Divergent T-cell cytokine patterns in inflammatory arthritis.

Abstract

A major immunoregulatory mechanism in inflammatory infections and allergic dies Is the control of the balance of cytokines secreted by Thl/Th2 subsets of T helper (Th) cells. This might also be true in autoimmune diseas; a Th2 pattern that prevents an effective immune response in infections with intracellular bacteria may favor immunosuppression in autoimmune disease. The pattern of cytokine expression was compared in the synovial tissue from patients with a typical autoimmune disease, rheumatoid arthritis, and with a disorder with similar synovial pathology but driven by persisting exogenous antigen, reactive arthritis. We screened 12 rheumatoid and 9 reactive arthritis synovial tissues by PCR and in situ hybridization for their expression of T-cell cytokines. The cytokine pattern differs significantly between the two diseases; rheumatoid arthritis samples express a Thllike pattern whereas in reactive arthritis interferon y expression is accompanied by that of interleukin 4. Studying the expression of cytokines by in situ hybridization confimed the results found by PCR; they also show an extremely low frequency of cytokine-transcribing cells. In a double-staining experiment, it was demonstrated that interleukin 4 is made by CD4 cells. These experiments favor the possibility of therapeutic intervention in inflammatory rheumatic diseases by means of inhibitory cytokines.The control of the balance of cytokines secreted by differing T-cell subsets is emerging as a major immunoregulatory mechanism (1, 2). The division ofT helper (Th) cells into Thl [secreting interferon y (IFN-y) and interleukin (IL) 2] and Th2 (secreting IL-4 and IL-5) found in the mouse (3) holds good for humans (2), provided that attention is focused on IL-4 (4). Cytokines of the Thl spectrum are generally elevated in successful responses to a variety of intracellular pathogens (5), and Th2 cytokines are elevated in allergic diseases and in helminth infections (6, 7). The balance appears to be maintained not only by the cytokines considered originally to be of Thl/Th2 type but also by other inhibitory cytokines such as transforming growth factor (3 and I1-10, which are not confined to one ofthe original subsets and can additionally be secreted by non-T cells (8,9). In this context the pattern of T-cell cytokines in reactive and rheumatoid arthritis is of particular interest. Not only is rheumatoid arthritis among the commonest of the candidate autoimmune diseases, it also offers easy access to the site of inflammation. Reactive and rheumatoid arthritis are sister diseases, in the sense that both are characterized by inflammation of joints and the development of similar synovial pathology. Reactive arthritis is triggered by intracellular bacteria that persist in the joint (10,11), whereas for rheumatoid arthritis, the triggering events are unknown but thought not to involve persistent infection. Comparison ofthe two diseases should be informative.The importance of T cells in initiating and maintaining inflammation in the rheumatic diseases...

Role of Th17 cells in human autoimmune arthritis

“…Considerable evidence, however, supports the notion that CD4 T cells from patients with RA express some striking abnormalities in their differentiation into effector cells, in their functional capabilities, and in their responsiveness to regulatory forces. A shift in the Th1/ Th2 balance toward Th1 has been described in patients with RA, and this also has prognostic value for the course of the disease (26,27). In our previous study, we identified an impaired capacity of RA CD4 T cells to differentiate into Th2 cells at the onset of the disease (28), which could potentially contribute to the evolution of sustained autoimmune inflammation.…”

Increased macrophage activation mediated through toll‐like receptors in rheumatoid arthritis

“…Further, treatment of monocytes with interferon-␥ (IFN␥) resulted in increased cell surface expression of both TLR-2 and TLR-4 (18,42), and IFN␥ sensitized the monocytes to respond to LPS (43). Although the levels of IFN␥ detected in SF of patients with established RA were low (44), IFN␥ mRNA was present in synovial tissue lymphocytes (45), and it is possible that IFN␥ contributes to sensitizing macrophages to express increased levels of TLR-2 and TLR-4 in vivo. Other cytokines expressed locally, including IL-10 and macrophage colonystimulating factor, may also contribute to the increased TLR-2 expression in the RA joint (17).…”

The functional CD40 antigen of fibroblasts may contribute to the proliferation of rheumatoid synovium

“…The decreased CD40 expression is likely to result from ligand-induced receptor endocytosis inasmuch as CD40 mRNA levels are comparable (as demonstrated by Northern blot analysis) in cells that are cultured without or with L-CD40 L (data not shown). The presence of IFN--producing cells [34,35] within the synovium and the CD40-inducing capacity of IFN-may explain why CD40 expression on rheumatoid synovial pannus was so easily detected.…”