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

R G Phelps, V Jones, A J Rees, A Neil Turner

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1135-43
Number of pages9
JournalInternational immunology
Volume12
Issue number8
Publication statusPublished - Aug 2000

Keywords

  • 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
  • HLA-DR Antigens
  • HLA-DR Serological Subtypes
  • HLA-DR7 Antigen
  • HLA-DRB1 Chains
  • Hemagglutinin Glycoproteins, Influenza Virus
  • Hemagglutinins, Viral
  • Humans
  • L Cells (Cell Line)
  • Mice
  • Molecular Sequence Data
  • Myelin Basic Protein
  • Peptide Fragments
  • Protein Binding
  • Transfection

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