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This study examined the development and persistence of immunity In humans presenting defined states of Onchocerca volvuhus infection, i.e. in exposed endemic control individual 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 interferony (IFN-γ) (P < 0.0l) 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-gamma; 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 205000-12000 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/IgGl 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. [ABSTRACT FROM AUTHOR]

The proliferation and cytokine profiles of peripheral blood mononuclear cells (PBMC) from microfilaraemic (Mf+) subjects infected by Loa loa in response to antigens of several parasitic stages were compared with those from amicrofilaraemic (Mf+) individuals. While a strong lymphoproliferative response and consistent levels of both Th1 (IL-2, interferon-gamma (IFN-γ)) and Th2 (IL-4, IL-5) type cytokines were observed in response to adult worm (AW) and microfilariae (Mf) antigen in Mf- individuals, Mf+ subjects were characterized by a T cell unresponsiveness. including proliferation. cytokine production and IL-2 mRNA expression. Conversely, T cell responsiveness to mitogens and non-specific antigen were similar in the two endemic populations. Depletion of lymphocyte subpopulations indicated that T CD4+ were mainly involved in the specific cellular response. In contrast to other cytokines, IL-10 was produced in response to all parasitic stages, in both Mf+ and Mf- patients. Neutralization of IL-10 did not restore cytokine production in Mf+ patients, while B7 mRNA expression was similar between Mf+ and Mf- subjects in response to Mf antigen, suggesting that IL-10 was not the only factor responsible for T cell unresponsiveness. Mf+ patients have lower Mf antigen-specific IgG levels compared with Mf- and there is a significant correlation between Mf antigen-specific antibodies and IL-5 responses. These findings suggest that Mf- status is correlated with T helper responsiveness, including proliferation and production of both Th1- and Th2-type cytokines, whereas Mf+ status is characterized by unresponsiveness of the same cell population, induced and or maintained by microfilariae. [ABSTRACT FROM AUTHOR]

Mansonella perstans (Mp) filariasis is present in large populations in sub-Saharan Africa, and to what extent patent Mp infection modulates the expression of immunity in patients, notably their cellular cytokine and chemokine response profile, remains not well known. We studied the spontaneous and inducible cellular production of chemokines (C-X-C motif) ligand 9 (CXCL9) [monokine induced by interferon (IFN)-γ (MIG)], CXCL-10 [inducible protein (IP)-10], chemokine (C-C motif) ligand 24 (CCL24) (eotaxin-2), CCL22 [macrophage-derived chemokine (MDC)], CCL13 [monocyte chemotactic protein-4 (MCP-4)], CCL18 [pulmonary and activation-regulated chemokine (PARC)], CCL17 [thymus- and activation-regulated chemokine (TARC)] and interleukin (IL)-27 in mansonelliasis patients (Mp-PAT) and mansonelliasis-free controls (CTRL). Freshly isolated peripheral mononuclear blood cells (PBMC) were stimulated with helminth, protozoan and bacterial antigens and mitogen [phytohaemagglutinin (PHA)]. PBMC from Mp-PAT produced spontaneously (without antigen stimulation) significantly higher levels of eotaxin-2, IL-27, IL-8, MCP-4 and MDC than cells from CTRL, while IFN-γ-IP-10 was lower in Mp-PAT. Helminth antigens activated IL-27 and MCP-4 only in CTRL, while Ascaris antigen, Onchocerca antigen, Schistosoma antigen, Entamoeba antigen, Streptococcus antigen, Mycobacteria antigen and PHA stimulated MIG release in CTRL and Mp-PAT. Notably, Entamoeba antigen and PHA strongly depressed (P < 0·0001) eotaxin-2 (CCL24) production in both study groups. Multiple regression analyses disclosed in Mp-PAT and CTRL dissimilar cellular chemokine and cytokine production levels being higher in Mp-PAT for CCL24, IL-27, IL-8, MCP-4, MDC and PARC (for all P < 0·0001), at baseline (P < 0·0001), in response to Entamoeba histolytica strain HM1 antigen (EhAg) (P < 0·0001), Onchocerca volvulus adult worm-derived antigen (OvAg) (P = 0·005), PHA (P < 0·0001) and purified protein derivative (PPD) (P < 0·0001) stimulation. In Mp-PAT with hookworm co-infection, the cellular chemokine production of CXCL10 (IP-10) was diminished. In summary, the chemokine and cytokine responses in Mp-PAT were in general not depressed, PBMC from Mp-PAT produced spontaneously and selectively inducible inflammatory and regulatory chemokines and cytokines at higher levels than CTRL and such diverse and distinctive reactivity supports that patent M. perstans infection will not polarize innate and adaptive cellular immune responsiveness in patients., (© 2018 British Society for Immunology.)

Chemokine and antibody response profiles were investigated in children and adults with severe or uncomplicated Plasmodium falciparum malaria; the aim was to reveal which profiles are associated with severe disease, as often seen in nonimmune children, or with mild and uncomplicated disease, as seen in semi-immune adults. Blood samples were obtained from children under 5 years of age as well as adults with falciparum malaria. Classification of malaria was performed according to parasite densities and hemoglobin concentrations. Plasma levels of chemokines (IL-8, IP-10, MCP-4, TARC, PARC, MIP-1δ, eotaxins) were quantified, and antibody responses (IgE, IgG1, and IgG4) to P. falciparum, Entamoeba histolytica-specific antigen, and mite allergen extracts were determined. In children with severe malaria proinflammatory, IL-8, IP10, MIP-1δ, and LARC were at highly elevated levels, suggesting an association with severe disease. In contrast, the Th2-type chemokines TARC, PARC, and eotaxin-2 attained in children the same levels as in adults suggesting the evolution of immune regulatory components. In children with severe malaria, an elevated IgG1 and IgE reactivity to mite allergens and intestinal protozoan parasites was observed. In conclusion, exacerbated proinflammatory chemokines together with IgE responses to mite allergens or E. histolytica-specific antigen extract were observed in children with severe falciparum malaria.

Purpose: To study the impact of certain allergens on the manifestations of tropical endemic limbo-conjunctivitis (TELC) in Togolese children., Methods: This is a 3-year prospective study of 36 Togolese children with acute recurrences of TELC after 1 to 5 months of remission. Skin prick tests were conducted with five perennial respiratory allergens (dust mites, paper mites, roaches, dog and cat, grass pollen) and three food allergens (egg, peanut, shrimp). The reactions were compared to a negative control (saline solution) and a positive control (histamine or codeine sulfate). Length of remissions between acute exacerbations before and after allergy testing were noted., Results: Thirty-five children were polysensitive. Individual allergens were: dust mites (83.3%), followed by cockroach (72.2%), shrimp (61.1%), peanuts (55.6%), eggs (44.4%), the cat and/or dog dander (38.9%), and grass pollen (22.2%). The rate of remission prior to allergy testing was 77.8% within 2 months after treatment of an exacerbation; with allergy management, 55.5% of patients experienced remission beyond 1 year., Discussion: The literature reports that TELC is caused by multiple antigens. The clear predominance of respiratory and food allergens may lead to a new pathway for managing TELC in Togolese children., Conclusion: Allergy testing is of great importance for patients with frequent acute exacerbations of TELC., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

In this study parasite-specific antibody, cellular reactivity and Thl-type or Th2-type cytokine responses were investigated in humans concurrently infected with Necator americanus and Oesophagostomum bifurcum. The prospects for O. bifurcum-specific serodiagnosis based on IgG4 and IgE were evaluated. IgG4 showed low specificity for O. bifurcum due to antigen cross-reactivity with N. americanus, while IgE specifically distinguished between hookworm and O. bifurcum, and, in doubly infected patients, levels of O. bifurcum-specific as well as N. americanus-specific IgE were significantly elevated compared to those with N. americanus mono-infections. Cellular immunity was not strictly dominated by a Thl- or Th2- type reactivity. In co-infected patients cellular unresponsiveness to parasite antigens was observed, while cellular production of tumour necrosis factor alpha (TNF-alpha) and gamma-interferon (IFN-gamma) was greater in those doubly infected. Th2-type cytokines (interleukin-5 and interleukin-10) were produced in equal amounts by peripheral blood mononuclear cells from individuals with mono- and coinfections. Such mixed Thl-type and Th2-type immune responsiveness associated with persisting gastrointestinal parasitic nematodes may reflect a state of infection at which parasite-induced inflammatory and enteropathogenic responses co-exist, and furthermore, helminth coinfection will not only suppress parasite-specific cellular responsiveness but may also direct cytokine production towards a "permissive Th1-type cytokine profile" that favours parasite persistence.

Filarial infections of humans are chronic diseases. Despite an ongoing immune response, adult filariae continuously produce their offspring, the microfilariae (Mf), which are able to persist in sufficient numbers to ensure transmission. In this study, host- and parasite-derived factors, which contribute to persistence of Mf, were investigated using the filariasis model of Litomosoides sigmodontis in mice. Different strains of mice were found to differ widely in their capability to eliminate circulating Mf. Studies of congenic mouse strains showed that early and rapid clearance of Mf was mediated by activation pathways relevant to innate immunity, whereas late or delayed clearance of Mf was pre-determined by MHC-related factors. Genetic knock-out of genes for the MHC class-II molecules totally abrogated resistance. Most interestingly, the presence of only I adult female, but not male worms, renders all mice susceptible, irrespective of the genetic background, enabling Mf to circulate for extended periods of time. Such prolonged microfilaraemia was also observed in L. sigmodontis-infected animals challenged with heterologous Mf of Acanthocheilonema viteae. The use of cytokine gene knock-out mice showed that persistence of L. sigmodontis Mf was facilitated by IL-10, but not by IL-4 or IFN-gamma. In conclusion, irrespective of a resistant or susceptible host genetic background, survival of Mf of L. sigmodontis in mice is decisively regulated by the presence of adult female L. sigmodontis which will skew and exploit immune responses to facilitate the survival and persistence of their offspring in the infected host.

Nitric oxide (NO) has been shown to be an important effector mechanism in the defence against various pathogens, including filariae. The production of NO, as well as H2O2, is induced by the Th1 cytokine IFN-gamma. Therefore, the microfilariae (mf) of filarial nematodes, which are known to elicit the release of IFN-gamma, may be a target of NO release. In this study, we found that mf of the filarial species Litomosoides sigmodontis were resistant to the attack of H2O2, but vulnerable to NO exposure in vitro by a chemical NO donor, as well as activated macrophages. Adult worms were considerably less affected by exposure to NO. In-vivo production of NO following injection of mf, in this and previous studies, suggested a central role in the defence to filariae. However, neither pharmaceutical inhibition of nitric oxide synthesis, nor genetic knockout of the gene for inducible nitric oxide synthase (iNOS), abrogated resistance to circulating mf in mice. Interestingly, however, iNOS-KO mice showed higher interleukin (IL)-2 responses and lower IL-10 production, compared to their wild-type counterparts. In conclusion, despite its effectiveness in vitro and the observed production of NO by ex vivo cells following infection, nitric oxide seems not to be an important factor in elimination of mf of L. sigmodontis in vivo. However, it may have a regulatory role in the immune response.

In human alveolar echinococcosis, asexually proliferating metacestodes of Echinococcus multilocularis progressively infiltrate host tissues and cause serious pathology to the affected organs. This study employed an in vitro culture of E. multilocularis and examined the production of cytokines and chemokines by peripheral blood cells from echinococcosis patients in response to viable proliferating E. multilocularis metacestode vesicles (Em-vesicles). A significant interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) production was elicited in echinococcosis patients when their cells were cocultured with viable Em-vesicles and autologous immune sera. Furthermore, in echinococcosis patients, substantial amounts of cytokines were detected; and the levels of IL-12 and IL-13 found in patients correlated with the actual state of clinical disease. These observations suggest that viable E. multilocularis vesicles will induce significant cellular production of cytokines and chemokines in patients, and that such immune mediators may activate and enhance antibody-dependent cellular effector mechanism against proliferating metacestodes of E. multilocularis.

The present study investigated in vitro the regulatory effects of T helper 1 (Th1)-type (interferon-gamma, IFN-gamma; interleukin-12, IL-12) and Th2-type cytokines (IL-10, IL-13) on Onchocerca volvulus-specific cellular reactivity in onchocerciasis patients, and in exposed endemic control individuals presenting no clinical and parasitological signs of disease. In both patients and controls, addition of IL-10 dose-dependently depressed O. volvulus antigen (OvAg)-specific cellular proliferation, and peripheral blood mononuclear cells (PBMC) from patients who were more sensitive to the suppressive effect of IL-10 than those from endemic controls. However, neutralization of IL-10 by specific antibody did not reverse cellular hyporesponsiveness. In contrast to the inhibitory effects of IL-10, exogenous IL-12 and IL-13 augmented PBMC proliferative responses to OvAg both in patients and controls (P<0. 01) and neutralizing of IL-12 or IL-13 significantly decreased OvAg-specific proliferation in both groups. Exogenous IFN-gamma did not activate OvAg-specific proliferative responses in patients, but anti-IFN-gamma antibodies abolished cellular reactivity to OvAg. Antibody to IL-10 increased (P<0.05) OvAg-specific production of IL-5, IL-12 and IFN-gamma, and inversely, anti-IFN-gamma enhanced IL-10 (in patients only) and IL-5 and IL-13 in both patients and controls. Neutralization of IL-12 activated OvAg-specific production of IL-10, IL-2 and IFN-gamma. In conclusion, despite of an overproduction of IL-10, which suppressed cellular reactivity in patients and control individuals, OvAg-specific cellular responses were activated in vitro by exogenous supplementation with IL-12 and IL-13, and cytokine neutralization experiments confirmed that distinct type 1 and type 2 T helper cytokines cross-regulate expression and magnitude of O. volvulus-specific cellular responsiveness in humans.

Peripheral blood mononuclear cells (PBMC) from 8 onchocerciasis patients, treated or not with ivermectin, were analyzed for phenotypic cell surface markers. A significant increase (P < .05) in gamma/delta T cells expressing the V delta 1 chain compared with normal and endemic controls was detected in all patients. PBMC populations from onchocerciasis patients were not expanded after restimulation with Onchocerca volvulus antigens in vitro, but both V delta 1 and V delta 2 T cells from normal donors were increased significantly in response to O. volvulus and Mycobacterium tuberculosis (P < .05), respectively. Frozen sections of all 5 onchocerca nodules tested demonstrated an increased number of CD3+ cells in the vicinity of the adult worm, in all cases expressing the alpha/beta T cell receptor and in 2 patients also expressing the gamma/delta T cell receptor; 60% of T cells expressed the activation marker Ki67. These data suggest that O. volvulus provides ligands to V delta 1 T cells.

As part of an ivermectin dose-ranging study of onchocerciasis patients in Togo, 55 onchocerciasis patients with concomitant mansonelliasis received single oral doses either of ivermectin (100 to 200 micrograms/kg body weight) or placebo. As expected, Onchocerca volvulus microfilariae in the skin were greatly reduced in number soon after drug treatment, but microfilariae of Mansonella perstans reacted differently. Microfilarial densities of M. perstans were assessed with a filtration technique both before, and 4 times after, treatment. In untreated patients microfilarial densities were stable until the end of the study at 6 months. In patients receiving ivermectin, microfilarial densities dropped on average to less than 60% of the pre-treatment level and remained there until the final post-treatment examination. This partial reduction was probably not caused by a microfilaricidal effect of ivermectin, but rather by an altered distribution of microfilariae in the peripheral blood and in a suspected microfilarial reservoir.

Nine of 18 chimpanzees inoculated with 250 infective third-stage larvae (L3) each developed patent (i.e., positive for microfilariae) Onchocerca volvulus infection. Four of 6 infected chimpanzees that received 200 micrograms/kg ivermectin at 28 days postinfection (pi) became patent, whereas, when ivermectin was given concurrently with L3 challenge only 1 of 6 infected animals developed patent infection. The antibody response to O. volvulus adult worm-derived antigens (OvAg) showed clear differences between patent and nonpatent chimpanzees. Three months pi, all sera detected several OvAg in the range of M(r) 35-120 k. Sera collected 6 mo pi from later patent animals recognized increasing numbers of OvAg, especially in the lower MW range of M(r) 13 to 33 k. Beginning 10 months pi Onchocerca-antigens of M(r) 21, 24, 26, and 28 k were detected only by patent chimpanzee's sera. The antibody response in nonpatent chimpanzees consistently recognized fewer OvAg, most of which were limited to the higher M(r) range (35-120 k). The reactivity of sera from infected chimpanzees to a low molecular weight fraction (LMW) of total OvAg doubled within 6 months pi, and increased continuously in patent animals from 13 until 30 months pi. Serological reactivity of nonpatent animals to LMW-OvAg remained low. The titers of circulating IgG directed against total OvAg increased in all infected chimpanzees, and continued to rise with patency. In nonpatent chimpanzees the antibody production gradually returned to preinfection values. Total and OvAg-specific IgE increased in patent and nonpatent chimpanzees. Also, during prepatency the granulocyte and antibody-mediated in vitro killing of microfilariae of O. volvulus increased in subsequently patent chimpanzees. The in vitro immobilization of L3 remained low.