Rheumatic Inflammation Is Driven by Activated Th1 Cells

Various epidemiological and clinical observations suggest a pathogenic Th1 drive in rheumatoid inflammation. For several decades, clinical observations have highlighted the ameliorating effect of pregnancy on the course of RA (Da Silva and Spector 1992). Pregnancy improves the symptoms of RA in about 75% of women, leading to a significant resolution of inflammation and a relief of symptoms, which enables the patients to taper or even stop the use of medications. In fact, the effect of pregnancy on RA activity is greater than the effect of some of the newer therapeutic agents. Although the mechanisms for this phenomenon are still unclear, a marked decrease in Th1-mediated immunity during pregnancy has been firmly established. For example, pregnant women have a higher incidence of infections compared to nonpregnant females, in particular infections with intracellular pathogens. Most recently, a placental derived protein (placental protein 14) was identified; it inhibits

Th1 immune responses and synergizes with IL-4 to promote Th2 immunity by inhibiting the downmodulation of the Th2 specific transcription factor, GATA-3 (Mishan-Eisenberg et al. 2004). These data suggest that pregnancy induces a shift from Th1 to Th2 immune responses, thereby increasing anti-inflammatory cytokines, which may contribute to the gestational amelioration of RA. Interestingly, relapses of RA occur within 6 months postpartum in 90% of the cases. At that time, pregnancy-associated alterations in Th subset activation can no longer be found (Da Silva and Spector 1992), suggesting that the beneficial Th2 shift has resolved and has allowed the Th1 dominated autoimmune inflammation to recur.

Patients with RA have a decreased prevalence of allergic diseases (Verhoef et al. 1998). Moreover, those patients with RA who, for example, have hay fever have less severe disease compared with control patients with RA without hay fever (Verhoef et al. 1998). As expected, atopic RA patients have higher levels of serum IgE and peripheral blood eosinophils, but their T cells produce less IFN-Y after maximum in vitro stimulation (Verhoef et al. 1998). As allergy is the prototype Th2 disease and activated Th2 cells are able to inhibit the generation and the function of Th1 effectors, these studies support the contention that the occurrence of a Th2-mediated immune response might be beneficial in RA by inhibiting Th1-driven immunity.

In addition to these clinical observations, various experimental approaches have also emphasized the dominance of activated Th1 effector cells in rheumatoid inflammation. For example, the vast majority of T cell clones from the human rheumatoid synovial membrane functionally represent the Th1 subset, producing large amounts of IFN-y but no IL-4 upon challenge with their specific antigens (Miltenburg et al. 1992; Quayle et al. 1993). In the majority of synovial biopsies, IFN-y, as assessed by different techniques, prevails, whereas IL-4 is rarely found (Canete et al. 2000; Kusaba et al. 1998). Importantly, synovial fluid- and synovial tissue-derived T cells express activation markers on their surface, indicating that these IFN-y expressing cells are actively engaged in driving synovial inflammation. The frequency of IFN-y producing CD4 T cells is significantly increased in the synovial fluid compared to the peripheral blood (Davis et al. 2001), resulting in a markedly elevated Th1/Th2 ratio in the synovial fluid that correlates with disease activity (van der Graaff et al. 1999). Likewise, drastically reduced synthesis of IL-4 and IL-10 mRNA by synovial fluid mononuclear cells of RA patients correlates with disease activity (Miyata et al. 2000). Together, these data strongly suggest that CD4 T cells from the inflamed rheumatoid synovium represent activated Th1 cells, secreting IFN-y, which, in turn, orchestrates synovial inflammation.

Activated CD4 T cells expressing elevated mRNA levels for IL-2 and/or for IFN-y can also be detected in the peripheral blood of patients with active RA

(Schulze-Koops et al. 1995). Most interestingly, when re-entry of circulating T cells into sites of inflammation in vivo was blocked by administration of a monoclonal antibody (mAb) to intercellular adhesion molecule (ICAM)-1 (CD54), a significant increase in IFN-y mRNA levels in the peripheral blood occurred that might reflect a redistribution of activated Th1 cells from sites of inflammation into the peripheral circulation (Schulze-Koops et al. 1995). Moreover, the frequencies of IFN-y secreting peripheral blood T cells in patients with new onset synovitis (<1 year duration) correlate well with disease activity, emphasizing the role of Th1 cells in the initiation of the disease (Kanik et al. 1998).

The arguments depicted here in detail demonstrate that Th1 cells and their cytokines are not only present in RA but contribute to the perpetuation of chronic inflammation. However, the data do not yet allow a conclusion about whether Th1 cells are the initiators of rheumatoid inflammation or rather appear as a consequence of it. In order to delineate the mechanisms underlying the dominant Th1 drive in RA, studies were carried out to assess the functional capability of T cells in RA patients. Isolated memory CD4 T cells from the majority of patients with early RA manifested a profound inability to mount Th2 responses (Skapenko et al. 1999). Thus, those patients cannot generate immunoregulatory Th2 cells that might downmodulate ongoing Th1-mediated inflammation. Failure to downregulate activated Th1 cells might allow Th1 inflammation to persist and evolve into chronic inflammation, characterized by the continuous activation of T cells, macrophages, fibroblasts, and osteoclasts and, subsequently, the destruction of tissue. As this functional abnormality of CD4 T cells in RA is evident at the time of initial clinical symptoms of arthritis (Skapenko et al. 1999), the data strongly suggest that the Th1 dominated immunity is the basis of rheumatoid inflammation and is not merely its consequence.

Together, these data indicate that Th1 cells and their cytokines promote many aspects of synovial inflammation. Moreover, evidence is accumulating that dysregulated T cell differentiation with impaired Th2 cell generation is instrumental in allowing the initial Th1-driven autoimmune response in RA to evolve into chronic inflammation. Interference with the activation and generation of Th1 cells and with the activity of their secreted cytokines might, therefore, be beneficial in the treatment of RA.

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