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

Goodpasture's disease provides an opportunity to analyse molecular mechanis ms that may underlie MHC class II associations with autoimmune disease beca use it is caused by autoimmunity to a defined antigen [the 230 amino acid N C1 domain of the alpha 3 chain of type IV collagen (w alpha 3(1V)NC1)] and has strong HLA class II associations. We compared the alpha 3(1V)NC1 peptid e binding of class II molecules with strong positive (DR15) and dominant ne gative (DR7/1) associations using an inhibition binding assay and short syn thetic peptides spanning the sequence of alpha 3(1V)NCI. DR15 in general bo und the peptides with low affinity (three of 23 < 100 nM) compared to DR1 a nd DR7 (12 and 10 < 100 nM respectively), and no peptide bound DR15 with mu ch 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 alpha 3(IV)NC1-derived peptide uniquely well and DR1/7 are un likely to protect by their inability to present particular peptides. Howeve r DR1/7 could protect by capturing a3(1V)NCI peptides and preventing their display bound to DR15; the binding data suggest that all the major (biochem ically detectable) alpha 3(1V)NCI peptides presented bound to DR15 by DR15 homozygous antigen-presenting cells (APC) would bind preferentially to DR1/ 7 in DR15, 1/7 heterozygote APC.