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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Autores principales:	Vincent van Drongelen, Bruna Miglioranza Scavuzzi, Sarah Veloso Nogueira, Frederick W. Miller, Amr H. Sawalha, Joseph Holoshitz
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1ae9febf53314ba98be06bb35628670a
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spelling	oai:doaj.org-article:1ae9febf53314ba98be06bb35628670a2021-12-02T13:57:49ZHLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization10.1038/s41598-021-82195-32045-2322https://doaj.org/article/1ae9febf53314ba98be06bb35628670a2021-01-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82195-3https://doaj.org/toc/2045-2322Abstract 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.Vincent van DrongelenBruna Miglioranza ScavuzziSarah Veloso NogueiraFrederick W. MillerAmr H. SawalhaJoseph HoloshitzNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q 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
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.
format	article
author	Vincent van Drongelen Bruna Miglioranza Scavuzzi Sarah Veloso Nogueira Frederick W. Miller Amr H. Sawalha Joseph Holoshitz
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 Portfolio
publishDate	2021
url	https://doaj.org/article/1ae9febf53314ba98be06bb35628670a
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HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or protection activate reciprocal macrophage polarization

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