Epitope spreading and autoimmune glomerulonephritis in rats induced by a T cell epitope of Goodpasture's antigen.
An amino-terminal region of alpha3 chain of type IV collagen noncollagenous domain [alpha3(IV)NC1] that induces experimental autoimmune glomerulonephritis (EAG) in rats has been identified. Only recombinant antigens that contain a nine-amino acid (AA) span of alpha3(IV)NC1, consistent with a T cell epitope, could induce EAG. It was hypothesized that synthetic peptides of this region should induce EAG. Human and rat peptides of this region were synthesized and rats were immunized to define the nephritogenic epitope. A 13-AA rat peptide induced EAG with proteinuria, decreased renal function, and glomerular basement membrane (GBM)-bound deposits in half of the rats. This peptide induces lymph node cell proliferation and development of antibodies to epitopes of alpha3(IV)NC1 external to the peptide immunogen. Carboxy-terminal extension to 21 amino acids results in all rats' demonstrating anti-GBM antibody and severe EAG. Asparagine at position 19 is critical for EAG induction. None of the 50 rats that were immunized with peptide that contained human sequence with isoleucine at position 19 developed EAG, whereas rat sequence with asparagine 19 induced EAG. Truncation of amino terminal AA of the peptide aborts EAG induction. These studies demonstrate that a T cell epitope of alpha3(IV)NC1 induces lymph node cell proliferation, EAG, and intramolecular epitope spreading; that the length of this peptide influences the formation of anti-GBM antibody; and that the presence of asparagine at position 19 of the peptide is critical to disease induction.
Bolton
Warren Kline
WK
Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908-0133, USA. wkb5s@virginia.edu
Chen
Lanlin
L
Hellmark
Thomas
T
Wieslander
Jörgen
J
Fox
Jay W
JW
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000209:etiology* / Q000276:immunology; D001324:Autoantigens / Q000008:administration & dosage* / Q000235:genetics; D024141:Collagen Type IV / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000235:genetics; D005260:Female; D006801:Humans; D007114:Immunization; D008969:Molecular Sequence Data; D051381:Rats; D011921:Rats, Inbred WKY; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
D001324:Autoantigens; D024141:Collagen Type IV; D018984:Epitopes, T-Lymphocyte; D011993:Recombinant Fusion Proteins; C057112:type IV collagen alpha3 chain