315-162X PMID: 9034980 Document Number: 477195
The association of individual autoimmune diseases with multiple HLA molecules has remained an enigma. That T cells can recognize the same peptide presented by several different HLA-DR alleles (i.e., promiscuous recognition) has been well documented. To explain this, we propose the "DR restrictive supertype pattern (DR RSP)" hypothesis. We focus on the known amino acid polymorphisms at positions beta-70, beta-71, and beta-74 located within pocket 4 of the DR molecule and their potential influence on promiscuous T cell recognition. We have shown that HLA-DR alleles may be grouped, on the basis of their polymorphisms at these positions, into at least 6 sets of DR alleles, 4 of which share, respectively, one of the RSP: A (Q/RR/KA), D (DE/R(K)A/L), E (Q/RRE), or R (QKR/Q) and 2 of which share the restrictive patterns Q (DRQ) or a (QAA). Most of the RSP have been shown to be associated with promiscuous T cell recognition of antigenic peptides. We also provide a rationale on how different DR alleles, exhibiting a particular RSP, might be capable of binding an antigenic peptide and presenting it, in a promiscuous fashion, to peptide-specific T cells. By identifying these RSP represented by DR alleles that have been clinically associated with certain autoimmune diseases, we also extend the DR RSP hypothesis to account for the association of certain autoimmune diseases with multiple HLA-DR alleles.