Bruton’s tyrosine kinase in chronic inflammation: from pathophysiology to therapy

Abstract

Bruton's tyrosine kinase (Btk) not only plays a role in differentiation and activa- tion of B-cells but is also involved in regulating signaling in myeloid cell populations, mast cells, platelets, and osteoclasts. Btk plays a critical role in B-cell receptor signaling and has been shown to be involved in CD40 ligation, Toll-like receptor triggering, and Fc-receptor signaling as well, suggesting that targeting Btk might be particularly useful in autoimmune diseases characterized by pathologic antibodies, macrophage activation, and myeloid-derived type I interferon responses. Btk knockout and X-linked immunodeficiency mouse material and X-linked agammaglobulinemia patient samples are powerful tools to examine the role of Btk in health and disease. In addition, the recent development of several covalent and noncovalent small-molecule inhibitors specifically targeting Btk can contribute to our understanding of the functional role of Btk in several cell types and disease mechanisms. Specific Btk inhibitors have been used in both in vitro and in vivo models for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, and Sjogren's syndrome. The current small-molecule Btk inhibitors have demonstrated potent and selective Btk inhibition in preclinical studies, and some inhibitors have propelled the clinical develop- ment of such molecules toward clinical trials in patients with rheumatoid arthritis. Future studies on the effectiveness of Btk inhibition in other autoimmune diseases could further broaden the understanding of the disease mechanisms as well as lead to new targeted therapies.