Article

B-cell targeted therapies in human autoimmune diseases: an updated perspective

ITGR Biomarker Discovery Group, Genentech, South San Francisco, CA 94080, USA.
Immunological Reviews (Impact Factor: 12.91). 09/2010; 237(1):264-83. DOI: 10.1111/j.1600-065X.2010.00945.x
Source: PubMed

ABSTRACT The advent of therapies that specifically target the B-lymphocyte lineage in human disease has rejuvenated interest in the mechanistic biology by which B cells mediate autoimmunity. B cells have a multitude of effector functions including production of self-reactive antibodies, ability to present antigen to T lymphocytes in the context of costimulation, involvement in generation and maintenance of neo-organogenesis at sites of disease, and opposing function through production of both immunostimulatory and immunomodulatory cytokines. In this review, we first discuss the role of B cells in driving autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and Sjögren's syndrome, and discuss how studies in these diseases have revealed differentially important roles for the multiple B-cell effector functions. These data reveal the complex and interrelated roles of B cells working in concert with other components of the innate and adaptive immune system to drive pathogenesis. We then focus on data from mouse and human in which B cells in the setting of disease have been targeted with drugs directed against CD20, CD22, and the BAFF (B-cell activating factor belonging to the tumor necrosis factor family)/APRIL (a proliferation inducing ligand) pathways. Pre-clinical studies in animal models in addition to and clinical trials targeting B cells have added further to the understanding of the differential roles B cells play in disease both through demonstration of clinical efficacy in the context of B-cell depletion or modulation, and also by failure of B-cell targeting in some diseases and disease patient subgroups. Moving forward, it will be imperative to apply these lessons to new interventional trials to ensure better targeting of the B-cell lineage and concomitantly better selection of patients most likely to benefit from these therapies.

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    • "Defining specific pathogenic mediators that may trigger the development or progression of an autoimmune disease remains a focus of intense research. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell hyperactivity resulting in overproduction of autoantibodies against cytoplasmic, nuclear, and surface antigens and immune complex formation [4] [5]. "
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    10/2012; 2012:321614. DOI:10.1155/2012/321614
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    • "s in WAS patients ( Park et al . , 2005 ) , it would be worth to investigate whether receptor editing is defective also in the absence of WASP . Furthermore , in the periph - ery , survival of autoreactive B cells is supported by high levels of BAFF and APRIL , members of the TNF superfamily , found to be increased in several autoimmune diseases ( Townsend et al . , 2010 ) and lymphopenic conditions ( Cassani et al . , 2010 ) . This represents an important mechanism involved in the regulation of peripheral human B cell tolerance that would be interesting to investigate in WAS . Finally , a new function as regulator of immune response has been described for B cells and is mainly mediated by the secretion"
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    Frontiers in Immunology 07/2012; 3:209. DOI:10.3389/fimmu.2012.00209
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    • "Syk inhibition may, therefore, have the desirable double effect of preventing the production of pathogenic autoantibodies, via inhibiting B cell activation via the BCR, and simultaneously inhibiting their downstream effects via disrupting signalling from their receptors. It is encouraging that other therapeutic approaches that target B-cells have recently shown efficacy in clinical practice (Townsend, Monroe et al. 2010). Interestingly, however, clinical benefit cannot always be attributed to eradication of circulating autoantibody, and it is probable that effects on other B cell functions, such as antigen presentation, cytokine production, and provision of co-stimulation to other immune cells, contribute to the benefit seen. "
    Immunosuppression - Role in Health and Diseases, 02/2012; , ISBN: 978-953-51-0152-9