Inhibition of T cell apoptosis in the rheumatoid synovium.
Synovial T cells in rheumatoid arthritis are highly differentiated and express a phenotype suggesting susceptibility to apoptosis (CD45RB dull, CD45RO bright, Bcl-2 low, Bax high, Fas high). However, no evidence of T cell apoptosis was found in synovial fluid from any of 28 patients studied. In contrast, synovial fluid from 10 patients with crystal arthritis showed substantial levels of T cell apoptosis. The failre of apoptosis was not an intrinsic property of rheumatoid synovial T cells, as they showed rapid spontaneous apoptosis on removal from the joint. Synovial T cells from rheumatoid arthritis and gout patients could be rescued from spontaneous apoptosis in vitro either by IL-2R gamma chain signaling cytokines (which upregulate Bcl-2 and Bcl-XL) or by interaction with synovial fibroblasts (which upregulates Bcl-xL but not Bcl-2). The phenotype of rheumatoid synovial T cells ex vivo (Bcl-2 low, Bcl-xL high) suggested a fibroblast-mediated mechanism in vivo. This was confirmed by in vitro culture of synovial T cells with fibroblasts which maintained the Bcl-xL high Bcl-2 low phenotype. Synovial T cells from gout patients were Bcl-2 low Bcl-xL low and showed clear evidence of apoptosis in vivo. Inhibition experiments suggested that an integrin-ligand interaction incorporating the Arg-Gly-Asp motif is involved in fibroblast-mediated synovial T cell survival. We propose that environmental blockade of cell death resulting from interaction with stromal cells is a major factor in the persistent T cell infiltration of chronically inflamed rheumatoid synovium.
Salmon
M
M
Department of Rheumatology, The University of Birmingham, United Kingdom.
Scheel-Toellner
D
D
Huissoon
A P
AP
Pilling
D
D
Shamsadeen
N
N
Hyde
H
H
D'Angeac
A D
AD
Bacon
P A
PA
Emery
P
P
Akbar
A N
AN
D017209:Apoptosis / Q000276:immunology*; D015210:Arthritis, Gouty / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D018920:Coculture Techniques; D005347:Fibroblasts; D005434:Flow Cytometry; D019254:Genes, bcl-2; D006801:Humans; D016023:Integrins / Q000502:physiology; D017493:Leukocyte Common Antigens / Q000276:immunology; D008213:Lymphocyte Activation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D015375:Receptors, Interleukin-2 / Q000502:physiology; D015398:Signal Transduction; D013582:Synovial Fluid / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D015854:Up-Regulation; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; D016023:Integrins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D015375:Receptors, Interleukin-2; D051020:bcl-X Protein; D017493:Leukocyte Common Antigens