Bcl-2 overexpression ameliorates immune complex-mediated arthritis by altering FcγRIIb expression and monocyte homeostasis

Journal of Leukocyte Biology

Annemarie van Nieuwenhuijze⁴  Scott D. Smith⁴  James E. Vince²  Andreas Strasser  and³  Ian K. Campbell⁴  Karen L. Parker⁴  Kate E. Lawlor⁵  Sarah F. Drake⁴  Ian P. Wicks, –¹ 

[1] The Reid Rheumatology Laboratory, Division of Inflammation,  Department of Medical Biology, the University of Melbourne, Parkville, Victoria, Australia; and –Rheumatology Unit, Royal Melbourne Hospital, Parkville, Victoria, AustraliaCell Signalling and Cell Death Division, and  Department of Medical Biology, the University of Melbourne, Parkville, Victoria, Australia;Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia;  Department of Medical Biology, the University of Melbourne, Parkville, Victoria, Australia;The Reid Rheumatology Laboratory, Division of Inflammation, Molecular Genetics of Cancer Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia;The Reid Rheumatology Laboratory, Division of Inflammation, Cell Signalling and Cell Death Division, and  Department of Medical Biology, the University of Melbourne, Parkville, Victoria, Australia;

关键词: apoptosis;    inflammation;    autoimmunity;   

DOI  :  10.1189/jlb.0412190

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

RA is a chronic autoimmune disease characterized by accumulation of inflammatory cells within synovial joints. RA is associated with a failure of apoptosis of infiltrating leukocytes, thought to be a result of overexpression of prosurvival Bcl-2 proteins. Overexpression of Bcl-2 in hematopoietic cells can result in spontaneous autoimmunity. We therefore hypothesized that increased Bcl-2 in the hematopoietic compartment would reduce apoptosis and thereby, exacerbate inflammatory arthritis. Paradoxically, we found that overexpression of Bcl-2 in mice (vav-bcl-2) markedly reduced pathology in antibody-dependent models of RA (CIA and K/BxN serum transfer arthritis). No such protection was observed in a model of CD4+ T cell-dependent, B cell-independent arthritis (mBSA/IL-1-induced arthritis). In CIA, vav-bcl-2 Tg mice had lower antibody production to CII, which might explain reduced disease. However, Bcl-2 overexpression also reduced passive K/BxN serum transfer arthritis. Overexpression of Bcl-2 caused a monocytosis, with preferential expansion of Ly6Clo monocytes and increased expression of the inhibitory receptor for IgG, FcγRIIb, on leukocytes. Skewing of the myeloid cell population, increases in FcγRIIb, and reduced arthritis were independent of the hypergammaglobulinemia found in vav-bcl-2 Tg mice. These data reveal selective effects of the Bcl-2-regulated apoptotic pathway on monocyte differentiation and the expression of FcRs critical for regulation of antibody/immune complex-mediated disease.

【 授权许可】

Unknown