A feature of most individuals with chronic schistosome infection is the down-regulation of their T cell immune response to schistosome and third party antigens. This may adversely affect the efficacy of drug treatment and will present a challenge to the delivery of a prophylactic vaccine where a hyper-responsive immune system is desirable. The ability of most infected individuals to harbour worms for decades suggests the parasite has evolved to modulate the host’s immune response to prevent elimination. On the other hand, immune regulation benefits the host by modulating over-vigorous immunopathology (e.g. hepatosplenic or urogenital disease), such that most individuals do not develop severe disease.
Our testable hypothesis is that parasite molecules are recognised by cells of the innate immune response (i.e. antigen presenting cells; APCs, dendritic cells; DCs, macrophages/monocytes; MΦ) that become ‘tolerised’ under conditions of repeated and/or long-term stimulus, and so cause down-regulation of cells of the acquired immune system. Different parasite-derived molecules can stimulate overlapping yet distinct regulatory pathways – one operative in down-regulating anti-parasite immune responses and another in down-regulating host tissue pathology. By identifying and differentiating the molecular pathways that lead to the down-regulation of protective immune responses, and dampening of the reactions involved in tissue damage, we will seek strategies that can be used to manipulate the host immune response.
Evidence of immune regulation. The presence of schistosome eggs and the concomitant release of antigens cause the formation of immune granulomas, which ultimately results in serious pathology (e.g. hepatosplenomegaly, hepatic/bladder fibrosis) particularly in individuals with long-term infection. Indeed, morbidity is linked to the level of parasite exposure and hence an individual’s egg burden, although host genetics, and co-infections are also important influencing factors. Nevertheless, in the majority of individuals, modulation of immune responses is observed as a decrease in the ability of PBMCs to proliferate in vitro to schistosome antigens, or antigens such as tetanus toxoid. In contrast, patients with the more severe forms of S. mansoni or S. haematobium are more immuno-responsive and have elevated levels of proinflammatory TNFα and IFNγ or an elevated ratio of TNFα:IL-10. Although the underlying immunoregulatory mechanisms are poorly understood, IL-10 has a central role in modulation of the host’s response. As such, PBMCs from patients with ‘intestinal’ S. mansoni disease had a low capacity to proliferate in vitro, which can be restored by the addition of anti-IL-10 antibodies, and patients with chronic schistosomiasis had high levels of IL-10 that correlated with a lack of skin-responses to house dust mite allergens. Although our understanding of the mechanism(s) leading to immune regulation in infected individuals remains limited, studies on mice (which are fully permissive to S. mansoni) have yielded important information on the development of egg-induced immunopathology. In this model, egg-induced granulomas reach a peak size 8-10 weeks post-infection but by week 14 they are smaller, indicating some form of immune down-regulation. Although the precise role of various cytokines in the regulation of hepatic granulomas is still debated, IL-10 has again emerged as the pivotal factor. Little is known about the cellular origin of IL-10, although CD25+CD4+ regulatory T cells and innate immune response cells are possible sources. IL-10 has wide-ranging regulatory effects upon the tolerisation of innate immune response cells, co-stimulation and the development of acquired T cell responses and is clearly an important immunoregulatory mediator. An understanding of immune regulation, the pathways that lead to pathology, and the effect and source of immunoregulatory mediators remains poor. This knowledge is essential if we are to consider new real possibilities to control infection and pathology.
Immunoregulation induced by schistosome larvae? There is increasing evidence that immune regulation can also be also induced by products released by skin invading larvae. In this context, many individuals in endemic countries will be exposed on a daily basis to a large but unknown number of schistosome cercariae. In this context and using an experimental model, it has been discovered that repeated stimulation of the innate immune response by S. mansoni cercariae dramatically down-regulates the proliferation of CD4+ cells in the skin draining lymph nodes (Fig 1). Repeated exposure of the skin to S. mansoni, or the bird schistosome Trichobilharzia regenti, causes a massive increase in IL-10 secretion by the skin within 1-3 hours of re-exposure, suggesting it exists in a pre-formed state. As yet, a cellular source is not known but may include cells of the innate response (MΦ and DC), keratinocytes, and regulatory T cells (Treg). Multiple infections cause CD4+ hypo-responsiveness, mediated largely by dermal APCs that have a so-called ‘modified’ phenotype. These APCs are not stimulatory and express higher levels of receptors that belong to the innate immune system (e.g. mannose receptor), as well as higher levels of immunoregulatory costimulatory molecules such as PD-L1 (Fig 1). This is consistent with the notion that APCs can be involved in immunoregulation, as well as immunostimulation.