Autoreactive B cells in rheumatoid arthritis include mainly activated CXCR3+ memory B cells and plasmablasts

Abstract

Many autoimmune diseases (AIDs) are characterized by the persistence of autoreactive B cell responses, which have been directly implicated in disease pathogenesis. How and why these cells are generated or how they are maintained for years is largely unknown. Rheumatoid arthritis (RA) is among the most common AIDs and is characterized by autoantibodies recognizing proteins with posttranslational modifications (PTMs). This PTM-directed autoreactive B cell compartment is ill defined. Here, we visualized the B cell response against the three main types of PTM antigens implicated in RA by spectral flow cytometry. Our results showed extensive cross-reactivity of PTM-directed B cells against all three PTM antigens (citrulline, homocitrulline, and acetyllysine). Unsupervised clustering revealed several distinct memory B cell (mBC) populations. PTM-directed cells clustered with the most recently activated class-switched mBC phenotype, with high CD80, low CD24, and low CD21 expression. Notably, patients also harbored large fractions of PTM-directed plasmablasts (PBs). Both PTM-directed mBCs and PBs showed high expression of CXCR3, a receptor for chemokines present in abundance in arthritic joints. Together, our data provide detailed insight into the biology of B cell autoreactivity and its remarkable, seemingly exhaustless persistence in a prominent human AID.

Autoantibodies in rheumatoid arthritis – rheumatoid factor, anticitrullinated protein antibodies and beyond

“…However, such methods have now become available allowing to obtain detailed insight into on the phenotypic peculiarities of the AMPA-producing B cell compartment. As expected, a significant portion of AMPA-expressing B cells reacts to multiple modified antigens, indicating a promiscuous AMPA response at the cellular level [49 ▪ ]. B cells responding to citrullinated antigens are more prevalent and often “monoreactive” compared to those reacting to carbamylated and acetylated antigens, suggesting that reactivity to citrullinated proteins also dominate the AMPA response in RA at the cellular level.…”

“…Although the reason for these finding are not known, they could relate to barrier breaches by bacteria at mucosal sites such as the oral cavity [ 50 ]. The latter notion is reinforced by the observation that RA patients can harbor significant PTM-antigen-directed plasma blasts, recently activated, antibody-secreting B cells [ 49 ▪ ]. Notably, the composition of the “AMPA B cell compartment,” resembles the composition of the B cell response to SARS-CoV-2 spike protein one week after mRNA booster vaccination [ 51 ].…”

An anti-CD19/CTLA-4 switch improves efficacy and selectivity of CAR T cells targeting CD80/86-upregulated DLBCL

“…In addition, the application of switch CAR/CCR T cell strategy to other areas such as B cell-mediated autoimmune diseases is also conceivable, as autoreactive B cells clusters with the most recently activated class-switched mBC (memory B cell) phenotype exhibit high CD80 and CD86 expression. 59 , 60 …”

Single-cell insights into immune dysregulation in rheumatoid arthritis flare versus drug-free remission

“…B cells are important players in RA pathogenesis, and can contribute to immune dysregulation through antigen presentation, autoantibody production, and inflammatory cytokine production 29 . B cells likely also play a role in perpetuation of chronic synovitis—for example, expansion of circulating CD21lo/negative autoreactive B cells and plasmablasts have been observed in patients with established RA 30 , 31 . Furthermore, clonally-expanded autoreactive plasma cells are present in inflamed RA synovium 32 , and can be driven within the synovial microenvironment by CD4 + peripheral helper T cells (Tph) 33 .…”