Differential binding of cross-reactive anti-DNA antibodies to mesangial cells: The role of α-actinin

Zeguo Zhao, Bisram Deocharan, Philipp E. Scherer, Laurie J. Ozelius, Chaim Putterman

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)7704-7714
Number of pages11
JournalJournal of Immunology
Volume176
Issue number12
StatePublished - Jun 15 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Zhao, Z., Deocharan, B., Scherer, P. E., Ozelius, L. J., & Putterman, C. (2006). Differential binding of cross-reactive anti-DNA antibodies to mesangial cells: The role of α-actinin. Journal of Immunology, 176(12), 7704-7714.