Megalin (gp330) possesses an antigenic epitope capable of inducing passive Heymann nephritis independent of the nephritogenic epitope in receptor-associated protein.
The Heymann nephritis antigenic complex (HNAC) consists of two glycoproteins, megalin (gp330), and the receptor-associated protein (RAP). HNAC is expressed on the surface of the glomerular epithelium where it plays a primary role in the pathogenesis of Heymann nephritis (HN). Several models were previously proposed describing how antibody binding epitopes in HNAC may contribute to the initiation and progression of HN. Although these models suggest that nephritogenic epitopes capable of initiating HN are present in both megalin and RAP, the structural relationship between these epitopes has not been established. Previously a nephritogenic epitope was identified and characterized in RAP that initiates immune complex formation in HN. In this report, the immunologic relationship between nephritogenic epitopes in megalin and RAP were examined to determine whether these epitopes are immunologically distinct or antigenically related. To this end, a polyclonal antibody to megalin was generated that does not recognize RAP by immunoblotting or immunoprecipitation and whether this antibody is capable of inducing passive HN was determined. It was found that antimegalin antibodies devoid of RAP cross-reactivity induced the formation of subepithelial immune deposits (passive HN) when injected into rats. Antibodies eluted from glomeruli of the injected rats recognized only megalin by immunoblotting a cortical extract and did not recognize a RAP fusion protein or any other renal protein. In addition, the eluted antibodies immunoprecipitated two proteolytic fragments of megalin (140 and 75 kd) identifying a pathogenic epitope within a smaller fragment of megalin.(ABSTRACT TRUNCATED AT 250 WORDS)
Orlando
R A
RA
Division of Cellular and Molecular Medicine, University of California, San Diego, La Jolla 92093, USA.
Kerjaschki
D
D
Farquhar
M G
MG
D000818:Animals; D000918:Antibody Specificity; D001324:Autoantigens; D003429:Cross Reactions; D004195:Disease Models, Animal; D000939:Epitopes; D005921:Glomerulonephritis / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D026541:Heymann Nephritis Antigenic Complex; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D016253:Microscopy, Immunoelectron; D010446:Peptide Fragments / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew
D001324:Autoantigens; D000939:Epitopes; D026541:Heymann Nephritis Antigenic Complex; D008562:Membrane Glycoproteins; D010446:Peptide Fragments