Volume 1 Supplement 1
Contribution of T Cell Subsets to Joint Degradation
- Pierre Miossec1
© Current Science Ltd 2000
Published: 15 November 1999
The role of T cells in the pathogenesis of rheumatoid arthritis (RA) has been and remains a matter of debate. One of the arguments for discussing such contribution has been the difficulty to measure the production of cytokines described as characteristic of T cells such as IFNγ . However, when the technology used to raise antigen specific T cell clones was applied to T cells from RA synovium, such cells were found to be fully able to produce IFNγ . In addition, RA synovium immunostaining revealed the presence of IFNγ producing cells. Conversely, the production of IL-4, another T cell cytokine, was found to be low and, to some extent, defective. Such findings led to the classification of RA as a Th1-associated disease. More recently, IL-17 has been described as a proinflammatory cytokine specifically produced by T cells. Studies with supernatants of RA synovium explants showed a high production of bioactive IL-17. Such an effect was linked to a synergistic interaction between IL-17 and the major monocyte-derived cytokines IL-1 and TNFα. Similarly, staining of RA synovium showed the presence of IL-17-producing T cells. Extension of studies with T cell clones from RA synovium indicated that a subset of IFNγ, but not of IL-4-producing T cells, was able to produce IL-17, allowing the classification of IL-17 as a Th1 cytokine.
The addition of blocking anti-IL-17 antibody to culture supernatants was able to reduce by approximately 50% the production of IL-6 LIF as well as that of MMP-1. Such an effect resulted in an important decrease of extracellular matrix destruction when IL-17 was inhibited. Conversely, when the anti-inflammatory cytokines IL-4, IL-13, and, to a lesser extent, IL-10 were added, production of proinflammatory cytokines was inhibited, including that of IL-17. Similarly, this resulted in an increase of TIMP production associated with reduced destruction. In the same conditions, increased repair as indicated by collagen synthesis was observed.
Through their production of cytokines, a subset of Th1 T cells can aggravate the proinflammatory and destructive pattern associated with monocyte activation. Manipulation of the cytokine profile of such a subset may control the destructive pattern, which remains a therapeutic target difficult to control.
- Miossec P, Briolay J, Dechanet J, Wijdenes J, Martinez-Waldez H, Banchereau J: Inhibition of the production of proinflammatory cytokines and immunoglobulins by Interleukin 4 in an ex vivo model of rheumatoid synovitis. Arthritis Rheum. 1992, 35: 874-883.PubMedView Article
- Quayle AJ, Chomarat P, Miossec P, Kjeldsen-Kragh J, Forre O, Natvig JB: Rheumatoid inflammtory T cell clones express mostly TH1, but also TH2 and mixed (TH0-like) cytokine patterns. Scand J Immunol. 1993, 38: 75-82.PubMedView Article
- Miossec P, van den Berg W: The Th1/Th2 cytokine balance in arthritis. Arthritis Rheum. 1997, 40: 2105-2115.PubMedView Article
- Miossec P, van den Berg W, Firestein G: . T cells in arthritis. Basel: Birkhauser. 1998View Article
- Chabaud M, Durand JM, Fossiez F, Frappard L, Miossec P: IL-17, a T cell derived proinflammatory cytokine produced by the rheumatoid synovium. Arthritis Rheum. 1999, 42: 963-970. 10.1002/1529-0131(199905)42:5<963::AID-ANR15>3.0.CO;2-E.PubMedView Article
- Aavak T, Chabaud M, Miossec P, Natvig JB: IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells. J Immunol . 1999, 162: 1246-1251.