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

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 ‘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-64Arg59-71, vimentin-64Cit59-71 and fibrinogen β−74Cit69-81 were solved using X-ray crystallography. Vimentin-64Cit59-71-specific and vimentin59-71-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 vimentin59-71 were observed in patients with HLA-DRB1*14:02+ RA and at-risk ACPA- first-degree relatives. HLA-DRB1*14:02-vimentin59-71-specific and HLA-DRB1*14:02-vimentin-64Cit59-71-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

A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis

Rheumatoid arthritis (RA) is strongly associated with the human leukocyte antigen (HLA)- DRB1 locus that possesses the shared susceptibility epitope (SE) and the citrullination of self-antigens. We show how citrullinated aggrecan and vimentin epitopes bind to HLADRB1* 04:01/04. Citrulline was accommodated within the electropositive P4 pocket of HLA-DRB1*04:01/04, whereas the electronegative P4 pocket of the RA-resistant HLADRB1* 04:02 allomorph interacted with arginine or citrulline-containing epitopes. Peptide elution studies revealed P4 arginine-containing peptides from HLA-DRB1*04:02, but not from HLA-DRB1*04:01/04. Citrullination altered protease susceptibility of vimentin, thereby generating self-epitopes that are presented to T cells in HLA-DRB1*04:01+ individuals. Using HLA-II tetramers, we observed citrullinated vimentin- and aggrecan-specific CD4+ T cells in the peripheral blood of HLA-DRB1*04:01+ RA-affected and healthy individuals. In RA patients, autoreactive T cell numbers correlated with disease activity and were deficient in regulatory T cells relative to healthy individuals. These findings reshape our understanding of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in RA

Genetics of rheumatoid arthritis: what have we learned?

Rheumatoid arthritis (RA) is a chronic autoimmune disease affecting 0.5–1% of the population worldwide. The disease has a heterogeneous character, including clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and APCA-negative disease. Although the pathogenesis of RA is poorly understood, progress has been made in identifying genetic factors that contribute to the disease. The most important genetic risk factor for RA is found in the human leukocyte antigen (HLA) locus. In particular, the HLA molecules carrying the amino acid sequence QKRAA, QRRAA, or RRRAA at positions 70–74 of the DRβ1 chain are associated with the disease. The HLA molecules carrying these “shared epitope” sequences only predispose for ACPA-positive disease. More than two decades after the discovery of HLA-DRB1 as a genetic risk factor, the second genetic risk factor for RA was identified in 2003. The introduction of new techniques, such as methods to perform genome-wide association has led to the identification of more than 20 additional genetic risk factors within the last 4 years, with most of these factors being located near genes implicated in immunological pathways. These findings underscore the role of the immune system in RA pathogenesis and may provide valuable insight into the specific pathways that cause RA

Note to MD-PDB files

<p>Note to molecular dynamics files</p

EM DQ8_002.PDB

<p>DQ8-DERAA complex. for more details: see note</p

EM DQ8_004.PDB

<p>DQ8-DERAA complex. for more details: see note</p

EM DQ8_003.PDB

<p>DQ8-DERAA complex. for more details: see note</p

DQ8 MD-PDB file

<p>DQ8-vinculin complex. for more details: see note</p

HLA and rheumatoid arthritis: How do they connect?

Pathophysiology and treatment of rheumatic disease