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

Department of Cell Biology, Albert Einstein College of Medicine, New York, New York, United States
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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    • "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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    • "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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