Intestinal pathology during acute toxoplasmosis is IL-4 dependent and unrelated to parasite burden

The role of interleukin-4 (IL-4) during the course of Toxoplasma gondii infection was studied using IL-4-/- mice and their wild-type (WT) counterparts on a C57BL/6 background. Following oral infection with T. gondii tissue cysts an exacerbative role for IL-4 was demonstrated and IL-4-/- mice were found to be more resistant to infection than WT mice as measured by significantly reduced mortality. Furthermore pathology in the small intestine was less severe in IL-4-/- mice although conversely liver pathology was greater than in wild-type mice. Significantly, plasma IL-12 and IFN-gamma levels, which peaked at days 6 and 8, respectively, were higher in IL-4-/- mice. The exacerbatory role of IL-4 in the intestine was found by competitive RT-PCR not to be associated with increased parasite burdens but was related to comparative expression of IL-10.     

Filaria/Wolbachia activation of dendritic cells and development of Th1-associated responses is dependent on Toll-like receptor 2 in a mouse model of ocular onchocerciasis (river blindness)

Toll-like receptors (TLRs) regulate dendritic cell function and activate signals that mediate the nature of the adaptive immune response. The current study examined the role of TLRs in dendritic cell activation and in regulating T cell and antibody responses to antigens from the filarial parasites Onchocerca volvulus and Brugia malayi, which cause river blindness and lymphatic filariasis, respectively. Bone-marrow-derived CD11c(+) cells from C57BL/6 and TLR4(-/-) mice produced high levels of IL-6 and RANTES, and showed elevated surface CD40 expression, whereas CD11c(+) cells from myeloid differentiation factor 88(-/-) (MyD88(-/-)), TLR2(-/-) and TLR2/4(-/-) mice were not activated. Similarly, IFN-gamma production by splenocytes from immunized TLR2(-/-) mice was significantly impaired compared with splenocytes from C57BL/6 and TLR4(-/-) mice. In contrast, there was no difference among these strains in Th2-associated responses including IL-5 production by splenocytes from immunized animals, serum IgE and IgG(1), or eosinophil infiltration into the corneal stroma. Neutrophil recruitment to the cornea and CXC chemokine production was inhibited in immunized TLR2(-/-) mice compared with C57BL/6 and TLR4(-/-) mice. Taken together, these findings demonstrate an essential role for TLR2 in filaria-induced dendritic cell activation, IFN-gamma production and neutrophil migration to the cornea, but does not affect filaria-induced Th2-associated responses.     

The in vivo role of stem cell factor (c-kit ligand) on mastocytosis and host protective immunity to the intestinal nematode Trichinella spiralis in mice

The role of stem cell factor (SCF) in the generation of intestinal mast cell hyperplasia and host protective immunity following helminth infection was investigated using the Trichinella spiralis/mouse model. In vivo administration of a monoclonal antibody specific for the receptor for SCF (c-kit) was found to completely prevent the generation of intestinal mastocytosis normally observed following T. spiralis infection. This was reflected by markedly reduced intestinal mast cell protease (IMCP) levels in both tissue and serum. Moreover, animals treated with anti-c-kit antibody failed to show any evidence of worm expulsion from the gut. The data demonstrate for the first time, a critical role for the SCF in the generation of mucosal mastocytosis and host protective immunity following an intestinal helminth infection.     

Contributions to the study of Trichinella spiralis TSL-1 antigens in host immunity

The observation on different hosts infected with Trichinella spiralis that recognized similar muscle larvae (ML) antigens and the fact that different monoclonal antibodies (mAb) had a similar reactivity to ML components prompted a proposal to define a useful classification system for these antigens. For this purpose, an international workshop provided a platform for the classification of T. spiralis antigens. ML antigens were classified in eight groups -- Trichinella spiralis larvae groups, TSL-1 to TSL-8. TSL-1 antigens are highly immunogenic and a number of important studies have been performed to analyse the role of these antigens in the host-parasite interplay. In this context, we have focused on the analysis of the role of TSL-1 antigens in the induction of innate immune responses with particular emphasis on the activation of mast cells (MC) by an IgE-independent pathway. These studies provided evidence on the role of mediator release from TSL-1-activated MC in the development of Type 2 immune responses. The protective role of TSL-1 in T. spiralis-infected mice has been described. In addition, it has been demonstrated that the use of TSL-1 antigens allows for a more sensitive and specific diagnosis of human and animal trichinellosis.     

Priming of the immune response by schistosome eggs

Schistosomiasis mansoni is a chronic disease caused by infection with helminths of the genus Schistosoma mansoni. Adult schistosomes live intravascularly, and for transmission of this infection it is necessary for parasite eggs to traverse the endothelium, and migrate to the intestinal lumen, from where they can exit the body to continue the lifecycle. This process is dependent on an intact host CD4 T helper (Th) cell response to egg antigens. Perhaps because of this, eggs have evolved to be highly immunogenic and capable of inducing potent Th responses. The egg-induced Th response is unusual in that it is highly Th2-polarized. The selective pressure on the host to mount a Th2 response against eggs is apparent in the fact that Th2 response-defective mice develop acutely lethal disease when infected with schistosomes. In this review I will focus on the underlying basis for the Th2 bias in the immune response to egg antigens.     

Trichinella spiralis antigens prime mixed Th1/Th2 response but do not induce de novo generation of Foxp3+ T cells in vitro

Many parasitic helminth infections induce Th2-type immune responses and engage the regulatory network. In this study, we specifically investigated the influence of antigens derived from different life stages of the helminth Trichinella spiralis on the polarization of naive CD4(+) T cells by dendritic cells. Results obtained from C57BL/6 mice showed that T. spiralis derived antigens have the capacity to induce bone marrow-derived dendritic cells to acquire an incompletely mature phenotype that promotes a significant proliferation of naive CD4(+) T cells and a mixed Th1/Th2 cytokine profile with the predominance of Th2 cytokines. Increased production of IL-4, IL-9, IL-10 and IL-13 accompanied increased IFN-γ. Furthermore, dendritic cells pulsed with T. spiralis antigens did not induce an increase in the population of Foxp3(+) T regulatory cells. Although other helminth antigens have demonstrated the capacity to induce de novo generation of Foxp3(+) T regulatory cells, here our in vitro studies provide no evidence that T. spiralis antigens have this capacity.     

Cellular immune responses of a Senegalese community recently exposed to Schistosoma mansoni: correlations of infection level with age and inflammatory cytokine production by soluble egg antigen-specific cells

A recently reported epidemic of Schistosoma mansoni infection in Senegal provided an opportunity to study the dynamics of the development of immunity to human schistosomiasis. We report here on the cell-mediated immune response in a population of 99 females and 95 males, with particular emphasis on the relationship between intensity of infection and age. We found that the intensity of infection correlated negatively with age in females but not in males. In men and women, both Th1- and Th2-type cytokines were detected upon in vitro stimulation of PBMCs with soluble egg antigen (SEA) or soluble adult worm antigens (SWAP). In the female group, SEA-induced PBMC proliferation was associated with the production of IFN-gamma, IL-2 and IL-5, all of which correlated negatively with intensity of infection. Most cytokine production correlated positively with age. Spontaneous production of TNF-alpha, IL-6 and IL-10 was higher in the infected population than in an uninfected control group. Our results suggest that immunity to infection could be more pronounced in the female population and associated with a Th0/1 + 2 pattern of cytokine secretion mediated by soluble egg antigen (SEA).     

The lack of suppressor of cytokine signalling-1 (SOCS1) protects mice from the development of cerebral malaria caused by Plasmodium berghei ANKA

Cerebral malaria is a severe complication of infection with Plasmodium berghei ANKA involving the Th1 cytokines TNF-alpha and IFN-gamma. Suppressor of cytokine signalling-1 (SOCS1) is an important component in the regulatory cascade controlling inflammatory responses and signalling through IFN-gamma. Contrary to the expectation that SOCS1-deficient mice, in which IFN-gamma responses are uncontrolled and which are more sensitive to IFN-gamma, may show heightened susceptibility, mice lacking SOCS1 were protected from cerebral malaria. Unlike the controls and despite similar parasitaemia, infected SOCS1 null mice showed no inflammation or haemorrhaging in the brains. Mice lacking SOCS1 exhibited decreased splenic cellularity and a reduced ratio of CD4 : CD8 lymphocytes, which were maintained during infection. However, the ratio of IFN-gamma to IL-4 mRNA expression during infection was similar in SOCS1 -/- and control mice suggesting that a dramatic shift in the ratio of Th1 : Th2 responses does not account for the resistance to disease. Resistance conferred by the lack of SOCS1 is specific since the related SOCS2, also implicated in Th1-mediated responses, did not seem to be involved in the development of disease. Understanding the mechanism by which SOCS1 deficiency protects mice from cerebral malaria may allow the manipulation of its activity and alleviate pathology.     

Ov-ASP-1, the Onchocerca volvulus homologue of the activation associated secreted protein family is immunostimulatory and can induce protective anti-larval immunity

Vaccination of mice with a recombinant protein, Ov-ASP-1, the Onchocerca volvulus homologue of the activation associated secreted gene family stimulated very high titres of both IgG1 and IgG2a without adjuvant. rOv-ASP-1 was also immuno-reactive with IgG isotypes from both O. volvulus-infected (INF) and putatively immune (PI) humans, with higher IgG4 in the former group. The protein also stimulated IFN-gamma secretion by PBMC from INF and PI and IL-5 only in INF. Using a mouse diffusion chamber model, vaccination with rOv-ASP-1 resulted in partial but significant protection against challenge with infective third-stage larvae (L3) but only when formulated with Freund's complete adjuvant (FCA) or alum. Protection was Th1-dependent (highly elevated IgG2a) with FCA and contingent on a strongly Th2-skewed (IgG1) response with alum. IgE responses to rOv-ASP-1 with or without adjuvant were weak or absent. When immunization using rOv-ASP-1 in adjuvant failed to induce adequate Th1 (FCA) or Th2 (alum) responses, protection efficacy was compromised. The recombinant protein appears to stimulate a mixed Th1/Th2 response but the outcome in terms of protective immunity is the result of a subtle interplay of its intrinsic and adjuvant-augmented properties. Ov-ASP-1 is potentially secreted based on its localization in the secretory granules of L3.     

SAAG-4 is a novel mosquito salivary protein that programmes host CD4+ T cells to express IL-4

Mosquitoes represent the most important vector for transmitting pathogens that cause human disease. Central to pathogen transmission is the ability to divert the host immune system away from Th1 and towards Th2 responsiveness. Identification of the mosquito factor(s) critical for programming Th2 responsiveness should therefore lead to strategies to neutralize their function and thus prevent disease transmission. In the current study, we used a TCR transgenic adoptive transfer system to screen gene products present in the saliva of the mosquito Aedes aegypti for their ability to programme CD4 T cells to express the signature Th2 cytokine IL-4. The clone SAAG-4 encodes a secreted protein with a predicted size of 20 kDa whose function has previously been uncharacterized. Notably, SAAG-4 reduced host CD4 T cell expression of the signature Th1 cytokine IFN-γ while simultaneously increasing expression of IL-4. SAAG-4 is therefore the first identified mosquito factor that can programme Th2 effector CD4 T cell differentiation.     

Functional correlations between mucosal mast cell activity and immunity to Trichinella spiralis in high and low responder mice

Levels of intestinal mast cell protease (IMCP) were quantified in serum, gut tissue and in intestinal fluids taken from mice infected with Trichinella spiralis during primary and secondary infections. The ability to generate a mast cell response was dependent on the response phenotype of the mouse strain used. The mast cell response in rapid responder mice (NIH) occurred sooner and was more pronounced than in either intermediate (SWR) and low responder (B1O) mice. This pattern was also reflected in the concentration of IMCP found in various tissues examined. The correlations between IMCP concentrations in blood, and worm expulsion, are discussed.     

Mechanisms of modulation of experimental autoimmune encephalomyelitis by chronic Trichinella spiralis infection in Dark Agouti rats

Trichinella spiralis is a helminth that provokes Th2 and anti‐inflammatory type responses in an infected host. Our previous studies using Dark Agouti (DA) rats indicated that T. spiralis infection reduced experimental autoimmune encephalomyelitis (EAE) severity in rats. The aim of this study was to analyse the mechanisms underlying EAE suppression driven by T. spiralis infection. Reduced clinical and histological manifestations of the disease were accompanied by increased IL‐4 and IL‐10 production and decreased IFN‐γ and IL‐17 production in draining lymph node cells. This indicates that T. spiralis infection successfully maintains a Th2 cytokine bias regardless of EAE induction. High IL‐10 signifies parasite‐induced anti‐inflammatory and/or regulatory cell responses. Transfer of splenic T cell‐enriched population of cells from T. spiralis‐infected rats into EAE immunized rats caused amelioration of EAE and in some cases protection from disease development. This population of cells contained higher proportion of CD4⁺ CD25⁺ Foxp3⁺ regulatory cells and produced high level of IL‐10 when compared with uninfected rats.     

Evaluation of T cell responses in healing and nonhealing leishmaniasis reveals differences in T helper cell polarization ex vivo and in vitro

Experimental leishmaniasis is widely used to study the effector functions of T helper cell subsets in vivo . Healing and nonhealing Leishmania major infections have been correlated with T helper 1 and T helper 2 responses, respectively. In the present study, we determined T cell effector functions ex vivo , without any further restimulation and compared them to those obtained following antigen-specific restimulation in vitro . Our results show that T helper cell responses are significantly less polarized when determined ex vivo as compared to those measured after restimulation in vitro . Moreover, the differences in CD4⁺ T cell proliferation observed between healer and nonhealer strains of mice differed ex vivo and in vitro . Our results suggest that determination of both ex vivo as well as in vitro T cell responses is crucial to characterize immune responses during experimental leishmaniasis.     

CTL responses to Leishmania mexicana gp63-cDNA vaccine in a murine model

Immunity to Leishmania is believed to be strongly dependent upon the activation of Th1 immune responses, although the exact role of cytotoxic T lymphocytes (CTLs) has not yet been determined. The aims of this study were to establish a suitable cytotoxicity assay to measure CTL activity and to compare immunity induced by Leishmania mexicana gp63 cDNA via i.m. injection and gene gun immunization in the BALB/c mouse model. The CTL activity was evaluated by short-term ⁵¹Cr-release cytotoxicity assays against CT26 tumour cells transfected with L. mexicana gp63 cDNA and dendritic cells (DCs) loaded with soluble Leishmania antigen (SLA) as targets. The results clearly demonstrated that higher protection to L. mexicana infection was induced by gene gun DNA-immunization vs. i.m. injection. Cytotoxic T lymphocyte activity of splenocytes was observed in mice immunized either with L. mexicana gp63 cDNA or SLA and long-lived CTL activity was observed in immunized and/or re-challenged mice but not naïve mice infected with the parasite.     

Contribution of IL-33-activated type II innate lymphoid cells to pulmonary eosinophilia in intestinal nematode-infected mice

When animals are infected with helminthic parasites, resistant hosts show type II helper T immune responses to expel worms. Recently, natural helper (NH) cells or nuocytes, newly identified type II innate lymphoid cells, are shown to express ST2 (IL-33 receptor) and produce IL-5 and IL-13 when stimulated with IL-33. Here we show the relevant roles of endogenous IL-33 for Strongyloides venezuelensis infection-induced lung eosinophilic inflammation by using Il33(-/-) mice. Alveolar epithelial type II cells (ATII) express IL-33 in their nucleus. Infection with S. venezuelensis or intranasal administration of chitin increases in the number of ATII cells and the level of IL-33. S. venezuelensis infection induces pulmonary accumulation of NH cells, which, after being stimulated with IL-33, proliferate and produce IL-5 and IL-13. Furthermore, S. venezuelensis infected Rag2(-/-) mice increase the number of ATII cells, NH cells, and eosinophils and the expression of IL-33 in their lungs. Finally, IL-33-stimulated NH cells induce lung eosinophilic inflammation and might aid to expel infected worms in the lungs.     

树突状细胞及其在呼吸道炎症中的作用

树突状细胞是免疫应答的始动者,具有很强的异质性。体内有各种树突状细胞亚群发挥不尽相同的作用。树突状细胞在肺内呈网络状分布。在诱导肺部Th1／Th2免疫反应中以及诱导肺部免疫耐受中起着重要作用。     

树突细胞在旋毛虫感染免疫中作用的研究进展

旋毛虫病是一种常见的人兽共患寄生虫病,也是一种重要的食源性寄生虫病,严重危害着人体的健康.树突状细胞是固有性免疫细胞的一种,也是宿主肠道黏膜免疫系统最重要的一种抗原呈递细胞,与宿主肠道免疫系统关系密切.近年来有关树突状细胞在寄生虫感染与宿主免疫应答中的作用,尤其在旋毛虫感染与免疫的作用,备受人们的关注.该文就目前国内有关旋毛虫感染后,宿主树突状细胞参与肠黏膜的一系列免疫应答反应和发挥作用的研究进展做一综述.     

Limit dilution analysis of mast cell precursor frequency in the gut epithelium of normal and Trichinella spiralis infected mice

Previous studies have established that the gut nematode Trichinella spiralis induces a dramatic thymus dependent intestinal mastocytosis which peaks within 6 to 12 days after primary oral infection. It is not known, however, if the increase in gut mast cells results from the influx of mast cells or their precursors, or from the expansion and differentiation of mast cell precursors (MCP) that are normally present in the small intestinal epithelium. In the present study, the number of mucosal MCP in the intraepithelial lymphocyte (IEL) population and in bone marrow (BM) cells from normal and 4 day T. spiralis infected mice was compared by culturing the cells at limiting dilutions in medium containing interleukin-3 (IL-3). While the MCP frequency in IEL from infected mice was found to be significantly increased in comparison with that found in normal mice, the numbers of MCP in BM from the two groups were equivalent. Resident intraepithelial mucosal MCP therefore undergo a local expansion before the occurrence of an overt T dependent intestinal mastocytosis. This finding lends support to the view that local mucosal T cells are involved in regulating mast cell numbers in response to intestinal helminth infection.     

The role of macrophages in protective and pathological responses to Toxoplasma gondii

The ability of Toxoplasma gondii to cause clinical disease in immune-competent and immune-deficient hosts coupled with its ease of use in vitro and availability of murine models has led to its use as a model organism to study how the immune system controls an intracellular infection. This article reviews the studies that established the role of the cytokine IFN-γ in the activation of macrophages to control T gondii and the events that lead to the mobilization and expansion of macrophage populations and their ability to limit parasite replication. Macrophages also have pro-inflammatory functions that promote protective NK and T-cell activities as well as regulatory properties that facilitate the resolution of inflammation. Nevertheless, while macrophages are important in determining the outcome of infection, T gondii has evolved mechanisms to subvert macrophage activation and can utilize their migratory activities to promote dissemination and these two properties underlie the ability of this parasite to persist and cause disease.     

影响支气管哮喘Th1/Th2失衡的因素及治疗的新视点

支气管哮喘(简称哮喘)是由嗜酸粒细胞、肥大细胞和T细胞等多种炎性细胞参与的气道慢性炎症性疾病,其发病机制极为复杂,近来研究发现Th1/Th2失衡是哮喘免疫学发病机制中的一个重要环节,本文就Th1/Th2失衡与哮喘的关系,Th1/Th2平衡的调节及其在哮喘治疗中的价值作一综述.