Helminth infections and host immune regulation

Abstract

Helminth parasites infect almost one-third of the world's population, primarily in tropical regions. However, regions where helminth parasites are endemic record much lower prevalences of allergies and autoimmune diseases, suggesting that parasites may protect against immunopathological syndromes. Most helminth diseases are spectral in nature, with a large proportion of relatively asymptomatic cases and a subset of patients who develop severe pathologies. The maintenance of the asymptomatic state is now recognized as reflecting an immunoregulatory environment, which may be promoted by parasites, and involves multiple levels of host regulatory cells and cytokines; a breakdown of this regulation is observed in pathological disease. Currently, there is much interest in whether helminth-associated immune regulation may ameliorate allergy and autoimmunity, with investigations in both laboratory models and human trials. Understanding and exploiting the interactions between these parasites and the host regulatory network are therefore likely to highlight new strategies to control both infectious and immunological diseases.

Fig 1

Spectrum of pathology in chronic tissue helminth infections. In areas where schistosome and filarial diseases are endemic, a spectrum of pathology is seen, with some individuals developing chronic debilitating pathologies and others showing a tolerant phenotype. The tolerant phenotype is characterized by the production of transforming growth factor β and IL-10 and the expansion of Forkhead box P3⁺ Tregs. These cytokines lead to IgG4 production by B cells, suppressed parasite-specific T cell proliferation in PBMCs (peripheral blood mononuclear cells), reduced levels of Th2 cytokines, and ablated Th1 cytokines. Thus, the parasite survives productively in the host (schistosome eggs are deposited in the feces, or microfilariae circulate in the blood), with minimal collateral damage. In individuals with chronic pathology, the parasite may be killed or kept at low levels, at the cost of damaging immunopathology. High levels of Th1 and Th2 cytokines are seen, with the emergence of a Th17 response. B cells produce high levels of IgE against parasite antigens (Ag). Th1 and Th17 responses lead to inflammation and fibrosis around deposited schistosome eggs and lymph stasis, leading to secondary infections in lymphatic filariasis.

Fig 2

Immunoregulatory effects of helminths on bystander responses. Helminths can suppress a wide range of bystander immune responses, including those of both immunopathogenic and protective natures. Coinfection with helminths suppresses antibacterial, antiviral, and antiprotozoal immunity, leading to increased susceptibility and attenuated immunopathology or, in some cases, exacerbated pathology due to higher infection burdens. Antitumor immunity may be suppressed by helminth infections, which may also release directly carcinogenic factors, potentially leading to increased numbers of malignancies in infected individuals. Vaccine efficacy is compromised by helminth infections due to suppressed immune responses. Immunopathologies such as asthma, autoimmune diseases, and inflammatory bowel diseases are all reduced in prevalence in areas where helminth disease is endemic, and direct effects of helminth infections on the suppression of disease have been shown in clinical trials for inflammatory bowel diseases.

Fig 3

Suppressive mechanisms of Heligmosomoides polygyrus and Schistosoma mansoni on immunopathologies. Of all the helminths that infect mice, the effects of H. polygyrus (red arrows) and S. mansoni (blue arrows) on immunopathology models have been best characterized. Both parasites effectively suppress immune responses and pathology in models of allergy, autoimmunity, and colitis. CD4⁺ Foxp3⁺ (Forkhead box p3) Tregs (regulatory T cells) are induced by both H. polygyrus and S. mansoni through secretory molecules affecting the TGF-β (transforming growth factor β) and/or retinoic acid pathways, and these Tregs can suppress all immunopathologies. Suppressive Bregs (regulatory B cells) are also induced by both parasites, and functional suppression has been shown in allergy and autoimmunity through B cell IL-10 production (S. mansoni) or an IL-10-independent mechanism (H. polygyrus). H. polygyrus has also been shown to induce a regulatory population of CD8⁺ T cells in the gut, which may, along with CD4⁺ Foxp3⁺ Tregs, be involved in the suppression of colitis in an IL-10-independent, TGF-βR-dependent manner. S. mansoni eggs and their products (especially the RNase ω-1) are powerful Th2 (T helper type 2) inducers, and skewing toward a Th2 response is protective in some models of autoimmunity. Th2 cytokines also induce the alternative activation of macrophages, which are functionally suppressive. Macrophages induced by S. mansoni infections (whether alternatively activated or not) are suppressive in all models of immunopathology studied. Finally, S. mansoni eggs induce the expansion of NKT (natural killer T) cells, which are deficient in the diabetic NOD mouse, and protect against disease.