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Receptor Signaling Is Essential for the Initiation, Acceleration, and Destruction of Autoimmune Kidney Disease in MRL-Faslpr Mice1
Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women’s Hospital, Boston, MA 02115
CSF-1 and TNF-
in the kidney of
MRL-Faslpr mice are proximal events
that precede and promote autoimmune lupus nephritis, while apoptosis of
renal parenchymal cells is a feature of advanced human lupus nephritis.
In the MRL-Faslpr kidney,
infiltrating T cells that secrete IFN-
are a hallmark of disease. To
examine the impact of IFN- on renal injury in
MRL-Faslpr mice, we constructed a
IFN-R-deficient strain. In
MRL-Faslpr mice lacking IFN-R,
circulating and intrarenal CSF-1 were absent, TNF- was markedly
reduced, survival was extended, lymphadenopathy and splenomegaly were
prevented, and the kidneys remained protected from destruction.
Mesangial cells (MC) that were signaled through the IFN-R induced
CSF-1 and TNF- in MRL-Faslpr
mice. We detected a large number of apoptotic renal parenchymal cells
in advanced nephritis and determined that signaling via the IFN-R
induces apoptosis of tubular epithelial cells (TEC), but not MC. By
comparison, TNF- induces apoptosis in MC, but not TEC, of the
MRL-Faslpr strain. Thus, IFN- is
directly and indirectly responsible for apoptosis of TEC and MC in
MRL-Faslpr mice, respectively. In
conclusion, IFN-R signaling is essential for the initiation (CSF-1),
acceleration (CSF-1 and TNF-), and apoptotic destruction of renal
parenchymal cells in MRL-Faslpr
autoimmune kidney disease.
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K. Kinoshita, G. Tesch, A. Schwarting, R. Maron, A. H. Sharpe, and V. R. Kelley Costimulation by B7-1 and B7-2 Is Required for Autoimmune Disease in MRL-Faslpr Mice J. Immunol., June 1, 2000; 164(11): 6046 - 6056. [Abstract] [Full Text] [PDF]
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C. M. Reilly, J. C. Oates, J. A. Cook, J. D. Morrow, P. V. Halushka, and G. S. Gilkeson Inhibition of Mesangial Cell Nitric Oxide in MRL/lpr Mice by Prostaglandin J2 and Proliferator Activation Receptor-{gamma} Agonists J. Immunol., February 1, 2000; 164(3): 1498 - 1504. [Abstract] [Full Text] [PDF]
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G. H. Tesch, S. Maifert, A. Schwarting, B. J. Rollins, and V. R. Kelley Monocyte Chemoattractant Protein 1-Dependent Leukocytic Infiltrates Are Responsible for Autoimmune Disease in Mrl-Faslpr Mice J. Exp. Med., December 20, 1999; 190(12): 1813 - 1824. [Abstract] [Full Text] [PDF]
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A. Schwarting, G. Tesch, K. Kinoshita, R. Maron, H. L. Weiner, and V. R. Kelley IL-12 Drives IFN-{gamma}-Dependent Autoimmune Kidney Disease in MRL-Faslpr Mice J. Immunol., December 15, 1999; 163(12): 6884 - 6891. [Abstract] [Full Text] [PDF]
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A N Theofilopoulos Effector and predisposing genes in murine lupus Lupus, November 1, 1998; 7(9): 575 - 584. [Abstract] [PDF]
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