SUMMARYHuman hookworm infections are distributed widely in tropical areas and have a significant impact on host morbidity and human health. In the present study, we investigated the cellular responsiveness and cytokine production in peripheral blood mononuclear cells (PBMC) from Necator americanus-infected schoolchildren who had recently received chemotherapy, and compared them with non-infected endemic controls. Hookworm patients and treated, egg-negative individuals showed a lower cellular reactivity against phytohaemagglutinin (PHA) and hookworm antigen when compared with eggnegative endemic controls. The baseline production of proinflammatory tumour necrosis factor-a (TNFa ) in PBMC from infected patients and treated, egg-negative individuals was elevated. On the other hand, PHA-or hookworm antigen-induced interleukin (IL)-12 and interferon (IFN)-g secretion was higher in endemic controls than in hookworm patients, who either continued egg-positive or were eggnegative after treatment. Also, PBMC from endemic controls secreted more IL-5 and IL-13 than the other patient groups. Opposite to that, the spontaneous as well as the antigen-driven IL-10 secretion was lower in endemic controls when compared with the other groups. In summary, patently hookworminfected as well as egg-negative treated patients disclosed an elevated spontaneous cellular secretion of proinflammatory TNF-a , a prominent secretion of regulatory Th2-type IL-10 and an impaired production of IL-12, IFN-g , IL-5 and IL-13.

The impact of intestinal helminth infection, i.e. Ascaris lumbricoides and Trichuris trichiura, on cellular responsiveness and cytokine production was investigated in young adults. Ascaris-specific cellular responsiveness was higher in parasite-free endemic controls than in patients infected with T. trichiura, or A. lumbricoides, or patients co-infected with both parasites. Also, mitogen-induced tumour necrosis factor (TNF)-alpha, interleukin (IL)-12 and interferon (IFN)-gamma secretion by peripheral blood mononuclear cells (PBMC) was higher in negative endemic controls than in infected individuals. Ascaris antigen-specific production of TNF-alpha, IL-12 and IFN-gamma was low in singly Ascaris as well as in co-infected patients, whereas secretion of IL-10 and IL-13 was elevated and similarly high in all patient groups. The detection of Trichuris-specific and Ascaris-specific IgG4 revealed significantly higher serum antibody levels in Trichuris or Ascaris patients when compared to endemic controls (P < 0.05), whereas parasite-specific IgE antibody levels were similarly high in infected individuals and in endemic controls. In summary, chronically infected Ascaris and Trichuris patients with a high parasite load presented reduced cellular reactivity and lower type 1 TNF-alpha, IFN-gamma and IL-12 responses when compared with endemic controls, whereas type 2 IL-10 and IL-13 productions were similar in all groups from the endemic area. The former may support parasite persistence, whereas substantial type 2 cytokine release may promote protective immunity, suggesting an adaptation of the host to control the parasite burden while minimizing immune-mediated host self-damage.

No abstract

SummaryCytokine and chemokine levels were studied in infants (<5 years) with uncomplicated (MM) and severe malaria tropica (SM), and in Plasmodium falciparum infection-free controls (NEG). Cytokine plasma levels of interleukin (IL)-10, IL-13, IL-31 and IL-33 were strongly elevated in MM and SM compared to NEG (P < 0·0001). Inversely, plasma concentrations of IL-27 were highest in NEG infants, lower in MM cases and lowest in those with SM (P < 0·0001, NEG compared to MM and SM). The levels of the chemokines macrophage inflammatory protein (MIP3)-a/C-C ligand 20 (CCL20), monokine induced by gamma interferon (MIG)/CXCL9 and CXCL16 were enhanced in those with MM and SM (P < 0·0001 compared to NEG), and MIP3-a/CCL20 and MIG/CXCL9 were correlated positively with parasite density, while that of IL-27 were correlated negatively. The levels of 6Ckine/ CCL21 were similar in NEG, MM and SM. At 48-60 h post-anti-malaria treatment, the plasma concentrations of IL-10, IL-13, MIG/CXCL9, CXCL16 and MIP3-a/CCL20 were clearly diminished compared to before treatment, while IL-17F, IL-27, IL-31 and IL-33 remained unchanged. In summary, elevated levels of proinflammatory and regulatory cytokines and chemokines were generated in infants during and after acute malaria tropica. The proinflammatory type cytokines IL-31 and IL-33 were enhanced strongly while regulatory IL-27 was diminished in those with severe malaria. Similarly, MIP3-a/ CCL20 and CXCL16, which may promote leucocyte migration into brain parenchyma, displayed increased levels, while CCL21, which mediates immune surveillance in central nervous system tissues, remained unchanged. The observed cytokine and chemokine production profiles and their dynamics may prove useful in evaluating either the progression or the regression of malarial disease.

This study examined the development and persistence of immunity in humans presenting defined states of Onchocerca volvulus infection, i.e. in exposed endemic control individuals without microfilaridermia and clinical disease, in patients with patent or post‐patent onchocerciasis, and in patients concurrently infected with Mansonella perstans. Onchocerca volvulus antigen (OvAg)‐specific cellular reactivity was significantly diminished in microfilariae (mf)‐positive patients, while the highest reactivity was measured in exposed but mf‐negative endemic controls, those being free of any clinical signs of onchocercal disease. In patients who became post‐patent, responses to OvAg were significantly augmented, but did not approach entirely the magnitude observed in endemic controls. In onchocerciasis patients with concurrent mansonelliasis, cellular unresponsiveness to OvAg persisted, even when mf of O. volvulus were eliminated permanently by repeated ivermectin therapy. Cells from mf‐positive onchocerciasis patients produced significantly less interferon‐γ (IFN‐γ) (P<0·01) and interleukin‐5 (IL‐5) (P<0·05) in response to OvAg than those taken from endemic controls or post‐patent individuals in whom IFN‐γ and IL‐5 production was similarly high. In contrast, both OvAg‐driven as well as spontaneous IL‐10 secretion was higher in mf‐positive patients than in endemic controls or post‐patent cases. In all individuals examined, serological recognition of OvAg by immunoglobulins was dominated by IgG4; in mf‐positive patients OvAg of 205 000–12 000 molecular weight (MW) were strongly bound. In post‐patent individuals, and similarly in endemic controls, OvAg recognition by IgG4 varied from intense (with numerous antigens being recognized) to weak or absent antigen binding. Significantly elevated OvAg‐specific IgG isotypes were measured in mf‐positive onchocerciasis patients in comparison with endemic controls or post‐patent individuals (with the exception of IgG3). IgG1, IgG2 and IgE were higher, but IgG4 was lower in endemic controls compared with post‐patent onchocerciasis patients. The ratios of IgG4/IgG1 differed (P<0·001) between endemic controls and mf‐positive or post‐patent onchocerciasis patients, with IgG4/IgG1 ratios of R<3·0 being characteristic for endemic controls and post‐patent O. volvulus infection. In conclusion, this cross‐sectional immunoepidemiological investigation showed that distinct states of O. volvulus infection correlate with a particular cellular and humoral immune response. The mf‐free condition appeared to be associated with a vigorous parasite‐specific cellular reactivity and a particular cytokine production profile, while concurrent M. perstans infection depressed OvAg‐specific cellular responsiveness. Antibody responses, in all likelihood, reflected the intensity and state of infection, and not the degree of acquired immunity protective against parasite aggregation.

No abstract

SummaryInfection with the cestode Echinococcus multilocularis causes human alveolar echinococcosis (AE), a life-threatening disease affecting primarily the liver. Despite the severity of AE, clinical symptoms often develop only many years after infection, which suggests that E. multilocularis has developed mechanisms which depress anti-parasite immune response, thus favouring immune evasion. In this study we examined the production of cytokines, chemokines and the expression of CD molecules on peripheral blood mononuclear cells (PBMC) from AE patients and healthy controls in response to E. multilocularis metacestode culture supernatant, viable E. multilocularis vesicles and E. multilocularis vesicle fluid antigen in vitro . After 48 h of co-culture, E. multilocularis metacestode culture supernatant and E. multilocularis vesicles depressed the release of the proinflammatory cytokine interleukin (IL)-12 by PBMC. This effect was dose-dependent and a suppression of tumour necrosis factor (TNF)-α α α α and IL-12 was observed even when PBMC were activated with lipopolysaccharide (LPS). Comparing proinflammatory cytokine release by AE patients and controls showed that the release of IL-12 and TNF-α α α α was reduced in AE patients, which was accompanied by an increased number of CD4 + CD25 + cells and a reduced release of the Th2 type chemokine CCL17 (thymus and activation regulated chemokine, TARC), suggesting an antiinflammatory response to E. multilocularis metacestode in AE patients. Instead the production of interferon (IFN)-γ γ γ γ and the expression of CD28 on CD4 + T cells were increased in PBMC from AE patients when compared to controls. This was accompanied by a higher release of the Th2-type chemokine CCL22 (macrophage derived chemokine, MDC) supporting that E. multilocularis also generates proinflammatory immune responses. These results indicate that E. multilocularis antigens modulated both regulatory and inflammatory Th1 and Th2 cytokines and chemokines. Such a mixed profile might be required for limiting parasite growth but also for reducing periparasitic tissue and organ damage in the host.

The present investigation aimed to determine to what extent maternal helminth infection primes parasite-specific cellular responsiveness in neonates. Umbilical cord mononuclear blood cells (UCBC) and peripheral blood mononuclear cells (PBMC) from mothers proliferated in response to mitogenic stimulation with concanavalin A, as well as to bacterial Streptococcus pyogenes-derived (streptolysin O) and helminth-specific antigens of Necator americanus and Onchocerca volvulus. Cellular responses to Echinococcus multilocularis (Em) and Oesophagostomum bifurcum (Oes), helminth parasites not endemic in the study area, were absent (for Em) or very low (for Oes due to antigenic cross-reactivity). Cellular responsiveness to mitogen and antigens was higher in mothers than in their neonates. Several Th1-type (IL-2, IL-12, and IFN-gamma) and Th2-type (IL-5 and IL-10) cytokines were produced by UCBC from neonates and PBMC from mothers. Low levels of IFN-gamma were elicited by UCBC in response to helminth and bacterial antigens, while secretion of IL-2 was pronounced and similarly high in neonates and their mothers. Amounts of IL-5 produced by UCBC in response to bacterial SL-O and mitogenic stimulation (PHA) were low, but equivalent levels of IL-5 were induced by intestinal helminth and filaria-derived antigens in neonates and mothers. A pronounced production of IL-10 and IL-12 by UCBC was observed--spontaneous IL-10 and IL-12 secretion by UCBC was higher in neonates than by PBMC from mothers. Net amounts of IL-10 elicited by helminth antigens were similar, while net IL-12 in response to mitogen, and bacterial and helminth antigens was significantly higher in mothers than their offspring. Our results indicate that human maternal helminth infection does sensitize in utero for parasite-specific cellular responsiveness in offspring, and also activates specific production of several cytokines, and such children do not present a dominant expression of immunity of either Th1 or Th2.