Properties of HLA class II molecules divergently associated with Goodpasture's 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.
Department of Clinical and Surgical Sciences (Internal Medicine), University of Edinburgh, Royal Infirmary, Edinburgh EH3 9YW, UK.
R G
RG
Phelps
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V
Jones
A N
AN
Turner
A J
AJ
Rees
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D019867:Anti-Glomerular Basement Membrane Disease / Q000235:genetics / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology*; D001665:Binding Sites; D001667:Binding, Competitive; D003094:Collagen / Q000276:immunology* / Q000378:metabolism; D024141:Collagen Type IV; D000939:Epitopes / Q000276:immunology; D005799:Genes, Dominant; D005802:Genes, MHC Class II; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D059810:HLA-DR Serological Subtypes; D015809:HLA-DR7 Antigen / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D059811:HLA-DRB1 Chains; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007739:L Cells; D051379:Mice; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011485:Protein Binding; D014162:Transfection
D001324:Autoantigens; D024141:Collagen Type IV; D000939:Epitopes; D006684:HLA-DR Antigens; D059810:HLA-DR Serological Subtypes; C106559:HLA-DR15 antigen; D015809:HLA-DR7 Antigen; D059811:HLA-DRB1 Chains; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006389:Hemagglutinins, Viral; D004676:Myelin Basic Protein; D010446:Peptide Fragments; C081942:influenza hemagglutinin (307-319); C415981:myelin basic protein 86-98(98A); C057112:type IV collagen alpha3 chain; D003094:Collagen