The role of Bruton’s tyrosine kinase in autoimmunity and implications for therapy

Abstract

Summary Bruton’s tyrosine kinase (BTK) mediates B cell signaling and is also present in innate immune cells but not T cells. BTK propagates B cell receptor (BCR) responses to antigen-engagement as well as to stimulation via CD40, toll-like receptors (TLRs), Fc receptors (FCRs) and chemokine receptors. Importantly, BTK can modulate signaling, acting as a “rheostat” rather than an “on-off” switch; thus, overexpression leads to autoimmunity while decreased levels improve autoimmune disease outcomes. Autoreactive B cells depend upon BTK for survival to a greater degree than normal B cells, reflected as loss of autoantibodies with maintenance of total antibody levels when BTK is absent. This review describes contributions of BTK to immune tolerance, including studies testing BTK-inhibitors for treatment of autoimmune diseases.

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…Bruton's tyrosine kinase (BTK) pays a critical role in B-lymphocyte development and in mast cell activation through high-affinity IgE receptors (Crofford et al, 2016). Mutations of BTK are associated with X-linked agammaglobulinemia, which causes immunodeficiency.…”

Safety, Tolerability, Pharmacokinetics, Target Occupancy, and Concentration‐QT Analysis of the Novel BTK Inhibitor Evobrutinib in Healthy Volunteers

“…Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase expressed in cells of hematopoietic origin, including B cells and macrophages, but not T cells. As a member of the Tec kinase family, BTK is a key regulator of B cell receptor (BCR)‐mediated signaling, and plays pivotal roles in B cell development, differentiation, activation, class‐switching, proliferation, survival, and cytokine release . BTK also mediates Fc receptor (FcR) signaling and may have a role in toll‐like receptor signaling in myeloid cells.…”

Reply

“…6,7 This correlates with murine studies regarding the role of Btk in autoimmunity, as we and others have shown that Btk-deficiency protects against multiple forms of autoimmune disease in pre-clinical models. 2,8–13 Further, we have not found evidence that Btk-deficiency might induce autoimmunity on its own, never having seen spontaneous arthritis either in Btk-deficient C57BL/6 mice, nor on the autoimmune-prone NOD background.…”

“…Btk-deficiency in mice profoundly depletes autoreactive B cells, while normal B cells are less affected. 1,2 This contrasts human patients who lack BTK, in whom all B cell subsets are depleted. These patients have fewer than 1% normal numbers, with failure of humoral immunity known as X-linked agammaglobulinemia (XLA).…”