myelin-basic-protein and Anti-Glomerular-Basement-Membrane-Disease

Goodpasture's disease provides an opportunity to analyse molecular mechanisms that may underlie MHC class II associations with autoimmune disease because it is caused by autoimmunity to a defined antigen [the 230 amino acid NC1 domain of the alpha3 chain of type IV collagen (alpha3(IV)NC1)] and has strong HLA class II associations. We compared the alpha3(IV)NC1 peptide binding of class II molecules with strong positive (DR15) and dominant negative (DR7/1) associations using an inhibition binding assay and short synthetic peptides spanning the sequence of alpha3(IV)NC1. DR15 in general bound the peptides with low affinity (three of 23 < 100 nM) compared to DR1 and DR7 (12 and 10 < 100 nM respectively), and no peptide bound DR15 with much higher affinity (>10-fold) than both DR1 and DR7. Thus DR15 molecules are unlikely to increase susceptibility to Goodpasture's disease by presenting a particular alpha3(IV)NC1-derived peptide uniquely well and DR1/7 are unlikely to protect by their inability to present particular peptides. However DR1/7 could protect by capturing alpha3(IV)NC1 peptides and preventing their display bound to DR15; the binding data suggest that all the major (biochemically detectable) alpha3(IV)NC1 peptides presented bound to DR15 by DR15 homozygous antigen-presenting cells (APC) would bind preferentially to DR1/7 in DR15, 1/7 heterozygote APC.

Topics: Alleles; Amino Acid Sequence; Animals; Anti-Glomerular Basement Membrane Disease; Autoantigens; Autoimmune Diseases; Binding Sites; Binding, Competitive; Collagen; Collagen Type IV; Epitopes; Genes, Dominant; Genes, MHC Class II; Hemagglutinin Glycoproteins, Influenza Virus; Hemagglutinins, Viral; HLA-DR Antigens; HLA-DR Serological Subtypes; HLA-DR7 Antigen; HLA-DRB1 Chains; Humans; L Cells; Mice; Molecular Sequence Data; Myelin Basic Protein; Peptide Fragments; Protein Binding; Transfection