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      Nucleosome Effects on Mesangial Cell Matrix and Proliferation: A Possible Role in Early Lupus Nephritis

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          Abstract

          Background: Oligonucleosomes (ON) have been demonstrated in the circulation and biopsies of lupus nephritis patients. Their presence as immune complexes is an early and persistent finding in lupus nephritis as are changes in mesangial matrix. Since ON competitively bind to glomerular mesangial cells (MC) in a receptor-like fashion, the purpose of our study was to investigate what effects ON have on MC matrix and proliferation. Methods: Rat and mouse MCs grown with ON or DNA for 1 week were dissociated from their matrices with Triton-X and their proteins were determined. MC collagen production, using collagenase sensitive <sup>3</sup>H-proline incorporation, was measured after 48-hour incubation with ON and DNA. Similar experiments using 10-fold excess DNA were done to assess its blocking effect on ON induced collagen synthesis. ON interaction with matrix was evaluated by incubated <sup>125</sup>I-ON with MC matrix grown with ON or media alone for 1 week. Results: MCs stimulated by ON but not DNA significantly increased total matrix protein, total collagen and specifically, collagen type I synthesis. DNA inhibited ON-stimulated collagen synthesis. MC matrix incubated with ON binds 3 times more <sup>125</sup>I-ON than matrix generated in media alone. Histone, a major component of nucleosomes, significantly increased <sup>3</sup>H-thymidine incorporation. Conclusions: Oligonucleosomes, both qualitatively and quantitatively, influence mesangial cell function. These findings for the first time suggest ON to be pathogenic independent of their IC construct. DNA inhibition of ON induced mesangial matrix changes suggests participation of the ON/DNA receptor. Increased production of collagen type I may contribute to glomerulosclerosis.

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          Most cited references 2

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          Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus

           S Adams,  C Mohan,  SK Datta (1993)
          Only a fraction (12%) of 268 "autoreactive" T cell clones derived from lupus-prone mice can selectively induce the production of pathogenic anti-DNA autoantibodies in vitro and accelerate the development of lupus nephritis when transferred in vivo. The CDR3 loops of T cell receptor beta chains expressed by these pathogenic T helper (Th) clones contain a recurrent motif of anionic residues suggesting that they are selected by autoantigens with cationic residues. Herein, we found that approximately 50% of these pathogenic Th clones were specific for nucleosomal antigens, but none of them responded to cationic idiopeptides shared by variable regions of pathogenic anti-DNA autoantibodies. Nucleosomes did not stimulate the T cells as a nonspecific mitogen or superantigen. Only the pathogenic Th cells of lupus responded to nucleosomal antigens that were processed and presented via the major histocompatibility class II pathway. Although the presentation of purified mononucleosomes to the Th clones could be blocked by inhibitors of endosomal proteases, neither of the two components of the nucleosomes--free DNA or histones by themselves-- could stimulate the Th clones. Thus critical peptide epitopes for the Th cells were probably protected during uptake and processing of the nucleosome particle as a whole. The nucleosome-specific Th clones preferentially augmented the production of IgG autoantibodies to histone-DNA complex in vitro. In vivo, nucleosome-specific, CD4+ T cells were not detectable in normal mice, but they were found in the spleens of lupus-prone mice as early as 1 mo of age, long before other autoimmune manifestations. Immunization of young, preautoimmune lupus mice with nucleosomes augmented the production of autoantibodies and markedly accelerated the development of severe glomerulonephritis. Previously, crude preparations containing nucleosomes were shown by others to have polyclonal mitogenic activity for B cells from normal as well as lupus mice. Identification here of pure mononucleosome as a lupus-specific immunogen for the Th cells that selectively help the pathogenic anti-DNA autoantibody producing B cells of lupus could lead to the design of specific therapy against this pathogenic autoimmune response.
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            Lupus: key pathogenic mechanisms and contributing factors.

             S Datta,  T C Mohan (1995)
            The past 30 years of research on murine and human systemic lupus erythematosus has served to identify an array of immunological aberrations--some shared, some unique, some primary, others secondary-- that may underlie this disease. In integrating these findings, it appears that at least four distinct pathogenic events characterize lupus: (1) Anti-DNA Abs and immune complexes induce renal damage; (2) B-cells produce pathogenic anti-DNA antibodies; (3) Th cells drive lupus B-cells; and (4) Increased concentrations and abnormal presentation of nucleosomes. The purpose of this review is to examine the roles of these four events in the pathogenesis of lupus and to identify the different factors that can precipitate these pathogenic events.
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              Author and article information

              Journal
              EXN
              Nephron Exp Nephrol
              10.1159/issn.1660-2129
              Cardiorenal Medicine
              S. Karger AG
              1660-2129
              2002
              2002
              30 May 2002
              : 10
              : 3
              : 216-226
              Affiliations
              Departments of aMedicine and bPathology, Nassau University Medical Center, East Meadow, N.Y. and State University of New York Health Sciences Center at Stony Brook, N.Y., USA
              Article
              58348 Exp Nephrol 2002;10:216–226
              10.1159/000058348
              12053123
              © 2002 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: 10, Tables: 1, References: 41, Pages: 11
              Product
              Self URI (application/pdf): https://www.karger.com/Article/Pdf/58348
              Categories
              Original Paper

              Cardiovascular Medicine, Nephrology

              Nucleosomes, Lupus nephritis, Collagen, Mesangial cells, Matrix

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