Dual roles of immunoregulatory cytokine TGF-beta in the pathogenesis of autoimmunity-mediated organ damage.
Ample evidence suggests a role of TGF-beta 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-beta1-deficient mice. In this study, we show that lupus-prone (New Zealand Black and White)F(1) mice have reduced expression of TGF-beta1 in lymphoid tissues, and TGF-beta1 or TGF-beta1-producing T cells suppress autoantibody production. In contrast, the expression of TGF-beta1 protein and mRNA and TGF-beta signaling proteins (TGF-beta 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-beta1 in kidney tissue and urine correlate with the extent of chronic lesions that represent local tissue fibrosis. In vivo TGF-beta blockade by treatment of these mice with an anti-TGF-beta Ab selectively inhibits chronic fibrotic lesions without affecting autoantibody production and the inflammatory component of tissue injury. Thus, TGF-beta plays a dual, seemingly paradoxical, role in the development of organ damage in multiorgan autoimmune diseases. According to our working model, reduced TGF-beta 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-beta in target organs to counter inflammation. Enhanced TGF-beta in target organs, in turn, can lead to dysregulated tissue repair, progressive fibrogenesis, and eventual end-organ damage.
Saxena
Vijay
V
Autoimmunity and Tolerance Laboratory, Department of Medicine, University of California, Los Angeles 90095, USA.
Lienesch
Douglas W
DW
Zhou
Min
M
Bommireddy
Ramireddy
R
Azhar
Mohamad
M
Doetschman
Thomas
T
Singh
Ram Raj
RR
D000818:Animals; D001323:Autoantibodies / Q000276:immunology / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000235:genetics* / Q000473:pathology*; D005355:Fibrosis; D007668:Kidney / Q000276:immunology / Q000473:pathology*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000473:pathology*; D008221:Lymphoid Tissue / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics / Q000502:physiology*
D001323:Autoantibodies; D016212:Transforming Growth Factor beta