Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis

Stephen W. Scally, Soi Cheng Law, Yi Tian Ting, Jurgen Van Heemst, Jeremy Sokolove, Aaron J. Deutsch, E. Bridie Clemens, Antonis K. Moustakas, George K. Papadopoulos, Diane Van Der Woude, Irene Smolik, Carol A. Hitchon, David B. Robinson, Elizabeth D. Ferucci, Charles N. Bernstein, Xiaobo Meng, Vidyanand Anaparti, Tom Huizinga, Katherine Kedzierska, Hugh H. Reid & 5 others Soumya Raychaudhuri, René E. Toes, Jamie Rossjohn, Hani El-Gabalawy, Ranjeny Thomas

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Objective The pathogenetic mechanisms by which HLA-DRB1 alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 alleles are known to share a common motif, the â € shared susceptibility epitope (SE)'. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine. HLA-DRB1 His/Phe13β stratifies with ACPA-positive RA, while His13βSer polymorphisms stratify with ACPA-negative RA and RA protection. Indigenous North American (INA) populations have high risk of early-onset ACPA-positive RA, whereby HLA-DRB1∗04:04 and HLA-DRB1∗14:02 are implicated as risk factors for RA in INA. However, HLA-DRB1∗14:02 has a His13βSer polymorphism. Therefore, we aimed to verify this association and determine its molecular mechanism. Methods HLA genotype was compared in 344 INA patients with RA and 352 controls. Structures of HLA-DRB1∗1402-class II loaded with vimentin-64Arg 59-71, vimentin-64Cit 59-71 and fibrinogen βâ '74Cit 69-81 were solved using X-ray crystallography. Vimentin-64Cit 59-71-specific and vimentin 59-71-specific CD4+ T cells were characterised by flow cytometry using peptide-histocompatibility leukocyte antigen (pHLA) tetramers. After sorting of antigen-specific T cells, TCRα and β-chains were analysed using multiplex, nested PCR and sequencing. Results ACPA + RA in INA was independently associated with HLA-DRB1∗14:02. Consequent to the His13βSer polymorphism and altered P4 pocket of HLA-DRB1∗14:02, both citrulline and arginine were accommodated in opposite orientations. Oligoclonal autoreactive CD4+ effector T cells reactive with both citrulline and arginine forms of vimentin 59-71 were observed in patients with HLA-DRB1∗14:02 + RA and at-risk ACPA-first-degree relatives. HLA-DRB1∗14:02-vimentin 59-71-specific and HLA-DRB1∗14:02-vimentin-64Cit 59-71-specific CD4+ memory T cells were phenotypically distinct populations. Conclusion HLA-DRB1∗14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA.

Original languageEnglish
Pages (from-to)1915-1923
Number of pages9
JournalAnnals of the Rheumatic Diseases
Volume76
Issue number11
DOIs
Publication statusPublished - 1 Nov 2017

Keywords

  • autoimmunity
  • rheumatoid arthritis
  • T cells

Cite this

Scally, Stephen W. ; Law, Soi Cheng ; Ting, Yi Tian ; Heemst, Jurgen Van ; Sokolove, Jeremy ; Deutsch, Aaron J. ; Bridie Clemens, E. ; Moustakas, Antonis K. ; Papadopoulos, George K. ; Woude, Diane Van Der ; Smolik, Irene ; Hitchon, Carol A. ; Robinson, David B. ; Ferucci, Elizabeth D. ; Bernstein, Charles N. ; Meng, Xiaobo ; Anaparti, Vidyanand ; Huizinga, Tom ; Kedzierska, Katherine ; Reid, Hugh H. ; Raychaudhuri, Soumya ; Toes, René E. ; Rossjohn, Jamie ; El-Gabalawy, Hani ; Thomas, Ranjeny. / Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis. In: Annals of the Rheumatic Diseases. 2017 ; Vol. 76, No. 11. pp. 1915-1923.
@article{83429138c63e47a88f781301321aa970,
title = "Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis",
abstract = "Objective The pathogenetic mechanisms by which HLA-DRB1 alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 alleles are known to share a common motif, the {\^a} € shared susceptibility epitope (SE)'. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine. HLA-DRB1 His/Phe13β stratifies with ACPA-positive RA, while His13βSer polymorphisms stratify with ACPA-negative RA and RA protection. Indigenous North American (INA) populations have high risk of early-onset ACPA-positive RA, whereby HLA-DRB1∗04:04 and HLA-DRB1∗14:02 are implicated as risk factors for RA in INA. However, HLA-DRB1∗14:02 has a His13βSer polymorphism. Therefore, we aimed to verify this association and determine its molecular mechanism. Methods HLA genotype was compared in 344 INA patients with RA and 352 controls. Structures of HLA-DRB1∗1402-class II loaded with vimentin-64Arg 59-71, vimentin-64Cit 59-71 and fibrinogen β{\^a} '74Cit 69-81 were solved using X-ray crystallography. Vimentin-64Cit 59-71-specific and vimentin 59-71-specific CD4+ T cells were characterised by flow cytometry using peptide-histocompatibility leukocyte antigen (pHLA) tetramers. After sorting of antigen-specific T cells, TCRα and β-chains were analysed using multiplex, nested PCR and sequencing. Results ACPA + RA in INA was independently associated with HLA-DRB1∗14:02. Consequent to the His13βSer polymorphism and altered P4 pocket of HLA-DRB1∗14:02, both citrulline and arginine were accommodated in opposite orientations. Oligoclonal autoreactive CD4+ effector T cells reactive with both citrulline and arginine forms of vimentin 59-71 were observed in patients with HLA-DRB1∗14:02 + RA and at-risk ACPA-first-degree relatives. HLA-DRB1∗14:02-vimentin 59-71-specific and HLA-DRB1∗14:02-vimentin-64Cit 59-71-specific CD4+ memory T cells were phenotypically distinct populations. Conclusion HLA-DRB1∗14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA.",
keywords = "autoimmunity, rheumatoid arthritis, T cells",
author = "Scally, {Stephen W.} and Law, {Soi Cheng} and Ting, {Yi Tian} and Heemst, {Jurgen Van} and Jeremy Sokolove and Deutsch, {Aaron J.} and {Bridie Clemens}, E. and Moustakas, {Antonis K.} and Papadopoulos, {George K.} and Woude, {Diane Van Der} and Irene Smolik and Hitchon, {Carol A.} and Robinson, {David B.} and Ferucci, {Elizabeth D.} and Bernstein, {Charles N.} and Xiaobo Meng and Vidyanand Anaparti and Tom Huizinga and Katherine Kedzierska and Reid, {Hugh H.} and Soumya Raychaudhuri and Toes, {Ren{\'e} E.} and Jamie Rossjohn and Hani El-Gabalawy and Ranjeny Thomas",
year = "2017",
month = "11",
day = "1",
doi = "10.1136/annrheumdis-2017-211300",
language = "English",
volume = "76",
pages = "1915--1923",
journal = "Annals of the Rheumatic Diseases",
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Scally, SW, Law, SC, Ting, YT, Heemst, JV, Sokolove, J, Deutsch, AJ, Bridie Clemens, E, Moustakas, AK, Papadopoulos, GK, Woude, DVD, Smolik, I, Hitchon, CA, Robinson, DB, Ferucci, ED, Bernstein, CN, Meng, X, Anaparti, V, Huizinga, T, Kedzierska, K, Reid, HH, Raychaudhuri, S, Toes, RE, Rossjohn, J, El-Gabalawy, H & Thomas, R 2017, 'Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis' Annals of the Rheumatic Diseases, vol. 76, no. 11, pp. 1915-1923. https://doi.org/10.1136/annrheumdis-2017-211300

Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis. / Scally, Stephen W.; Law, Soi Cheng; Ting, Yi Tian; Heemst, Jurgen Van; Sokolove, Jeremy; Deutsch, Aaron J.; Bridie Clemens, E.; Moustakas, Antonis K.; Papadopoulos, George K.; Woude, Diane Van Der; Smolik, Irene; Hitchon, Carol A.; Robinson, David B.; Ferucci, Elizabeth D.; Bernstein, Charles N.; Meng, Xiaobo; Anaparti, Vidyanand; Huizinga, Tom; Kedzierska, Katherine; Reid, Hugh H.; Raychaudhuri, Soumya; Toes, René E.; Rossjohn, Jamie; El-Gabalawy, Hani; Thomas, Ranjeny.

In: Annals of the Rheumatic Diseases, Vol. 76, No. 11, 01.11.2017, p. 1915-1923.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis

AU - Scally, Stephen W.

AU - Law, Soi Cheng

AU - Ting, Yi Tian

AU - Heemst, Jurgen Van

AU - Sokolove, Jeremy

AU - Deutsch, Aaron J.

AU - Bridie Clemens, E.

AU - Moustakas, Antonis K.

AU - Papadopoulos, George K.

AU - Woude, Diane Van Der

AU - Smolik, Irene

AU - Hitchon, Carol A.

AU - Robinson, David B.

AU - Ferucci, Elizabeth D.

AU - Bernstein, Charles N.

AU - Meng, Xiaobo

AU - Anaparti, Vidyanand

AU - Huizinga, Tom

AU - Kedzierska, Katherine

AU - Reid, Hugh H.

AU - Raychaudhuri, Soumya

AU - Toes, René E.

AU - Rossjohn, Jamie

AU - El-Gabalawy, Hani

AU - Thomas, Ranjeny

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Objective The pathogenetic mechanisms by which HLA-DRB1 alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 alleles are known to share a common motif, the â € shared susceptibility epitope (SE)'. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine. HLA-DRB1 His/Phe13β stratifies with ACPA-positive RA, while His13βSer polymorphisms stratify with ACPA-negative RA and RA protection. Indigenous North American (INA) populations have high risk of early-onset ACPA-positive RA, whereby HLA-DRB1∗04:04 and HLA-DRB1∗14:02 are implicated as risk factors for RA in INA. However, HLA-DRB1∗14:02 has a His13βSer polymorphism. Therefore, we aimed to verify this association and determine its molecular mechanism. Methods HLA genotype was compared in 344 INA patients with RA and 352 controls. Structures of HLA-DRB1∗1402-class II loaded with vimentin-64Arg 59-71, vimentin-64Cit 59-71 and fibrinogen βâ '74Cit 69-81 were solved using X-ray crystallography. Vimentin-64Cit 59-71-specific and vimentin 59-71-specific CD4+ T cells were characterised by flow cytometry using peptide-histocompatibility leukocyte antigen (pHLA) tetramers. After sorting of antigen-specific T cells, TCRα and β-chains were analysed using multiplex, nested PCR and sequencing. Results ACPA + RA in INA was independently associated with HLA-DRB1∗14:02. Consequent to the His13βSer polymorphism and altered P4 pocket of HLA-DRB1∗14:02, both citrulline and arginine were accommodated in opposite orientations. Oligoclonal autoreactive CD4+ effector T cells reactive with both citrulline and arginine forms of vimentin 59-71 were observed in patients with HLA-DRB1∗14:02 + RA and at-risk ACPA-first-degree relatives. HLA-DRB1∗14:02-vimentin 59-71-specific and HLA-DRB1∗14:02-vimentin-64Cit 59-71-specific CD4+ memory T cells were phenotypically distinct populations. Conclusion HLA-DRB1∗14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA.

AB - Objective The pathogenetic mechanisms by which HLA-DRB1 alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 alleles are known to share a common motif, the â € shared susceptibility epitope (SE)'. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine. HLA-DRB1 His/Phe13β stratifies with ACPA-positive RA, while His13βSer polymorphisms stratify with ACPA-negative RA and RA protection. Indigenous North American (INA) populations have high risk of early-onset ACPA-positive RA, whereby HLA-DRB1∗04:04 and HLA-DRB1∗14:02 are implicated as risk factors for RA in INA. However, HLA-DRB1∗14:02 has a His13βSer polymorphism. Therefore, we aimed to verify this association and determine its molecular mechanism. Methods HLA genotype was compared in 344 INA patients with RA and 352 controls. Structures of HLA-DRB1∗1402-class II loaded with vimentin-64Arg 59-71, vimentin-64Cit 59-71 and fibrinogen βâ '74Cit 69-81 were solved using X-ray crystallography. Vimentin-64Cit 59-71-specific and vimentin 59-71-specific CD4+ T cells were characterised by flow cytometry using peptide-histocompatibility leukocyte antigen (pHLA) tetramers. After sorting of antigen-specific T cells, TCRα and β-chains were analysed using multiplex, nested PCR and sequencing. Results ACPA + RA in INA was independently associated with HLA-DRB1∗14:02. Consequent to the His13βSer polymorphism and altered P4 pocket of HLA-DRB1∗14:02, both citrulline and arginine were accommodated in opposite orientations. Oligoclonal autoreactive CD4+ effector T cells reactive with both citrulline and arginine forms of vimentin 59-71 were observed in patients with HLA-DRB1∗14:02 + RA and at-risk ACPA-first-degree relatives. HLA-DRB1∗14:02-vimentin 59-71-specific and HLA-DRB1∗14:02-vimentin-64Cit 59-71-specific CD4+ memory T cells were phenotypically distinct populations. Conclusion HLA-DRB1∗14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA.

KW - autoimmunity

KW - rheumatoid arthritis

KW - T cells

UR - http://www.scopus.com/inward/record.url?scp=85031021509&partnerID=8YFLogxK

U2 - 10.1136/annrheumdis-2017-211300

DO - 10.1136/annrheumdis-2017-211300

M3 - Article

VL - 76

SP - 1915

EP - 1923

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

IS - 11

ER -