Posttreatment Changes in Cytokines Induced by Schistosoma mansoni Egg and Worm Antigens: Dissociation of Immunity- and Morbidity-Associated Type 2 Responses

Wilson, Shona; Jones, Frances M.; Kenty, LeeCarol; Mwatha, Joseph K.; Kimani, Gachuhi; Kariuki, H. Curtis; Dunne, David W.

doi:10.1093/infdis/jit826

Cited by 12 publications

(13 citation statements)

References 33 publications

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“…Moreover, using pretreatment worm burden as a proxy for antigen release, the modest increase seen to AscAg was not correlated with burden of Ascaris lumbricoides at pretreatment, nor were responses to nonrelated antigens correlated with baseline worm burden. These findings argue that observed boosted immune responses would not be due to release of antigens from dying worms, which has been shown to account for part of the increase in immune responses after treatment in schistosomiasis (25), but rather be due to the decrease in immune regulation.…”

Section: Discussionmentioning

confidence: 82%

Community deworming alleviates geohelminth-induced immune hyporesponsiveness

Wammes

Hamid

Wiria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In cross-sectional studies, chronic helminth infections have been associated with immunological hyporesponsiveness that can affect responses to unrelated antigens. To study the immunological effects of deworming, we conducted a cluster-randomized, double-blind, placebo-controlled trial in Indonesia and assigned 954 households to receive albendazole or placebo once every 3 mo for 2 y. Helminthspecific and nonspecific whole-blood cytokine responses were assessed in 1,059 subjects of all ages, whereas phenotyping of regulatory molecules was undertaken in 121 school-aged children. All measurements were performed before and at 9 and 21 mo after initiation of treatment. Anthelmintic treatment resulted in significant increases in proinflammatory cytokine responses to Plasmodium falciparum-infected red blood cells (PfRBCs) and mitogen, with the largest effect on TNF responses to PfRBCs at 9 moestimate [95% confidence interval], 0.37 [0.21-0.53], P value over time (P time ) < 0.0001. Although the frequency of regulatory T cells did not change after treatment, there was a significant decline in the expression of the inhibitory molecule cytotoxic T lymphocyteassociated antigen 4 (CTLA-4) on CD4 + T cells of albendazoletreated individuals, -0.060 [-0.107 to -0.013] and -0.057 [-0.105 to -0.008] at 9 and 21 mo, respectively; P time = 0.017. This trial shows the capacity of helminths to up-regulate inhibitory molecules and to suppress proinflammatory immune responses in humans. This could help to explain the inferior immunological responses to vaccines and lower prevalence of inflammatory diseases in low-compared with high-income countries.helminths | albendazole | cytokine responses | Indonesia | deworming S oil-transmitted helminths (STHs) represent the most common infectious disease worldwide (1). In addition to specific worm-associated morbidities, it has been argued that chronic STH infections may magnify health-related burdens in communities remote from health care facilities, exacerbating anemia, poor nutritional status, and possibly poor cognitive development (1). However, this was not fully supported by the latest analysis of the Cochrane database (2).Immunologically, cellular immune hyporesponsiveness is a hallmark of chronic helminth infections that may allow parasites' longterm survival (3). The consequences of immunosuppression are manifold with potentially major public health relevance. Immune hyporesponsiveness could curtail effective immune responses, thereby increasing susceptibility to pathogens, and helminths are associated with suboptimal vaccine responses (4-6). The helminthrelated dampened immune responses might nevertheless help to prevent immunopathology during coinfections and, possibly, aberrant reactivity to environmental or self-antigens (7). With respect to the latter, there is currently much interest in the use of helminth infections to treat allergies and autoimmune diseases, exploiting their ability to induce immune hyporesponsiveness (8).Suppressed lymphocyte responses were described in the 19...

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Section: Discussionmentioning

confidence: 82%

Community deworming alleviates geohelminth-induced immune hyporesponsiveness

Wammes

Hamid

Wiria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…A study conducted in Kenya showed that in schoolchildren infected with Schistosoma mansoni , type 2 cytokine responses including IL‐4, IL‐5, IL‐9 and IL‐13 were significantly increased upon stimulation with egg antigen 1 and 2 years post‐treatment . Another study in Gabon showed that specifically IL‐5, but neither IL‐4 nor IL‐13, was downregulated during an active S. haematobium infection as only IL‐5 responses to worm antigens were increased in subjects who remained free from infection 2 years after helminth clearance, compared to subjects who became reinfected …”

Section: Discussionmentioning

confidence: 99%

“…This enhanced cytokine response can be due to either removal of the immunosuppressive effects of active infection or immunological boosting by antigens released from dying parasites . Although it is possible that treatment boosts the antigen‐specific responses, often also responses to unrelated antigens such as PHA are enhanced by anthelmintic treatment.…”

Section: Discussionmentioning

confidence: 99%

The effect of three‐monthly albendazole treatment on Th2 responses: Differential effects on IgE and IL‐5

Ruiter

Tahapary

Wammes

et al. 2017

Parasite Immunology

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Helminth parasites induce a strong Th2 response, characterized by high levels of IgE and elevated signature cytokines such as IL-5. As many global deworming programmes are underway, there is concern that this might lead to emergence of Th1-mediated pathologies when the counterbalancing helminth-induced Th2 response is absent. Therefore, we assessed the effect of deworming on Th2-mediated responses in a household-clustered randomized controlled trial in Indonesia. Total plasma IgE and whole-blood IL-5 responses to mitogen phytohaemagglutinin (PHA) were measured in 1494 and 682 subjects, respectively, at baseline, 9 and 21 months after three-monthly single-dose treatment with albendazole or placebo. Anthelmintic treatment did not result in complete removal of helminth infections in the community. However, treatment significantly decreased IgE levels in albendazole- compared to placebo-treated subjects. IL-5 responses to PHA were not significantly affected by anthelmintic treatment and tended to increase in albendazole-treated subjects, indicating that intensive treatment of helminth parasites has different outcomes on B-cell (IgE levels) and T-cell (IL-5) responses. The data shows that 2 years of deworming can have differential effects on responses typified as Th2-mediated, which needs to be taken into account when examining the impact of helminths on noncommunicable diseases.

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“…Infections are distributed in age-dependent patterns; that is, infection intensities increase with age in younger children before falling to lower levels in adulthood [3,4]. Resulting morbidity manifests from CD4 + T cell-mediated granulomatous tissue responses to eggs, not adult worms that are swept into the liver or become trapped in the intestine or urogenital tissues [11]. The cycle is completed by the excretion of viable eggs from the definitive host into these water sources [5,6].…”

Section: Introductionmentioning

confidence: 99%

“…In severe cases of S. mansoni infections this results in liver fibrosis, portal hypertension and intestinal bleeding. Resulting morbidity manifests from CD4 + T cell-mediated granulomatous tissue responses to eggs, not adult worms that are swept into the liver or become trapped in the intestine or urogenital tissues [11]. Data from murine studies have shown that initially, immune responses start with a Th1 response against the migrating schistosomula and immature adult worms inducing interferon (IFN)-γ.…”

Section: Introductionmentioning

confidence: 99%

Schistosoma mansoni PCR+-infected individuals in the Sudan present elevated systemic levels of chemokines when compared to uninfected and egg+ cohorts

Arndts

Elfaki

Jelden

et al. 2019

Clinical and Experimental Immunology

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Infections withSchistosoma mansoni remain a major health problem in the Sudan where endemic communities, such as those in Kassala and Khartoum states, continue to face severe social-economic difficulties. Our previous immunoepidemiological findings revealed different immune [cytokine and S. mansoni egg (SEA) antibody] profiles in individuals with active infections (eggs in stool n = 110), individuals positive for S. mansoni via polymerase chain reaction (PCR) using sera (Sm PCR + n = 63) and those uninfected (Sm uninf). As antibody responses to eggs and worms are known to change during infection, we have expanded the profiling further by determining levels of adult worm (SWA) antibodies and nine chemokines in the serum of each individual in the three different cohorts.With the exception of C-C motif chemokine ligand (CCL)2, all measured chemokines were significantly higher in SmP CR + individuals when compared to the egg + group and in addition they also presented elevated levels of SWA-specific immunoglobulin (Ig)G2. Multivariable regression analysis further revealed that infection per se was strongly linked to SWA-specific IgG3 levels and CCL5 was strongly associated with a Sm PCR + diagnostic state. In the absence of PCR diagnostics that recognize juvenile worms or schistosomulae motives, identifying schistosome-specific traits should provide better insights into current prevalence rates in endemic communities and, in doing so, take into consideration PCR + non-egg + individuals in current treatment programmes.

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Posttreatment Changes in Cytokines Induced by Schistosoma mansoni Egg and Worm Antigens: Dissociation of Immunity- and Morbidity-Associated Type 2 Responses

Cited by 12 publications

References 33 publications

Community deworming alleviates geohelminth-induced immune hyporesponsiveness

Community deworming alleviates geohelminth-induced immune hyporesponsiveness

The effect of three‐monthly albendazole treatment on Th2 responses: Differential effects on IgE and IL‐5

Schistosoma mansoni PCR+-infected individuals in the Sudan present elevated systemic levels of chemokines when compared to uninfected and egg+ cohorts

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