Antigen Presentation-Independent Reciprocal Immune Modulation by HLA-DRB1 Allelic Epitopes that Associate with Autoimmune Disease Risk or Protection

Abstract Statistical associations between particular human leukocyte antigen (HLA) alleles and susceptibility to - or protection from - autoimmune diseases have been long observed. Allele-specific antigen presentation (AP) has been widely proposed as a culprit mechanism; however, direct evidence to substantiate that hypothesis is scant. Here we demonstrate AP-independent differential macrophage activation by HLA-DRB1 alleles known to associate with autoimmune disease risk or protection with resultant polarization of pro-inflammatory (“M1”) versus anti-inflammatory (“M2”) macrophages, respectively. RNA-sequencing analyses of in vitro -polarized macrophages in the presence of AP-incompetent short synthetic peptides corresponding to the third allelic hypervariable regions coded by those two HLA-DRB1 alleles showed reciprocal activation of pro- versus anti-inflammatory transcriptomes, with implication of corresponding gene ontologies and upstream regulators. These results identify a previously unrecognized mechanism of differential immune modulation by short HLA-DRB1 -coded allelic epitopes independent of AP, and could shed new light on the mechanistic basis of HLA-disease association.