Genetic Control of Severe Egg-Induced Immunopathology and IL-17 Production in Murine Schistosomiasis

Abstract

Infection with the trematode parasite Schistosoma mansoni results in a distinct heterogeneity of disease severity, both in humans and in an experimental mouse model. Severe disease is characterized by pronounced hepatic egg-induced granulomatous inflammation in a proinflammatory cytokine environment, whereas mild disease corresponds with reduced hepatic inflammation in a Th2 skewed cytokine environment. This marked heterogeneity indicates that genetic differences play a significant role in disease development, yet little is known about the genetic basis of dissimilar immunopathology. To investigate the role of genetic susceptibility in murine schistosomiasis, quantitative trait loci analysis was performed on F2 progeny derived from SJL/J and C57BL/6 mice, which develop severe and mild pathology, respectively. In this study, we show that severe liver pathology in F2 mice 7 wk after infection significantly correlated with an increase in the production of the proinflammatory cytokines IL-17, IFN-γ, and TNF-α by schistosome egg Ag-stimulated mesenteric lymph node cells. Quantitative trait loci analysis identified several genetic intervals controlling immunopathology as well as IL-17 and IFN-γ production. Egg granuloma size exhibited significant linkage to two loci, D4Mit203 and D17Mit82, both of which were inherited in a BL/6 dominant manner. Furthermore, a significant reduction of hepatic granulomatous inflammation and IL-17 production in interval-specific congenic mice demonstrated that the two identified genetic loci have a decisive effect on the development of immunopathology in murine schistosomiasis.

Ellagic acid reduces murine schistosomiasis mansoni immunopathology via up-regulation of IL-10 and down-modulation of pro-inflammatory cytokines production

“…Similar findings have also been reported in murine model of asthma 11 , human PBMC 45 , and rat basophilic leukemia cells 55 . In fact, several studies have concluded that IL-17 is most directly associated with the severity of hepatic granulomatous inflammation and exacerbated immunopathology in experimental schistosomiasis 36,80,92,93 . The pathology of schistosomiasis was markedly reduced in IL-17-deficient mice 28 and by administration of anti-IL-17 antibody 37,94,95 .…”

“…Experiments with IFN-c-deficient mice 83 and anti-IFN-c mAb 96 treated mice have shown that IFN-c is critical in the development of granulomas and contributes to the recruitment of neutrophils to the granulomatous response. It has been reported that severe liver pathology in S. mansoni infection is correlated with increased specific IFN-c production by stimulated mesenteric lymph node cells 93 . Herein, we reported a decrease in specific IFN-c production by stimulated splenocytes in response to in vivo ( Figure 2G) or ex vivo (Table 2) EA-treatment.…”

Schistosomamansonitriggers Dectin-2, which activates the Nlrp3 inflammasome and alters adaptive immune responses

“…All three of these effector T cell populations (Th1, Th2, and Th17) can be induced by IL-1 family members, and it has been demonstrated that IL-1 signaling is required in DCs to mediate Th17 cell differentiation and that, moreover, IL-1β itself can induce IL-17A from Th17 cells (36). With regard to S. mansoni infection, increased levels of IL-17 have been associated with enlarged granuloma development (37), and blocking TGF-β (a known instigator of Th17 cells) during infection reduces serum IL-17 levels and alters schistosome-specific IgG responses (38). Interestingly, granuloma development actually protects the host from severe liver damage caused by the release of diffusible hepatotoxins from dying eggs (8).…”

High Schistosoma mansoni Disease Burden in a Rural District of Western Zambia

“…6,35 In endemic areas, most people infected with S. mansoni present with LIP C and D forms of fibrosis, 36 whereas severe disease characterized with advanced fibrosis (LIPs E and F) is only observed in 5-10% of the people. 37 In our study population, advanced fibrosis characterized with LIPs E and F was recorded in 4.8% and 1.2% of the participants, respectively. The observed prevalence of advanced portal fibrosis cases in this study correlates with the findings from other studies.…”