A growing collection of research reveals a connection between B cells and rheumatoid arthritis (RA). ¹ For example, indicators of RA include the presence of rheumatoid factor (RF) and antibodies against citrullinated peptides (anti-CCP), which point toward a central role of activated B cells and plasma cells producing autoreactive immunoglobulin. In the last few years, basic and clinical research have shown that B cells can affect RA in many ways.

In affected tissues of autoimmune patients, lymphoid follicles with germinal centers (GCs) - the so-called tertiary lymphoid structures - frequently form. This clearly indicates B-cell activation and differentiation into plasma cells and memory B cells. These aggregates - T cells surrounding CD20 ⁺ B cells - form GC-like structures in patients with RA or other autoimmune diseases. Moreover, Seisuke Takemura of the Mayo Clinic and colleagues demonstrated in mice that T-cell activation in RA is B-cell dependent. ² Treatment with B cell-depleting antibodies destroyed the extrafollicular GCs, removed dendritic follicular cell networks, and disrupted T-cell activation.

In autoimmunity, B cells participate in various processes. ³ For instance, B cells produce proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6. On the other hand, B cells produce IL-10, which inhibits inflammation.

B cells also make autoantibodies that can trigger autoimmunity. Patients with RA, for example, often exhibit autoantibodies against immunoglobulin G (IgG), IgM-RF, and anti-CCP. It is interesting that most of the autoantibodies occur years before the onset of the disease. ⁴

An important function of memory B cells is antigen presentation via human leukocyte antigen (HLA) class II molecules. Here the DR4 shared epitope sequences pose a genetic risk factor for the development of RA, because these sequences trigger anti-CCP production, in particular when smoking is an environmental factor. ⁵

Recent randomized clinical trials using B-cell depletion in RA and data in other autoimmune diseases support the concept that B cells play a central role in RA pathogenesis. The encouraging data close the loop that the characteristic autoantibodies in autoimmunity represent intimate disturbances of B-cell differentiation. However, not all patients respond sufficiently to B-cell depletion, due to inherent heterogeneity.

Thomas Dörner is professor of clinical hemostaseology and rheumatology, Charite University Hospital Berlin and Deutsches Rheumaforschungszentrum.