The effects of helminths on the immune system
The effect that helminths have on the immune system is exceedingly complex, is brought about by immune mechanisms that do not fit into linear models of immunology, and is more a case of subtle modulation (balancing or quieting) than of suppression. Helminths achieve this effect by employing an orchestra of chemicals that are excreted/secreted with the primary intention of keeping themselves and their host alive and well for as long as possible. The direct benefits derived by the host as a result of this activity include a reduction of inflammation and the prevention of allergy, autoimmune disease, neuropsychiatric disorders and metabolic diseases.
What helminths do has been summarised as follows.
Helminths, as long-lived parasites, are remarkable for their ability to manipulate host immunity, protecting themselves from elimination and minimizing severe pathology in the host.[1][2][3][4] Immunomodulation by parasitic helminths is a general phenomenon that is conserved across species, classes, and even phyla.[5] Therefore, parasitic infections are a major theme in the hygiene hypothesis. Allergies and autoimmune diseases are less prevalent in countries with higher burdens of helminths and other parasitic organisms.[6] There are strong epidemiological evidences to support the premise that the dramatic increase in atopic disease in the developed world is a direct consequence of the eradication of helminth infections.[7] At least some helminthes seem to have antiallergic or anti-inflammatory effects in humans. Experimental evidences have also shown the significant suppression for the development of airway hyperresponsiveness (AHR) in mice infected with numerous helminths, including blood fluke Schistosoma japonicum,[8] filaria Litomosoides sigmodontis,[9] nematode Heligmosomoides polygyrus,[10] and Nippostrongylus brasiliensi.[11] These mice show attenuated airway inflammation with reduced infiltration of eosinophilia in the BAL and lung and allergen-specific IgE in sera. Many studies have also demonstrated that helminth infections lower the risk of autoimmunity. Experimental studies have also shown protective effects of helminth infections in animal models of autoimmunity. Surprisingly, helminths have been shown to suppress various types of autoimmune disease, such as collagen-induced arthritis, experimental autoimmune encephalomyelitis, and type 1 diabetes in murine models as reviewed recently.[12] Helminth infections might be beneficial to the induction of multiple regulatory mechanisms, including various regulatory cell populations, inhibitory receptors, blocking antibodies, and two prominent cytokines: IL-10 and TGF-β.[5][13] Thus, it is not surprising that helminths can modulate immunopathology, whether in the context of allergic inflammation or autoimmune disease, either directly or indirectly.[6] (Source: Effects of Invariant NKT Cells on Parasite Infections and Hygiene Hypothesis.)
The immune response to helminths is generally characterized by a T helper type 2 (Th2) pattern with high levels of the cytokines IL-4, IL-5, IL-9, IL-10, and IL-13, as well as eosinophilia, goblet and mast cell hyperplasia, and IgE-biased antibody isotype switching.[14]
However, we need to bear in mind that understanding of exactly how helminths produce these effects is still limited. As Elliott & Weinstock have said,
In most circumstances, little is known regarding the molecular signals exchanged between helminth and host to mediate this process. Even less is known about which helminth products influence disease and how they work.[15]
People considering the use of helminthic therapy are frequently concerned that the treatment might not be appropriate for them depending on whether they have a condition known to be associated with a Th1 or a Th2 response,[16] but parasitic infections increase the population of regulatory T-cells, or TREGs,[17] which control the excesses of both Th1 and Th2 cells, and the extracellular vesicles secreted by many nematodes generate potent suppression of both type 1 and type 2 immune-response-associated molecules.[18]
We show here that the local cytokine response to TSO treatment included upregulation of not only Th2 and regulatory cytokines and transcription factors but also Th1/Th17 cytokines.[19]
A study in patients with Multiple Sclerosis found that those with an existing Epstein-Barr virus infection did not experience a reactivation of their EBV following inoculation with the hookworm, Necator americanus (NA), indicating that the NA had not compromised the antiviral Th1 response. [20]
Helminth infection can result in the production of hybrid Th2/1 cells which express both Th2 and Th1 cytokines.[21]
As a result of these, and perhaps other yet-to-be-identified means, helminths are able to ameliorate both allergies and autoimmune diseases.
Another common concern is that helminthic therapy might reduce a host’s ability to fight other types of infection but, far from making the immune system lazy or less effective, helminths actually make it smarter.
People who host helminths can still mount an inflammatory attack on pathogens, but they don't set off self-destructive immune bombs against harmless substances or their own cells. (William Parker, Duke University)[22]
Specific effects of immune modulation by helminths
Effects on inflammatory pathways
Effects on immune cells
- Induction of IL10-producing Tr1 cells [36]
- Induction of innate lymphoid cells [43]
See also
References
- ↑ Helminths in the hygiene hypothesis: sooner or later?
- ↑ Diversity and dialogue in immunity to helminths.
- ↑ Immune regulation by helminth parasites: cellular and molecular mechanisms.
- ↑ Parasitic helminth infections and the control of human allergic and autoimmune disorders.
- ↑ 5.0 5.1 Secretory products of helminth parasites as immunomodulators.
- ↑ 6.0 6.1 Regulation of allergy and autoimmunity in helminth infection.
- ↑ Induction of regulatory cells by helminth parasites: exploitation for the treatment of inflammatory diseases.
- ↑ Schistosoma japonicum infection modulates the development of allergen-induced airway inflammation in mice.
- ↑ Helminth infection with Litomosoides sigmodontis induces regulatory T cells and inhibits allergic sensitization, airway inflammation, and hyperreactivity in a murine asthma model.
- ↑ Suppression of allergic airway inflammation by helminth-induced regulatory T cells.
- ↑ Helminth infection modulates the development of allergen-induced airway inflammation.
- ↑ Parasitic helminths: new weapons against immunological disorders.
- ↑ Helminth infections and allergic diseases: from the Th2 paradigm to regulatory networks.
- ↑ Helminth-Tuberculosis Co-infection: An Immunologic Perspective
- ↑ Helminth-host immunological interactions: prevention and control of immune-mediated diseases.
- ↑ Th1/Th2 Model for helper T cells
- ↑ Regulatory T cells in Parasite Infection
- ↑ Extracellular Vesicles from a Helminth Parasite Suppress Macrophage Activation and Constitute an Effective Vaccine for Protective Immunity
- ↑ Immune responses and parasitological observations induced during probiotic treatment with medicinal Trichuris suis ova in a healthy volunteer
- ↑ An Absence of Epstein-Barr Virus Reactivation and Associations with Disease Activity in People with Multiple Sclerosis Undergoing Therapeutic Hookworm Vaccination.
- ↑ Th2/1 Hybrid Cells Occurring in Murine and Human Strongyloidiasis Share Effector Functions of Th1 Cells
- ↑ The New (Ancient) Cure for Immune Disorders
- ↑ 23.0 23.1 Intestinal helminths regulate lethal acute graft-versus-host disease and preserve the graft-versus-tumor effect in mice
- ↑ 24.0 24.1 Heligmosomoides polygyrus promotes regulatory T-cell cytokine production in the murine normal distal intestine
- ↑ 25.0 25.1 Role of T cell TGF-beta signaling in intestinal cytokine responses and helminthic immune modulation
- ↑ 26.0 26.1 Colonization with Heligmosomoides polygyrus suppresses mucosal IL-17 production
- ↑ 27.0 27.1 27.2 Heligmosomoides polygyrus inhibits established colitis in IL-10-deficient mice
- ↑ 28.0 28.1 Exposure to schistosome eggs protects mice from TNBS-induced colitis
- ↑ Helminth-induced regulation of T-cell transfer colitis requires intact and regulated T cell Stat6 signaling in mice
- ↑ Intestinal nematode infection ameliorates experimental colitis in mice
- ↑ 31.0 31.1 Protective effect of Schistosoma japonicum eggs on TNBS-induced colitis is associated with regulating Treg/Th17 balance and reprogramming glycolipid metabolism in mice
- ↑ Helminth secretions induce de novo T cell Foxp3 expression and regulatory function through the TGF-β pathway
- ↑ Intestinal helminths protect in a murine model of asthma
- ↑ STAT6 and Furin Are Successive Triggers for the Production of TGF-β by T Cells
- ↑ Regulatory T-cells in helminth infection: induction, function and therapeutic potential
- ↑ At homeostasis filarial infections have expanded adaptive T regulatory but not classical Th2 cells
- ↑ Extracts of the rat tapeworm, Hymenolepis diminuta, suppress macrophage activation in vitro and alleviate chemically induced colitis in mice
- ↑ Helminth infections decrease host susceptibility to immune-mediated diseases
- ↑ 39.0 39.1 The IL-25-dependent tuft cell circuit driven by intestinal helminths requires macrophage migration inhibitory factor (MIF)
- ↑ Reduced helminth burden increases allergen skin sensitization but not clinical allergy: a randomized, double-blind, placebo-controlled trial in Vietnam
- ↑ Heligmosomoides polygyrus infection can inhibit colitis through direct interaction with innate immunity
- ↑ Heligmosomoides polygyrus bakeri induces tolerogenic dendritic cells that block colitis and prevent antigen-specific gut T cell responses
- ↑ Concerted IL-25R and IL-4Rα signaling drive innate type 2 effector immunity for optimal helminth expulsion
- ↑ Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites
- ↑ Allergy, parasites, and the hygiene hypothesis