Tissue-specific immunity in helminth infections

Abstract

A characteristic feature of host responses to helminth infections is the development of profound systemic and tissue-localised Type 2 immune responses that play critical roles in immunity, tissue repair and tolerance of the parasite at tissue sites. These same Type 2 responses are also seen in the tissue-associated immune-pathologies seen in asthma, atopic dermatitis and many forms of allergies. The recent identification of new subtypes of immune cells and cytokine pathways that influence both immune and non-immune cells and tissues creates the opportunity for reviewing helminth parasite-host responses in the context of tissue specific immunity. This review focuses on the new discoveries of the cells and cytokines involved in tissue specific immune responses to helminths and how these contribute to host immunity against helminth infection and allow the host to accommodate the presence of parasites when they cannot be eliminated.

Fig. 1. Hookworm life cycle.

Infective larvae (iL3) survive in warm humid environments. Upon contact with the human host, they penetrate the skin (1), migrate through the circulatory vasculature to the lung (2), where they molt, and are carried up by the trachea by the host muco-ciliary ladder and swallowed. Larvae are retained in the small intestine (3) where they develop to the adult stage, mate, and produce eggs. Eggs are released with the feces into the environment, they hatch, develop through three stages to the infective L3. This review will focus on the immune responses elicited in the skin, lungs and intestine by this and related parasites.

Fig. 2. Basophil responses in the skin.

Infective L3 penetrate the skin causing damage of the epithelial cells. Alarmins such as IL-33 and TSLP are released from damaged epithelial cells. Both IL-33 and TSLP can activate basophils, which can release IL-4. IL-4 is necessary for 1) the development of T_H2 cells and the release of IL-5 involved in eosinophil recruitment, and 2) B cell IgE class switching. Basophil activity is directed against the parasite upon binding of IgE through high affinity receptors and trapping infective larvae. TSLP together with IL-3 induces recruitment of basophils at the site of skin inflammation.

Fig. 3. Immune responses against invading parasite in the lung.

Hookworm larvae can cause extensive damage during the lung migratory phase. The release of IL-33 and IL-25, from damaged epithelial cells, and NMU from neurons drives the activation of ILC2s. Activated ILC2s release IL-5 and ACh, involved in eosinophils recruitment, and IL-13 that acts on goblet cells and increases mucus production. Both the presence of activated eosinophils and increased mucus production help with the killing and removal of parasites.

Fig. 4. Intestinal ILC2 activation during helminth infection.

Adult hookworm can establish chronic infection in the intestinal tract. Several factors contribute to the activation of intestinal ILC2s. IL-33 released from epithelial cells and from ATP-activated mast cell can directly activate ILC2s. IL-25 and leukotrienes (LTs) produced by tuft cells, and NMU by enteric neurons induce production of IL-13. IL-13 induces hyperplasia of goblet cells and mucus production, and it acts on progenitor intestinal cells to promote goblet cells and tuft cells development. In contrast, IL-33 released from DCs induces expansion of ST2⁺ T_REG that suppress ILC2s activation, reducing type 2 immune responses.