Article: article from journal or magazin.
TNF deficiency fails to protect BAFF transgenic mice against autoimmunity and reveals a predisposition to B cell lymphoma.
Journal of Immunology
TNF is well characterized as a mediator of inflammatory responses. TNF also facilitates organization of secondary lymphoid organs, particularly B cell follicles and germinal centers, a hallmark of T-dependent Ab responses. TNF also mediates defense against tumors. We examined the role of TNF in the development of inflammatory autoimmune disorders resembling systemic lupus erythematosus and Sjögren's syndrome induced by excess B cell-activating factor belonging to the TNF family (BAFF), by generating BAFF-transgenic (Tg) mice lacking TNF. TNF(-/-) BAFF-Tg mice resembled TNF(-/-) mice, in that they lacked B cell follicles, follicular dendritic cells, and germinal centers, and have impaired responses to T-dependent Ags. Nevertheless, TNF(-/-) BAFF-Tg mice developed autoimmune disorders similar to that of BAFF-Tg mice. Disease in TNF(-/-) BAFF-Tg mice correlates with the expansion of transitional type 2 and marginal zone B cell populations and enhanced T-independent immune responses. TNF deficiency in BAFF-Tg mice also led to a surprisingly high incidence of B cell lymphomas (>35%), which most likely resulted from the combined effects of BAFF promotion of neoplastic B cell survival, coupled with lack of protective antitumor defense by TNF. Thus, TNF appears to be dispensable for BAFF-mediated autoimmune disorders and may, in fact, counter any proneoplastic effects of high levels of BAFF in diseases such as Sjögren's syndrome, systemic lupus erythematosus, and rheumatoid arthritis.
Animals, Antigens, T-Independent/physiology, Autoantibodies/biosynthesis, B-Cell Activating Factor, B-Lymphocyte Subsets/metabolism, B-Lymphocyte Subsets/pathology, CD4-Positive T-Lymphocytes/pathology, Genetic Predisposition to Disease, Glomerulonephritis/genetics, Glomerulonephritis/immunology, Lupus Erythematosus, Systemic/genetics, Lupus Erythematosus, Systemic/immunology, Lymphoma/genetics, Lymphoma/immunology, Lymphoma, B-Cell/genetics, Lymphoma, B-Cell/immunology, Membrane Proteins/genetics, Membrane Proteins/physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Sjogren's Syndrome/genetics, Sjogren's Syndrome/immunology, Splenomegaly/genetics, Splenomegaly/immunology, Tumor Necrosis Factor-alpha/deficiency, Tumor Necrosis Factor-alpha/genetics, Up-Regulation/genetics, Up-Regulation/immunology
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