Differential binding of cross-reactive anti-DNA antibodies to mesangial cells: the role of alpha-actinin.
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.
Zhao
Zeguo
Z
The Irving and Ruth Claremon Research Laboratory, Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Deocharan
Bisram
B
Scherer
Philipp E
PE
Ozelius
Laurie J
LJ
Putterman
Chaim
C
D000185:Actinin / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000097:blood / Q000378:metabolism*; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001483:Base Sequence; D001666:Binding Sites, Antibody; D002460:Cell Line; D003429:Cross Reactions; D005920:Glomerular Mesangium / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D008840:Microfilament Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D017354:Point Mutation; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000502:physiology; D014162:Transfection
C491752:Actn4 protein, mouse; D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D008840:Microfilament Proteins; D020033:Protein Isoforms; D000185:Actinin