Distinct HLA Associations with Rheumatoid Arthritis Subsets Defined by Serological Subphenotype

Abstract

Rheumatoid arthritis (RA) is the most common immune-mediated arthritis. Anti-citrullinated peptide antibodies (ACPA) are highly specific to RA and assayed with the commercial CCP2 assay. Genetic drivers of RA within the MHC are different for CCP2-positive and -negative subsets of RA, particularly at HLA-DRB1. However, aspartic acid at amino acid position 9 in HLA-B (B pos-9 ) increases risk to both RA subsets. Here we explore how individual serologies associated with RA drive associations within the MHC. To define MHC differences for specific ACPA serologies, we quantified a total of 19 separate ACPAs in RA-affected case subjects from four cohorts (n = 6,805). We found a cluster of tightly co-occurring antibodies (canonical serologies, containing CCP2), along with several independently expressed antibodies (non-canonical serologies). After imputing HLA variants into 6,805 case subjects and 13,467 control subjects, we tested associations between the HLA region and RA subgroups based on the presence of canonical and/or non-canonical serologies. We examined CCP2(+) and CCP2(−) RA-affected case subjects separately. In CCP2(−) RA, we observed that the association between CCP2(−) RA and B pos-9 was derived from individuals who were positive for non-canonical serologies (omnibus_p = 9.2 × 10 −17 ). Similarly, we observed in CCP2(+) RA that associations between subsets of CCP2(+) RA and B pos-9 were negatively correlated with the number of positive canonical serologies (p = 0.0096). These findings suggest unique genetic characteristics underlying fine-specific ACPAs, suggesting that RA may be further subdivided beyond simply seropositive and seronegative.

Presence of autoantibodies in “seronegative” rheumatoid arthritis associates with classical risk factors and high disease activity

“…Other ACPA did not co-occur to the same extent, which may suggest different triggering mechanisms for different ACPA finespecificities. This, we have recently explored in a separate study, demonstrating unique genetic characteristics for different ACPA fine-specificities [36]. We did not find an association between HLA-DRB1 SE and RF in anti-CCP2-negative RA, supporting data generated from single-cell RNA sequencing of RF-positive and ACPApositive B cells, which suggest a T cell-dependent affinity maturation for the generation of ACPA, but innate immune pathways for the generation of RF [37].…”

The importance of differences; On environment and its interactions with genes and immunity in the causation of rheumatoid arthritis

“…The use of this aa-and antigen-binding grovecentric analysis was further utilized to analyse whether there was any preference for certain variants in the antigen-binding groves and presence of antibody reactivity to different citrullinated peptides. A recent analysis using this approach indeed demonstrated that aspartic acid in position 9 of HLA-B preferably associated with RA subsets defined by the presence of antibodies against distinct citrullinated peptides (defined as 'noncanonical' specificities), whereas valine in position 11 of the HLA-DR beta chain associated with the presence of a large group of mostly cross-reactive antibodies against several citrullinated peptides and proteins (defined as 'canonical' specificities) [50]. When this analysis of serologically defined subsets was extended to the anti-CCP-negative subset, it was also shown that a small group of individuals positive for antibodies against certain fibrinogen, vimentin and enolase-derived citrullinated peptides associated with HLA-DR SE alleles [20].…”

Profiling of IgG antibodies targeting unmodified and corresponding citrullinated autoantigens in a multicenter national cohort of early arthritis in Germany

“…A diagnosis of early "seronegative" RA, in this context defined as a lack of both RF and ACPA, may be particularly challenging. This "serological gap" [23] may progressively be closed by antibodies to post-translationally modified antigens such as antibodies to citrullinated or carbamylated proteins [9,10,24] and by the identification of hitherto unrecognized unmodified autoantigenic targets, as we and others have previously shown [12,13,18,25].…”

“…As a consequence, efforts have been undertaken to close the "serological gap" of RA diagnosis by various strategies. For instance, tuning of fine specificities of the ACPA assays, potentially also including non-canonical citrullinated antigens, was recently shown to carry the potential for increased RA detection rates [9,10]. Moreover, the inclusion of different isotypes of ACPA alters diagnostic properties and shows potential in seronegative patients [11].…”