HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization

Vincent Van Drongelen,Amr H Sawalha,Bruna Miglioranza Scavuzzi,Joseph Holoshitz,Sarah Veloso Nogueira,Frederick W Miller

doi:10.1038/s41598-021-82195-3

Abstract

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, but it is unclear whether HLA molecules might also have non-AP, disease-modulating effects. Here we demonstrate 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.

Highlights

Associations between particular human leukocyte antigen (HLA) alleles and susceptibility to—or protection from—autoimmune diseases have been long observed
The findings of this study suggest that aside from their nominal role in antigen presentation (AP), which is widely considered an underlying mechanism in HLA-disease association, HLA-DR molecules exhibit allele-specific, AP-independent modulatory effects, which might play a role in autoimmune disease pathogenesis as well
Given the known pivotal role that macrophages play in regulating pro- and anti-inflammatory events, here we focused on these cells

Summary

Introduction

Associations between particular human leukocyte antigen (HLA) alleles and susceptibility to—or protection from—autoimmune diseases have been long observed. We demonstrate 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. SE-coding HLA-DRB1 alleles have been found to associate with type 1 diabetes, autoimmune hepatitis, polymyalgia rheumatica, temporal arteritis and Parkinson’s d isease[17,18,19,20,21], among other

Methods

Results

Conclusion