Impact of Schistosoma japonicum Infection on Collagen-Induced Arthritis in DBA/1 Mice: A Murine Model of Human Rheumatoid Arthritis

Abstract

BackgroundThe hygiene hypothesis suggests that helminth infections prevent a range of autoimmune diseases.Methodology/Principal FindingsTo investigate the effects of S. japonicum infection on collagen-induced arthritis (CIA), 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. S. japonicum infection prior to CII immunization significantly reduced the severity of CIA. ELISA (enzyme linked immunosorbent assay) showed that the levels of anti-CII IgG and IgG2a were reduced in prior schistosome-infected mice, while anti-CII IgG1 was elevated. Splenocyte proliferation against both polyclonal and antigen-specific stimuli was reduced by prior schistosome infection as measured by tritiated thymidine incorporation (3H-TdR). Cytokine profiles and CD4+ T cells subpopulation analysis by ELISA and flow cytometry (FCM) demonstrated that prior schistosome infection resulted in a significant down-regulation of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-1β and IL-6) and Th1 cells, together with up-regulation of the anti-inflammatory cytokine IL-10 and Th2 cells. Interestingly, the expansion of Treg cells and the reduction of Th17 cells were only observed in bisexually infected mice. In addition, prior schistosome infection notably reduced the expression of pro-inflammatory cytokines 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/SignificanceOur data provide direct evidence that the Th2 response evoked by prior S. japonicum infection can suppress the Th1 response and pro-inflammatory mediator and that bisexual infection with egg-laying up-regulates the Treg response and down-regulates the Th17 response, resulting in an amelioration of autoimmune arthritis. The beneficial effects might depend on the establishment of a Th2-dominant response rather than the presence of the eggs. Our results suggest that anti-inflammatory molecules from the parasite could treat autoimmune diseases.

Tim-2 up-regulation and galectin-9-Tim-3 pathway activation in Th2-biased response in Schistosoma japonicum infection in mice

“…Our data might shade a light on current understandings of the molecular mechanisms of pathogenic Th2 response in schistosomiasis. Together with the emerging evidence of the inhibitory Th2 dominant response induced by helminth or helminth-derived antigen on Th1-mediated autoimmune disease and Th2-mediated hypersensitivity [17,18,20], this study might also has a significance in exploring new interventions and finding new therapeutic targets for hepatic fibrosis in schistosomiasis, and autoimmune disease and allergy as well.…”

“…Classical reaction of the host to helminth is the induction of Th2 responses which was important for host resistance to helminth infections [17][18][19][20]. Despite induction of a strong Th2 response, total clearance of the parasites rarely occurs in their hosts.…”

Helminth Infections Decrease Host Susceptibility to Immune-Mediated Diseases

“…S. japonicum , also protects mice from collagen-induced arthritis. The infection results in suppressed IFNγ but augmented IL4 and IL10 secretion by mitogen-stimulated splenocytes (83, 84). …”

Fasciola hepatica Tegumental Coat Impairs Mast Cells’ Ability To Drive Th1 Immune Responses

“…However, they can prevent the initiation and perpetuation of many Th1 immune disorders, such as multiple sclerosis and Crohn's disease (13,14), in these populations. Helminth-driven regulatory networks, through the induction of regulatory cytokines TGF-b and IL-10, can suppress these proinflammatory Th1 immune responses (14,15). Furthermore, helminths release molecules that directly impair the ability of innate immune cells to drive Th1/Th17 immune responses (10,16).…”