Expansion of Activated Peripheral Blood Memory B Cells in Rheumatoid Arthritis, Impact of B Cell Depletion Therapy, and Biomarkers of Response

Abstract

Although B cell depletion therapy (BCDT) is effective in a subset of rheumatoid arthritis (RA) patients, both mechanisms and biomarkers of response are poorly defined. Here we characterized abnormalities in B cell populations in RA and the impact of BCDT in order to elucidate B cell roles in the disease and response biomarkers. In active RA patients both CD27+IgD- switched memory (SM) and CD27-IgD- double negative memory (DN) peripheral blood B cells contained significantly higher fractions of CD95+ and CD21- activated cells compared to healthy controls. After BCD the predominant B cell populations were memory, and residual memory B cells displayed a high fraction of CD21- and CD95+ compared to pre-depletion indicating some resistance of these activated populations to anti-CD20. The residual memory populations also expressed more Ki-67 compared to pre-treatment, suggesting homeostatic proliferation in the B cell depleted state. Biomarkers of clinical response included lower CD95+ activated memory B cells at depletion time points and a higher ratio of transitional B cells to memory at reconstitution. B cell function in terms of cytokine secretion was dependent on B cell subset and changed with BCD. Thus, SM B cells produced pro-inflammatory (TNF) over regulatory (IL10) cytokines as compared to naïve/transitional. Notably, B cell TNF production decreased after BCDT and reconstitution compared to untreated RA. Our results support the hypothesis that the clinical and immunological outcome of BCDT depends on the relative balance of protective and pathogenic B cell subsets established after B cell depletion and repopulation.

Robust memory responses against influenza vaccination in pemphigus patients previously treated with rituximab

“…To our knowledge, there is only one report of human antigen-specific MBCs surviving in the spleen after rituximab depletion (14). Several mechanisms underlying the persistence of B cells in tissues have been proposed, including resistance of activated B cells to rituximab-mediated depletion (61,63), effect of Fc glycosylation on rituximab and its resulting interaction with Fc receptors on accessory cells (64), the inflammatory or cytokine milieu allowing for B cells to survive (65,66), or possibly the inability of rituximab to fully access tissues to deplete B cells (67). It is also possible that CD20 expression is downregulated in B cells residing in tissues.…”

B Cell–Specific Biomarkers for Optimal Antibody Responses to Influenza Vaccination and Molecular Pathways That Reduce B Cell Function with Aging

“…We found that only memory B cells express SASP markers, especially the terminally differentiated B cell subset (CD19+IgD− CD27−), called late-memory/exhausted-memory, tissuelike, or double negative, which of all B cell subsets is the most pro-inflammatory. This subset has been reported to be increased in the blood of healthy elderly individuals 85,90 and in patients with autoimmune 96–101 and infectious diseases, 102–104 suggesting that, in a favorable inflammatory microenvironment, these cells may expand in vivo in the presence of autoantigens or pathogen-derived antigens, leading to the production of pathogenic (autoimmune) or protective antibodies, respectively.…”

Peripheral VH4+ plasmablasts demonstrate autoreactive B cell expansion toward brain antigens in early multiple sclerosis patients

“…Indeed, this break in tolerance could involve both B cell intrinsic and extrinsic mechanisms. Furthermore the rapid return of memory B cells in the periphery following B cell depletion is a strong indicator of poor response to therapy [1], and further emphasizes the importance of studying the development of autoreactive B cells in the blood.…”

“…Although MS was historically thought to be driven by T cells [44], evidence for the importance of B cells in MS produced a shift in this perspective [25, 26]. The efficacy of B cell depletion therapy (BCDT) [40, 50], the prevalence of B cells in type II MS lesions [61], and the inverse correlation between memory B cell repopulation and benefit from BCDT [1]all support the hypothesis that B cells play a central role in pathogenesis [25, 26]. …”