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* Autoimmunity and Tolerance Laboratory, Department of Medicine,
Department of Pathology and Laboratory Medicine, and
Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095;
Department of Internal Medicine and
¶ Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267
Ample evidence suggests a role of TGF-β in preventing autoimmunity. Multiorgan inflammatory disease, spontaneous activation of self-reactive T cells, and autoantibody production are hallmarks of autoimmune diseases, such as lupus. These features are reminiscent of the immunopathology manifest in TGF-β1-deficient mice. In this study, we show that lupus-prone (New Zealand Black and White)F1 mice have reduced expression of TGF-β1 in lymphoid tissues, and TGF-β1 or TGF-β1-producing T cells suppress autoantibody production. In contrast, the expression of TGF-β1 protein and mRNA and TGF-β signaling proteins (TGF-β receptor type II and phosphorylated SMAD3) increases in the target organs, i.e., kidneys, of these mice as they age and develop progressive organ damage. In fact, the levels of TGF-β1 in kidney tissue and urine correlate with the extent of chronic lesions that represent local tissue fibrosis. In vivo TGF-β blockade by treatment of these mice with an anti-TGF-β Ab selectively inhibits chronic fibrotic lesions without affecting autoantibody production and the inflammatory component of tissue injury. Thus, TGF-β plays a dual, seemingly paradoxical, role in the development of organ damage in multiorgan autoimmune diseases. According to our working model, reduced TGF-β in immune cells predisposes to immune dysregulation and autoantibody production, which causes tissue inflammation that triggers the production of anti-inflammatory cytokines such as TGF-β in target organs to counter inflammation. Enhanced TGF-β in target organs, in turn, can lead to dysregulated tissue repair, progressive fibrogenesis, and eventual end-organ damage.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grants AR47322, AR050797, and DK69282.
2 V.S. and D.W.L. contributed equally to this work.
3 Current address: University of Arizona, Tucson, AZ 85724.
4 Address correspondence and reprint requests to Dr. Ram Raj Singh, David Geffen School of Medicine, University of California Los Angeles, 1000 Veteran Avenue, Room 32-59, Rehab Center, Los Angeles, CA 90095. E-mail address: RRSingh{at}mednet.ucla.edu
5 Abbreviations used in this paper: SLE, systemic lupus erythematosus; AP, alkaline phosphatase; BWF1, (New Zealand Black and White (NZB x NZW))F1; CI, chronicity index; CWF1, (BALB/c x NZW)F1; ANA, antinuclear Ab; GAI, glomerular activity index; PAS, periodic acid Schiff; RF, rheumatoid factor; TβRII, TGF-β receptor type II; TβRI, TGF-β receptor type I; TII, tubulointerstitial index.
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  S. Yu, G. C. Sharp, and H. Braley-Mullen TGF-{beta} Promotes Thyroid Epithelial Cell Hyperplasia and Fibrosis in IFN-{gamma}-Deficient NOD.H-2h4 Mice J. Immunol., August 1, 2008; 181(3): 2238 - 2245. [Abstract] [Full Text] [PDF]
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