Mechanisms of immune-deposit formation and the mediation of immune renal injury |
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Authors: | Masaomi Nangaku William G Couser |
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Institution: | (1) Division of Nephrology and Endocrinology, University of Tokyo School of Medicine, 7-3-1 Bunkyo-ku, Tokyo 113-8655, Japan;(2) Division of Nephrology, University of Washington, Seattle, WA, USA |
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Abstract: | The passive trapping of preformed immune complexes is responsible for some forms of glomerulonephritis that are associated
with mesangial or subendothelial deposits. The biochemical characteristics of circulating antigens play important roles in
determining the biologic activity of immune complexes in these cases. Examples of circulating immune complex diseases include
the classic acute and chronic serum sickness models in rabbits, and human lupus nephritis. Immune deposits also form “in situ”.
In situ immune deposit formation may occur at subepithelial, subendothelial, and mesangial sites. In situ immune-complex formation
has been most frequently studied in the Heymann nephritis models of membranous nephropathy with subepithelial immune deposits.
While the autoantigenic target in Heymann nephritis has been identified as megalin, the pathogenic antigenic target in human
membranous nephropathy had been unknown until the recent identification of neutral endopeptidase as one target. It is likely
that there is no universal antigen in human membranous nephropathy. Immune complexes can damage glomerular structures by attracting
circulating inflammatory cells or activating resident glomerular cells to release vasoactive substances, cytokines, and activators
of coagulation. However, the principal mediator of immune complex-mediated glomerular injury is the complement system, especially
C5b-9 membrane attack complex formation. C5b-9 inserts in sublytic quantities into the membranes of glomerular cells, where
it produces cell activation, converting normal cells into resident inflammatory effector cells that cause injury. Excessive
activation of the complement system is normally prevented by a series of circulating and cell-bound complement regulatory
proteins. Genetic deficiencies or mutations of these proteins can lead to the spontaneous development of glomerular disease.
The identification of specific antigens in human disease may lead to the development of fundamental therapies. Particularly
promising future therapeutic approaches include selective immunosuppression and interference in complement activation and
C5b-9-mediated cell injury. |
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Keywords: | Complement Glomerulonephritis Membranous nephropathy C5b-9 Complement inhibitor Hemolytic uremic syndrome |
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