Abstract
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.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Alleles
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Amino Acid Sequence
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Animals
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Anti-Glomerular Basement Membrane Disease / genetics
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Anti-Glomerular Basement Membrane Disease / immunology*
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Autoantigens / immunology*
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Autoantigens / metabolism
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology*
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Binding Sites
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Binding, Competitive
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Collagen / immunology*
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Collagen / metabolism
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Collagen Type IV*
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Epitopes / immunology
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Genes, Dominant
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Genes, MHC Class II*
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HLA-DR Antigens / genetics
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HLA-DR Antigens / immunology*
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HLA-DR Antigens / metabolism
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HLA-DR Serological Subtypes
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HLA-DR7 Antigen / genetics
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HLA-DR7 Antigen / immunology*
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HLA-DR7 Antigen / metabolism
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HLA-DRB1 Chains
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Hemagglutinin Glycoproteins, Influenza Virus
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Hemagglutinins, Viral / immunology
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Hemagglutinins, Viral / metabolism
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Humans
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L Cells
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Mice
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Molecular Sequence Data
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Myelin Basic Protein / immunology
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Myelin Basic Protein / metabolism
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Peptide Fragments / genetics
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Peptide Fragments / immunology*
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Peptide Fragments / metabolism
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Protein Binding
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Transfection
Substances
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Autoantigens
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Collagen Type IV
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Epitopes
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HLA-DR Antigens
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HLA-DR Serological Subtypes
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HLA-DR15 antigen
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HLA-DR7 Antigen
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HLA-DRB1 Chains
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Hemagglutinin Glycoproteins, Influenza Virus
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Hemagglutinins, Viral
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Myelin Basic Protein
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Peptide Fragments
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influenza hemagglutinin (307-319)
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myelin basic protein 86-98(98A)
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type IV collagen alpha3 chain
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Collagen