Interfering with baffled B cells at the lupus tollway: Promises, successes, and failed expectations

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:137

Article

Singh, Namrata¹  Kumar, Bharat¹  Aluri, Vijay¹  Lenert, Petar¹ 

[1] Univ Iowa, Dept Internal Med, Div Immunol, Carver Coll Med, Iowa City, IA 52242 USA

关键词: B cells;    systemic lupus erythematosus;    Toll-like receptors;    B-cell receptor for antigen;    type I interferon;    B cell activating factor;    Bruton tyrosine kinase;    spleen tyrosine kinase;    Lyn;   

DOI  :  10.1016/j.jaci.2015.12.1326

来源: Elsevier

【 摘 要 】

B cells play an important role in systemic lupus erythematosus by acting not only as precursors of autoantibody-producing cells but also as antigen-presenting, cytokine-secreting, and regulatory cells. Unopposed activation of B cells through their B-cell receptor for antigen, as seen in B cells lacking Lyn kinase, results in systemic autoimmunity. The B-cell activating factor of the TNF family (BAFF), nucleic acid-sensing Toll-like receptors (TLRs), and type I interferon can affect B-cell survival and decrease their threshold for activation. Herein we discuss both direct and indirect strategies aimed at targeting B cells in patients with lupus by blocking BAFF, type I interferon, or TLR7 to TLR9. Although BAFF-depleting therapy with belimumab achieved approval for lupus, other BAFF inhibitors were much less beneficial in clinical trials. Inhibitors of the B-cell receptor for antigen signaling and antibodies against type I interferon are in the pipeline. The TLR7 to TLR9 blocker hydroxychloroquine has been in use in patients with lupus for more than 50 years, but oligonucleotide-based inhibitors of TLR7 to TLR9, despite showing promise in animal models of lupus, have not reached the primary end point in a recent phase 1 trial. These data point toward possible redundancies in B-cell signaling/survival pathways, which must be better understood before future clinical trials are executed.

【 授权许可】

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