BAFF and innate immunity: new therapeutic targets for systemic lupus erythematosus.
Recently, the B cell has emerged as a cornerstone of systemic lupus erythematosus (SLE) pathogenesis. This has been highlighted by studies of the cytokine B-cell-activating factor of the tumour necrosis factor (TNF) family (BAFF), a crucial factor regulating B-cell maturation, survival and function. Overexpression of BAFF in mice leads to the development of an SLE-like disease, independent of T cells but instead relying on innate immunity mechanisms. Moreover, BAFF has been shown to be elevated in the serum of patients suffering from autoimmune conditions, especially SLE, and may correlate with disease activity. These findings challenge the previous notion that T:B-cell collaboration is the sole driver of SLE. In recent years, controlled trials have for the first time tested targeted therapeutics for SLE. However, agents designed to target B cells failed to meet primary endpoints in clinical trials in SLE, suggesting that a more complex role for B cells in SLE awaited elucidation. By contrast, on 9 March 2011, the US Food and Drug Administration approved belimumab, a fully human anti-BAFF monoclonal antibody, as a new B-cell-specific treatment for SLE. This article will review over 10 years of research on the BAFF system, key findings that led to this recent positive clinical outcome and propose a model potentially explaining why this B-cell-specific therapy has yielded positive results in clinical trials. We will also review promising therapies presently in clinical trials targeting innate immunity, which are likely to revolutionize SLE management towards a personalized and targeted therapy approach.
Department of Immunology, Monash University, Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), Melbourne, Victoria, Australia. vincent.fabien@gmail.com
Fabien B
FB
Vincent
Eric F
EF
Morand
Fabienne
F
Mackay
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D053264:B-Cell Activating Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D017277:Drug Approval; D006801:Humans; D007113:Immunity, Innate; D007167:Immunotherapy / Q000639:trends; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D057285:Precision Medicine
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D053264:B-Cell Activating Factor; C505720:Tnfsf13b protein, mouse; C511911:belimumab