Ap. Cope et al., T cell responses to a human cartilage autoantigen in the context of rheumatoid arthritis-associated and nonassociated HLA-DR4 alleles, ARTH RHEUM, 42(7), 1999, pp. 1497-1507
Objective. To analyze the CD4+ T cell responses to the human cartilage anti
gen glycoprotein-39 (HCgp-39) in the context of rheumatoid arthritis (RA)-a
ssociated (DR alpha beta 1*0401) and nonassociated (DR alpha beta 1*0402) H
LA class II molecules.
Methods, Large numbers of HCgp-39-specific T cell hybridomas were generated
following immunization of HLA-DR4/human CD4 transgenic, murine major histo
compatibility complex class II deficient mice with native HCgp-39. Fine epi
tope mapping of DR alpha beta 1*0401 and DR alpha beta 1*0402-restricted T
cell hybridomas was performed using overlapping synthetic peptides. Antigen
-specific cytokine production by lymph node T cells was evaluated after imm
unization with native antigen. Proliferative T cell responses of healthy hu
man subjects were compared with the T cell responses of patients with activ
e RA using HCgp-39 epitopes defined in HLA-DR4 transgenic mice.
Results, CD4+ T cells from DR alpha beta 1*0401 and DR alpha beta 1*0402 tr
ansgenic mice identified completely different immunodominant peptide epitop
es of HCgp-39, and this was not explained by known DR4-binding motifs or di
rect peptide-binding studies, DR alpha beta 1*0401-restricted, antigen-spec
ific T cells produced significantly more interferon-gamma and tumor necrosi
s factor alpha in response to HCgp-39 than did T cells from DR alpha beta 1
*0402 transgenic mice. Finally, HCgp-39 peptides defined in DR alpha beta 1
*0401 transgenic mice stimulated T cells from HLA-DR4 positive human subjec
ts and RA patients, but not T cells from HLA-DR4 negative individuals.
Conclusion. T cell epitopes of HCgp-39 that were defined in HLA-DR4 transge
nic mice stimulated T cells from human subjects carrying RA-associated HLA-
DR4 alleles. HLA-DR4 molecules may influence the disease process in RA both
by presentation of selected peptide epitopes and by promoting the producti
on of proinflammatory cytokines in synovial-joints.