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Differential Binding of Cross-Reactive Anti-DNA Antibodies to Mesangial Cells: The Role of -Actinin¹

Zeguo Zhao^*, Bisram Deocharan, Philipp E. Scherer^,, Laurie J. Ozelius^¶ and Chaim Putterman^2,*,

^* The Irving and Ruth Claremon Research Laboratory, Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY 10461; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461; Department of Cell Biology and Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461; and ^¶ Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461

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 -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 -actinin reactive. Furthermore, a pathogenic anti-DNA/-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 -actinin expression may be contributing to nephritis. In the current study, we established that two isoforms of -actinin that are present in the kidney, -actinin 1 and -actinin 4, can both be targeted by anti--actinin Abs. We found novel sequence polymorphisms between MRL-lpr/lpr and BALB/c in the gene for -actinin 4. Moreover, -actinin 4 and a splice variant of -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--actinin Abs. We conclude that enhanced -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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The JI 2006 176: 7141-7142. [Full Text]  

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