Localization of a critical restriction site on the I-A beta chain that determines susceptibility to collagen-induced arthritis in mice

Type II collagen-induced arthritis (CIA) in mice is an autoimmune experimental model for rheumatoid arthritis. Susceptibility to CIA is associated with certain major histocompatibility complex class II haplotypes. The two very closely related haplotypes H-2q and H-2p differ in susceptibility to CIA. Only mice of H-2q (DBA/1, B10G strains) but not mice of H-2p-expressing strains (like strain B10P) develop CIA and an autoimmune response to type II collagen (CII) after immunization with CII. In contrast to H-2p, the H-2q haplotype does not express I-E molecules. The purpose of the present study was to identify, at the molecular level, the structures on major histocompatibility complex class II molecules determining susceptibility to CIA and CII responsiveness. We first excluded the possible suppressive involvement of Ep or Ap molecules by showing that F1 hybrids between H-2p and H-2q haplotype strains, expressing Ep and Ap, are responders to CII and fully susceptible to CIA. Secondly, because A alpha chains appear identical, we sequenced the A beta first-domain exons of p and q allotypes and found only four diverging amino acids in the predicted amino acid sequence. These variable residues were closely located at positions 85, 86, 88, and 89 at the end of the postulated alpha-helix, which is of importance for interactions with the antigenic peptide and the T-cell receptor. We suggest that this region is a critical major histocompatibility complex restriction site for CIA and CII responsiveness in H-2q mice as compared with H-2p mice. The CIA will now be an excellent autoimmune model for studies on interactions between autoantigenic peptide, autoreactive T cells, and a particular major histocompatibility complex molecule, as has been postulated to be the initial event also in rheumatoid arthritis.