Regulatory T cells in human geohelminth infection suppress immune responses to BCG and <i>Plasmodium falciparum</i>

Wammes, Linda J.; Hamid, Firdaus; Wiria, Aprilianto E.; Gier, Brechje de; Sartono, Erliyani; Maizels, Rick M.; Luty, Adrian J. F.; Fillié, Yvonne E.; Brice, Gary T.; Supali, Taniawati; Smits, Hermelijn H.; Yazdanbakhsh, Maria

doi:10.1002/eji.200939699

Cited by 125 publications

(101 citation statements)

References 14 publications

(16 reference statements)

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“…With regard to immune regulation, no treatment-related change in Treg frequencies was seen, consistent with the finding of similar Treg frequencies in STH-infected and -uninfected children reported from the same study area (12). The proportion of PD-1-expressing CD4 + T cells was not significantly altered by albendazole treatment over 2 y, although in the first year posttreatment this was significantly lower.…”

Section: Discussionsupporting

confidence: 87%

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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: Discussionsupporting

confidence: 87%

“…Several regulatory cells and molecules are thought to play an important role in the regulatory network (3). Within T-cell responses, expansion of Tregulatory cells (Tregs) is reported in both animal models (10) and some human studies (11,12). Tregs suppress helminthspecific and bystander proliferative and proinflammatory responses.…”

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confidence: 99%

Community deworming alleviates geohelminth-induced immune hyporesponsiveness

Wammes

Hamid

Wiria

et al. 2016

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

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“…parasites. 15,16 One may, therefore, speculate that malariaspecific immune responses may be impaired in subjects chronically infected with helminths. However, studies that have assessed this question have yielded conflicting results indicating that larger and better designed studies are needed.…”

Section: Introductionmentioning

confidence: 99%

Associations Between Helminth Infections, Plasmodium falciparum Parasite Carriage and Antibody Responses to Sexual and Asexual Stage Malarial Antigens

Ateba-Ngoa

Jones

Zinsou

et al. 2016

The American Society of Tropical Medicine and Hygiene

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Abstract. Infections with helminths and Plasmodium spp. overlap in their geographical distribution. It has been postulated that helminth infections may influence malarial transmission by altering Plasmodium falciparum gametocytogenesis. This cross-sectional study assessed the effect of helminth infections on P. falciparum gametocyte carriage and on humoral immune responses to sexual stage antigens in Gabon. Schistosoma haematobium and filarial infections as well as P. falciparum asexual forms and gametocyte carriage were determined. The antibody responses measured were to sexual (Pfs230, Pfs48/45) and asexual P. falciparum antigens (AMA1, MSP1, and GLURP). A total of 287 subjects were included. The prevalence of microscopically detectable P. falciparum asexual parasites was higher in S. haematobiuminfected subjects in comparison to their uninfected counterparts (47% versus 26%, P = 0.003), but this was not different when filarial infections were considered. Plasmodium falciparum gametocyte carriage was similar between Schistosomaor filaria-infected and uninfected subjects. We observed a significant decrease of Pfs48/45 immunoglobulin G titer in S. haematobium-infected subjects (P = 0.037), whereas no difference was seen for Pfs230 antibody titer, nor for antibodies to AMA1, MSP1, or GLURP. Our findings suggest an effect of S. haematobium on antibody responses to some P. falciparum gametocyte antigens that may have consequences for transmission-blocking immunity.

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“…Thus, helminth infections might interfere with vaccination efficiency in the human population (4). Indeed, a reduced humoral and cellular immune response was observed in helminth-infected individuals after cholera (5), bacillus Calmette-Guérin (6,7), and tetanus toxoid (8-10) vaccination, whereas de-worming increased purified protein derivative-specific immune response (6). Regarding situations of coinfection, helminth-induced immune modulation may interfere with the control of coinfecting parasites but may also help to avoid immune pathology such as development of cerebral malaria (11,12).…”

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confidence: 99%

Pathogenic Nematodes Suppress Humoral Responses to Third-Party Antigens In Vivo by IL-10–Mediated Interference with Th Cell Function

Hartmann

Haben

Fleischer

et al. 2011

The Journal of Immunology

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One third of the human population is infected with helminth parasites. To promote their longevity and to limit pathology, helminths have developed several strategies to suppress the immune response of their host. As this immune suppression also acts on unrelated third-party Ags, a preexisting helminth infection may interfere with vaccination efficacy. In this study, we show that natural infection with Litomosoides sigmodontis suppressed the humoral response to thymus-dependent but not to thymus-independent model Ags in C57BL/6 mice. Thereby, we provide evidence that reduced humoral responses were mediated by interference with Th cell function rather than by direct suppression of B cells in L. sigmodontis-infected mice. We directly demonstrate suppression of Ag-specific proliferation in OVA-specific Th cells after adoptive transfer into L. sigmodontis-infected mice that led to equally reduced production of OVA-specific IgG. Transferred Th cells displayed increased frequencies of Foxp3+ after in vivo stimulation within infected but not within naive mice. Helminth-mediated suppression was induced by established L. sigmodontis infections but was completely independent of the individual worm burden. Using DEREG mice, we rule out a central role for host-derived regulatory T cells in the suppression of transferred Th cell proliferation. In contrast, we show that L. sigmodontis-induced, host-derived IL-10 mediated Foxp3 induction in transferred Th cells and significantly contributed to the observed Th cell hypoproliferation within infected mice.

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Regulatory T cells in human geohelminth infection suppress immune responses to BCG and Plasmodium falciparum

Cited by 125 publications

References 14 publications

Community deworming alleviates geohelminth-induced immune hyporesponsiveness

Community deworming alleviates geohelminth-induced immune hyporesponsiveness

Associations Between Helminth Infections, Plasmodium falciparum Parasite Carriage and Antibody Responses to Sexual and Asexual Stage Malarial Antigens

Pathogenic Nematodes Suppress Humoral Responses to Third-Party Antigens In Vivo by IL-10–Mediated Interference with Th Cell Function

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