Induction and regulation of pathogenic Th17 cell responses in schistosomiasis

Abstract

Schistosomiasis is a major tropical disease caused by trematode helminths in which the host mounts a pathogenic immune response against tissue-trapped parasite eggs. The immunopathology consists of egg antigen-specific CD4 T cell-mediated granulomatous inflammation that varies greatly in magnitude in humans and among mouse strains in an experimental model. New evidence, covered in this review, intimately ties the development of severe pathology to CD4 T helper 17 cells, a finding that adds a new dimension to the traditional CD4 Th1 vs. Th2 cell paradigm. Most examined mouse strains, in fact, develop severe immunopathology with substantial Th17 as well as Th1 and Th2 cell responses; a Th2 polarized response is an exception that is only observed in low-pathology strains such as the C57BL/6.The ability to mount pathogenic Th17 cell responses is genetically determined and depends on the ability of antigen presenting cells to produce IL-23 and IL-1â following recognition of egg antigens; analyses of several F2 progenies of (high × low)-pathology strain crosses demonstrated that quantitative trait loci governing IL-17 levels and disease severity vary substantially from cross to cross. Low pathology is dominant, which may explain the low incidence of severe disease in humans; however, coinfection with nematodes can also dampen pathogenic Th17 responses by promoting regulatory mechanisms such as those afforded by alternatively activated macrophages and T regulatory cells. A better understanding of the pathways conducive to severe forms of schistosomiasis and their regulation should lead to interventions similar to those presently used to manage other immune-mediated diseases.

Fucose-specific DC-SIGN signalling directs T helper cell type-2 responses via IKKε- and CYLD-dependent Bcl3 activation

“…Both IL-23 and IL-6 are crucial cytokines for the induction and maintenance of T H 17 cells 45 . The induction of T H 17 responses is associated with severe forms of schistosomiasis with granulomatous inflammation in host tissues, both in mice and humans, although with relatively low incidence in humans 46,47 . S. mansoni SEA has been reported to suppress T H 17 differentiation 48 .…”

CD209a Synergizes with Dectin-2 and Mincle to Drive Severe Th17 Cell-Mediated Schistosome Egg-Induced Immunopathology

“…Infection with S. mansoni results in hepatic and intestinal granulomatous inflammation around deposited parasite eggs. Most individuals develop a mild chronic gastrointestinal form of disease, but a minority of 5%–10% suffers from life-threatening hepatosplenic schistosomiasis, in which there is severe hepatic fibrosis with consequent portal hypertension, portal-systemic shunting, splenomegaly, ascites, and death (Larkin et al, 2012; Pearce and MacDonald, 2002). …”

Avian Schistosomes and Outbreaks of Cercarial Dermatitis

“…IFN-␥ and IL-12 are associated with Th1 cell differentiation, and IL-1␤ and IL-6 are important in Th17 polarization (228). Although the role of Th17 in host tissue immunopathology has been described for some infections by helminths (e.g., human schistosomes) (228), participation of Th17 cells in the processes associated with skin penetration by avian schistosomes needs to be clarified.…”

“…Larger amounts of IL-12 correlated with elevated production of gamma interferon (IFN-␥) in the cell culture supernatant (antigen-stimulated lymphocytes) from the skin draining lymph nodes (227). IFN-␥ and IL-12 are associated with Th1 cell differentiation, and IL-1␤ and IL-6 are important in Th17 polarization (228). Although the role of Th17 in host tissue immunopathology has been described for some infections by helminths (e.g., human schistosomes) (228), participation of Th17 cells in the processes associated with skin penetration by avian schistosomes needs to be clarified.…”