New information about how helminths regulate their hosts’ immune system may provide valuable insight for therapies to fight inflammatory diseases.
Helminths (namely, cestode tapeworms, nematode roundworms, and trematode flukes) are long-lived worm parasites that have evolved methods to dampen the host’s immune response, protecting the parasite from elimination by the host, and minimizing severe disease in the host. In a recent review article, in the Journal of Allergy and Clinical Immunology, Rick M. Maizels, PhD, from the University of Glasgow, Scotland, and Henry J. McSorley, from the University of Edinburgh, Scotland, discuss some of immunomodulatory mechanisms associated with helminth infections, how they apply to human disease, and possible areas for future research.
Helminths are very successful parasites and their success results from their active regulation of the host immune response. Although only about a dozen helminth species are widespread in humans, together they infect almost one-third of the world’s population—often for up to 20 years. “Their extraordinary prevalence bears witness to their success at defeating host defences,” the authors write. This reflects their ability to manipulate the host’s immune system and dampen responses that could eliminate them. Studies have shown the ability of helminths to induce, modulate, or suppress certain pathways of immune activation in the host.
Induction of T helper (Th) type 2 immune responses with a regulatory component is a classic host response to helminth infections, and dendritic cells play a key role in this induction. Although exactly how these cells recognize the presence of helminths remains unknown, KLF4 factor is an essential intracellular signal that allows dendritic cells to promote Th2 responses.
A critical link has also emerged between helminth infection and increased production of regulatory cells, especially regulatory T cells (Tregs)—including those expressing the transcription factor Foxp3—that block protective immune responses. These cells are essential to allow helminths to survive in the host and avoid being expelled, but evidence shows that they may also protect the host from pathology. Helminth-induced regulatory B cells (Bregs) also play an important role in modulating the immune response during helminth infection. Emerging evidence also suggests that these cells can suppress allergic inflammation. “Along with Treg[s], Bregs are strongly implicated in the development of tolerance to allergens and strategies to encourage their expansion could increase the efficacy of allergen-specific immunotherapy,” the authors write.
Helminths can effectively modulate the adaptive immune response to enable them to survive in the host. For example, they can promote Treg differentiation, either directly by producing a TGF-β-like mimic or indirectly by inducing host TGF-β and retinoic acid (RA) production by dendritic cells and macrophages. This allows the parasites to hijack the host’s TGF-β signaling pathway, suppress the host’s protective Th2 response, and thereby avoid immune attack.
Helminths suppress some key pathways of immune activation in the host. For example,
when helminths cause tissue damage during infection, they trigger release of alarmin cytokines, including interleukin 33 which activates innate lymphoid cells that promote development of the type 2 response against the helminths; the parasites also inhibit toll-like receptor (TLR) responses of dendritic cells. However, with repeated infection, the host’s immune responses are dampened: helminths can effectively block alarmin production and TLR function, ultimately preventing the T helper (Th) type 2 immune response.
Helminth-induced immunomodulation can be beneficial for the host, as well as the parasite. “It has been noted since 1968 that inflammatory disorders such as arthritis are much less frequent in low-income countries with high levels of parasite infection,” the authors note. And regions of the world where helminth parasites are endemic have a lower prevalence of allergies and autoimmune conditions—as well as increases in allergic reactivity and autoimmune antibodies after anthelmintic treatment. According to the authors, helminths probably affect the immune system at two levels—by modifying the level of host reactivity during development of the immune system during infancy, and by suppressing immune responses in mature individuals who may be exposed to helminths for the first time in adulthood. “It is the latter setting that led to the proposal that helminths or their products could be used as therapies for inflammatory diseases in the parasite-free developed world,” they say. Similarly, evidence is mounting to suggest that helminth infections may protect against allograft rejection in transplant recipients.
The authors also stress that increased understanding of immunosuppressed responses to helminths, and of how to neutralize these responses, may improve understanding of anti-cancer responses. “Parasitic infection could increase carcinogenesis through associated low-grade chronic inflammatory response (in the absence of parasite ejection), secretion of directly pro-carcinogenic factors, or suppression of immune surveillance,” they state. “Epidemiological data in this area is presently lacking, and the effects of parasitic infection in cancer progression requires further attention.
“As we discover more about how productive anti-parasite responses are produced, we are also discovering new pathways for immunomodulation of these pathways by helminth infections, and exploring new possibilities for exploiting parasite molecules as therapies for inflammatory diseases,” the authors conclude.
Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals, and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.