| Deficiency of gelatinase B/MMP-9 aggravates lpr-induced lymphoproliferation and lupus-like systemic autoimmune disease. | |
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MedLine Citation:
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PMID: 21376533 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Gelatinase B/matrix metalloproteinase-9 (MMP-9) is a key enzyme involved in inflammatory, hematological, vascular and neoplastic diseases. In previous studies, we explored the intracellular substrate set or 'degradome' of MMP-9 and found many systemic autoantigens as novel intracellular gelatinase B substrates. Little is known, however, about the functional role of MMP-9 in the development of systemic autoimmunity in vivo. B6(lpr/lpr) mice with defective Fas-mediated apoptosis were used to investigate the functions of MMP-9 in lymphocyte proliferation and in the development of systemic autoimmunity. Combined Fas and gelatinase B deficiency resulted in extreme lymphoproliferative disease with enhanced lymphadenopathy and splenomegaly, and significantly reduced survival compared with single Fas deficiency. At the cellular level, this was corroborated by increased lymph node accumulation of 'double negative' T cells, B cells and myeloid cells. In addition, higher autoantibody titers and more pronounced autoimmune tissue injury were found in the absence of MMP-9, culminating in chronically enhanced systemic lupus erythematosus (SLE)-like autoimmunity. After cleavage by MMP-9 the SLE autoantigens U1snRNP A and ribosomal protein P0 were hardly recognized by plasma samples of both B6(lpr/lpr).MMP-9(-/-) and B6(lpr/lpr).MMP-9(+/+) mice, pointing to a destruction of B cell epitopes by MMP-9-mediated proteolysis. In addition, the same loss of immunodominant epitopes was observed with plasma samples from SLE patients, suggesting that MMP-9 suppresses systemic antibody-mediated autoimmunity by clearance of autoepitopes in immunogenic substrates. Thus, new protective functions for MMP-9 were revealed in the suppression of lymphoproliferation and dampening of systemic autoimmunity, cautioning against the long-term use of MMP inhibitors in autoimmune lymphoproliferative syndrome (ALPS) and SLE. |
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Authors:
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Bénédicte Cauwe; Erik Martens; Xavier Sagaert; Chris Dillen; Nathalie Geurts; Sandra Li; Jan Mertens; Greet Thijs; Philippe E Van den Steen; Hubertine Heremans; Rita De Vos; Daniel Blockmans; Bernd Arnold; Ghislain Opdenakker |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-3-2 |
Journal Detail:
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Title: Journal of autoimmunity Volume: - ISSN: 1095-9157 ISO Abbreviation: - Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-3-7 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8812164 Medline TA: J Autoimmun Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 Elsevier Ltd. All rights reserved. |
Affiliation:
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Laboratory of Immunobiology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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