Editorial: Btk—friend or foe in autoimmune diseases?

B cells are critical players in the development of a broad range of autoimmune diseases, including systemic lupus erythematosus, type I diabetes, rheumatoid arthritis, and multiple sclerosis. In addition to the secretion of autoantibodies, B cells can potentiate autoimmunity by several additional means, such as their function as APCs and the secretion of proinflammatory cytokines. Also, the successful use of B cell-depletion therapies for the treatment of autoimmune disorders has supported the fundamental role of B cells in the development and sustaining of autoimmunity. All of these factors lead to a growing interest in understanding how autoreactive B cells develop and how their activation is controlled in health and disease. In the current issue of the Journal of Leukocyte Biology, Nundel and colleagues [1] provide new insight into these questions by exploring the role of Btk signaling in autoreactive B cell development and activation in response to nucleic acidassociated autoantigens. Systemic autoimmune diseases are frequently associated with the production of autoantibodies that recognize nuclear or cytosolic cellular components. Cellular debris derived from dying cells is likely to induce activation of autoreactive B cells and subsequent production of autoantibodies. In this context, the activation of autoreactive B cells that express low-affinity receptors for nucleic acids (or nucleic acid-associated autoantigens) is prompted by signals that originate from the engagement of TLRs with nucleic acids [2]. Hence, in addition to BCR stimulation, the binding of RNAor DNA-containing antigen to the BCR leads to receptor internalization and delivery of antigen to intracellular compartments containing TLR7 and TLR9. As a model system to understand development and activation of these autoreactive B cells, Nundel and colleagues [1] take advantage of mice expressing a prototypic RF BCR, encoded by heavy and light-chain, sitedirected transgenes (AM14 mice). These mice possess a highly homogeneous B cell pool, in which essentially all B cells express the same BCR. RF B cells have a low-affinity receptor and proliferate in response to IgG2a immune complexes that incorporate DNA or RNA. Therefore, AM14 mice allow evaluation of the effect of individual signaling molecules in the homeostasis, differentiation, and activation of autoreactive B cells, irrespectively of BCR specificity. Among the many molecules involved in BCR signaling, Btk is known to be essential for B cell activation and differentiation in both mouse and humans. As such, mutations in Btk result in XLA in humans and xid in mice. Importantly, xid mice, Btk-deficient mice, and XLA patients show a reduction in mature peripheral B cells [3]. In general, mutations in components of the BCR– Btk pathway result in a loss of follicular B cells and comparative preservation of MZ B cells. Accordingly, Nundel and colleagues [1] show that whereas Btksufficient RF B cells develop into a homogenous follicular B cell population, Btk deficiency leads to an increased proportion of RF B cells with a MZ phenotype. Therefore, the loss in signal strength derived from Btk deficiency favors differentiation of the MZ compartment. Interestingly, AM14-xid mice show a marked increase in the number of MZ precursors relative to the number of MZ B cells, suggesting that Btk could be required for survival of MZ RF B cells. Nevertheless, it is worth mentioning that some clones of transgenic B cells that recognize self-antigens have shown a requirement for Btk for differentiation to MZ B cells [4–6]. Consequently, although MZ B cells seem to be able to differentiate in the absence of Btk, it is possible that some clones (maybe with very low BCR affinity) might need Btk signaling to enter and/or survive in the MZ B cell pool. In addition to the altered splenic B cell populations, xid and Btk-deficient mice show a severe drop in the numbers of CD5 B1 peritoneal B cells and remarkably low levels of circulating IgM and IgG3 [3]. Interestingly, Btk-sufficient AM14 mice lack CD5 peritoneal B cells and display low levels of serum IgM compared with WT counterparts. Depletion of Btk in AM14 mice induces a further drop in IgM, suggesting that Btk could affect circulating IgM levels separately from the contribution of B1 cells.