Crossreactivity to vinculin and microbes provides a molecular basis for HLA-based protection against rheumatoid arthritis

Abstract

The HLA locus is the strongest risk factor for anti-citrullinated protein antibody (ACPA) þ rheumatoid arthritis (RA). Despite considerable efforts in the last 35 years, this association is poorly understood. Here we identify (citrullinated) vinculin, present in the joints of ACPA þ RA patients, as an autoantigen targeted by ACPA and CD4 þ T cells. These T cells recognize an epitope with the core sequence DERAA, which is also found in many microbes and in protective HLA-DRB1*13 molecules, presented by predisposing HLA-DQ molecules. Moreover, these T cells crossreact with vinculin-derived and microbial-derived DERAA epitopes. Intriguingly, DERAA-directed T cells are not detected in HLA-DRB1*13 þ donors, indicating that the DERAA epitope from HLA-DRB1*13 mediates (thymic) tolerance in these donors and explaining the protective effects associated with HLA-DRB1*13. Together our data indicate the involvement of pathogen-induced DERAA-directed T cells in the HLA-RA association and provide a molecular basis for the contribution of protective/predisposing HLA alleles.

The oral and gut microbiomes are perturbed in rheumatoid arthritis and partly normalized after treatment

“…10 and Supplementary Tables 20 and 21). Thus, both the gut and the oral microbiome might contribute to RA through molecular mimicry of self-antigens 34,35 .…”

Associations of human leukocyte antigens with autoimmune diseases: challenges in identifying the mechanism

“…A recent study revealed that the citrullinated DERAA motif, which was found in the protective DRB1 allele products, including DRB1*13 protein, and in vinculin, can be presented by the DQ proteins that were encoded on the RA susceptible DR-DQ haplotypes. 20 The protective effect of DRB1*13 against RA was explained by the cross-reactivity of self-reactive T cells to the citrullinated DERAA motif in vinculin and DRB1*13 protein, and the absence of these self-reactive T cells in the DR4/DR13 heterozygotes. 20 Self-peptides that are derived from other potential self-antigens, including type II collagen and nuclear ribonucleoprotein A2 can also be presented to the susceptible DR or DQ allele products and are involved in the pathogenesis of RA.…”

“…20 The protective effect of DRB1*13 against RA was explained by the cross-reactivity of self-reactive T cells to the citrullinated DERAA motif in vinculin and DRB1*13 protein, and the absence of these self-reactive T cells in the DR4/DR13 heterozygotes. 20 Self-peptides that are derived from other potential self-antigens, including type II collagen and nuclear ribonucleoprotein A2 can also be presented to the susceptible DR or DQ allele products and are involved in the pathogenesis of RA. [21][22][23][24][25] The binding affinity of DR4 with class II-associated invariant chain peptide (CLIP) may also affect RA risk.…”

“…18 The proposed mechanism of protection against RA also involves the allele-specific presentation of self-peptides. 20 Therefore, the selective presentation of self-peptides on the susceptible and protective HLA allele products might be one of the key mechanisms of DR-DQ haplotype associations with RA ( Figure 2a). …”

Problems of Rheumatoid Arthritis Immunopathology: Evolution of the Disease

“…Высказано предположение, что HLA-DRB1*13 участвует не в «презен-тации» аутоантигенов, а в делеции в тимусе Т-клеток, об-ладающих перекрестной реактивностью с антигенами ми-кроорганизмов и аутоантигенами [177].…”