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

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.

Anti-alpha-actinin antibodies are part of the anti-cell membrane antibody spectrum that characterize patients with lupus nephritis

“…These observations, together with the reports that kidney a-actinin expression is increased in the lupus-prone mouse model MRL/lpr due to ACTN polymorphism [37] and the demonstration that a-actinin immunization generates nephritogenic autoantibodies, strongly support a role for a-actinin as an important factor in LN [38]. In human, results are more contrasted with studies, including ours, showing that patients with active LN displayed an increased binding to a-actinin, and that anti-a-actinin detection was associated with LN when comparing LN and non-LN patients [13,16], while others failed to confirm such association [39].…”

Lupus nephritis. How latest insights into its pathogenesis promote novel therapies

“…It was proposed that this process involves crossreactivity with a-actinin or annexin II on mesangial cells [45,46], but this concept could not be confirmed by the recent studies [47 && ,48]. Ligation of Toll-like receptors, complement receptors and Fc receptors activate renal cells for a local release of proinflammatory cytokines and chemokines as well as the induction of adhesion molecules of the renal vasculature [49,50].…”

The Pathogenesis of Lupus Nephritis

“…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].…”