Abstract
B cells play a central role in the pathogenesis of multiple sclerosis (MS), as demonstrated through the success of various B cell-depleting monoclonal antibodies. Bruton’s tyrosine kinase (BTK) is a critical molecule in intracellular signaling from the receptor of B cells and receptors expressed in the cells of the innate immune system. BTK inhibitors may be a non-cell-depleting alternative to B cell modulation. In this review, the structure, signaling, and roles of BTK are reviewed among the different inhibitors assayed in animal models of MS and clinical trials.
Highlights
Multiple sclerosis (MS) has classically been considered an autoimmune disease of the central nervous system (CNS) with a degenerative component that becomes increasingly more evident as the disease progresses
Even though immunoglobulin abnormalities found in the cerebrospinal fluid (CSF) are the most conspicuous immunological finding, it was still believed that anomalies of the humoral response did not have the same pathogenetic relevance as those of the cellular response
Strong support against this view was provided by the results of a phase II clinical trial with rituximab, a monoclonal antibody depleting CD20+ B cells in patients with relapsing-remitting MS who showed a rapid and profound response in clinical and magnetic resonance imaging (MRI) parameters [1]
Summary
Multiple sclerosis (MS) has classically been considered an autoimmune disease of the central nervous system (CNS) with a degenerative component that becomes increasingly more evident as the disease progresses. Knowledge derived from experimental autoimmune encephalomyelitis (EAE) has contributed to the view of MS as a T-cell disease Strong support against this view was provided by the results of a phase II clinical trial with rituximab, a monoclonal antibody depleting CD20+ B cells in patients with relapsing-remitting MS who showed a rapid and profound response in clinical and magnetic resonance imaging (MRI) parameters [1]. BTK is a member of the TEC family of protein-tyrosine kinases, belonging to the group of nRTKs, and composed of five members They play critical roles in the growth and differentiation of blood cells, being part of the intracellular signaling mechanisms [33]. BTK levels were thought to be absent or undetectable in NK cells or T cells; this kinase is required for NK activation [39] and may be upregulated in T cells from patients with aplastic anemia [40]
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