Rheumatoid arthritis synovial T cells regulate transcription of several genes associated with antigen-induced anergy.
Rheumatoid arthritis (RA) is a chronic, inflammatory synovitis whose pathogenesis may involve autoimmune mechanisms. Anergy is a state of T-cell nonresponsiveness characterized by downregulated IL-2 production. Paradoxically, RA T cells are hyporesponsive and proliferate poorly to antigens and mitogens, thus sharing some characteristics with anergic T cells. We analyzed the molecular basis of anergy in cloned human CD4+ T cells using differential display RT-PCR and subsequently examined the levels of differentially expressed transcripts in RA and, as control, reactive arthritis (ReA) synovium. Several transcriptional events were common to anergic T cells and RA synovium. These included downregulation of CALMODULIN:, which is critical to T-cell activation, and of cellular apoptosis susceptibility protein, which may mediate resistance to apoptosis in RA. Transcription of CALMODULIN: in RA synovium was less than 1% of that in ReA and was lower in RA synovial fluid mononuclear cells than in paired PBMCs. Following anti-TNF-alpha therapy in vivo, RA PBMC CALMODULIN: transcripts increased five- to tenfold. Pharmacological calmodulin blockade in vitro impaired antigen-specific proliferation. These data provide a link between reduced CALMODULIN: transcription and impaired T-cell responsiveness in RA. The identification of transcriptional changes common to anergic and RA synovial T cells should help interpret some of the characteristic RA cellular defects.
Ali
M
M
Rheumatology and Rehabilitation Research Unit, Clinical Sciences Building, St. James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
Ponchel
F
F
Wilson
K E
KE
Francis
M J
MJ
Wu
X
X
Verhoef
A
A
Boylston
A W
AW
Veale
D J
DJ
Emery
P
P
Markham
A F
AF
Lamb
J R
JR
Isaacs
J D
JD
D000941:Antigens / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000235:genetics; D006801:Humans; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D016133:Polymerase Chain Reaction; D000091402:Prohibitins; D013583:Synovial Membrane / Q000276:immunology*; D013601:T-Lymphocytes / Q000502:physiology*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D000941:Antigens; D002147:Calmodulin; C000717331:PHB2 protein, human; D000091402:Prohibitins; D014409:Tumor Necrosis Factor-alpha