Therapeutic Targeting of B Lymphocyte Stimulator (BLyS) in the Rheumatic Diseases

Division of Rheumatology, University of Southern California, 2011 Zonal Ave. HMR 711, Los Angeles, CA 90033, USA.
Endocrine Metabolic & Immune Disorders - Drug Targets(Formerly Current Drug Targets - Immune Endocrine & Metabolic Disorders) 01/2007; 6(4):351-8. DOI: 10.2174/187153006779025801
Source: PubMed


B lymphocyte stimulator (BLyS) is a vital B cell survival factor. Overexpression of BLyS in mice can lead to clinical and serological features of systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). Treatment with BLyS antagonists of mice with established SLE ameliorates disease progression and enhances survival. Moreover, similar treatment of mice with inflammatory arthritis ameliorates the ongoing inflammation and subsequent joint destruction. In humans, BLyS overexpression is common in patients with several rheumatic diseases, including SLE, rheumatoid arthritis (RA), Sjögren's syndrome, scleroderma, Wegener's granulomatosis, and ANCA-associated vasculitis. Results from phase-II clinical trials with a BLyS antagonist in human SLE and RA have shown the antagonist to have biological and clinical activity along with a favorable safety profile. These features collectively point to BLyS as an attractive therapeutic target in human rheumatic diseases.

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    • "On the other hand, reports in the literature suggest a role for BAFF/BLyS in the pathogenesis of B-cell-dependent autoimmune diseases [4] [11]. For instance, apoptosis of tumor cells [16] [17] – and for autoimmune diseases [18] [19] [20]. Neutrophils have been lately " re-discovered " as very versatile cells, contrary to their traditional description as terminally differentiated effectors of inflammation [21]. "
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    ABSTRACT: The expression and production of cytokines by cells of the innate immune system, including monocytes/macrophages, dendritic and NK cells, play a critical role not only in defensive and inflammatory but also in immunoregulatory and anti-/pro-tumoral processes. Studies performed in the last years have well ascertained that polymorphonuclear neutrophils can also be induced to express and produce chemokines, proinflammatory, anti-inflammatory, immunoregulatory, angiogenic and fibrogenic cytokines, as well as ligands belonging to the TNF superfamily. Among the latter group of molecules, B-cell-activating factor (BAFF)/B lymphocyte stimulator (BLyS), known to be essential for B lymphocyte homeostasis and related pathologies, has recently been identified as one of the factors potentially expressed by human neutrophils. The addition of this novel TNF superfamily member, and more recently also of the closely related "A Proliferation-Inducing Ligand" (APRIL), to the list of cytokines produced by neutrophils not only testifies to the continuous growth of this area of investigation, but also implies the involvement of neutrophils in B-cell-dependent autoimmune diseases and tumors.
    Immunology Letters 03/2008; 116(1):1-6. DOI:10.1016/j.imlet.2007.11.009 · 2.51 Impact Factor
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    • "As recently reviewed by Keystone and by Looney, the targeting and depletion of B cells with a mouse–human chimeric monoclonal antibody against the B-cell-specific antigen CD20 resulted in a significant beneficial effect in RA patients [69,70]. Moreover, treatment of RA patients with a fully human monoclonal antibody against the B-lymphocyte stimulator, which is a growth and survival factor for B cells, appears to be a promising therapy for the future [71]. "
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    ABSTRACT: Synovial pathophysiology is a complex and synergistic interplay of different cell populations with tissue components, mediated by a variety of signaling mechanisms. All of these mechanisms drive the affected joint into inflammation and drive the subsequent destruction of cartilage and bone. Each cell type contributes significantly to the initiation and perpetuation of this deleterious concert, especially in rheumatoid arthritis. Rheumatoid arthritis synovial fibroblasts and macrophages, both cell types with pivotal roles in inflammation and destruction, but also T cells and B cells are crucial for complex network in the inflamed synovium. An even more complex cellular crosstalk between these key players maintains a process of chronic inflammation. As outlined in the present review, in the past year substantial progress has been made to elucidate further details of the rich pathophysiology of rheumatoid arthritis, which may also facilitate the identification of novel targets for future therapeutic strategies.
    Arthritis research & therapy 02/2007; 9(2):209. DOI:10.1186/ar2140 · 3.75 Impact Factor
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