Regulation of pathogenesis and immunity in helminth infections

Abstract

Helminths are multicellular eukaryotic parasites that infect over one quarter of the world's population. Through coevolution with the human immune system, these organisms have learned to exploit immunoregulatory pathways, resulting in asymptomatic tolerance of infections in many individuals. When infections and the resulting immune responses become dysregulated, however, acute and chronic pathologies often develop. A recent international meeting focused on how these parasites modulate host immunity and how control of parasitic and immunopathological disease might be achieved.

The intestinal helminth H. polygyrus. IMAGE COURTESY OF CONSTANCE FINNEY.

Figure 1.

Helminth infections. A summary of the major helminth infections of humans and their mouse model counterparts. Estimates of human infection numbers are taken from Hotez et al. (2008). Note that the schematic does not include highly prevalent helminth infections such as Ascaris lumbricoides (807 million estimated infections), other important human parasites, or the prominent veterinary helminth organisms.

Figure 2.

Expression of RELM proteins after exposure to helminth parasites. RELMα (green) is expressed by mannose receptor–positive cells (red) in the lungs of C57BL/6 mice challenged i.v. with S. mansoni eggs (A), and RELMβ is expressed by goblet cells of the gastrointestinal tract in C57BL/6 mice infected orally with T. muris eggs (B). Image courtesy of Meera Nair and David Artis, University of Pennsylvania.

Figure 3.

Cellular interactions in the immune response to helminths. Helminths are complex eukaryotic pathogens with multiple life stages that can affect different tissues within the parasitized host. Helminth-derived antigens can drain directly to secondary lymphoid organs or interact with cells at the site of infection, including DCs (1) or epithelial cells (2). Many helminth antigens inhibit the production of proinflammatory cytokines by DCs (3), and trigger the production of cytokines such as TSLP from epithelial cells, which inhibits IL-12 production by DCs. Antigen-carrying DCs activate naive Th cells (4), which proliferate and differentiate into precursor Th2 cells (5). pTh2 cells can then become Th2 cells (6) or Tfh cells (7). Th2 cells release various cytokines, including IL-5, which drives eosinophilia (8), and IL-4/-13, which stimulate AAMs (9). AAMs in turn produce molecules such as arginase-1 and YM-1, which dampen Th2 responses. Tfh produce IL-4 and provide help to B cells for IgG1 and IgE production (10). During the early response to helminth infections, MHC class II–expressing basophils (11) enter the reactive secondary lymphoid organs and may help to polarize the Th2 response. IgE can then activate basophils (12), which in turn produce cytokines that activate alternative macrophages. Helminth infections can also promote the development of T reg cell responses (13).