HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization
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 hav...
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doaj-1ae9febf53314ba98be06bb35628670a2021-01-31T16:24:06ZengNature Publishing GroupScientific Reports2045-23222021-01-0111111510.1038/s41598-021-82195-3HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarizationVincent van Drongelen0Bruna Miglioranza Scavuzzi1Sarah Veloso Nogueira2Frederick W. Miller3Amr H. Sawalha4Joseph Holoshitz5Department of Internal Medicine, University of MichiganDepartment of Internal Medicine, University of MichiganDepartment of Internal Medicine, University of MichiganEnvironmental Autoimmunity Group, National Institute of Environmental Health SciencesDepartment of Internal Medicine, University of MichiganDepartment of Internal Medicine, University of MichiganAbstract 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.https://doi.org/10.1038/s41598-021-82195-3 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Vincent van Drongelen Bruna Miglioranza Scavuzzi Sarah Veloso Nogueira Frederick W. Miller Amr H. Sawalha Joseph Holoshitz |
spellingShingle |
Vincent van Drongelen Bruna Miglioranza Scavuzzi Sarah Veloso Nogueira Frederick W. Miller Amr H. Sawalha Joseph Holoshitz HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization Scientific Reports |
author_facet |
Vincent van Drongelen Bruna Miglioranza Scavuzzi Sarah Veloso Nogueira Frederick W. Miller Amr H. Sawalha Joseph Holoshitz |
author_sort |
Vincent van Drongelen |
title |
HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization |
title_short |
HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization |
title_full |
HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization |
title_fullStr |
HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization |
title_full_unstemmed |
HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization |
title_sort |
hla-drb1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2021-01-01 |
description |
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. |
url |
https://doi.org/10.1038/s41598-021-82195-3 |
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