Critical roles of regulatory B and T cells in helminth parasite-induced protection against allergic airway inflammation

Abstract

The prevalence of allergic asthma and incidences of helminth infections in humans are inversely correlated. Although experimental studies have established the causal relation between parasite infection and allergic asthma, the mechanism of the parasite-associated immunomodulation is not fully elucidated. Using a murine model of asthma and nematode parasite Heligmosomoides polygyrus, we investigated the roles of regulatory B cells (B reg ) and T cells (T reg ) in mediation of the protection against allergic asthma by parasite. H. polygyrus infection significantly suppressed ovalbumin (OVA)-induced allergic airway inflammation (AAI) evidenced by alleviated lung histopathology and reduced numbers of bronchoalveolar inflammatory cell infiltration, and induced significant responses of interleukin (IL)-10 + B reg , IL-10 + T reg and forkhead box protein 3 (FoxP3) + T reg in mesenteric lymph node and spleen of the mice. Adoptive transfer of IL-10 + B reg and IL-10 + T reg cell prevented the lung immunopathology in AAI mice. Depletion of FoxP3 + T reg cells in FoxP3-diphtheria toxin (DT) receptor transgenic mice by diphtheria toxin (DT) treatment exacerbated airway inflammationin parasite-free AAI mice and partially abrogated the parasite-induced protection against AAI. IL-10 + B reg cells were able to promote IL-10 + T reg expansion and maintain FoxP3 + T reg cell population. These two types of T regs failed to induce CD19 + B cells to transform into IL-10 + B reg cells. These results demonstrate that B reg , IL-10 + T reg and FoxP3 + T reg cells contribute in A discrepant manner to the protection against allergic airway immunopathology by parasiteS. B reg cell might be a key upstream regulatory cell that induces IL-10 + T reg response and supports FoxP3 + T reg cell population which, in turn, mediate the parasite-imposed immunosuppression of allergic airway inflammation. These results provide insight into the immunological relationship between parasite infection and allergic asthma.

Dirofilaria immitis Could Be a Risk Factor for the Development of Allergic Diseases in Humans

“…Several parasitic molecules have been implicated in modulating the immune and allergic response of helminth-infected hosts [ 27 ]. It has been described that parasite infections can develop a strong response and high levels of IgE in allergic sufferers, i.e., asthma or tropical pulmonary eosinophilia [ 28 , 29 , 30 , 31 ]. Moreover, it seems that infections by A. lumbricoides, T. canis, T. trichiura , hookworm, and S. mansoni can cause allergic reactions in humans [ 15 , 16 , 17 , 18 , 19 ].…”

Harnessing helminth-driven immunoregulation in the search for novel therapeutic modalities

“…Indeed, from a clinical perspective, molecules that drive expansion, mobilization, or increased mucosal homing of 9Tregs are the holy grail for many disorders that result from immune dysregulation [57,58], and we will provide defined examples later in this review. Regulatory B cells (Bregs) are also a feature of helminth infections [59] and are the primary source of IL-10 and other tissue-protective proteins, including (Resistin-like molecule-α) RELMα [60,61]. Indeed, in mice infected with H. polygyrus, IL-10 + Breg cells were able to promote expansion and maintenance of IL-10 + FOXP3 + Treg cell populations [61].…”

“…Regulatory B cells (Bregs) are also a feature of helminth infections [59] and are the primary source of IL-10 and other tissue-protective proteins, including (Resistin-like molecule-α) RELMα [60,61]. Indeed, in mice infected with H. polygyrus, IL-10 + Breg cells were able to promote expansion and maintenance of IL-10 + FOXP3 + Treg cell populations [61]. Fig 3 summarizes the multitude of cellular immune pathways upon which helminths and their ESPs impact, including the well-established influence of DCs, but also the emerging potential roles for factors produced by microbes, sensory neurons, and specialized intestinal epithelial cells that initiate the very early response to helminth exposure via ILC2s and innate granulocytes [62,63].…”

“…Helminths penetrate and migrate through skin and tissues without causing significant damage. The mechanisms employed by helminths to concurrently reduce injury and stimulate healing in the host are currently being explored [61,[84][85][86]. Most of the existing literature focuses on the role of the T H 2 response-type 2 macrophages in particular-in driving wound repair; however, a handful of helminth-secreted molecules with wound healing properties have been described.…”

Important Role of Immunological Responses to Environmental Exposure in the Development of Allergic Asthma

“…Cell transfer and depletion experiments demonstrated that IL-10 + Breg, IL-10 + Treg and FoxP3 + Treg cells participated in the parasite-induced immunosuppression of allergic airway inflammation. 99 …”