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      Autoimmune Renal Injury in C3- and C4-Deficient Mice: A Histological and Functional Study

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          Abstract

          Background: Complement deficiency predisposes to autoimmune renal disease. Since complement deficient mice are increasingly used to study the immunopathogenesis of renal disease we have determined whether mice deficient in C3 or C4 are susceptible to spontaneous immune-mediated renal injury. Methods: C3-deficient, C4-deficient and complement-sufficient, wild-type mice were maintained in standard conditions for 1 year at which stage renal function, renal histology, circulating antibody and autoantibody levels were assessed. Results: No significant decline in renal function was demonstrated in the complement-deficient mice. However, there was histological evidence of glomerular injury in both the C3- and C4-deficient mice, but of insufficient severity to alter function. Serum IgG2a concentration was significantly lower in C3- and C4-deficient mice. In contrast C3-deficient mice had higher concentrations of serum IgG2b. There was a tendency for mice from all groups, including the complement-sufficient mice, to develop autoantibodies. C4-deficient mice had higher titres of anti-dsDNA IgG but otherwise deficient mice had similar autoantibody titres to controls. Conclusion: We conclude that C4-deficient mice demonstrate a small increase in autoantibody production at 1 year of age compared to C3-deficient and wild-type mice. Furthermore, although complement-deficient mice exhibit glomerular changes, they are of minor functional significance, and are unlikely to affect the study of experimentally induced renal disease in these mice.

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          Most cited references 12

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          A Hierarchical Role for Classical Pathway Complement Proteins in the Clearance of Apoptotic Cells in Vivo

          The strongest susceptibility genes for the development of systemic lupus erythematosus (SLE) in humans are null mutants of classical pathway complement proteins. There is a hierarchy of disease susceptibility and severity according to the position of the missing protein in the activation pathway, with the severest disease associated with C1q deficiency. Here we demonstrate, using novel in vivo models of apoptotic cell clearance during sterile peritonitis, a similar hierarchical role for classical pathway complement proteins in vivo in the clearance of apoptotic cells by macrophages. Our results constitute the first demonstration of an impairment in the phagocytosis of apoptotic cells by macrophages in vivo in a mammalian system. Apoptotic cells are thought to be a major source of the autoantigens of SLE, and impairment of their removal by complement may explain the link between hereditary complement deficiency and the development of SLE.
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            Structure and biology of complement protein C3, a connecting link between innate and acquired immunity.

             A Sahu,  John Lambris (2001)
            Complement protein C3 is a central molecule in the complement system whose activation is essential for all the important functions performed by this system. After four decades of research it is now well established that C3 functions like a double-edged sword: on the one hand it promotes phagocytosis, supports local inflammatory responses against pathogens, and instructs the adaptive immune response to select the appropriate antigens for a humoral response; on the other hand its unregulated activation leads to host cell damage. In addition, its interactions with the proteins of foreign pathogens may provide a mechanism by which these microorganisms evade complement attack. Therefore, a clear knowledge of the molecule and its interactions at the molecular level not only may allow the rational design of molecular adjuvants but may also lead to the development of complement inhibitors and new therapeutic agents against infectious diseases.
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              Regulation of B lymphocyte responses to foreign and self-antigens by the CD19/CD21 complex.

              The membrane protein complex CD19/CD21 couples the innate immune recognition of microbial antigens by the complement system to the activation of B cells. CD21 binds the C3d fragment of activated C3 that becomes covalently attached to targets of complement activation, and CD19 co-stimulates signaling through the antigen receptor, membrane immunoglobulin. CD21 is also expressed by follicular dendritic cells and mediates the long-term retention of antigen that is required for the maintenance of memory B cells. Understanding of the biology of this receptor complex has been enriched by analyses of genetically modified mice; these analyses have uncovered roles not only in positive responses to foreign antigens, but also in the development of tolerance to self-antigens. Studies of signal transduction have begun to determine the basis for the coreceptor activities of CD19. The integration of innate and adaptive immune recognition at this molecular site on the B cell guides the appropriate selection of antigen by adaptive immunity and emphasizes the importance of this coreceptor complex.
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                Author and article information

                Journal
                NEE
                Nephron Exp Nephrol
                10.1159/issn.1660-2129
                Cardiorenal Medicine
                S. Karger AG
                1660-2129
                2004
                January 2004
                17 November 2004
                : 96
                : 1
                : e14-e22
                Affiliations
                Department of Nephrology and Transplantation, Guy’s Hospital, King’s College London, London, UK
                Article
                75572 Nephron Exp Nephrol 2004;96:e14–e22
                10.1159/000075572
                14752244
                © 2004 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, Tables: 5, References: 34, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/75572
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