Modulation of innate and adaptive immunity by Fasciola hepatica

Abstract

Helminth parasites have developed highly effective mechanisms of immune subversion that helps prolong their survival in the host, resulting in the development of chronic infections. A bystander effect of this imm une modulation is the simultaneous suppression of immune responses that are pathogenic in autoimmune diseases. This forms the basis of the hygiene hypothesis, which has attributed the rise in allergy and autoimmune diseases in developed countries to the si multaneous decrease in the incidence of infectious disease , in particular helminth infection . The experimenta l evidence to support the hygiene hypothesis has inevitably led to the study of l ive helminth therapy for the treatment of autoimmune diseases in the clinic , however , most studies have failed to show significant beneficial effects in patients. Furthermore, the logistic al and ethical obstacles associated with the use of live infection has motivated the search for helminth - derived immunomodulatory molecules. Helminth - derived products provide an invaluable tool for the study of helminth - induced immune modulation, without t he complication of pathological responses associated with helminth infection. This study focussed on the immunomodulatory properties of total extract from Fasciola hepatica (FHTE). The results revealed that FHTE enhanced IL - 10 and IL - 1RA production, but s uppressed LPS - induced IL - 1β, IL - 23 and IL - 12p40 production by dendritic cells (DCs). Interestingly, FHTE also trained macrophages to be more anti - inflammatory. Bone - marrow derived macrophages trained in vitro with FHTE produced more IL - 10 and less TNF in r espo nse to restimulation with LPS and Pam3Cys. Furthermore, training of mice with FHTE in vivo polarised M2 macrophages and suppressed neutrophil recruitment, resulting in subsequent impairment of pathogenic T cell responses in the periphery and protection against the T cell - mediated autoimmune disease, experimental autoimmune encephalomyelitis ( EAE). This was associated with a significant reduction of IL - 17 - producing γδ and CD4 T cells infiltrating the central nervous system (CNS). Furthermore, attenuation of EAE by innate immune training was mediated by components that segregated in the high mol ecular weight fraction of FHTE and the immunomodulatory effects were found to be protein - mediated. Although most research to date on parasite - mediated immune subversion has focused on modulation of innate immune responses and induction of regulatory T cell s, t his study demonstrated that helminth products can directly supress effector a nd pathogenic T cells. FHTE was found to have a potent suppressive effect on IL - 1R1 and IL - 23R expression on γδ T cells, resulting in reduced receptor signalling and suppressed IL - 17 A production. Further investigation revealed that the immunomodulatory acti vity was present in the fraction that contained low molecular weight non - protein components. FHTE also suppressed activation of autoantigen - specific T cells, impairing their ability to proliferate and to induce EAE upon transfer to naive mice. This was acc ompanied by suppressed infiltration of IL - 17A - producing CD4 T cell s and γδ T cells into the CNS. Furthermore, t his is the first demonstration of direct immunosuppressive effect of helminth s on T cells. The findings demonstrate that helminth - derived products provide useful tools to study the mechanisms of helminth immunom odulation and the bystander effect of suppressing pathogenic T cells responses that mediate allergy and autoimmunity. As well as providing further validation of the hygiene hypothesis, the study has identified two novel mechanisms of helminth - mediated subv ersion strategies that directly target innate or adaptive immune responses.