Therapeutic Cytokine Inhibition Modulates Activation and Homing Receptors of Peripheral Memory B Cell Subsets in Rheumatoid Arthritis Patients

Abstract

Memory B cells have known to play an important role in the pathogenesis of rheumatoid arthritis (RA). With the emergence of B cell-targeted therapies, the modulation of memory B cells appears to be a key therapeutic target. Human peripheral memory B cells can be distinguished based on the phenotypic expression of CD27 and IgD, characterizing the three major B cell subpopulations: CD27+IgD+ pre-switch, CD27+IgD-post-switch, and CD27-IgD-double-negative memory B cells. We evaluated different memory cell populations for activation markers (CD95 and Ki-67) and chemokine receptors (CXCR3 and 4) expressing B cells in active RA, as well as under IL6-R blockade by tocilizumab (TCZ) and TNF-α blockade by adalimumab (ADA). Memory B cells were phenotypically analyzed from RA patients at baseline, week 12, and week 24 under TCZ or ADA treatment, respectively. Using flow cytometry, surface expression of CD95, intracellular Ki-67, and surface expressions of CXCR3 and CXCR4 were determined. Compared with healthy donors (n = 40), the phenotypic analysis of RA patients (n = 80) demonstrated that all three types of memory B cells were activated in RA patients. Surface and intracellular staining of B cells showed a significantly higher percentage of CD95+ (p < 0.0001) and Ki-67+ (p < 0.0001) cells, with numerically altered CXCR3+ and CXCR4+ cells in RA. CD95 and Ki-67 expressions were highest in post-switch memory B cells, whereas CD19+CXCR3+ and CD19+CXCR4+ expressing cells were substantially higher in the pre-switch compartment. In all subsets of the memory B cells, in vivo IL-6R, and TNF-α blockade significantly reduced the enhanced expressions of CD95 and Ki-67. Based on our findings, we conclude that the three major peripheral memory B cell populations, pre-, post-switch, and double-negative B cells, are activated in RA, demonstrating enhanced CD95 and Ki-67 expressions, and varied expression of CXCR3 and CXCR4 chemokine receptors when compared with healthy individuals. This activation can be efficaciously modulated under cytokine inhibition in vivo.

TLR-8, TNF-α, and ESR-1α Gene Polymorphism Susceptibility in Onset of Arthritis

“…However, contrary to current findings, another study conducted on the Pakistani population reported a positive association between rs361525 and OA development in the Pakistani population [40]. Like the findings of the current study, no positive association has been reported in the Chinese, Mexican, and Iraqi populations [40][41][42].…”

Monoclonal Antibodies for Chronic Pain Treatment: Present and Future

“…RA causes pain, stiffness, and swelling joints, leading to loss of physical function, work disability, and decreased quality of life of patients [ 85 ]. Its pathogenesis is still unclear, but it is known that pro-inflammatory cytokines such as IL-6 and TNF are involved in joint inflammation and extra-articular manifestations [ 86 , 87 , 88 , 89 , 90 , 91 ].…”

Lymphocyte subsets in the peripheral blood are disturbed in systemic sclerosis patients and can be changed by immunosuppressive medication

“…Double negative (DN) B cells (CD19 + /CD27 − /IgD − ), although lacking CD27-expression, show somatic hypermutation of the B cell receptor and are, therefore, attributed to the memory compartment [18]. DN B cells play a pathogenic role in autoimmune diseases, as they are enhanced and activated in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) [18][19][20].…”