Review series on helminths, immune modulation and the hygiene hypothesis: immunity against helminths and immunological phenomena in modern human populations: coevolutionary legacies?

Abstract

Although the molecules and cells involved in triggering immune responses against parasitic worms (helminths) remain enigmatic, research has continued to implicate expansions of T-helper type 2 (Th2) cells and regulatory T-helper (T(reg)) cells as a characteristic response to these organisms. An intimate association has also emerged between Th2 responses and wound-healing functions. As helminth infections in humans are associated with a strong Th2/T(reg) immunoregulatory footprint (often termed a 'modified Th2' response), plausible links have been made to increased susceptibility to microbial pathogens in helminth-infected populations in the tropics and to the breakdowns in immunological control (allergy and autoimmunity) that are increasing in frequency in helminth-free developed countries. Removal of helminths and their anti-inflammatory influence may also have hazards for populations exposed to infectious agents, such as malaria and influenza, whose worst effects are mediated by excessive inflammatory reactions. The patterns seen in the control of helminth immunity are discussed from an evolutionary perspective. Whilst an inability to correctly regulate the immune system in the absence of helminth infection might seem highly counter-adaptive, the very ancient and pervasive relationship between vertebrates and helminths supports a view that immunological control networks have been selected to function within the context of a modified Th2 environment. The absence of immunoregulatory stimuli from helminths may therefore uncover maladaptations that were not previously exposed to selection.

Figure 1

The immune system evolved in the presence of helminths. The earliest dates of colonization by helminth lineages are mapped onto a phylogenetic history of vertebrates. Also mapped are major putative events in immune system evolution and the appearance of mediators of importance in anti-helminth responses. Divergence times of the major vertebrate groups from the mammalian lineage are indicated (Mya, million years ago). Macrophage-, eosinophil- and mast- like cells occur in Agnathans (lampreys) predating the appearance of classical adaptive immunity. The evolution of classical adaptive immunity was possibly preceded by two rounds of whole genome, or large-scale partial genome, duplication (4n and then 8n). Insertion of recombination activating (RAG) genes into the genome then allowed the evolution of the recombinatorial receptor system underpinning T-cell and B-cell functions. This occurred at some point between the divergences of the Agnatha (lampreys and hagfishes) and the Chondricthyes (sharks and rays). Colonization by platyhelminths occurred within this period, with all extant parasitic groups believed to be derived from a single common parasitic ancestor. The earliest evidence of Th2 cytokines– and alternatively (aaMΦ) versus classically (caMΦ) activated macrophages, is found in the Actinopterygii (bony fishes). Colonization of land probably allowed the invasion of primitive tetrapods by parasitic nematodes, (molecular phylogenetic analyses suggest at least four independent invasions). The immunoglobulin E (IgE) isotype, important in anti-helminth responses, is a recent innovation in the mammalian lineage. Ig, immunoglobulin; Mφ, macrophage.

Figure 2

The wide range of organ systems targeted by a selection of the helminth parasites occurring in humans.

Figure 3

Cells and molecules involved in the generation of immune responses in helminth infections. Solid arrows indicate signalling influences on cells (with important signalling molecules indicated alongside), and dashed arrows indicate the developmental trajectory of an individual cell type. (a) A widely accepted hypothesis for the function of mediators and effectors involved in the modified Th2 response against helminths. Pathogen-associated molecular patterns (PAMPs) from helminths may stimulate the differentiation of dendritic cells (DCs) that bias T-helper (Th) cell polarization towards Th2 or regulatory T (T_reg) cell subsets. Th2 cells produce a range of cytokines driving effector responses, including: eosinophil responses, mast cell responses, isotype-switched B-cell responses, increases in intestinal permeability, smooth muscle contractility and mucus production, and the differentiation of alternatively activated macrophages (aaMΦ). T_reg cells induced in the periphery and producing suppressive cytokines [interleukin (IL)-10 and transforming growth factor (TGF)-β] dampen levels of innate and adaptive immune activation. (b) A model incorporating alternative hypotheses for early events in the initiation of anti-helminth responses. Helminth PAMPs might stimulate signalling activity in other ‘front-line’ cell types (eosinophils, basophils, mast cells or intestinal epithelial cells) which, in turn, influences DCs or even naïve Th (Th0) cells. Damage-associated molecular patterns (DAMPs) released by dying cells, or signals resulting from apoptosis, might also influence either DCs or Th0 cells. EDN, eosinophil-derived neurotoxin; TSLP, thymic stromal lymphopoetin.