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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    ABSTRACT: Autoimmune diseases occur in 3-5% of the population. Study included 30 patients with clinically diagnosed SLE and 30 healthy controls (American college of Rheumatology, 1997). SLE was diagnosed according to criteria issued in 1997 by the American College of Rheumatology (ACR). The aim of this study was to evaluate concentration values of each antigen of ENA-6 profile in SLE, to investigate possible correlation between the concentration of Sm antibodies and CIC, and to test their use as possible immunobiological markers in SLE. Furthermore, the aim of our study was to determine whether there is a correlation between Sm antibodies and CIC and SLE activity. The results revealed that all of these ENA-6 and Sm antibodies as biomarkers complement diagnoses of active SLE but their use as solo markers does not allow classifying patients with SLE. Our study has shown that based on calculations from ROC curves, Sm/RNP was clearly a very important marker for diagnosis of SLE (cut off ≥ 9.56 EU, AUC 0,942). The high incidence of Scl-70 (10%) reactivity suggests that ELISA monitoring of this antibody produces more false positive results than other multiplex assay. An important conclusion that can be drawn from the results of our study is that laboratory tests are no more effective than clinical examination for detecting disease relapse, but are helpful in the confirmation of SLE activity.
    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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    ABSTRACT: Wiskott-Aldrich Syndrome (WAS) is a severe X-linked Primary Immunodeficiency that affects 1-10 out of 1 million male individuals. WAS is caused by mutations in the WAS Protein (WASP) expressing gene that leads to the absent or reduced expression of the protein. WASP is a cytoplasmic protein that regulates the formation of actin filaments in hematopoietic cells. WASP deficiency causes many immune cell defects both in humans and in the WAS murine model, the Was(-/-) mouse. Both cellular and humoral immune defects in WAS patients contribute to the onset of severe clinical manifestations, in particular microthrombocytopenia, eczema, recurrent infections, and a high susceptibility to develop autoimmunity and malignancies. Autoimmune diseases affect from 22 to 72% of WAS patients and the most common manifestation is autoimmune hemolytic anemia, followed by vasculitis, arthritis, neutropenia, inflammatory bowel disease, and IgA nephropathy. Many groups have widely explored immune cell functionality in WAS partially explaining how cellular defects may lead to pathology. However, the mechanisms underlying the occurrence of autoimmune manifestations have not been clearly described yet. In the present review, we report the most recent progresses in the study of immune cell function in WAS that have started to unveil the mechanisms contributing to autoimmune complications in WAS patients.
    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