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      Blockade of B-cell-activating factor suppresses lupus-like syndrome in autoimmune BXSB mice

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          Abstract

          B-cell-activating factor (BAFF), a member of the tumour necrosis factor superfamily, plays a critical role in the maturation, homeostasis and function of B cells. In this study, we demonstrated the biological outcome of BAFF blockade in BXSB murine lupus model, using a soluble fusion protein consisting of human BAFF-R and human mutant IgG4 Fc. Mutation of Leu 235 to Glu in IgG4 Fc eliminated antibody-dependent cell cytotoxicity (ADCC) and complement lysis activity, and generated a protein devoid of immune effector functions. Treatment of BXSB mice with BAFF-R-IgG4mut fusion protein for 5 weeks resulted in significant B-cell reduction in both the peripheral blood and spleen. Treated mice developed lower proteinuria, reduced glomerulonephritis and much delayed host death than untreated animals. Thus, BAFF blockade with BAFF-R-IgG4mut protein is an effective strategy to treat B-cell-mediated lupus-like pathology. Moreover, compared with other IgG isotypes with undesired effector functions, mutant IgG4 Fc should prove useful in constructing novel therapeutic reagents to block immune molecule signalling in various diseases.

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          Most cited references29

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          BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator.

          The tumor necrosis factor (TNF) superfamily of cytokines includes both soluble and membrane-bound proteins that regulate immune responses. A member of the human TNF family, BLyS (B lymphocyte stimulator), was identified that induced B cell proliferation and immunoglobulin secretion. BLyS expression on human monocytes could be up-regulated by interferon-gamma. Soluble BLyS functioned as a potent B cell growth factor in costimulation assays. Administration of soluble recombinant BLyS to mice disrupted splenic B and T cell zones and resulted in elevated serum immunoglobulin concentrations. The B cell tropism of BLyS is consistent with its receptor expression on B-lineage cells. The biological profile of BLyS suggests it is involved in monocyte-driven B cell activation.
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            TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease.

            B cells are important in the development of autoimmune disorders by mechanisms involving dysregulated polyclonal B-cell activation, production of pathogenic antibodies, and co-stimulation of autoreactive T cells. zTNF4 (BLyS, BAFF, TALL-1, THANK) is a member of the tumour necrosis factor (TNF) ligand family that is a potent co-activator of B cells in vitro and in vivo. Here we identify two receptors for zTNF4 and demonstrate a relationship between zTNF4 and autoimmune disease. Transgenic animals overexpressing zTNF4 in lymphoid cells develop symptoms characteristic of systemic lupus erythaematosus (SLE) and expand a rare population of splenic B-Ia lymphocytes. In addition, circulating zTNF4 is more abundant in NZBWF1 and MRL-lpr/lpr mice during the onset and progression of SLE. We have identified two TNF receptor family members, TACI and BCMA, that bind zTNF4. Treatment of NZBWF1 mice with soluble TACI-Ig fusion protein inhibits the development of proteinuria and prolongs survival of the animals. These findings demonstrate the involvement of zTNF4 and its receptors in the development of SLE and identify TACI-Ig as a promising treatment of autoimmune disease in humans.
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              BAFF AND APRIL: a tutorial on B cell survival.

              BAFF, a member of the TNF family, is a fundamental survival factor for transitional and mature B cells. BAFF overexpression leads to an expanded B cell compartment and autoimmunity in mice, and elevated amounts of BAFF can be found in the serum of autoimmune patients. APRIL is a related factor that shares receptors with BAFF yet appears to play a different biological role. The BAFF system provides not only potential insight into the development of autoreactive B cells but a relatively simple paradigm to begin considering the balancing act between survival, growth, and death that affects all cells.
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                Author and article information

                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                jcmm
                Journal of Cellular and Molecular Medicine
                Blackwell Publishing Ltd (Oxford, UK )
                1582-1838
                1582-4934
                June 2010
                20 July 2009
                : 14
                : 6b
                : 1717-1725
                Affiliations
                [a ]Department of Nephrology, Sichuan Provincial People’s Hospital Chengdu, China
                [b ]Department of Nephrology, Southwest Hospital, The Third Military Medical University Chongqing, China
                [c ]Department of Nephrology, Daping Hospital, The Third Military Medical University Chongqing, China
                [d ]Department of Immunology, Institute of Immunology PLA, The Third Military Medical University Chongqing, China
                [e ]The Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, MA, USA
                [f ]Department of Medicine, Boston University Medical Center Boston, MA, USA
                Author notes
                *Correspondence to: Dr. Li WANG, Department of Nephrology, Sichuan Provincial People’s Hospital. Chengdu, Sichuan, 610072, P. R. China. E-mail: scwangli62@ 123456163.com
                Article
                10.1111/j.1582-4934.2009.00817.x
                3829033
                19627403
                dd81110b-6e99-4406-a441-a921543d6a67
                © 2009 The Authors Journal compilation © 2010 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd
                History
                : 20 November 2008
                : 13 May 2009
                Categories
                Original Articles

                Molecular medicine
                baff,receptor antagonist,lupus, autoimmunity,bxsb mice
                Molecular medicine
                baff, receptor antagonist, lupus, autoimmunity, bxsb mice

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