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 language | English |
|---|---|
| Pages (from-to) | 1915-1923 |
| Number of pages | 9 |
| Journal | Annals of the Rheumatic Diseases |
| Volume | 76 |
| Issue number | 11 |
| DOIs | |
| Publication status | Published - 1 Nov 2017 |
Keywords
- autoimmunity
- rheumatoid arthritis
- T cells
Cite this
}
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 journal › Article › Research › peer-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 -