Homocysteine could modify HLA B27 through Cys67; it could also modify other HLA antigens, represented by A68 in the figure, that do not contain unpaired cysteine residues through peptides bound to them.
HLA B27, a class I product of the human major histocompatibility complex, is strongly associated with ankylosing spondylitis (AS) and reactive arthritis (ReA): 70% of patients with ReA and 90% with AS posses the B27 gene compared with 7% of the general population. The research of my group is focused on the role of HLA B27 in these disorders.
We have shown that homocysteine-treated cells can be specifically lysed, in a HLA-restricted fashion, by cytotoxic T lymphocytes (CTL) identifiable in patients with AS and ReA. Homocysteine-specific CTL (Hom-CTL) are present in about 50% of patients and in only 10% of the normal subjects, indicating that they may play an essential role in the development and/or pathogenesis of sera-negative arthropathies. Most of the Hom-CTL identified in B27-positive patients are restricted by B27. It is likely that the unpaired cysteine residue at position 67 (Cys67) of the B27 heavy chain could form a disulfide bond with homocysteine, causing a conformational change in B27, thereby triggering autoimmune CTL responses.
Experiments are undertaken to (1) determine the mechanisms of homocysteine-HLA interaction in detail; (2) analyse T cell receptor usage by Hom-CTL from different patients; and (3) measure serum levels of homocysteine and related metabolites in the plasma of patients with AS or RA. Our results may provide the missing link between B27, AS and ReA.