Helminth parasites inhabit immune-competent hosts for long periods of time and appear to develop strategies to induce strong anti-inflammatory responses in the infected host. Loss of natural helminth exposure as a result of improved hygiene and wide-use of anti-helminth drugs result increased incidences of immune-mediated disorders evidenced by epidemiological studies. On the other hand, the helminths provide the host with more balanced immuno-homeostasis and demonstrate beneficial effects against various kinds of autoimmune diseases in animal studies. In fact several clinical trials have attempted to use helminth to treat autoimmune disease in patients and showed that exposure to helminths can reduce disease activity in patients with immune-mediated disease like ulcerative colitis. In this study, we investigated the beneficial effect of schistosome infection on less-well studied collagen-induced arthritis mouse model. The beneficial effect is found to be associated with reduced anti-collagen II IgG production and with a Th2 cytokine environment induced at egg-stage of infection.
The anti-CII antibodies have been recognized as important pathogenic factors in the initiation and development of CIA in mice. It has been reported that arthritis can be transferred passively to naive animals with CII-reactive serum , and by monoclonal antibody to CII . In fact, a different mouse model collagen antibody-induced arthritis (CAIA) for human RA is established by passively transferring arthritogenic antibodies against collagen. Further studies using the CAIA model found that the subclass of IgG2a appears to be more efficient in inducing RA probably due to its strong capacity to activate complement through the classical pathway . The ability of inhibiting arthritis by egg-stage Sj infection in ASCIA mice but not by early stage infection found in our study was well correlated with reduced levels of anti-CII IgG, especially the levels of IgG2a. This alteration in class switch may reflect the significantly repressed IgG2a-promoting cytokine IFN-γ production found in ASCIA group. On the other hand, the positive association between elevated IgG2a and the occurrence of arthritis indicates the pathogenic role played by Th1 cells and the beneficial role played by Th2 cells. Consequently, beneficial effects against CIA can only be found in the acute or egg-stage of Sj infection but not in early stage infection before eggs are produced in large quantity.
Schistosomiasis is a well-characterized Th2 response-dominated disease . Shortly after the beginning of egg deposition, a strong egg-specific Th2 response develops characterized by high levels of IL-4, IL-5, and IL-13 which decreases when the infection enters the chronic stage [17, 30]. Not surprisingly the negative effect of schistosome infection on the induction and development of type I diabetes in NOD model , multiple sclerosis in EAE model  and in mouse model of Graves' hyperthyroidism  has repeatedly been reported in mice infected by schistosme for 6-8 weeks before autoimmune diseases were induced. By comparison between the beneficial effects of Sj infection and the IL-4 production profiles, our study clearly demonstrated that the presence of Th2 at the beginning stage of autoimmune attack was important in conferring the protection. In addition, our study also demonstrated a positive correlation between the prolonged presence of elevated Th2 levels during the development stage of autoinflammatory response and the absence of disease.
We noticed the different result obtained by Osada et al  in which 2 weeks prior Schistosome infection was shown to offer protection in CIA. An obvious difference between our study and that of Osada's was that different strains of Schistosoma were used, ie, Sm in their study and Sj in ours. Since the amount of eggs along with the levels of Th2 response induced are low after 2 weeks Sm infection , Osada's study seems to suggest that the Th2 milieu present at initiation phase of autoimmune attack is not crucial to achieve the protection. In addition, elevated IL-4 production was still found to be produced by activated splenocytes from infected and CFA injected mice, suggesting that the injection of the Th1-promoting agent CFA in their study has little impact on the development of the Th2 response. It is not clear at present that if different strains of worms used can fully explain the different results obtained.
Another possible protective mechanism involved in our study was likely associated with the enhanced production of regulatory cytokine IL-10 by activated T cells found in protected animals. Th2 cells, FoxP3+ CD4+ Treg cells and FoxP3- IL-10-producing CD4+ so called Tr1 cells may all contribute to this induced production of T cell-derived IL-10. Although no significant increase in Treg numbers was found in protected group, the possibility that the activities of Treg and Tr1 cells were enhanced can not be excluded. No significant difference on production of IL-17 was found among protected mice, unprotected mice and CIA mice, even though Th17 appears to be accepted as the more critical pathogenic Th cells in the CIA model than Th1 .
Our study also provided an approach to explore the plasticity of Th subsets in vivo. In vitro studies have demonstrated that Th17 is an unstable subset , whereas Th1 and Th2 subsets, once they are well established, are not reversible . With the application of Th1-promoting agent CFA at different time point, we found that CFA together with collagen is able to inhibit the Th2 response only at 2 weeks but not at 7 weeks of Sj infection when Th2 development is at an early stage but not well-established. Thus our results for the first time in vivo indicated that a well established Th2 response can not be reversed, whereas an early stage Th2 response can be reversed in the presence of CFA treatment. This phenomenon may serve as the basis for the beneficial effects by Sj infection in maintaining immune-homeostasis in infected host hence providing protection against immune-mediated diseases.