HLA-B27 lacking associated β2-microglobulin rearranges to auto-display or cross-display residues 169–181: a novel molecular mechanism for spondyloarthropathies

Abstract

Expression of the MHC class I allelle, HLA-B27, is correlated with autoimmune disease. The misfolding and association of B27 heavy chains through non-native disulfide bonds has recently been implicated. Here, we propose that β2m-free, peptide-free heavy chains support a helix-coil transition in the segment leading from the α2 domain to the α3 domain, facilitating rotation of backbone angles around residues 167/168, and allowing residues 169–181 (identical to a known B27 ligand) to loop around and occupy the molecule's own peptide-binding cleft. Such `auto-display', occurring either within B27 molecules, or between B27 molecules, could provoke autoimmune attack.