Abstract
Anti-glomerular basement membrane (GBM) Ab-induced glomerulonephritis (GN) at late stage is thought to be mediated by T cells. However, signaling pathways of T cells that are involved in the development of anti-GBM Ab-induced GN are unclear. We have recently established transgenic mice expressing Smad7, an inhibitor of TGF-beta signaling, in mature T cells, where signaling by TGF-beta was blocked specifically in T cells. In this study, we showed that anti-GBM Ab-induced GN was suppressed in several measures in the transgenic mice including the severity of glomerular changes, proteinuria, renal function, and CD4 T cell infiltration into the glomeruli without down-regulation of CD62 ligand (CD62L) (L-selectin) expression on CD4 T cells. Furthermore, treatment with the soluble fusion protein of CD62L and IgG enhanced anti-GBM Ab-induced GN. These findings indicated that blockade of TGF-beta signaling in T cells prevented the development of anti-GBM Ab-induced GN. Because CD62L on T cells appears to be inhibitory for the development of anti-GBM Ab-induced GN, persistent expression of CD62L on CD4 T cells may explain, at least in part, the suppression of anti-GBM Ab-induced GN in the transgenic mice. Our findings suggest that the development of anti-GBM Ab-induced GN requires TGF-beta/Smad signaling in T cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies / metabolism
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Antibodies / toxicity
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Autoantibodies / metabolism
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Autoantibodies / toxicity
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Basement Membrane / immunology
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Basement Membrane / pathology
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / pathology
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Cell Movement / genetics
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Cell Movement / immunology
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Complement C3 / metabolism
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology
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Glomerulonephritis / genetics
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Glomerulonephritis / immunology*
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Glomerulonephritis / pathology
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Glomerulonephritis / prevention & control*
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Humans
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Injections, Intravenous
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Kidney Glomerulus / immunology
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Kidney Glomerulus / metabolism
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Kidney Glomerulus / pathology
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L-Selectin / biosynthesis
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L-Selectin / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Smad7 Protein
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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T-Lymphocytes / pathology
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Trans-Activators / genetics
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Trans-Activators / physiology
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Transforming Growth Factor beta / antagonists & inhibitors*
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Transforming Growth Factor beta / physiology*
Substances
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Antibodies
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Autoantibodies
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Complement C3
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DNA-Binding Proteins
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SMAD7 protein, human
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Smad7 Protein
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Smad7 protein, mouse
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Trans-Activators
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Transforming Growth Factor beta
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antiglomerular basement membrane antibody
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L-Selectin