Please use this identifier to cite or link to this item: https://hdl.handle.net/20.500.12202/959
Title: Cross reactive renal antigens for pathogenic anti-dsDNA antibodies in lupus nephritis
Authors: Deocharan, Bisram
Keywords: Immunology.
Issue Date: 2008
Publisher: ProQuest Dissertations & Theses
Citation: Source: Dissertation Abstracts International, Volume: 69-03, Section: B, page: 1553.;Advisors: Chaim Putterman.
Abstract: Auto-antibodies are serological hallmarks of systemic lupus erythematosus (SLE), with anti-ds (double stranded) DNA antibodies being characteristic of lupus nephritis (LN). Anti-dsDNA Abs can be found deposited in the kidney; however the cross-reactive renal target antigens for these antibodies have not been conclusively identified. In identifying the in-vivo renal antigens for anti-dsDNA Abs, we found that pathogenic anti-dsDNA antibodies as well as immunoglobulin eluted from kidneys of nephritic lupus mice cross-react with alpha-actinin. Furthermore, there was enhanced binding to alpha-actinin derived from lupus prone MRL-lpr/lpr mouse mesangial cells (MCs) as compared with non-autoimmune BALB/c MCs due to alpha-actinin 4 being expressed at significantly higher levels in the MRL-lpr/lpr MCs. We also found novel sequence polymorphisms between MRL- lpr/lpr and BALB/c alpha-actinin 4. To determine if antibodies generated against alpha-actinin in vivo can cross-react with nuclear antigens, we immunized BALB/c mice with alpha-actinin. Immunized, but not control mice displayed high titers of anti-nuclear antibodies and IgG anti-chromatin autoantibodies, hypergammaglobulinemia, renal immunoglobulin deposition and proteinuria. The specificity of the anti-chromatin response as determined by Western and proteomic analysis, was a 25 kDa protein doublet, conclusively identified as High Mobility Group Box Proteins (HMGB 1 & 3), and a 70 kDa protein identified as heat shock protein 70 (HSP70), both of which are known antigenic targets in murine lupus. Importantly, a panel of pathogenic monoclonal autoantibodies had significantly higher affinity for alpha-actinin, chromatin, HMGB and HSP70 as compared to non-pathogenic antibodies, suggesting a common motif within these antigens that is targeted by pathogenic antibodies. Our studies indicate that alpha-actinin's differential expression and sequence motifs make it a target of pathogenic autoantibodies. Moreover, Abs to alpha-actinin may be used as a biomarker of active LN.
URI: https://ezproxy.yu.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:3304526
https://hdl.handle.net/20.500.12202/959
Appears in Collections:Albert Einstein College of Medicine: Doctoral Dissertations

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