B cells and rheumatoid factors in autoimmunity

In the current issue of this journal two very different research studies are published that relate to the possible roles that rheumatoid factor (RF) and B cells play in autoimmunity. In the article by McComish et al., a cross-sectional analysis of various peripheral blood B cell subsets in a cohort of patients with rheumatoid arthritis (RA) was carried out. Patients at diagnosis and not on treatment (disease-modifying anti-rheumatic drug [DMARD]na€ıve) were compared with patients on treatment and both groups of patients compared with normal controls. The authors then studied if any of the changes observed reflected how active the disease was, response to treatment, whether patients had high titre anti-cyclic citrullinated peptide antibodies (anti-CCP) at diagnosis or to what extent some of the differences could be explained by differences in age and sex between the groups. In view of the well known importance of B cells in the pathogenesis of RA, studying changes in the peripheral blood B cell subsets could reflect changes in B cell homeostasis associated with the disease and could be used as a biomarker of patient characteristics and their responses to treatment. In summary, the study found that various B cell subsets (mainly memory B cell subsets) were reduced at diagnosis when compared with controls, with further decreases seen in patients on treatment with DMARDs. The authors found lower proportion and numbers of total memory and unswitched memory B cell subsets in patients at diagnosis. Patients on treatment showed further decreases in total numbers of these subsets and also of switched memory, CD21 low and transitional B cells and of plasmablasts. However, patients on treatment had lower proportion and number of total B cells and many of the differences between the two patient groups could be due to this as proportions were not significantly different except for plasmablasts. There was some suggestion that changes in particular subsets may be associated with response to therapy, need for more intensive therapy or the therapy itself. Good response to treatment and a state of remission or low disease activity as defined by the Disease Activity Score of 28 joints (DAS28) was associated with lower switched memory and immunoglobulin M (IgM)-only memory B cells. High anti-CCP antibodies were associated with lower unswitched memory B cell subsets in both subgroups of patients and also with lower switched memory B cells in the DMARD-na€ıve group. Some of the differences could be due at least partially to differences in age between the cohorts. The authors have an error in methodology but this probably does not affect the results. Their statement regarding CD38 expression on the different B cell subpopulations is not correct. Despite this error and the absence of any example of gating strategy for the readers to check, the use of CD27 to characterize memory B cell populations and the fact that the percentages of plasmablasts and transitional B cells are what would be expected means that the results are probably correct. There are only a small number of studies looking at peripheral blood B cell subsets in patients with RA outside the context of patients treated with B cell depletion therapy. Previous studies found also decreased unswitched memory B cells but also an increase in switched memory B cells with increased disease duration. In early arthritis, short-term treatment with methotrexate and corticosteroids was not associated with changes in peripheral blood B cell subsets. Treatment with antitumor necrosis factor (TNF) agents in patients with established arthritis was associated with an increase in unswitched memory B cells. We do not know where the majority of pathogenic B cells reside in RA and to what extent they circulate in the peripheral blood. Samuels et al. have documented the presence of RFand CCP-specific circulating B cells in patients with RA. Older studies had shown ex vivo spontaneous production of RF by peripheral blood mononuclear cells and changes in response to treatment. Early flare following B cell depletion with rituximab is associated with repopulation with relatively higher proportions of circulating memory B cells. Usually, as in the current study, changes in peripheral blood B cell subsets in RA are interpreted as mirroring or being the reverse of what happens in the RA synovia.