Modulation of granulomatous hypersensitivity. I. Characterization of T lymphocytes involved in the adoptive suppression of granuloma formation in Schistosoma mansoni-infected mice.

The cellular basis of the spontaneous modulation of the granulomatous response to schistosome eggs was analyzed in mice infected with Schistosoma mansoni. Spleen cells of 20 or 32 week-infected mice undergoing modulation, when transferred to 6 week-infected recipients, suppressed the maximal granulomatous response at 8 weeks. Suppression of both naturally forming asynchronous liver and synchronously induced lung lesions was achieved. Specificity of this effect was demonstrated by the suppression of egg granulomas but not antigen-coated bead granulomas developing simultaneously in the lungs of cell recipients. Further characterization showed that suppression was abrogated by pretreating transferred cells with either anti-Thy 1.2 or anti-Iak alloantisera and C. Transfer of macrophage-depleted or fractionated T and B spleen cells confirmed that T cells alone transferred suppression. Moreover, an Ia antigen-bearing (Ia+) subpopulation of T cells was required in the transferred suppression. Moreover, an Ia antigen-bearing (Ia+) subpopulation of T cells was required in the transferred population. An examination of T cells obtained from isolated, dispersed lung granulomas from control and adoptively suppressed mice revealed an increased proportion of Ia+ cells in the latter. It is suggested that Ia+ T cells may be involved in the local modulation of the granulomatous response.     

Modulation of granulomatous inflammation in murine schistosomiasis mansoni by enteric exposure to schistosome ova: in vitro characterization of a regulatory mechanism within the granuloma

Enteric immunization with schistosome ova results in a diminished granulomatous response. This study explored a mechanism by which enteric immunization may decrease granuloma size. Granulomas from livers of acutely infected mice were dissociated and the dispersed cells were depleted of macrophages. As defined by a direct in vitro migration inhibition factor (MIF) assay, the macrophage-depleted cells, composed of lymphocytes and eosinophils, inhibited the migration of normal peritoneal exudate cells when exposed to soluble egg antigens. Anti-Thy 1.2 or -Lyt 1.1, but not -Lyt 2.1, treatment of these cells abrogated MIF activity. Next, mice were exposed enterically to eggs 4 weeks prior to sacrifice. Cells from granulomas isolated from these animals demonstrated no MIF activity unless treated with anti-Lyt 2.1. When granuloma cells from enterically immunized mice were mixed with those from unimmunized animals, MIF activity by the latter was abrogated. Treatment of cells from immunized mice with anti-Lyt 2.1 or -Thy 1.2, but not -Lyt 1.1 prior to mixing once again permitted MIF activity. These results suggest that the diminished granulomatous response induced by enteric immunization could be mediated by Lyt 2+ suppressor T cells. These suppressor cells may regulate the MIF activity of Lyt 1+ T lymphocytes residing within these lesions.     

Hymenolepis nana: passive transfer of mouse immunity by T-cell subset of phenotype Lyt-1

Mesenteric lymph node cells obtained from donor mice (BALB/c strain) actively immunized by oral inoculation with Hymenolepis nana eggs were syngeneically transferred by intravenous injection into athymic nude mice previously uninfected. The adoptively immunized recipients were then challenged with 1000 H. nana eggs 2 days after cell transfer. The degree of immunity transferred was assessed by examining cysticercoids developed in the intestinal villi of the recipients on Day 4 of challenge infection. The criterion for success in cell transfer of immunity was the complete rejection of cysticercoids as was generally expected in mice infected previously. The transfer of 1.5 X 10(8) immune mesenteric lymph node cells obtained from donors immunized 4 days before cell collection resulted invariably in the complete rejection of cysticercoids, though not less than this cell dosage. The immunity was passively transferable to recipients by T cells, especially by T-cell subset of phenotype Lyt-1 but not those of phenotype Lyt-2.3 and Lyt-1.2.3. However, 1.5 X 10(8) immune mesenteric lymph node cells obtained from donors immunized 21 days before cell transfer and 1.5 X 10(8) immune spleen cells obtained from donors immunized 4 days before cell transfer had little or no effect on the rejection of cysticercoids.     

Nippostrongylus brasiliensis: intestinal goblet-cell response in adoptively immunized rats.

Goblet-cell differentiation was studied in the intestinal epithelium of rats infected with the nematode Nippostrongylus brasiliensis. An increase in the proportion of goblet cells occurred at the time of worm expulsion in rats infected with 1000 or 4000 third stage larvae. Adoptive immunization of infected rats with immune-thoracic duct lymphocytes (TDL) induced extensive goblet-cell differentiation whereas the transfer of immune-TDL into normal rats had no effect. The extent of goblet-cell differentiation in adoptively immunized infected rats was proportional to the number of cells transferred. A goblet-cell response also occurred in adoptively immunized rats harboring implanted “normal” and “damaged” worms but recipients of normal worms which were not given cells were unable either to expel their worm burden or to induce a goblet-cell response. Experiments in which the parasites were expelled with an anthelmintic drug suggested that the goblet-cell increase was not simply a repair process associated with the expulsion of the parasites. In all situations where immune expulsion of the parasites occurred, there was a concomitant rise in the proportion of goblet cells. These experiments suggest that thoracic duct lymphocytes either directly or indirectly regulate the differentiation of intestinal goblet cells.     

Vasoactive intestinal peptide and substance P-like immunoreactivities in the enteric nervous system of the pig correlate with the severity of pathological changes induced by Schistosoma japonicum

Limited studies have shown that in intestinal schistosomosis, the enteric nervous tissue becomes inflamed, disrupted and destroyed by granulomas and peptides, amines and neurofilaments contents are altered. Therefore, immunoreactivities of vasoactive intestinal peptide and substance P were correlated to pathological lesions in the large intestine from pigs infected with Schistosoma japonicum. Ganglia situated within or near granulomas showed ganglionitis, and necrosis of neurons as well as infiltration by eosinophils, mast cells, lymphocytes, plasma cells, neutrophils and macrophages. The inner submucous and mucous plexuses were the most damaged. In all categories of inflamed areas, the vasoactive intestinal peptide-like immunoreactive was reduced in all plexuses whereas, that of substance P was increased both in the enteric nerve plexuses and enterochromaffin cells in lightly, moderately and severely inflamed tissues. However, both peptides were highly diminished or absent in very severe lesions and areas surrounding schistosome eggs and mature worms laying eggs in the submucosal veins. The alterations of the levels of vasoactive intestinal peptide and substance P were correlated with severity of inflammation. Our observations show alterations of vasoactive intestinal peptide and substance P contents in the local microenvironment in the vasoactive intestinal peptide- and substance P-mediated reflex pathways which regulate intestinal motility, epithelial transport and modulate immunity. These changes could cause alterations in bowel motility, electrolyte and fluid secretion, vascular and immune functions during S. japonicum infections in the pig. This may, therefore, partly play a role in the pathobiology of migration and egress of schistosome eggs as well as influence trapping of eggs in granulomas, and account for diarrhoea, loss of body weight and failure to thrive, which are recorded in schistosomosis.     

Adoptive suppression of granuloma formation by T lymphocytes and by lymphoid cells sensitive to cyclophosphamide.

Egg-induced granulomas formed in mice with chronic Schistosoma mansoni infection are smaller than those which develop during early (8-week) infection. Adoptive transfer of spleen cells from chronically infected mice (15–25 week), which displayed modulated granulomas, to 6-week-infected recipients effectively suppressed active granuloma formation in the recipients by 8 weeks after infection. Pretreatment of these suppressive spleen cells with anti-Thy 1.2 serum and complement eliminated their suppressive capacity. Administration of cyclophosphamide (CY) (20 mg/kg, 3 times/week for 3 weeks) to 12- to 15-week-infected mice reversed modulation of granuloma formation resulting in larger granulomas at 15 weeks. This abrogation of suppression was reflected in the spleens of the CY-treated mice, as seen by the inability of their spleen cells to adoptively transfer suppression to 6-week-infected mice. This regimen of CY treatment did not significantly alter anti-schistosome egg antigen hemagglutinating antibody titers. It is reasoned that the modulation of granuloma formation observed during chronic schistosomiasis mansoni is in part dependent upon a T lymphocyte and a CY-sensitive spleen cell.     

Pathogenesis of pipe-stem fibrosis of the liver (experimental observation on murine schistosomiasis)

Mice infected with 30 cercariae of Schistosoma mansoni developed portal and septal fibrosis due to the massive and concentrated deposition of eggs in the periportal areas which occurred following the 16th week after infection. The lesion resembled pipe-stem fibrosis seen in human hepatosplenic schistosomiasis in the following characters: portal fibrosis interconnecting portal spaces as well as portal spaces and central canals; portal inflammation; periovular granulomas; vascular obstruction and telangiectasia. The liver parenchyma maintained its normal architecture. Vascular injection techniques with Indian ink and vinylite revealed that the portal system developed numerous dilated collateral venules coming from the large and medium-sized portal branches, about 10 weeks after schistosome infection. The lodging of schistosome eggs into these collaterals resulted in granulomatous inflammation and fibrosis along all the portal tracts, thus forming the pipe-stem lesion. Although not readily demonstrable grossly, the pipe-stem fibrosis of murine schistosomiasis has many similarities with the human lesion and can be considered to have the same basic pathogenesis.     

Glycans of Schistosoma mansoni and keyhole limpet haemocyanin induce hepatic granulomas in vivo

Schistosoma mansoni eggs trapped in the liver of an infected host cause the major pathological manifestations of schistosomiasis. Miracidia within the deposited eggs secrete soluble egg antigens (SEA) that induce periovular granuloma formation, which may lead to severe hepatic fibrosis. Several reports have highlighted the immunomodulatory capacities of carbohydrate determinants present in the glycoproteins of SEA. These glycans contain among others the immunogenic Galbeta1-4(Fucalpha1-3)GlcNAc (LewisX) and GalNAcbeta1-4(Fucalpha1-2Fucalpha1-3)GlcNAc (LDN-DF) elements. Due to cross-reactivity with schistosomal glycan antigens, keyhole limpet haemocyanin (KLH) has been used extensively for diagnostic and therapeutic studies on schistosomiasis. In the present study, a granulomatous response with numerous eosinophils towards SEA- and KLH-coated beads implanted in the liver by mesenteric injection was observed. Immunophenotyping of these experimentally induced granulomas for cellular recruitment, chemokines, adhesion and extracellular matrix proteins revealed very close resemblance with hepatic lesions evoked by native schistosome eggs, hence demonstrating the usefulness of the bead model, in general, as well as of KLH as a model antigen to study the immunopathological mechanisms of schistosome infections. While trypsin digestion of KLH did not alter its antigenic characteristics, beads coated with SEA or KLH treated with sodium periodate to destroy the immunological properties of their carbohydrate chains, yielded only a monolayer of macrophages similar to negative control beads. Up-regulation of ICAM-1, LFA-1 and fibronectin in SEA-induced granulomas and in native and trypsinised KLH-induced granulomas indicates a major role of the carbohydrate elements of SEA and KLH in the initiation and homeostasis of the inflammatory response. These data provide new insights in the complex and multifactorial carbohydrate-dependent host-parasite immunological interactions.     

Leaky livers, portal shunting and immunity to schistosomes

In mice, concomitant immunity to schistosomes seems to be largely dependent on factors that lack immunological specificity. In this review Alan Wilson describes the anatomical changes stimulated in the host's vasculature after the formation of granulomas around schistosome eggs in the liver. The blockage of portal venules by the granulomas leads to portal hypertension and the development of anastomoses that direct blood flow, schistosomula and eggs from the liver. An intact portal vasculature is required for schistosome maturation; some strains of mice appear to be resistant to schistosome infection because they have a predisposition to form anastomoses in the absence of infection.     

Changes in the virulence of Mycobacterium avium after passage through embryonated hens' eggs

Eight-day-old embryonated hen's eggs were used as a model to study Mycobacterium avium virulence. Strains isolated from human patients caused 20-90% mortality when eggs were infected by injection of bacterial suspensions into the amniotic sac. Virulence of examined strains subsequently decreased with passage through eggs to between 0 and 40% mortality in four passages. Virulence of the egg-attenuated strains could be restored by passage through human peripheral blood mononuclear cells. The site of infection in the egg was usually the mesodermal layer of the chorioallantoic membrane. A few small granulomas containing acid-fast bacteria were seen in the liver, but not in other organs. Death of chicken embryos may have resulted from destruction of the mesodermal layer of the chorioallantoic membrane with consequent respiratory failure. PBMCs infected with less virulent egg-passaged strains of M. avium produced higher levels of tumor necrosis factor-alpha than did peripheral blood mononuclear cells infected with more virulent nonpassaged strains.     

Prophylactic immunization against experimental leishmaniasis. III. Protection against fatal Leishmania tropica infection induced by irradiated promastigotes involves Lyt-1+2- T cells that do not mediate cutaneous DTH

Protective immunity against fatal L. tropica infection in genetically vulnerable BALB/c mice can be induced by prophylactic immunization with irradiated promastigotes even when heat-killed. Such immunity is adoptively transferable transiently into intact or durably into sub-lethally irradiated (200 or 550 rad) syngeneic recipients by splenic T but not B cells. The effector T cells are of the Lyt-1+2- phenotype, devoid of demonstrable cytotoxic activity. The immune splenic T cell population expresses specific helper activity for antibody synthesis. A causal role for helper T cells in this capacity, however, seems unlikely, because it was shown in the accompanying paper that antibody does not determine the protective immunity against L. tropica. The immunized donors show no detectable cutaneous DTH or its early memory recall in response to live or killed promastigotes or a soluble L. tropica antigen preparation. Spleen, lymph node, and peritoneal exudate cells from protectively immunized donors similarly fail to transfer DTH locally or systemically. These cells also lack demonstrable suppressive activity against the expression or induction of DTH to L. tropica. Thus, protection against L. tropica induced by prophylactic i.v. immunization with irradiated promastigotes appears to be conferred by Lyt-1+2- T cells that are distinguishable from T cells mediating either both DTH and T help, or cytotoxicity.     

Prophylactic immunization against experimental leishmaniasis. V. Mechanism of the anti-protective blocking effect induced by subcutaneous immunization against Leishmania major infection

The responsiveness of BALB/c mice to protective i.v. immunization with 150,000-rad irradiated or heat-killed Leishmania major promastigotes can be totally suppressed by prior subcutaneous (s.c.) injection of the same "vaccine." Induction of this effect is leishmania specific for although prevention of protection against L. major infection can be obtained with either homologous or Leishmania donovani promastigotes, it does not follow s.c. administration of an immunogenic Trypanosoma cruzi epimastigote preparation. Multiple s.c. injections of irradiated L. major promastigotes do not inhibit the subsequent antibody response of any major isotype to i.v. immunization, but rather induce some priming. The same s.c. injections induced delayed-type hypersensitivity (DTH) reactivity that could be transferred locally or systemically, although it was weaker than in mice with cured infections. Parallel cell-mediated immunity (CMI) responses were also reflected in vitro in specific lymphocyte transformation assays. Despite this evidence of a DTH/helper type of T cell response, transfer of 5 X 10(7) viable T cell-enriched spleen cells from 4 X s.c. immunized donors to normal recipients completely abrogated the protective response to i.v. immunization. Conversely, T cell-depleted (anti-Thy-1.2 + C treated) cells were without effect. The inhibitory T cells were defined by monoclonal antibody pretreatment as possessing an Lyt-1+2-,L3T4+ phenotype. T cells from s.c. immunized donors were also shown, by mixed transfer experiments, to counteract completely the protective effect of T cells from i.v. immunized donors in 550-rad irradiated recipients. They were as potent as suppressor T cells from donors with progressive disease both in this capacity and in abrogating the prophylactic effect of sublethal irradiation itself. The similarities and differences between suppressor and immune effector T cells induced by s.c. or i.v. immunization and those arising in response to leishmanial infection itself are discussed.     

Apoptosis by neglect of CD4+ Th cells in granulomas: a novel effector mechanism involved in the control of egg-induced immunopathology in murine schistosomiasis

In infection with Schistosoma mansoni, parasite eggs precipitate an intrahepatic granulomatous and fibrosing inflammation that is mediated by CD4(+) Th cells. Compared with CBA mice, C57BL/6 mice develop smaller granulomas composed of cells that exhibit reduced proliferative responses to schistosome egg Ags. In the present study, we investigated CD4(+) T cell apoptosis as a possible mechanism that could account for this subdued response. We found throughout the course of several infection weeks a markedly higher proportion of apoptotic CD4(+) T cells in granulomas from C57BL/6 mice than in those from CBA mice ex vivo; the apoptosis further increased upon cell cultivation in vitro. Activation-induced cell death or CD8(+) T cells failed to account for the enhanced apoptosis as infected Fas-, Fas ligand,- and CD8-deficient mice exhibited similar apoptosis to that seen in wild-type counterparts. However, a strikingly lower IL-2 production by schistosome egg Ag-stimulated C57BL/6 granuloma and mesenteric lymph node cells suggested the possibility of apoptosis due to growth factor deprivation. Indeed, the CD4(+) T cell apoptosis was significantly reversed by addition of rIL-2 in vitro, or by injection of rIL-2 in vivo, which also resulted in significant exacerbation of granulomatous inflammation. These findings indicate that apoptosis by neglect can represent a significant means of controlling CD4(+) T cells that mediate the immunopathology in schistosomiasis.     

Infection with a helminth parasite prevents experimental colitis via a macrophage-mediated mechanism

The propensity of a range of parasitic helminths to stimulate a Th2 or regulatory cell-biased response has been proposed to reduce the severity of experimental inflammatory bowel disease. We examined whether infection with Schistosoma mansoni, a trematode parasite, altered the susceptibility of mice to colitis induced by dextran sodium sulfate (DSS). Mice infected with schistosome worms were refractory to DSS-induced colitis. Egg-laying schistosome infections or injection of eggs did not render mice resistant to colitis induced by DSS. Schistosome worm infections prevent colitis by a novel mechanism dependent on macrophages, and not by simple modulation of Th2 responses, or via induction of regulatory CD4+ or CD25+ cells, IL-10, or TGF-beta. Infected mice had marked infiltration of macrophages (F4/80+CD11b+CD11c(-)) into the colon lamina propria and protection from DSS-induced colitis was shown to be macrophage dependent. Resistance from colitis was not due to alternatively activated macrophages. Transfer of colon lamina propria F4/80+ macrophages isolated from worm-infected mice induced significant protection from colitis in recipient mice treated with DSS. Therefore, we propose a new mechanism whereby a parasitic worm suppresses DSS-induced colitis via a novel colon-infiltrating macrophage population.     

Egg deposition is the major stimulus for the production of Th2 cytokines in murine schistosomiasis mansoni.

To characterize Th cell populations induced by helminth infection, spleen cells from mice infected with Schistosoma mansoni were stimulated with parasite (worm or egg Ag) or mitogen (Con A) and the supernatants assayed for the Th1-specific cytokines IFN-gamma and IL-2 and the Th2-specific cytokines IL-4 and IL-5. Th2 cytokine production was not detected in substantial quantity until the 6 to 8th wk of infection and after reaching peak levels at 8 to 12 wk declined slowly thereafter. The time courses of IL-4 and IL-5 production, whereas differing from each other, closely resembled corresponding published data on IgE and peripheral blood eosinophil levels during murine schistosome infection. In contrast, Th1 cytokine responses occurred only during the first 6 wk of infection and were virtually absent during the peak period of Th2 production. To assess the role of egg deposition in the observed pattern of Th response, cytokine production was assayed in mice carrying unisexual schistosome infections in which parasite eggs are absent. Splenocytes from these animals displayed only marginal Th2 cytokine synthesis but greater Th1 cytokine responses than the corresponding cells from mice with bisexual infections. Moreover, cultures of liver tissue or isolated granulomas from infected mice constitutively produced high levels of IL-4 and IL-5 but failed to synthesize significant amounts of IL-2 and IFN-gamma even when stimulated with egg Ag or mitogen. Taken together the data indicate that egg deposition is the major stimulus of Th2 cytokine response in S. mansoni-infected mice and suggest that T cells belonging to this subset must play a major role in egg granuloma formation.     

Schistosoma mansoni: immunization of cynomolgus monkeys by injection of irradiated schistosomula.

Although the immunization of primates with irradiated schistosome cercariae has been demonstrated, no success has been reported by injection with the irradiated schistosomule stage. The present investigation was designed to test whether cynomolgus monkeys could be protectively immunized with ⁶⁰Co-irradiated Schistosoma mansoni schistosomula. Monkeys injected once with 10⁴ irradiated schistosomula (50 krad at 4 krad/min) had 52% fewer challenge worms than the control group at necropsy. Four immunizations did not induce a higher level of resistance. At 50 days post-challenge, the immunized monkeys excreted 80% fewer eggs than did the control animals. An attempt to enhance irradiated schistosomule-induced protection with tetramisole · HCl was unsuccessful.     

Induction of delayed-type hypersensitivity and antitumor immunity by systemic BCG

Both delayed-type hypersensitivity (DTH) and antitumor resistance induced in mice by intravenous (i.v.) and local injection of highly immunogenic irradiated Meth A cells were potentiated by prior systemic BCG infection. DTH and antitumor immunity were not elicited by i.v. injection of poorly immunogenic irradiated mastocytoma cells, P 815 (MA), but were induced by the local injection of these cells when animals were systemically infected with BCG. The level of the potentiated response corresponded with the dose of immunogen up to an optimum, beyond which additional immunogen was suppressive. At all dose levels the subcutaneous (s.c.) route of immunogen inoculation was more effective than the i.v. route. Significant DTH was first detected 7 days after the local administration of immunogen and was correlated with antitumor immunity. Systemically administered BCG grew mainly in the liver and spleen until the development of maximal tuberculin sensitivity when the number of organisms decreased. However, the small number of mycobacteria that reached the peripheral lymph nodes remained constant after maximal tuberculin sensitivity but failed to augment the cell proliferation that occurred in these lymph nodes as a result of the local inoculation of irradiated tumor cells. Autoradiographs of such nodes revealed proliferation in the thymus-dependent areas whereas nodes from mice immunized with immunogen alone manifested B- as well as T-cell activity. Local immunization in both BCG-infected and uninfected hosts was also associated with a proliferative response in the red pulp of the spleen but the BCG-infected hosts differed conspicuously by virtue of the presence of tubercles and depletion of lymphoid cells from the periarteriolar sheath. Immunity generated by the local administration of immunogen in systemically infected mice was tumor specific and could be adoptively transferred with spleen cells.     

IL-23 is required for the development of severe egg-induced immunopathology in schistosomiasis and for lesional expression of IL-17

In infection with the trematode helminth Schistosoma mansoni, the severity of CD4 T cell-mediated hepatic granulomatous and fibrosing inflammation against parasite eggs varies considerably in humans and among mouse strains. In mice, either the natural high pathology, or high pathology induced by concomitant immunization with schistosome egg Ags (SEA) in CFA (SEA/CFA), results from a failure to contain a net proinflammatory cytokine environment. We previously demonstrated that the induction of severe immunopathology was dependent on the IL-12/IL-23 common p40 subunit, and correlated with an increase in IL-17, thus implying IL-23 in the pathogenesis. We now show that mice lacking the IL-23-specific subunit p19 are impaired in developing severe immunopathology following immunization with SEA/CFA, which is associated with a marked drop of IL-17 in the granulomas, but not in the draining mesenteric lymph nodes, and with a markedly suppressed SEA-specific IFN-gamma response regulated by a striking increase in IL-10. The granulomas are characterized by a significant reduction in Gr-1(+) cell recruitment and by alternative macrophage activation. Taken together, these results demonstrate that IL-23 per se is not necessary for the generation of IL-17-producing T cells, but is essential for the development of severe schistosome egg-induced immunopathology, and its absence cannot be overcome with other possible compensatory mechanisms.     

Alterations of the intestinal innervation in mice infected with Schistosoma mansoni.

Schistosomiasis mansoni is a parasitic disease in which granulomas form around schistosome eggs in the liver and intestines. The purpose of this study was to determine the alterations in the intrinsic innervation of the distal ileum and proximal colon resulting from schistosomiasis. Using murine schistosomiasis mansoni, we examined light microscopic preparations stained with osmium-zinc iodide or the dihydronicotinamide adenine dinucleotide: nitro BT oxidoreductase (NADH) method. We also examined specific populations of peptidergic nerves (vasoactive intestinal polypeptide and substance P) using an avidin-biotin complex (ABC) immunohistochemical technique. We found that granulomas focally destroyed the enteric nerves. Occasionally nerves were found within granulomas, particularly at the periphery of the lesions. Nerve cell bodies close to granulomas had altered staining, which included increased staining for vasoactive intestinal polypeptide. The distribution of nerve injury varied between the 2 enteric segments studied. In the distal ileum, the principal injury was to the myenteric plexus; whereas, the submucous and mucosal plexuses were predominantly damaged in the proximal colon. The physiologic significance of this injury to the enteric nerves requires elucidation.     

Schistosome eggs stimulate reactive oxygen species production to enhance M2 macrophage differentiation and promote hepatic pathology in schistosomiasis

Schistosomiasis is a neglected tropical disease of public health concern. The most devastating pathology in schistosomiasis japonica and mansoni is mainly attributed to the egg-induced granulomatous response and secondary fibrosis in host liver, which may lead to portal hypertension or even death of the host. Schistosome eggs induce M2 macrophages-rich granulomas and these M2 macrophages play critical roles in the maintenance of granuloma and subsequent fibrosis. Reactive oxygen species (ROS), which are highly produced by stimulated macrophages during infection and necessary for the differentiation of M2 macrophages, are massively distributed around deposited eggs in the liver. However, whether ROS are induced by schistosome eggs to subsequently promote M2 macrophage differentiation, and the possible underlying mechanisms as well, remain to be clarified during S. japonicum infection. Herein, we observed that extensive expression of ROS in the liver of S. japonicum-infected mice. Injection of ROS inhibitor in infected mice resulted in reduced hepatic granulomatous responses and fibrosis. Further investigations revealed that inhibition of ROS production in S. japonicum-infected mice reduces the differentiation of M2, accompanied by increased M1 macrophage differentiation. Finally, we proved that S. japonicum egg antigens (SEA) induce a high level of ROS production via both nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2) and mitochondria in macrophages. Our study may help to better understand the mechanism of schistosomiasis japonica-induced hepatic pathology and contribute to the development of potential therapeutic strategies by interfering with ROS production.