The Roles of Various Immune Cell Populations in Immune Response against Helminths

Abstract

Helminths are multicellular parasites that are a substantial problem for both human and veterinary medicine. According to estimates, 1.5 billion people suffer from their infection, resulting in decreased life quality and burdens for healthcare systems. On the other hand, these infections may alleviate autoimmune diseases and allergy symptoms. The immune system is programmed to combat infections; nevertheless, its effector mechanisms may result in immunopathologies and exacerbate clinical symptoms. This review summarizes the role of the immune response against worms, with an emphasis on the Th₂ response, which is a hallmark of helminth infections. We characterize non-immune cells (enteric tuft cells-ETCs) responsible for detecting parasites, as well as the role of hematopoietic-derived cells (macrophages, basophils, eosinophils, neutrophils, innate lymphoid cells group 2-ILC2s, mast cells, T cells, and B cells) in initiating and sustaining the immune response, as well as the functions they play in granulomas. The aim of this paper is to review the existing knowledge regarding the immune response against helminths, to attempt to decipher the interactions between cells engaged in the response, and to indicate the gaps in the current knowledge.

Keywords: B cells; ETC; ILC2; T cells; basophils; eosinophils; granuloma; helminths; immune response; macrophages; neutrophils.

Figure 1

Interaction of helminth antigens with PRRs. Natural ligands of PRRs (TLRs, CLRs, and NLRs) induce a proinflammatory response through the activation of the transcription factors NF-κB, AP-1, CREB, and NFAT. Blue, green, and red arrows represent classical signaling from TLRs, CLRs, and NLRs, respectively. Violet arrows indicate interference of helminths with PRR signaling. The parasites stimulate PRRs directly or interfere with their signaling pathways, inducing a Th₂/Th_reg response. A full description is given in the text (Section 3.1). Fh-CL3—F. hepatica cathepsin L3, Fh-HDM—fasciola hepatica helminth defense molecule, SEA—schistosoma-soluble egg antigens.

Figure 2

Response of enteric tuft cells (ETCs) to parasite antigens and their impact on type 2 innate lymphoid cells (ILC2s). Type 2 taste receptors (TAS2Rs) belong to G protein-coupled receptors (GPCRs) and sense parasites’ antigens, signaling through the G protein gustducin. Gustducin activates phospholipase β2 (PLCβ2), which hydrolyzes phosphatidylinositol biphosphate (PIP2) to diacylglycerol (DAG) and inositol trisphosphate (IP3). The latter compound induces the migration of calcium from the endoplasmic reticulum (ER) towards the cytoplasm, facilitating the influx of sodium ions into the cell through transient receptor potential cation channel subfamily M member 5 (TRPM5). This leads to the metabolism of arachidonic acid (AA) to cysteine leukotrienes (CysLTs) and the release of CysLTs and IL-25. Both mediators stimulate ILC2s to release IL-13, a powerful modulator of the Th₂ response. There is also a positive feedback loop between the secretion of IL-25 and CysLT from ETC. ILC2s, through the release of IL-13, stimulate intestinal stem cells (ISC) to differentiate into ETC, increasing their number during helminth infections.

Figure 3

Schematic representation of the interaction between the intestinal immune system during homeostasis (A) and helminth-induced inflammation (B). (A) Interactions between the immune system and gut microbiota. Dendritic cells function through both antigen presentation to naive B and T cells and by secreting IL-23, activating type 3 innate lymphoid cells (ILC3). Activated ILC3s release IL-22 and granulocyte–macrophage colony-stimulating factor (GM-CSF). IL-22 activates the epithelium, leading to the secretion of antimicrobial peptides (AMP) and an increase in IL-23 production by dendritic cells. Bacterial metabolites also directly interact with the immune system. For example, short-chain fatty acids (SCFAs) penetrate the epithelial barrier and upregulate anti-inflammatory cytokines. T regulatory cells are crucial for maintaining tolerance towards commensal microbiota. (B) Immune system–helminth interactions, illustrated using the example of H. polygyrus. Intestinal parasites release enzymes that digest the mucosal barrier, causing epithelial cell death. In response to the damage, intestinal epithelial cells release alarmins (IL-25, IL-33, TSLP), activating immune system cells. Alarmins activate basophils, mast cells, ILC2s, and neutrophils. Subsequently, eosinophils are activated by IL-5, Th2 cells by IL-4, and type 2 macrophages by IL-13. The role of neutrophils in the development of type 2 responses is not fully understood yet, but there is a suspicion that they may be capable of secreting IL-13 and IL-33. Other cells contribute to the inflammatory response, recruitment of immune cells, and coordination of the immune reaction.

Figure 4

Illustration of granuloma composition in H. polygyrus 4 days post-infection (A). T. canis 10 days post-infection (B) and T. canis 28 days post-infection (C).