Differential Binding of Cross-Reactive Anti-DNA Antibodies to Mesangial Cells: The Role of -Actinin

The Irving and Ruth Claremon Research Laboratory, Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
The Journal of Immunology (Impact Factor: 4.92). 07/2006; 176(12):7704-14. DOI: 10.4049/jimmunol.176.12.7704
Source: PubMed


Target Ag display is a necessary requirement for the expression of certain immune-mediated kidney diseases. We previously had shown that anti-DNA Abs that cross-react with alpha-actinin may be important in the pathogenesis of murine and human lupus nephritis; in murine models, we had found that a significant proportion of pathogenic serum and kidney-deposited Igs are alpha-actinin reactive. Furthermore, a pathogenic anti-DNA/alpha-actinin Ab showed enhanced binding to immortalized mesangial cells (MCs) derived from a lupus prone MRL-lpr/lpr mouse as compared with MCs from BALB/c mice which are not susceptible to spontaneous lupus, suggesting that kidney alpha-actinin expression may be contributing to nephritis. In the current study, we established that two isoforms of alpha-actinin that are present in the kidney, alpha-actinin 1 and alpha-actinin 4, can both be targeted by anti-alpha-actinin Abs. We found novel sequence polymorphisms between MRL-lpr/lpr and BALB/c in the gene for alpha-actinin 4. Moreover, alpha-actinin 4 and a splice variant of alpha-actinin 1 were both expressed at significantly higher levels (mRNA and protein) in MCs from the lupus prone MRL-lpr/lpr strain. Significantly, we were able to confirm these differences in intact kidney by examining glomerular Ig deposition of anti-alpha-actinin Abs. We conclude that enhanced alpha-actinin expression may determine the extent of Ig deposition in the Ab-mediated kidney disease in lupus. Modulation of Ag expression may be a promising approach to down-regulate immune complex formation in the target organ in individuals with circulating pathogenic Abs.

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    • "Anti-double-stranded DNA antibodies usually bindalpha-actinin, can bind mesangial cells and glomeruli ex vivo, and glomerular binding is not inhibited by DNase treatment but can be interrupted by alpha-actinin, indicating a role in cross-reactivity and potential induction of lesions in lupus nephritis [59]. In mouse models, two isoforms of alpha-actinin, alpha-actinin 1and alpha-actinin 4 can be targeted by anti-alpha-actinin antibodies, and enhanced alpha-actininexpression was observed in mesangial cells of lupus prone strains of mice, potentially allowing for increased antibody deposition [60]. In humans, anti-alpha-actinin antibodies correlate with glomerulonephritis, but whether they have predictive value for the development of SLE complications is not confirmed [61]. "
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    ABSTRACT: Lupus nephritis is a serious potential feature of systemic lupus erythematous (SLE). Though SLE typically cycles through periods of flares and remission, patients often eventually succumb to end-stage kidney or cardiovascular damage. This review of the pathogenesis of lupus nephritis examines the role of the complement cascade; the significance of autoantibodies, the breaking of tolerance, and the implications of altered apoptosis in breaking tolerance; and the contributions of adaptive immunity and cross-talk with the innate immune system in driving renal damage. Delineation of basic mechanisms underlying the development of acute and chronic renal damage in lupus nephritis can result in the continued development of more specific and effective treatments.
    04/2014; 5(2). DOI:10.4172/2155-9899.1000205
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    • "We have previously demonstrated that α-actinin expression is increased within the mesangium of patients with proliferative renal diseases [88]. Consistent with our finding, Zhao et al. also observed increased α-actinin expression in mesangial cells isolated from MRL/lpr mice [89], thereby suggesting increased availability of α-actinin for anti-dsDNA antibody binding. The pathogenic role of α-actinin as a cross-reactive antigen has recently been questioned by Mjelle et al. who demonstrated that anti-dsDNA antibodies did not colocalize with α-actinin in kidneys obtained from NZB/W F1 mice, but instead bound to glomerular structures containing extracellular nucleosomes [90]. "
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    ABSTRACT: Systemic lupus erythematosus is characterized by a breakdown of self-tolerance and production of autoantibodies. Kidney involvement (i.e., lupus nephritis) is both common and severe and can result in permanent damage within the glomerular, vascular, and tubulo-interstitial compartments of the kidney, leading to acute or chronic renal failure. Accumulating evidence shows that anti-dsDNA antibodies play a critical role in the pathogenesis of lupus nephritis through their binding to cell surface proteins of resident kidney cells, thereby triggering the downstream activation of signaling pathways and the release of mediators of inflammation and fibrosis. This paper describes the mechanisms through which autoantibodies interact with resident renal cells and how this interaction plays a part in disease pathogenesis that ultimately leads to structural and functional alterations in lupus nephritis.
    Clinical and Developmental Immunology 06/2012; 2012:139365. DOI:10.1155/2012/139365 · 2.93 Impact Factor
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    • "Il existe chez l'homme et chez l'animal des auto-Ac dotés de réactivité pour l'ADN et pour l'α-actinine : on les rencontre surtout dans la GN lupique. Chez la souris (mais pas encore chez l'homme), il y a un excès d'α-actinine à la surface des cellules mésangiales des animaux lupiques [20]. Enfin, on peut induire une GN en immunisant une souris normale par de l'α-actinine, mais ce n'est pas le cas si on injecte de l'ADN ou des nucléosomes [21]. "
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    ABSTRACT: The diagnosis and follow-up of systemic lupus erythematosus relies on a combination of clinical and biological criteria. Antidouble stranded (ds) desoxyribonucleic acid (DNA) antibodies (Ab) is used for diagnosis. Several methods have been set for their detection. However, evidence has since been accumulating that different subpopulations are detected according to the assay. What implies to associate anti-native DNA assay (indirect immunofluorescence test using Crithidia luciliae and/or Farr assay) and anti-dsDNA assay (e.g. ELISA) to improve the sensibility. In lupus nephritis, characterization of Ab resulted in the development of more reliable tests than anti-dsDNA: anti-alpha-actinin Ab and anti-C1q Ab.
    Immuno-analyse & Biologie Spécialisée 06/2008; 23(3):137-142. DOI:10.1016/j.immbio.2008.02.003 · 0.05 Impact Factor
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