The Helminth Parasite Heligmosomoides polygyrus Attenuates EAE in an IL-4Rα-Dependent Manner.

Madeleine P J White,Rick M Maizels,John R Grainger,Richard A O'Connor,Chris J C Johnston,Stephen M Anderton,Joanne E Konkel

doi:10.3389/fimmu.2020.01830

Abstract

Helminth parasites are effective in biasing Th2 immunity and inducing regulatory pathways that minimize excessive inflammation within their hosts, thus allowing chronic infection to occur whilst also suppressing bystander atopic or autoimmune diseases. Multiple sclerosis (MS) is a severe autoimmune disease characterized by inflammatory lesions within the central nervous system; there are very limited therapeutic options for the progressive forms of the disease and none are curative. Here, we used the experimental autoimmune encephalomyelitis (EAE) model to examine if the intestinal helminth Heligmosomoides polygyrus and its excretory/secretory products (HES) are able to suppress inflammatory disease. Mice infected with H. polygyrus at the time of immunization with the peptide used to induce EAE (myelin-oligodendrocyte glycoprotein, pMOG), showed a delay in the onset and peak severity of EAE disease, however, treatment with HES only showed a marginal delay in disease onset. Mice that received H. polygyrus 4 weeks prior to EAE induction were also not significantly protected. H. polygyrus secretes a known TGF-β mimic (Hp-TGM) and simultaneous H. polygyrus infection with pMOG immunization led to a significant expansion of Tregs; however, administering the recombinant Hp-TGM to EAE mice failed to replicate the EAE protection seen during infection, indicating that this may not be central to the disease protecting mechanism. Mice infected with H. polygyrus also showed a systemic Th2 biasing, and restimulating splenocytes with pMOG showed release of pMOG-specific IL-4 as well as suppression of inflammatory IL-17A. Notably, a Th2-skewed response was found only in mice infected with H. polygyrus at the time of EAE induction and not those with a chronic infection. Furthermore, H. polygyrus failed to protect against disease in IL-4Rα−/− mice. Together these results indicate that the EAE disease protective mechanism of H. polygyrus is likely to be predominantly Th2 deviation, and further highlights Th2-biasing as a future therapeutic strategy for MS.

Highlights

Over one-fourth of the global population are infected with helminth parasites, with the majority of these infections located within resource-poor tropical countries [1]; before sanitation improvements and widespread industrialization occurred within the last century, the prevalence of helminths was likely to be high across the globe
In the inguinal lymph nodes, there was a significant increase in T regulatory cell (Treg) frequency (Figure 2A), and while no change was seen in cells expressing the disease-driving Th17 cell marker RORγt (Figure 2B), cells expressing the Th2 marker GATA3 trended toward an increase (Figure 2C)
Helminth parasites have been hypothesized as important environmental regulators for immune tolerance in both model systems and in human populations [2, 17, 32], resulting in numerous studies assessing the use of helminths or their products as therapeutic agents in the fight against autoimmune disease

Summary

Introduction

Over one-fourth of the global population are infected with helminth parasites, with the majority of these infections located within resource-poor tropical countries [1]; before sanitation improvements and widespread industrialization occurred within the last century, the prevalence of helminths was likely to be high across the globe. MS is believed to be driven by autoreactive T helper cells, the Th1 and Th17 subsets, which enter and are reactivated in the central nervous system (CNS) resulting in the recruitment of additional T cells and macrophages to establish inflammatory lesions. These lesions result in loss of myelin, oligodendrocyte destruction and axonal damage and can account for the broad range of symptoms seen in patients with MS [5]. While CD4+ T helper cells are well-established as important for initiating MS disease; B cells, CD8+ T cells, and natural killer cells have been implicated as drivers of disease pathogenesis [6]

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