Rheumatoid arthritis patients display B-cell dysregulation already in the naïve repertoire consistent with defects in B-cell tolerance

Abstract

B cells are postulated to be central in seropositive rheumatoid arthritis (RA). Here, we use exploratory mass cytometry (n = 23) and next-generation sequencing (n = 19) to study B-cell repertoire shifts in RA patients. Expression of several B-cell markers were significantly different in ACPA+ RA compared to healthy controls, including an increase in HLA-DR across subsets, CD22 in clusters of IgM+ B cells and CD11c in IgA+ memory. Moreover, both IgA+ and IgG+ double negative (IgD− CD27−) CD11c+ B cells were increased in ACPA+ RA, and there was a trend for elevation in a CXCR5/CCR6high transitional B-cell cluster. In the RA BCR repertoire, there were significant differences in subclass distribution and, notably, the frequency of VH with low somatic hypermutation (SHM) was strikingly higher, especially in IgG1 (p < 0.0001). Furthermore, both ACPA+ and ACPA− RA patients had significantly higher total serum IgA and IgM compared to controls, based on serology of larger cohorts (n = 3494 IgA; n = 397 IgM). The observed elevated Ig-levels, distortion in IgM+ B cells, increase in double negative B cells, change in B-cell markers, and elevation of unmutated IgG+ B cells suggests defects in B-cell tolerance in RA. This may represent an underlying cause of increased polyreactivity and autoimmunity in RA.

Advances of Regulatory B Cells in Autoimmune Diseases

“…Collagen-induced arthritis (CIA) is induced by immunization bovine or chicken collagen in a susceptible strain of DBA/1 mice or C57/BL6 mice, and CIA mice have become useful animal models of RA (72,73). The involvement of B cells in RA has been well recognized, such as the precence of anti-citrullinated protein antibodies (ACPAs), rheumatoid factor (RF), higher total serum IgA, and elevated level of unmutated IgG + B cells compared to healthy controls (74,75). As important immune regulators, Bregs have been revealed in RA patients with impaired functions (76).…”

MicroRNA Expression Differences in Blood-Derived CD19+ B Cells of Methotrexate Treated Rheumatoid Arthritis Patients

“…Furthermore, B cells are major producers of chemokines and cytokines and can thereby influence RA pathogenesis (7). Disturbances in CD19+ B cell subpopulations have been observed in peripheral blood of RA patients, indicating breaks in tolerance within B cell development potentially leading to self-reactive B cells (8,9).…”

Expansion of Alternative Autoantibodies Does Not Follow the Evolution of Anti–Citrullinated Protein Antibodies in Preclinical Rheumatoid Arthritis: An Analysis in At‐Risk First Degree Relatives

“…It seems likely that appropriate signals from follicular helper T cells are essential for pathogenic autoantibodies to develop through somatic hypermutation in autoreactive B cells (44). Global failure of autoreactive B cell clearance can also be an underlying cause of pathogenic autoantibody appearance in circulation, which is facilitated by differential expression of major histocompatibility complex class II haplotypes, the nature of RA-and SLE-associated antigens, and/or differences in epitope binding to HLA-DRB1, resulting in a bystander activation of autoreactive immune cells (45)(46)(47).…”

“…Global failure of autoreactive B cell clearance can also be an underlying cause of pathogenic autoantibody appearance in circulation, which is facilitated by differential expression of major histocompatibility complex class II haplotypes, the nature of RA-and SLE-associated antigens, and/or differences in epitope binding to HLA-DRB1, resulting in a bystander activation of autoreactive immune cells (45)(46)(47). Also, it is worth considering the role of intrinsic factors such as aberrant germinal center interactions mediated through BAFF and IL-21, deficiency of regulatory B cells, increased frequency of activation-induced cytidine deaminase-mediated somatic hypermutation, and reduced sialylation via an IL-23-mediated pathway (38,44,(48)(49)(50)(51)(52)(53)(54). What is unknown is whether the altered tolerance mechanisms described above are specific to disease-associated autoantibodies or are at fault even for pathogenic alternative autoantibodies.…”