Btk in autoimmunity: too much of a good thing?

B lymphocytes are important effector cells of the immune system that individually produce specialized, unique antibodies to be able to bind virtually any molecule (antigen) present on invading micro-organisms. Before B cell activation, the antibody is retained on the cell surface and functions as activating receptor known as the B cell receptor (BCR). Bruton’s tyrosine kinase (Btk) is a crucial kinase signaling downstream the BCR whose expression levels are upregulated upon B cell activation. However, the consequences of increased Btk levels on B cell activation are unknown. Here we describe that continuously increased Btk levels in mice lower the threshold for B cell activation, leading to a T-cell driven autoimmune disease resembling systemic lupus erythematosus (SLE). In SLE patients, BTK protein levels in B cells proved to be dysregulated in vivo and upon in vitro activation. Furthermore, increased Btk expression in mice proved to enhance the formation of autoimmune arthritis. Finally, we demonstrate that enhanced Btk expression in B cells in mice enhances the susceptibility to develop chronic lymphocytic leukemia (CLL). Together, these studies plead for the testing of recently developed Btk-inhibitors in the treatment of patients with rheumatic autoimmune diseases and B cell malignancies.

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