Chronic Schistosoma Mansoni Infection Research Articles

Interleukin-5 (IL-5) Augments the Progression of Liver Fibrosis by Regulating IL-13 Activity

Eosinophils are frequently found in increased numbers in a variety of chronic fibrotic diseases; however, their role in the development of hepatic fibrosis has not been dissected in vivo. Here, we used interleukin-5 (IL-5) knockout (KO) mice to determine whether eosinophils contribute to the progressive liver fibrosis that develops in response to chronic Schistosoma mansoni infection. Although infection intensities were similar in C57BL/6 and IL-5 KO mice, the average size of granulomas was significantly smaller in both acutely and chronically infected IL-5 KO mice. Their granulomas were also completely devoid of eosinophils. In addition, the knockout mice displayed over a 40% reduction in hepatic fibrosis by week 16 postinfection. The reduced fibrosis was associated with increased production of the antifibrotic cytokine gamma interferon. Moreover, although IL-13 production did not decrease consistently in the absence of IL-5, IL-13-triggered responses were substantially reduced in the granulomatous tissues. This was confirmed by analyzing the expression of several genes associated with alternative macrophage activation, including arginase 1, Fizz-1, and YM-1. Importantly, all of these IL-13-regulated genes have been linked with the mechanisms of wound healing and fibrosis. In addition to IL-5 polarizing the antigen-specific CD4+ Th2 cell response, we found that granuloma eosinophils were themselves a significant source of IL-13. Thus, by producing profibrotic mediators and polarizing the Th2 response, these findings illustrate both direct and indirect roles for eosinophils and IL-5 in the pathogenesis of schistosomiasis-induced liver fibrosis. Thus, inhibiting the activity of IL-5 or eosinophils may prove effective for a variety of chronic fibrotic diseases.

SCHISTOSOMAL COLONIC POLYPOSIS

A 24 year old male who recently moved to the United States from Yemen presented complaining of change in bowel habits, fatigue and hematochezia. He denied any associated melena, weight loss, nausea, vomiting or abdominal pain. The patient denied any family history of cancer. The patient's laboratory values were significant for WBC of 4.4 Thous/mc L with an absolute eosinophil count of 691 Cells/mc L. The patient's basic metabolic panel and liver function tests were normal. Physical exam was only significant forheme positive brown stool. Colonoscopy was performed and revealed two large pedunculated polyps in the distal descending colon measuring 4 centimeters each. One polyp was removed successfully by snare cautery. The second polyp was removed partially by snare cautery with the intention to repeat the colonoscopy for completion of the polypectomy after the pathology results returned. Several random biopsies were obtained in the terminal ileum, cecum, ascending colon, transverse colon, descending colon and rectum. Microscopic examination of the random biopsies revealed intestinal colonic schistosomiasis with moderate chronic inflammation. The two descending colon polyps were diagnosed as inflammatory pseudopolyps due to extensive intestinal schistosomiasis. There was heavy egg burden noted in the mucosal vascular spaces associated with the presence of several adult worms in the submucosal vessels. The patient was started on praziquantel and noted clinical improvement. One month later, the patient presented for a follow-up colonoscopy which revealed complete resolution of the partially resected descending colon polyp. In addition, there was evidence of colitis in the rectum, rectosigmoid and descending colon which was biopsied. The biopsies revealed nonspecific chronic inflammation with occasional ova (mostly parasitic shells) of Schistosoma. There was no evidence of parasites in the terminal ileumorascending colon. Schistosomal colonic polyposis is a common complication of chronic Schistosoma mansoni infection in endemic areas, but it is rarely encountered in the United States. Colonoscopy typically shows primary involvement of the distal colon and polyps can be pedunculated or sessile, few or numerous. Our case demonstrates that colonoscopic polypectomy is safe and effective and may be required in combination with medical therapy for complete symptom relief and prevention of complications.

Clinical and immunological consequences of human T cell leukemia virus type-I and Schistosoma mansoni co-infection.

Human T cell leukemia virus type-I (HTLV-I) infection is associated with spontaneous T cell activation and uncontrolled lymphocyte proliferation. An exacerbated type-1 immune response with production of pro-inflammatory cytokines (interferon-gamma and tumor necrosis factor-alpha) is significantly higher in patients with myelopathy associated to HTLV-I than in HTLV-I asymptomatic carriers. In contrast with HTLV-I, a chronic Schistosoma mansoni infection is associated with a type-2 immune response with high levels of interleukin (IL-4, IL-5, and IL-10) and low levels of IFN-gamma. In this study, clinical and immunological consequences of the HTLV-I and S. mansoni infection were evaluated. The immune response in patients with schistosomiasis co-infected with HTLV-I showed low levels of IL-5 (p < 0.05) in peripheral blood mononuclear cells cultures stimulated with S. mansoni antigen (SWAP) and decreased SWAP-specific IgE levels when compared with patients with only schistosomiasis (p < 0.05). Liver fibrosis was mild in all HTLV-I co-infected patients. Immunological response was also compared in individuals who had only HTLV-I infection with those who were co-infected with HTLV-I and helminths (S. mansoni and Strongyloides stercoralis). In patients HTLV-I positive co-infected with helminths the IFN-gamma levels were lower than in individuals who had only HTLV-I. Moreover, there were fewer cells expressing IFN-gamma and more cells expressing IL-10 in individuals co-infected with HTLV-I and helminths. These dates indicate that HTLV-I infection decrease type 2-response and IgE synthesis and are inversely associated with the development of liver fibrosis. Moreover, helminths may protect HTLV-I infected patients to produce large quantities of pro-inflammatory cytokines such as IFN-gamma.

Schistosomiasis protects against multiple sclerosis.

The incidences of schistosomiasis and multiple sclerosis (MS) are mutually exclusive worldwide suggesting that schistosomiasis may offer protection against the induction of the immune-mediated disease, MS. Recent studies using the mouse model of MS, experimental autoimmune encephalomyelitis, support a direct suppression of the onset of MS by chronic Schistosoma mansoni infection. Self-reactive Th1 but not Th2 responses develop in infected mice immunized with myelin oligodendrocyte glycoprotein albeit at reduced levels indicating that the induction of auto-reactive T cells is not abolished nor phenotypically altered. CNS infiltration by inflammatory cells, particularly macrophages, is significantly reduced in S. mansoni-infected, immunized mice compared to uninfected, immunized mice. Because activated macrophages are crucial to the induction of clinical disease, these findings support the hypothesis that differences in macrophage activation may contribute to the reduced incidence and delayed progression of experimental autoimmune encephalomyelitis during schistosomiasis.

Schistosoma mansoni infection modulates the immune response against allergic and auto-immune diseases.

Chronic Schistosoma mansoni infection leads to a type 2-immune response with increased production of interleukin (IL-10). Evidence indicates chronic exposure to S. mansoni down regulates the type 1 immune response and prevents the onset of Th1-mediated diseases such as multiple sclerosis, diabetes mellitus and Crohn's disease. Furthermore, our own studies have revealed that chronic exposure to S. mansoni also down regulates atopic disease, Th2-mediated diseases. Our studies show an inverse association between the skin prick test reactivity and infection with S. mansoni and show the severity of asthma is reduced in subjects living in an endemic area of S. mansoni. Moreover, we hypothesize the mechanisms involved in the modulation of inflammatory response in atopic individuals, is likely dependent on IL-10 production, an anti-inflammatory cytokine elevated during helminth infections. Patients with asthma and helminth infections produced less IL-5 than patients with asthma without helminth infections, and this down regulation could, in part, be mediated by IL-10. In conclusion, helminthic infections, through induction of regulatory mechanisms, such as IL-10 production, are able to modulate the inflammatory immune response involved in the pathology of auto-immune and allergic disease.

Fibrose périportale chez les enfants en zone d’endémie à Schistosoma mansoni : évaluation échographique

Purpose To assess with ultrasound periportal fibrosis due to chronic Schistosoma mansoni infection in children living in an endemic region. Materials and methods A total of 441 children underwent two stool examinations and abdominal sonography. Liver echotexture was assessed by two observers and compared to pre-defined image patterns and a fibrosis score was assigned ranging from 0 to 8. Ultrasound features were correlated to age, sex, and parasitologic findings. Results Prevalence of Schistosoma mansoni infestation was 63%. Two cases of advanced fibrosis (E pattern or fibrosis score of 6) were observed. Fibrosis correlated with age. No correlation existed between fibrosis and intensity of egg-output. A correlation between the two examinors was noted in 84% of examinations with a kappa coefficient of 0.7. Conclusion Although severe periportal fibrosis is a rare finding in this endemic region, follow-up sonography must be performed because it is the only non invasive and reliable tool for detection of periportal fibrosis.

Dexamethasone treatment improves morphological and hematological parameters in chronic experimental schistosomiasis.

Schistosomiasis, a chronic disease with considerable social impact, is an important health problem in many countries. To investigate the possible use of immunomodulators as coadjuvants in the treatment of chronic Schistosoma mansoni infection, we evaluated the effect of dexamethasone on histological, hematological, and biochemical parameters that reflect disease severity and morbidity. Animals treated from the first day or after 35 days of infection, were analyzed. In both groups, dexamethasone: (1) induced a decrease in the number of granulomas in hepatic tissue without affecting the alanine aminotransferase profile, (2) reduced splenomegaly and hepatomegaly associated with disease, and (3) improved hemoglobin concentration, hematocrit values and reduced the percentage of reticulocytes, preventing the development of anemia that occurs in the chronic phase of infection. These data suggest that treatment with dexamethasone results in a mild course of murine schistosomiasis and point to this drug as a promising agent to complement S. mansoni specific treatment.

Antibody subclass profile and avidity during acute and chronic human Schistosoma mansoni infection

The avidity of IgA, IgM, IgG and IgG subclass antibodies against Schistosoma mansoni soluble egg antigen (SEA) was determined by ELISA in serum samples collected in 1995 from individuals in Brazil with acute ( n = 36) and chronic ( n = 40) schistosomiasis. Fifteen individuals at the acute phase were also evaluated 6 months after clinical diagnosis. Predominance of low-avidity IgG, IgG1, IgG2, IgG3 and IgA characterized the acute phase. IgG4 was detected in only 2 individuals with acute disease (5·6%). Levels of anti-SEA IgM were similar between the study groups. IgG1 avidity showed the strongest association with the chronological evolution of the infection, presenting 100% of low avidity during the acute infection and reaching 100% of high avidity 6 months after. It is suggested that distinct anti- Schistosoma egg antigens subclass profile and antibody avidity characterize the clinical phases of S. mansoni infection. In particular, determination of anti-SEA IgG1 offers a new tool for the laboratory analysis of the disease.

Differential Vbeta T-cell receptor usage during chronic experimental schistosomiasis corresponds with distinct pathological presentations.

CBA/J male mice with chronic Schistosoma mansoni infections display either moderate splenomegaly syndrome (MSS) or hypersplenomegaly syndrome (HSS). As MSS and HSS mice differ in several immunologic characteristics, we investigated T-cell receptor Vbeta usage. The groups had significantly different expression of several Vbetas, suggesting a relationship between the T-cell repertoire and schistosomiasis pathology.

Ultrasonography of the liver and spleen in Brazilian patients with hepatosplenic schistosomiasis and cirrhosis

Ultrasonography is now widely used in the diagnosis and management of patients with chronic Schistosoma mansoni infections. The present study was undertaken to evaluate the use of ultrasonography in patients with hepatosplenic schistosomiasis (HSS) with and without cirrhosis. Ninety-seven patients (52 males; median age 38 years, range 19–68 years) with HSS, 65 with well compensated (HSSC) and 32 with decompensated (HSSD) disease and cirrhosis, were systematically examined by ultrasound. Hepatic fibrosis was graded according to WHO recommendations. Typical atrophy of the right hepatic lobe accompanied by hypertrophy of the left lobe, with a rounded inferior marginal edge, was seen in 86 (88·7%) patients. Periportal fibrosis was observed in 83 (85·6%) cases and confirmed histologically in all. In 66 patients (68·0%) thickening of the gallbladder wall, associated with periportal fibrosis and extending from the branches of the porta hepatis, was noted. No evidence of biliary disease was found in these patients and gallstones were present in only 3 cases. Fourteen (43·8%) of the HSSD patients could not be classified for grade of fibrosis because of the advanced stage of cirrhosis related to hepatitis B or C viral infection. Of the remaining 18 HSSD patients, none had only grade I fibrosis (vs. 10·8% of HSSC, P = 0·054) and only 6 had grade II (vs. 67·7% of HSSC, P < 0·0005), while the frequency of grade III was significantly higher in the HSSD patients than in those with HSSC (37·5% vs. 21·5%, P = 0·049). These findings indicate that although ultrasonography is a very valid technique for assessing patients with pure HSS, and should be considered the ‘gold standard’, it is not reliable for assessing periportal fibrosis in patients with concomitant cirrhosis due to other causes.

Role of the spleen on the pathogenesis of schistosomal periportal (pipestem) fibrosis of the liver: an experimental approach.

Splenectomized and sham-operated mice with chronic Schistosoma mansoni infection were compared for the development of periportal fibrosis (pipestem fibrosis). Although this lesion appeared less frequently in splenectomized mice, it also developed in the absence of the spleen. The time of splenectomy, spleen weight, presence of anti-idiotypic antibodies, the number of eggs in the liver, and the type and size of periovular granulomas in the liver as evaluated by computerized morphometry did not show statistically significant differences between the two groups. It is concluded that the role of the spleen in the development of pipestem fibrosis seems ancillary and that multifactorial influences, including worm burden, hepatic vascular adjustment, and factors associated with the biology of extracellular matrix of the liver, probably play a more significant role.

Specific liver autoreactivity in schistosomiasis mansoni

To investigate the possible involvement of autoimmune mechanisms in the development of hepatosplenic schistosomiasis (HSS), 234 patients with chronic Schistosoma mansoni infections were screened for a wide range of non-organ-specific autoantibodies as well as for antibodies reacting with the GOR peptide and with a liver-specific autoantigen, the hepatic asialoglycoprotein receptor (ASGP-R). Thirty-five (15·0%) were seropositive for antinuclear, smooth muscle or gastric parietal cell antibodies at low titres (≤1:80), and 15 176 (8·5%) had anti-GOR, all of whom had concomitant hepatitis C viral (HCV) infections. Anti-ASGP-R was found in 64 (27·4%) of the 234 patients at titres similar to those found in 18 untreated auto-immune hepatitis patients studied concurrently. Anti-ASGP-R seropositivity occurred significantly ( P < 0·005) more frequently in patients with HSS ( 62 190 , 32·6%) than in those with hepatointestinal schistosomiasis ( 2 44 , 4·5%), but did not correlate with severity of liver disease or with the presence of the non-organ-specific autoantibodies. Anti-ASGP-R was found significantly ( P ⪡ 0·0005) less frequently in HSS patients who had had a splenectomy for portal hypertension ( 5 86 , 5·8%) than in those who had not had a splenectomy ( 57 104 , 54·8%). The findings suggest that liver-specific autoreactivity may play a role in the development of HSS.

Immunoregulatory idiotypes stimulate T helper 1 cytokine responses in experimental Schistosoma mansoni infections.

Inbred male CBA/J mice with chronic Schistosoma mansoni infections develop two distinct syndromes. Hypersplenomegaly syndrome (HSS) demonstrates pathologic similarities to the hepatosplenic form of chronic human schistosomiasis, and moderate splenomegaly syndrome (MSS) resembles the asymptomatic intestinal form. Immunoaffinity-purified Abs against S. mansoni soluble egg Ags (SEA) from infected patients' sera differ idiotypically according to the donor's clinical form of the disease. We now show that immunoaffinity-purified anti-SEA Abs (Id) from MSS or HSS mice parallel idiotypic preparations of the analogous human clinical form by their differential ability to stimulate the proliferation of anti-Id T cells. MSS Id preparations stimulate spleen cells from either MSS or HSS animals. In contrast, HSS Id does not stimulate spleen cells from either group. In an anti-SEA ELISA, MSS and HSS Id preparations contained comparable levels of IgM and IgG1. However, the MSS Id preparation had higher levels of SEA-specific IgG2a and IgG2b than did HSS Id. The Ig isotypes of these Id preparations suggested differences in cytokine expression patterns. Studies of the cytokine profiles of the spleen cells responding to anti-SEA Id preparations demonstrated that while Id preparations from acutely infected mice stimulate IL-4 and IL-10 production, Id preparations from chronic MSS mice stimulate IFN-gamma production. HSS Id did not stimulate the production of any of these cytokines. The possibility that distinct immunoregulatory environments may contribute to the development of MSS and HSS correlates with earlier hypotheses that hepatosplenic pathology results at least in part from a lack of development or expression of appropriate regulatory Ids.

Schistosoma mansoni:Relationship of Tumor Necrosis Factor-α to Morbidity and Collagen Deposition in Chronic Experimental Infection

Adewusi, O. I., Nix, N. A., Lu, X., Colley, D. G., and Secor, W. E. 1996.Schistosoma mansoni:Relationship of tumor necrosis factor-α to morbidity and collagen deposition in chronic experimental infection.Experimental Parasitology84,115–123. Chronic (20-week)Schistosoma mansoniinfections in male CBA/J mice present as one of two pathophysiologic forms: severe hypersplenomegaly syndrome (HSS) or a less severe, moderate splenomegaly syndrome (MSS). HSS mice are cachectic (including anemia and hypertriglyceridemia) and exhibit high levels of periportal and perioval fibrosis. Because tumor necrosis factor-α (TNF-α) is associated with the symptoms of cachexia, we measured TNF-α protein and mRNA levels in the livers of infected and uninfected animals. TNF-α levels in liver homogenates from mice with acute infections (8-week) were high (mean ± SEM; 41.0 ± 1.6 ng/g tissue) and remained high in livers of HSS mice (41.8 ± 3.0 ng/g tissue) while TNF-α levels in liver homogenates of MSS mice were significantly lower (27.9 ± 2.0 ng/g tissue). Similarly, hepatic TNF-α mRNA levels from HSS mice were two- to threefold higher than those from MSS mice. Hydroxyproline levels in these animals were determined as a measure of collagen deposition and fibrosis and showed increased overall levels in the livers of HSS animals. To investigate the progression of HSS development, hematocrit and serum triglyceride levels were followed over a 20-week period after infection. In mice that developed HSS, hematocrit levels decreased significantly and progressively from Weeks 10 through 20. These same animals showed significant increases in serum triglycerides compared to 8-week-infected mice or the mice which developed MSS over the same time period. These results suggest that failure to downregulate hepatic production of TNF-α correlates with, and may contribute to, the development of liver fibrosis and HSS in experimental schistosomiasis.

Hepatocellular carcinoma associated with chronic Schistosoma mansoni infection in a chimpanzee

Hepatocellular carcinoma associated with chronic Schistosoma mansoni infection in a chimpanzee, estimated to be a 12-year-old and born in West Africa, is reported. The hepatic tumor appeared as a solitary firm nodule, and histological examination revealed well-differentiated hepatocellular carcinoma with a trabecular pattern. Hepatitis B virus and hepatitis C virus infections were excluded by serological testing in that animal. This is the first report of hepatocellular carcinoma in the chimpanzee with schistosomiasis.

Efficacy of hepatitis B vaccination in primary school children from a village endemic for Schistosoma mansoni.

To determine whether chronic Schistosoma mansoni infection interferes with hepatitis B virus (HBV) immunization, 308 schoolchildren aged 6-12 years with no evidence of prior HBV infection (156 with active schistosomiasis) were vaccinated with three 5-micrograms injections of recombinant DNA-derived HBV vaccine. The vaccine was given in the deltoid muscle at time 0 and 1 and 7 months later. All vaccinees were examined 1 and 3 years after vaccination for quantitative antibody to hepatitis B surface antigen (anti-HBs). Seroconversion was detected in 284 vaccinated children (92%), of whom 271 had a good (51-300 mIU/mL) or excellent (greater than 300 mIU/mL) anti-HBs response. Sixteen other children (5%) had evidence of natural HBV infection (antibody to hepatitis B core antigen). Of those with good or excellent response, 99% retained high antibody titers for 3 years. Response was not influenced by S. mansoni infection. Hepatomegaly and splenomegaly were associated with reduced vaccine response.

Alternative patterns of MHC-restricted antibody responsiveness following intraperitoneal immunization of inbred mice with different preparations of an 86 kilodalton antigen of Schistosoma mansoni.

The investigation of MHC restricted antibody responses to an 86 kDa antigen (p86) during chronic Schistosoma mansoni infection has been extended to immunization with this antigen. In the absence of adjuvant, a similar pattern of responsiveness by mice expressing H-2k and H-2d but not H-2b was observed following immunization with unpurified adult worm homogenate. Adjuvant selectively abrogated the capacity of H-2d mice to respond and this was also the case when purified p86 with adjuvant was injected. Immunization with purified subfragments of p86 again demonstrated MHC restriction in the capacity to immunoprecipitate p86 in vitro translation product, the pattern varying according to the fragment used. Western blot analysis showed that in some, but not all instances of apparent 'non-responsiveness' characterized by immunoprecipitation, antibody specificities capable of recognizing p86 epitopes on the nitrocellulose bound p86 were, indeed, present. Thus the fine specificity as well as the absolute capacity to respond is influenced by both the MHC haplotype of the host and the nature of the immunizing antigen.

Regulation of Antigen-Induced Blastogenesis and Interleukin-2 Expression by Adherent Mononuclear Cells in Humans Infected with Schistosoma mansoni

The immune response and its regulation by adherent mononuclear cells were investigated in 39 Egyptians aged 13-30 (mean +/- SD, 16.2 +/- 3.6) with chronic Schistosoma mansoni infection (fecal egg excretion, 40-2480 eggs/g; mean, 709 +/- 612). Blastogenesis and production of interleukin-2 (IL-2) by peripheral blood mononuclear cells showed a significant correlation when streptolysin O but not when soluble worm antigenic preparation (SWAP) was used as stimulus. This suggested independent regulation of these responses to SWAP. Thirteen subjects showed SWAP-restricted suppression of blastogenesis but not IL-2 production by adherent cells. Compared with 24 other S. mansoni-infected subjects, they had depressed blastogenic responses to SWAP but comparable SWAP-induced IL-2 production and responsiveness to exogenous IL-2. This study indicates that IL-2 production is not the site of action of parasite antigen-restricted suppressor adherent cells in chronic S. mansoni infection.

Fractionated Sera from Schistosoma Mansoni Infected Patients Confers Passive Protection in Mice

Sera from humans with chronic Schistosoma mansoni infections (CHS) were chromatographed with CNBr-activated Sepharose 4 B conjugated with NP-40 extracts obtained from live 3 hr schistosomula. Both unbound (CHSUB) and bound (CHSB) fractions which contained IgG and IgM isotypes were characterized by ELISA, immunofluorescence, and complement-mediated in vitro killing assays. ELISA data showed that the CHSB fraction recognized schistosomula NP-40 extracts, whereas the CHSUB fraction did not. However, both CHSUB and CHSB fractions recognized 8 M urea adult worm extracts and 8 M urea egg extracts. By indirect immunofluorescence assay, the CHSB fraction recognized epitopes on the surface of live schistosomula 3 hr-29 days of age, whereas the CHSUB fraction showed surface fluorescence only on 24- and 29-day-old worms. The CHSB fraction mediated 95% killing of schistosomula in a complement dependent in vitro assay, the CHSUB fraction and the unfractionated CHS did not exhibit killing ability. The CHSUB fraction was able to titrate out the killing ability of the CHSB fraction in in vitro cytotoxic assays when mixed with the CHSB fraction at increasing concentrations. In passive immunization experiments, the CHSB fraction provided approximately 30% passive protection in mice when injected 1 day or 6 days after challenge and 20% protection when injected at 15 days, but failed to provide protection when administered greater than or equal to 24 days after challenge. Unfractionated CHS failed to mediate passive protection.

Schistosomiasis: Role of endogenous opioids in suppression of gonadal steroid secretion

1. 1. Radioimmunoassay of the opiate, β-endorphin, in mouse sera, indirect measurement of estrogen by examination of vaginal smears and indirect measurement of androgens by electrophoresis of major urinary proteins (MUP) revealed that β-endorphin increases while estrogen and androgen levels decrease in mice with chronic Schistosoma mansoni infection. 2. 2. Injections of the opiate antagonist, naltrexone, reversed the effects of schistosomiasis on estrogen and androgen levels. 3. 3. Because opiates are known to inhibit the secretion of releasing hormones by the hypothalamus, the data suggest that the inhibition of hypothalamic-pituitary-gonadal function that occurs in chronically infected male and female mice results from excessive β-endorphin. 4. 4. It is also suggested that the excessive β-endorphin may be secreted by T-lymphocytes and possibly macrophages involved in the cell-mediated immune response (CMIR) to the ova.