Infection outcome and cytokine gene expression in Brugia pahangi- infected gerbils (Meriones unguiculatus) sensitized with Brucella abortus.
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Filarial infections have been associated with the development of a strongly polarized Th2 host immune response and a severe impairment of mitogen-driven proliferation and type 1 cytokine production in mice and humans. The role of this polarization in the development of the broad spectra of clinical manifestations of lymphatic filariasis is still unknown. Recently, data gathered from humans as well as from immunocompromised mouse models suggest that filariasis elicits a complex host immune response involving both Th1 and Th2 components. However, responses of a similar nature have not been reported in immunologically intact permissive models of Brugia infection. Brucella abortus-killed S19 was inoculated into the Brugia-permissive gerbil host to induce gamma interferon (IFN-gamma) production. Gerbils were then infected with B. pahangi, and the effect of the polarized Th1 responses on worm establishment and host cellular response was measured. Animals infected with both B. abortus and B. pahangi showed increased IFN-gamma and interleukin-10 (IL-10) and decreased IL-4 and IL-5 mRNA levels compared with those in animals infected with B. pahangi alone. These data suggest that the prior sensitization with B. abortus may induce a down regulation of the Th2 response associated with Brugia infection. This reduced Th2 response was associated with a reduced eosinophilia and an increased neutrophilia in the peritoneal exudate cells. The changes in cytokine and cellular environment did not inhibit the establishment of B. pahangi intraperitoneally. The data presented here suggest a complex relationship between the host immune response and parasite establishment and survival that cannot be simply ascribed to the Th1/Th2 paradigm. (+info)
Nitric oxide limits the expansion of antigen-specific T cells in mice infected with the microfilariae of Brugia pahangi.
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Infection of BALB/c mice with the microfilariae (Mf) of the filarial nematode Brugia pahangi results in an antigen-specific proliferative defect that is induced by high levels of NO. Using carboxyfluorescein diacetate succinimydl ester and cell surface labeling, it was possible to identify a population of antigen-specific T cells from Mf-infected BALB/c mice that expressed particularly high levels of CD4 (CD4(hi)). These cells proliferated in culture only when inducible NO synthase was inhibited and accounted for almost all of the antigen-specific proliferative response under those conditions. CD4(hi) cells also expressed high levels of CD44, consistent with their status as activated T cells. A similar population of CD4(hi) cells was observed in cultures from Mf-infected gamma interferon receptor knockout (IFN-gammaR(-/-)) mice. Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling staining revealed that the CD4(+) T cells from Mf-infected wild-type mice were preferentially susceptible to apoptosis compared to CD4(+) T cells from IFN-gammaR(-/-) mice. These studies suggest that the expansion of antigen-specific T cells in Mf-infected mice is limited by NO. (+info)
Primed peritoneal B lymphocytes are sufficient to transfer protection against Brugia pahangi infection in mice.
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Lymphatic filariasis is a tropical disease caused by the nematode parasites Wuchereria bancrofti and Brugia malayi. Whereas the protective potential of T lymphocytes in filarial infection is well documented, investigation of the role of B lymphocytes in antifilarial immunity has been neglected. In this communication, we examine the role of B lymphocytes in antifilarial immunity, using Brugia pahangi infections in the murine peritoneal cavity as a model. We find that B lymphocytes are required for clearance of primary and challenge infections with B. pahangi third-stage larvae (L3). We assessed the protective potential of peritoneal B lymphocytes by adoptive transfer experiments. Primed but not naive peritoneal B cells from wild-type mice that had been immunized with B. pahangi L3 protected athymic recipients from challenge infection. We evaluated possible mechanisms by which B cells mediate protection. Comparisons of cytokine mRNA expression between B-lymphocyte-deficient and immunocompetent mice following B. pahangi infection suggest that B cells are required for the early production of Th2-type cytokines by peritoneal cells. In addition, B-cell-deficient mice demonstrate a defect in inflammatory cell recruitment to the peritoneal cavity following B. pahangi infection. The data demonstrate a critical role of B lymphocytes in antifilarial immunity in naive mice and in the memory response in primed mice. (+info)
Kinetics of cellular responses to intraperitoneal Brugia pahangi infections in normal and immunodeficient mice.
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Filarial infections evoke exuberant inflammatory responses in the peritoneal cavities of immunocompetent mice. Clearance of infection appears to be dependent on complex interactions between B1 and B2 B lymphocytes, T cells, eosinophils, macrophages, and the products of these cells. In an earlier communication, we described the course of infection in normal immunocompetent mice. In this study, we utilize mice with well-characterized mutations that disable one or more effector components of adaptive immunity in order to determine their roles in host protection. We characterize peritoneal exudate cells by flow cytometry and determine the kinetics of accumulation of each of the different cell types following infection with Brugia pahangi. We find that (i) four-color flow-cytometric analysis of peritoneal exudate cells using anti-CD3, -CD11b, -CD19, and -Gr1 can distinguish up to six different populations of cells; (ii) an initial influx of neutrophils occurs within 24 h of infection, independent of the adaptive immune status of mice, and these cells disappear by day 3; (iii) an early influx of eosinophils is seen at the site of infection in all strains studied, but a larger, second wave occurs only in mice with T cells; (iv) the presence of T cells and eosinophils is important in causing an increase in macrophage size during the course of infection; and (v) most unexpectedly, T-cell recruitment appears to be optimal only if B cells are present, since JHD mice recruit significantly fewer T cells to the site of infection. (+info)
Removal of Wolbachia from Brugia pahangi is closely linked to worm death and fecundity but does not result in altered lymphatic lesion formation in Mongolian gerbils (Meriones unguiculatus).
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Approximately 30 years ago, researchers reported intracellular bacteria in filarial nematodes. These bacteria are relatives of the arthropod symbiont Wolbachia and occur in many filarial nematodes, including Brugia pahangi and Brugia malayi. Wolbachia bacteria have been implicated in a variety of roles, including filaria development and fecundity and the pathogenesis of lymphatic lesions associated with filarial infections. However, the role of the bacteria in worm biology or filarial disease is still not clear. The present experiments support previous data showing that tetracycline eliminates or reduces Wolbachia bacteria in B. pahangi in vivo. The elimination of Wolbachia was closely linked to a reduction in female fecundity and the viability of both sexes, suggesting that the killing of Wolbachia is detrimental to B. pahangi. The gerbils treated with tetracycline showed reduced levels of interleukin-4 (IL-4) and IL-5 mRNA in renal lymph nodes and spleens compared with the levels in B. pahangi-infected gerbils not treated with tetracycline. However, similar findings were noted in B. pahangi-infected gerbils treated with ivermectin, suggesting that the loss of circulating microfilariae, not the reduction of Wolbachia bacteria, was associated with the altered cytokine profile. Despite the change in T-cell cytokines, there was no difference in the sizes of renal lymph nodes isolated from gerbils in each treatment group. Furthermore, the numbers, sizes, or cellular compositions of granulomas examined in the lymphatics or renal lymph nodes did not differ with treatment. These data suggest that Wolbachia may not play a primary role in the formation of lymphatic lesions in gerbils chronically infected with B. pahangi. (+info)
B cells play a regulatory role in mice infected with the L3 of Brugia pahangi.
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Mice infected with the L3 of the filarial nematode Brugia pahangi make a strong T(h)2 response characterized by elevated levels of antigen-specific IL-4, IL-5 and IL-10. Here we show that B cells from these animals are the major proliferating population in vitro with depletion of B cells or infection of muMT mice, resulting in reduced levels of antigen-specific proliferation. B cells also act as antigen-presenting cells (APC) to CD4(+) cells as demonstrated by the switch in cytokine profiles upon B cell depletion. The efficiency of B cells in antigen presentation is attenuated by IL-10 which down-regulates the expression of B7-1 and B7-2 on the surface of B cells both in vitro and in vivo. Thus, IL-10 may modulate CD4 responses in L3-infected mice by suppressing the expression of B7 ligands on B cells. In support of this hypothesis, blockade of the IL-10R in vivo results in increased proliferation of CD4(+) cells. We propose that B cells participate in a negative feedback loop: IL-10 elicited by infection with L3 and produced by B cells (and CD4(+) cells) down-regulates the expression of B7 molecules on the B cell surface, attenuating their efficiency as APC to CD4(+) T cells and restricting their expansion. (+info)
Regulatory T cells modulate Th2 responses induced by Brugia pahangi third-stage larvae.
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Infection of BALB/c mice with Brugia pahangi third-stage larvae (L3) results in the production of interleukin-4 (IL-4), IL-5, and IL-10 with a resultant down-regulation in Th1 responses. Previously, this was thought to reflect a skewing of immune responses towards a Th2 phenotype by the infective stage of the parasite. In this study, we show that exposure to the L3 of Brugia also induces the expansion of a population of CD4 cells that express CD25 and cytotoxic-T-lymphocyte-associated antigen 4 in an IL-4-independent fashion. By quantitative reverse transcription-PCR, we show that the CD25+ population is highly enriched in mRNA for the Foxp3 transcription factor and that these cells express significantly more IL-10 mRNA than the CD25- population, suggesting a likely regulatory phenotype. The functional capacity of these cells was demonstrated using a neutralizing CD25 monoclonal antibody (MAb). Mice treated with this MAb demonstrated elevated levels of antigen (Ag)-specific proliferation in vitro, and levels of Ag-specific Th2 cytokines were significantly increased. These results suggest a complex network of regulation in L3-infected mice with Th2 cells limiting the Th1 response, while T-regulatory cells modulate Th2 responses. (+info)
Critical role for IgM in host protection in experimental filarial infection.
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We have previously shown that B cells (in particular B1 cells) are important in host protection against brugian infections in a murine i.p. model. In this study, we show that mice deficient in circulating IgM (secIgM-/-), but otherwise normal in their humoral responses, manifest a significant impairment in worm elimination, suggesting that one critical B cell function is the production of Ag-specific IgM. Efficient elimination of larvae is IgM dependent for both primary and challenge infections. The ability to eliminate worms is restored in secIgM-/- mice by administering sera from primed mice. We corroborated these in vivo studies with in vitro observations which show that IgM is the only isotype that reacts strongly with the surface of Brugia L3. Furthermore, activated peritoneal exudate cells adhere to L3 only in the presence of filaria-specific sera or IgM purified from them. This attachment is not reduced by heat inactivation of the serum, suggesting complement independent activity. Peritoneal exudate cells from primed mice, especially activated macrophages, carry high levels of IgM on their surfaces. Our observations suggest that an IgM-mediated reaction initiates the formation of host-protective granulomas. (+info)