Impact Of Th-biased Immune Response Induced By Schistosoma Japonicum Infection On Collagen-induced Arthritis In DBA/1 Mice

Objective:The Hygiene Hypothesis suggests that parasites and microbes have been important for shaping and tuning the evolution of the human innune system. The fact that infections were no longer prevalent has led to the emergence of autoimmune inflammatory diseases in developed country. Chronic infections are characterized by a Th2-dominant response as well as an overall down-regulated immune system. This helminth-induced immunosuppression may spill over to un-related antigens, down-regulate the response to orther pathogens. Recent studies habe suggested that helminth infection is protective in murine models of autoimmune disorders and asthma. Nematodes have been used to effectively treat human inflammatory bowel disease (IBD).Rheumatoid arthritis (RA) is an immune mediated inflammatory disease of unknown etiology with significant morbidity and disability that is characterized by inflammation of the synovium leading to destruction of cartilage and bone. There is still no cure exists. Previous data demonstrated that the imbalance of CD4+ effective and regulatory T cell response is directly implicated in variety of the immune processes that are associated with the pathogenesis of RA. S. japonicum infection can evoke strong Th2 response and schistosome infection could reduce the level of blood sugar in NOD mice. According to classical Th1/Th2 dichotomy, we speculate that Th2-biased response induced by S. japonicum infection could ameliorate Th1 mediated CIA in DBA/1 mice—a traditional animal model of human RA. In this work, we try to characterize the immunomodulatory effects of both uni- and bi-sexual S. japonicum infection on autoimmune arthritis. Male DBA/1 mice were infected with uni- or bi-sexual S. japonicum cercariae before 2 weeks or at the onset of CIA. Possible anti-inflammatory mechanisms are examined by studying CD4+ T helper cell subpopulations and the cytokine expression profiles of the CIA mice infected by schistosomes.Methods:To determine immunological pathways induced by S. japonicum infection, male DBA/1 mice were challenged with unisexual or bisexual S. japonicum cercariae two weeks prior to bovine type II collagen (CII) immunization, or at the onset of CIA. The severity of arthritis was evaluated by clinical disease activity. CD4+T cells subpopulations in the spleen were measured by flow cytometry(FCM); the levels of cytokine production in the splenocytes culture supernatant, anti-IIC IgG and its subtypes in the sera were tested by enzyme linked immunosorbent assay(ELISA); and the mRNA expression of cytokines and RANKL in the inflamed joint were quantified by Real-time PCR.Results:Our study revealed that S. japonicum infection prior to CII immunization significantly reduced the severity of CIA. ELISA showed that the levels of pathogenic anti-CII IgG and IgG2a were reduced, and anti-CII IgG1 antibody was elevated in prior schistosome-infected mice. Splenocytes proliferation against both polyclone and antigen specific stimuli were reduced by prior schistosome infection as measured by tritiated thymidin incorporation (3H-TdR). Cytokine profiles and CD4+ T cells subpopulation analyzed by ELISA and FCM demonstrated that pre-infection of mice with S.japonicum significantly down-regulated expression of pro-inflammatory cytokines (INF-γ, TNF-α, IL-1βand IL-6) and Th1 cells and up-regulated anti-inflammatory cytokine (IL-10) and Th2 cells. Interestingly, we only observed the proliferation of Treg cells and reduction of Th17 cells in bisexually infected mice. Addition, prior schistosome infection notably reduced the expression of pro-inflammatory and receptor activator of NF-κB ligand (RANKL) in the inflamed joint. However, the disease was exacerbated at one week after infection when established CIA mice were challenged with bisexual cercariae.Conclusion:Our data provide the direct evidence that Th2 response evoked by prior S. japonicum infection can suppress Th1 response and pro-inflammatory mediator, and bisexual infection (eggs-laying) can up-regulate Treg response, down-regulate Th17 response, which results in ameliorating of autoimmune arthritis. The beneficial effects might be dependent on Th2-dominant response being established, not the presence of the eggs. Our results suggest that the anti-inflammatory molecules derived from the parasite may have a potential value for the therapeutic strategy of autoimmune diseases.