Properties of HLA class II molecules divergently associated with Goodpasture's disease

Int Immunol. 2000 Aug;12(8):1135-43. doi: 10.1093/intimm/12.8.1135.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Autoantigens
  • Collagen Type IV
  • Epitopes
  • HLA-DR Antigens
  • HLA-DR Serological Subtypes
  • HLA-DR15 antigen
  • HLA-DR7 Antigen
  • HLA-DRB1 Chains
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Hemagglutinins, Viral
  • Myelin Basic Protein
  • Peptide Fragments
  • influenza hemagglutinin (307-319)
  • myelin basic protein 86-98(98A)
  • type IV collagen alpha3 chain
  • Collagen