A small N-terminal 60-kD fragment of gp600 (megalin), the major autoantigen of active Heymann nephritis, can induce a full-blown disease.
Active Heymann nephritis of rat, an autoimmune glomerular disease, is an immunohistological, ultrastructural, and clinical model of human membranous glomerulonephritis. Both diseases in their full-blown form are characterized by (1) the formation of large, subepithelial glomerular immune deposits, which stain for IgG, C3, and membrane attack (C5b-9) components of complement and (2) the excretion of large amounts of protein in the urine (proteinuria). The target autoantigen of active Heymann nephritis is a large transmembrane renal glycoprotein with a molecular weight of approximately 600 kD, variously named gp600, gp330, LRP-2, or "megalin." This study was performed to identify the region in this enormously large glycoprotein that would produce full-blown active Heymann nephritis. A stable, small (60-kD) proteolytic fragment of gp600 was isolated and localized to the N-terminal end of the molecule using Western blot, sequencing, and amino acid analyses. Based on its primary structure, this fragment contains approximately 60 cysteine residues, the cross-linking of which to each other probably explains its stability. Immunization of rats with this fragment induced a full-blown disease that was comparable to the disease induced by a preparation containing the whole protein. These results indicate that this small fragment, retaining the natural disulfide bonds and probably its overall structure, contains those B and T cell epitopes that are sufficient to produce this organ-specific autoimmune disease.
Oleinikov
Andrew V
AV
Department of Pediatrics, Division of Nephrology, School of Medicine, University of California, Davis, California.
Feliz
Brady J
BJ
Department of Pediatrics, Division of Nephrology, School of Medicine, University of California, Davis, California.
Makker
Sudesh P
SP
Department of Pediatrics, Division of Nephrology, School of Medicine, University of California, Davis, California.
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D005921:Glomerulonephritis / Q000276:immunology*; D026541:Heymann Nephritis Antigenic Complex; D015151:Immunoblotting; D007678:Kidney Glomerulus / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000302:isolation & purification; D051381:Rats; D011917:Rats, Inbred Lew; D012016:Reference Values; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index
D001324:Autoantigens; D026541:Heymann Nephritis Antigenic Complex; D008562:Membrane Glycoproteins; D010446:Peptide Fragments