PMID- 33510427
OWN - NLM
STAT- MEDLINE
DCOM- 20211001
LR  - 20230128
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 11
IP  - 1
DP  - 2021 Jan 28
TI  - HLA-DRB1 allelic epitopes that associate with autoimmune disease risk or 
      protection activate reciprocal macrophage polarization.
PG  - 2599
LID - 10.1038/s41598-021-82195-3 [doi]
LID - 2599
AB  - 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.
FAU - van Drongelen, Vincent
AU  - van Drongelen V
AD  - Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, 
      USA.
FAU - Scavuzzi, Bruna Miglioranza
AU  - Scavuzzi BM
AD  - Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, 
      USA.
FAU - Nogueira, Sarah Veloso
AU  - Nogueira SV
AD  - Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, 
      USA.
FAU - Miller, Frederick W
AU  - Miller FW
AD  - Environmental Autoimmunity Group, National Institute of Environmental Health 
      Sciences, Research Triangle Park, Durham, NC, 27709, USA.
FAU - Sawalha, Amr H
AU  - Sawalha AH
AD  - Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, 
      USA.
AD  - Departments of Pediatrics and Internal Medicine, University of Pittsburgh, 
      Pittsburgh, PA, 15224, USA.
FAU - Holoshitz, Joseph
AU  - Holoshitz J
AD  - Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, 
      USA. jholo@med.umich.edu.
LA  - eng
GR  - R33 AR073014/AR/NIAMS NIH HHS/United States
GR  - HHSN273201600123P/ES/NIEHS NIH HHS/United States
GR  - R01AR059085/AR/NIAMS NIH HHS/United States
GR  - R01 AR074930/AR/NIAMS NIH HHS/United States
GR  - R01 AR059085/AR/NIAMS NIH HHS/United States
GR  - R61AR073014/AR/NIAMS NIH HHS/United States
GR  - R61 AR073014/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20210128
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (Epitopes)
RN  - 0 (HLA-DRB1 Chains)
SB  - IM
MH  - Animals
MH  - Autoimmune Diseases/*epidemiology/genetics
MH  - Cells, Cultured
MH  - Epitopes/*genetics
MH  - Flow Cytometry
MH  - HLA-DRB1 Chains/*genetics
MH  - Immunoblotting
MH  - Macrophage Activation/genetics/physiology
MH  - Male
MH  - Mice
MH  - Mice, Transgenic
MH  - RAW 264.7 Cells
MH  - RNA-Seq
PMC - PMC7844024
COIS- J.H. is an Inventor of Regents of the University of Michigan-owned technologies 
      that are licensed to Zydus-Cadila, to whom he is an unpaid consultant, or Alibion 
      AG, where he holds a 2.5% equity option, and to whom he is a paid consultant. All 
      other authors have no competing interests to declare.
EDAT- 2021/01/30 06:00
MHDA- 2021/10/02 06:00
PMCR- 2021/01/28
CRDT- 2021/01/29 05:53
PHST- 2019/12/14 00:00 [received]
PHST- 2021/01/18 00:00 [accepted]
PHST- 2021/01/29 05:53 [entrez]
PHST- 2021/01/30 06:00 [pubmed]
PHST- 2021/10/02 06:00 [medline]
PHST- 2021/01/28 00:00 [pmc-release]
AID - 10.1038/s41598-021-82195-3 [pii]
AID - 82195 [pii]
AID - 10.1038/s41598-021-82195-3 [doi]
PST - epublish
SO  - Sci Rep. 2021 Jan 28;11(1):2599. doi: 10.1038/s41598-021-82195-3.