Hepatic Granulomas Research Articles

Conundrums in leishmaniasis

Parasites of the genus Leishmania cause the disease leishmaniasis. As the sandfly vector transfers the promastigotes into the skin of the human host, the infection is either cured or exacerbated. In the process, there emerge several unsolved paradoxes of leishmaniasis. Chronologically, as the infections starts in skin, the role of the salivary proteins in supporting the infection or the host response to these proteins influencing the induction of immunological memory becomes a conundrum. As the parasite invokes inflammation, the infiltrating neutrophils may act as “Trojan Horse” to transfer parasites to macrophages that, along with dendritic cells, carry the parasite to lymphoid organs to start visceralization. As the visceralized infection becomes chronic, the acutely enhanced monocytopoiesis takes a downturn while neutropenia and thrombocytopenia ensue with concomitant rise in splenic colony-forming-units. These responses are accompanied by splenic and hepatic granulomas, polyclonal activation of B cells and deviation of T cell responses. The granuloma formation is both a containment process and a form of immunopathogenesis. The heterogeneity in neutrophils and macrophages contribute to both cure and progression of the disease. The differentiation of T-helper subsets presents another paradox of visceral leishmaniasis, as the counteractive T cell subsets influence the curing or non-curing outcome. Once the parasites are killed by chemotherapy, in some patients the cured visceral disease recurs as a cutaneous manifestation post-kala azar dermal leishmaniasis (PKDL). As no experimental model exists, the natural history of PKDL remains almost a black box at the end of the visceral disease.

Single oral fixed-dose praziquantel-miltefosine nanocombination for effective control of experimental schistosomiasis mansoni

BackgroundThe control of schistosomiasis has been centered to date on a single drug, praziquantel, with shortcomings including treatment failure, reinfection, and emergence of drug resistance. Drug repurposing, combination therapy or nanotechnology were explored to improve antischistosomal treatment. The aim of the present study was to utilize a novel combination of the three strategies to improve the therapeutic profile of praziquantel. This was based on a fixed-dose nanocombination of praziquantel and miltefosine, an antischistosomal repurposing candidate, co-loaded at reduced doses into lipid nanocapsules, for single dose oral therapy.MethodsTwo nanocombinations were prepared to provide 250 mg praziquantel-20 mg miltefosine/kg (higher fixed-dose) or 125 mg praziquantel-10 mg miltefosine/kg (lower fixed-dose), respectively. Their antischistosomal efficacy in comparison with a non-treated control and their praziquantel or miltefosine singly loaded counterparts was assessed in murine schistosomiasis mansoni. A single oral dose of either formulation was administered on the initial day of infection, and on days 21 and 42 post-infection. Scanning electron microscopic, parasitological, and histopathological studies were used for assessment. Preclinical data were subjected to analysis of variance and Tukeyʼs post-hoc test for pairwise comparisons.ResultsLipid nanocapsules (~ 58 nm) showed high entrapment efficiency of both drugs (> 97%). Compared to singly loaded praziquantel-lipid nanocapsules, the higher nanocombination dose showed a significant increase in antischistosomal efficacy in terms of statistically significant decrease in mean worm burden, particularly against invasive and juvenile worms, and amelioration of hepatic granulomas (P ≤ 0.05). In addition, scanning electron microscopy examination showed extensive dorsal tegumental damage with noticeable deposition of nanostructures.ConclusionsThe therapeutic profile of praziquantel could be improved by a novel multiple approach integrating drug repurposing, combination therapy and nanotechnology. Multistage activity and amelioration of liver pathology could be achieved by a new praziquantel-miltefosine fixed-dose nanocombination providing 250 mg praziquantel-20 mg miltefosine/kg. To the best of our knowledge, this is the first report of a fixed-dose nano-based combinatorial therapy for schistosomiasis mansoni. Further studies are needed to document the nanocombination safety and explore its prophylactic activity and potential to hinder the onset of resistance to the drug components.

Therapeutic potential of fucoidan in the reduction of hepatic pathology in murine schistosomiasis japonica

BackgroundHepatic granuloma formation and fibrosis as the consequence of tissue entrapped eggs produced by female schistosomes characterize the pathology of Schistosoma japonicum infection. It has been proposed that fucoidan, a sulfated polysaccharide existing naturally in brown seaweed Fucus vesiculosus, plays a diversified role to perform immunomodulatory activities. However, whether fucoidan functions in the host hepatic pathology is unknown and identifying the potential mechanism that is responsible for hepatic improvement is still necessary.MethodsWe evaluated the hepatic pathology from S. japonicum-infected mice after treatment with fucoidan. qRT-PCR and immunofluorescence were used to detect the pro- or anti-inflammatory factors and the phosphorylated p65 in the livers. In addition, flow cytometry was also performed to investigate the T cell subsets in the S. japonicum-infected mice after treatment with fucoidan, and functional molecules relatively specific to Treg cells were detected in vitro. Furthermore, macrophages were treated with fucoidan in vitro and to detect the inflammatory cytokines.ResultsTreatment with fucoidan significantly reduced the hepatic granuloma size and fibrosis response during S. japonicum infection. The attenuated phospho-p65 protein levels and the mRNA levels of pro-inflammatory cytokines (IL-6, IL-12 and TNF-α) were observed in the livers from fucoidan-treated S. japonicum-infected mice; however, the mRNA levels of anti-inflammatory cytokines (IL-4 and IL-13) were increased. In addition, the infiltration of Treg cells was significantly enhanced both in the livers and spleens from fucoidan-treated S. japonicum-infected mice. Consistent with this, the mRNA levels of IL-10 and TGF-β were dramatically increased in the livers from S. japonicum-infected mice after fucoidan treatment. Furthermore, in vitro stimulated splenocytes with fucoidan resulted in increasing Treg cells in splenocytes as well as the functional expression of CC chemokine receptor type 4 (CCR4) and CXC chemokine receptor type 5 (CXCR5) in Treg cells. Additionally, fucoidan promoted the mRNA levels of IL-4 and IL-13 in macrophages.ConclusionsThese findings suggest an important role of natural fucoidan in reducing hepatic pathology in the progress of S. japonicum infection with a stronger Treg response, which may reveal a new potential therapeutic strategy for hepatic disease caused by parasitic chronic infection.

Liver damage in schistosomiasis is reduced by adipose tissue-derived stem cell therapy after praziquanteltreatment.

BackgroundIn view of the potential immunosuppressive and regenerative properties of mesenchymal stem cells (MSC), we investigated whether transplantation of adipose tissue-derived stem cells (ASC) could be used to control the granulomatous reaction in the liver of mice infected with Schistosoma mansoni after Praziquantel (PZQ) treatment.Methodology/Prinicpal findingsC57BL/6 mice infected with S. mansoni were treated with PZQ and transplanted intravenously with ASC from uninfected mice. Liver morpho-physiological and immunological analyses were performed. The combined PZQ/ASC therapy significantly reduced the volume of hepatic granulomas, as well as liver damage as measured by ALT levels. We also observed that ASC accelerated the progression of the granulomatous inflammation to the advanced/curative phase. The faster healing interfered with the expression of CD28 and CTLA-4 molecules in CD4+ T lymphocytes, and the levels of IL-10 and IL-17 cytokines, mainly in the livers of PZQ/ASC-treated mice.ConclusionsOur results show that ASC therapy after PZQ treatment results in smaller granulomas with little tissue damage, suggesting the potential of ASC for the development of novel therapeutic approaches to minimize hepatic lesions as well as a granulomatous reaction following S. mansoni infection. Further studies using the chronic model of schistosomiasis are required to corroborate the therapeutic use of ASC for schistosomiasis.

An Insight into the Potential Parasitological Effect ofSchistosoma mansoniAntigens in Infected Mice: Prophylactic Role of Cercarial Antigen

Schistosomiasis is a multifactorial disease that includes environmental, behavioral, parasitic, vector, and host factors. This study aimed to assess the protective effect of single and polyvalent antigens from cercarial antigen preparations (CAPs), soluble worm antigen preparations (SWAPs), and soluble egg antigens (SEAs) which were used as candidate vaccines in an experimental model of Schistosoma mansoni-infected mice. The efficiency of the antigens was tested by determining their effects on fecal egg count, egg viability analysis, and tissue egg counts. Histological and morphometric analyses of granulomas in liver and intestine tissues were performed. In the present study, all immunized groups showed a significant reduction in the average fecal egg count and tissue egg load compared with infected mice. The most substantial reduction in fecal egg count was observed in the combined vaccinated group (23.23 ± 3.2). The group vaccinated with CAP before infection showed the highest reduction in tissue egg load (liver and intestine: 85.22 and 91.70%, respectively). Immunized animals showed a highly significant reduction in the numbers of hepatic granulomas compared with the infected non-immunized group. In conclusion, combining these different antigens (CAP, SWAP, and SEA) augments the protective immunity compared with other immunized groups.

In vivo studies of the effect of PPQ-6, a quinoline-based agent against Schistosoma mansoni in mice

Schistosomiasis is still a public health problem. Praziquantel is the only drug available for treatment of all forms of human schistosomiasis. Although praziquantel is an effective drug against all species of human schistosomes, concerns about resistance have been raised, especially in endemic areas. A hybrid compound containing several pharmacophore within a single molecule is a promising strategy. Here, we described the anti-schistosomal effect of 4-(2-Chloroquinolin-3-yl)-2-oxo-6-(p-tolyl)-1,2-dihydropyridine-3-carbonitrile (PPQ-6), a hybrid drug based on quinoline and pyridine. PPQ-6 was given as two regimens (20 or 40 mg/kg). In both regimens, PPQ-6 significantly reduced liver and spleen indices, nitric oxide production, tissue egg load, hepatic granuloma size and count, immature eggs and total worm burden especially females. Our findings suggested that PPQ-6 is a promising anti-schistosomal agent; however more research is needed to elucidate its mechanism of action and report its activity on juvenile schistosomes and other species of human schistosomes.

NLRP6 Plays an Important Role in Early Hepatic Immunopathology Caused by Schistosoma mansoni Infection.

Schistosomiasis is a debilitating parasitic disease that affects more than 200 million people worldwide and causes approximately 280,000 deaths per year. Inside the definitive host, eggs released by Schistosoma mansoni lodge in the intestine and especially in the liver where they induce a granulomatous inflammatory process, which can lead to fibrosis. The molecular mechanisms initiating or promoting hepatic granuloma formation remain poorly understood. Inflammasome activation has been described as an important pathway to induce pathology mediated by NLRP3 receptor. Recently, other components of the inflammasome pathway, such as NLRP6, have been related to liver diseases and fibrotic processes. Nevertheless, the contribution of these components in schistosomiasis-associated pathology is still unknown. In the present study, using dendritic cells, we demonstrated that NLRP6 sensor is important for IL-1β production and caspase-1 activation in response to soluble egg antigens (SEA). Furthermore, the lack of NLRP6 has been shown to significantly reduce periovular inflammation, collagen deposition in hepatic granulomas and mRNA levels of α-SMA and IL-13. Livers of Nlrp6–/– mice showed reduced levels of CXCL1/KC, CCL2, CCL3, IL-5, and IL-10 as well as Myeloperoxidase (MPO) and Eosinophilic Peroxidase (EPO) enzymatic activity. Consistently, the frequency of macrophage and neutrophil populations were lower in the liver of NLRP6 knockout mice, after 6 weeks of infection. Finally, it was further demonstrated that the onset of hepatic granuloma and collagen deposition were also compromised in Caspase-1–/–, IL-1R–/– and Gsdmd–/– mice. Our findings suggest that the NLRP6 inflammasome is an important component for schistosomiasis-associated pathology.

Therapeutic Potential of Human Umbilical Cord Blood Derived Mesenchymal Stem Cells in Murine Model of Hepatic Schistosomiasis

Background and Aim: The pathogenesis of schistosomiasis is mainly due to the host’s immune response against Schistosoma eggs trapped in tissues causing a granulomatous reaction. Recently, stem cell therapy has drawn much attention due to their potential for self-renewal and differentiation. The present study was designed to investigate the regenerative and antifibrotic potential of Human Umbilical Cord Blood derived Mesenchymal Stem Cells (HUCB-MSCs) in hepatic granuloma due to schistosomiasis mansoni in the experimental murine model. Material and Methods: Swiss Albino mice (n=70) were divided into 3 groups; Group A: 30 mice infected with S. mansoni cercariae and subjected to intrahepatic injection of HUCB-MSCs by a single dose of 1 million HUCB-MSCs at 12 weeks post infection (wpi), G (A1): 10 mice sacrificed at 16 (wpi), G (A2):10 mice sacrificed at 18 (wpi), G (A3): 10 mice sacrificed at 20 (wpi). Group B: 30 mice infected with S. mansoni cercariae (positive control), G (B1):10 mice sacrificed at 16 (wpi), G (B2):10 mice sacrificed at 18 (wpi), G (B3):10 mice sacrificed at 20 (wpi). Group C: 10 uninfected mice (negative control). Results: Treatment with HUCB-MSCs, showed an improvement in the histopathological picture of the liver with diminution in the size of granulomas and the overall fibrotic content. Hyperplasic changes in intrahepatic biliary radicals obviously decreased in test groups. Conclusion: The human umbilical cord blood-derived MSCs are promising and effective therapy for the treatment of diseased or damaged liver tissues.

EVALUATION OF PROTECTIVE EFFECTS OF SOLUBLE EGG ANTIGEN CONJUGATED WITH TREHALOSE DIMYCOLATE ADJUVANT IN EXPERIMENTAL SCHISTOSOMIASIS MANSONI

Schistosomiasis is the second most common parasitic infection all over the world. It is responsible for thousands of deaths per year. Control of this infection depends mainly on praziquantel which unfortunately has many defects e.g. occurrence of reinfection and risk of resistance. So, a suitable vaccine is an urgent need. The vaccination that elicits a combined Th1 and Th2 is considered a proper vaccine candidate. Trehalose Dimycolate (TDM) is an immunogen that proved potent activation of Th1 lymphocytes. Effects of its combination with the Th2 stimulant, soluble egg antigen (SEA) in protection against Schistosoma mansoni infection in experimental animals were studied. Combined SAE+TDM achieved statistically significant protection against infection causing reduction of the worm load and ova count. A large percentage of the laid ova were even immature. Combined immunization was associated with reduced hepatic granuloma number, diameter and hepatic fibrosis percentage. Moreover, SEA+TDM increased stimulation of M2 type macrophages that limited the spread of hepatic fibrosis. It was concluded that SEA+TDM achieved the best protection from infection and the resulting pathology.This can be regarded to increased activation of humoral and cellular wings of immunity and activations of both anti-S. mansoni and tissue protecting macrophages and cytokines.

EVALUATION OF PLUMBAGIN AS A POTENTIAL THERAPEUTIC AGENT FOR MURINE SCHISTOSOMIASIS MANSONI

Schistosomiasis still one of the major health problems worldwide, affecting millions of people in economically challenged tropical and subtropical countries of the world. Currently the treatment of schistosomiasis relies on a single anti-parasitic drug praziquantel; however it was found it is not fully effective and the potential for development of resistant to praziquantel has justified the research for new alternative chemotherapies especially from natural sources. The current study evaluated the anti-parasitic effect of plumbagin against S. mansoni infected mice either alone or in combination with praziquantel through, parasitological parameters (worm load, oogram pattern, liver and intestine egg load) and histopathological parameters (granuloma number and diameter). Plumbagin showed a significant reduction in total worm burden (P <0.05), increase in dead eggs in oogram pattern and reduction in tissue ova count. Mean hepatic granulomas number and diameter were decreased with elevation in percentage of degenerated ova, compared to control group. Results were improved when praziquantel was used in combination with plumbagin as no male or coupled worm were detected, no immature ova and highly significant reduction in tissue egg load in liver and intestine (P < 0.001) compared to infected control group.

EVALUATION OF PLUMBAGIN AS A POTENTIAL THERAPEUTIC AGENT FOR MURINE SCHISTOSOMIASIS MANSONI

Schistosomiasis still one of the major health problems worldwide, affecting millions of people in economically challenged tropical and subtropical countries of the world. Currently the treatment of schistosomiasis relies on a single anti-parasitic drug praziquantel; however it was found it is not fully effective and the potential for development of resistant to praziquantel has justified the research for new alternative chemotherapies especially from natural sources. The current study evaluated the anti-parasitic effect of plumbagin against S. mansoni infected mice either alone or in combination with praziquantel through, parasitological parameters (worm load, oogram pattern, liver and intestine egg load) and histopathological parameters (granuloma number and diameter). Plumbagin showed a significant reduction in total worm burden (P <0.05), increase in dead eggs in oogram pattern and reduction in tissue ova count. Mean hepatic granulomas number and diameter were decreased with elevation in percentage of degenerated ova, compared to control group. Results were improved when praziquantel was used in combination with plumbagin as no male or coupled worm were detected, no immature ova and highly significant reduction in tissue egg load in liver and intestine (P < 0.001) compared to infected control group.

Hipertensión portal secundaria a sarcoidosis hepática

The etiology of hepatic granulomas varies depending on the epidemiology. In developed countries, primary biliary chol­angitis (PBC) is the main cause followed by sarcoidosis. In developing countries, it is tuberculosis. We present the case of a patient with chronic liver disease, whose anatomo­pathological diagnosis was compatible with sarcoidosis. It was a 55-year-old woman, with a history of type 2 diabe­tes (DBT), insulin-requiring and overweight. Her disease debuted with SAE, subsequently presenting HDA of vari­ceal origin. She was referred to our institution for study. Physical examination has hepatosplenomegaly and in the laboratory FAL and yGT augmented with non-reactive anti-LKM and AMA. Ultrasonography of the abdomen showed hepatosplenomegaly, without focal images. Hepatic biopsy puncture was performed, which reported numerous portal-site granulomas. The ECA dose was increased. The diagnosis of sarcoidosis was established and treatment with deflazacort was started. She presented an upper gastrointes­tinal bleeding causing her death.

Chronic whipworm infection exacerbates Schistosoma mansoni egg-induced hepatopathology in non-human primates

BackgroundSchistosomiasis continues to inflict significant morbidity and mortality in the tropical and subtropical regions of the world. The disease endemicity overlaps with the transmission of other parasitic diseases. Despite the ubiquity of polyparasitism in tropical regions, particularly in rural communities, little is known about the impact of multiple helminth infections on disease progression. In this pilot study, we describe the influence of chronic Trichuris trichiura infection on Schistosoma mansoni egg-induced hepatopathology in infected baboons.MethodsBaboons with or without underlying whipworm infection were challenged with S. mansoni cercariae to establish schistosomiasis. Adult S. mansoni worms were recovered by perfusion and enumerated, hepatic granulomas were quantified via light microscopy, and transcriptional profiling of tissues were completed using RNA sequencing technologies.ResultsCo-infection with both S. mansoni and T. trichiura resulted in higher female schistosome worm burden and significantly larger liver granuloma sizes. Systems biology analyses of peripheral blood mononuclear cells (PBMC) revealed pathways associated with increased liver damage in co-infected baboons.ConclusionsUnderlying chronic whipworm infection intensified schistosome egg-induced liver pathology in infected baboons. RNA-Seq analysis provided insight into pathways associated with increased liver damage, corroborating histological findings.

Epigenetic and parasitological parameters are modulated in EBi3-/- mice infected with Schistosoma mansoni.

Schistosoma mansoni adaptive success is related to regulation of replication, transcription and translation inside and outside the intermediate and definitive host. We hypothesize that S. mansoni alters its epigenetic state in response to the mammalian host immune system, reprogramming gene expression and altering the number of eggs. In response, a change in the DNA methylation profile of hepatocytes could occurs, modulating the extent of hepatic granuloma. To investigate this hypothesis, we used the EBi3-/- murine (Mus musculus) model of S. mansoni infection and evaluated changes in new and maintenance DNA methylation profiles in the liver after 55 days of infection. We evaluated expression of epigenetic genes and genes linked to histone deubiquitination in male and female S. mansoni worms. Comparing TET expression with DNMT expression indicated that DNA demethylation exceeds methylation in knockout infected and uninfected mice and in wild-type infected and uninfected mice. S. mansoni infection provokes activation of demethylation in EBi3-/-I mice (knockout infected). EBi3-/-C (knockout uninfected) mice present intrinsically higher DNA methylation than WTC (control uninfected) mice. EBi3-/-I mice show decreased hepatic damage considering volume and reduced number of granulomas compared to WTI mice; the absence of IL27 and IL35 pathways decreases the Th1 response resulting in minor liver damage. S. mansoni males and females recovered from EBi3-/-I mice have reduced expression of a deubiquitinating enzyme gene, orthologs of which target histones and affect chromatin state. SmMBD and SmHDAC1 expression levels are downregulated in male and female parasites recovered from EBi3-/-, leading to epigenetic gene downregulation in S. mansoni. Changes to the immunological background thus induce epigenetic changes in hepatic tissues and alterations in S. mansoni gene expression, which attenuate liver symptoms in the acute phase of schistosomiasis.

T Lymphocyte-Mediated Liver Immunopathology of Schistosomiasis.

The parasitic worms, Schistosoma mansoni and Schistosoma japonicum, reside in the mesenteric veins, where they release eggs that induce a dramatic granulomatous response in the liver and intestines. Subsequently, infection may further develop into significant fibrosis and portal hypertension. Over the past several years, uncovering the mechanism of immunopathology in schistosomiasis has become a major research objective. It is known that T lymphocytes, especially CD4+ T cells, are essential for immune responses against Schistosoma species. However, obtaining a clear understanding of how T lymphocytes regulate the pathological process is proving to be a daunting challenge. To date, CD4+ T cell subsets have been classified into several distinct T helper (Th) phenotypes including Th1, Th2, Th17, T follicular helper cells (Tfh), Th9, and regulatory T cells (Tregs). In the case of schistosomiasis, the granulomatous inflammation and the chronic liver pathology are critically regulated by the Th1/Th2 responses. Animal studies suggest that there is a moderate Th1 response to parasite antigens during the acute stage, but then, egg-derived antigens induce a sustained and dominant Th2 response that mediates granuloma formation and liver fibrosis. In addition, the newly discovered Th17 cells also play a critical role in the hepatic immunopathology of schistosomiasis. Within the liver, Tregs are recruited to hepatic granulomas and exert an immunosuppressive role to limit the granulomatous inflammation and fibrosis. Moreover, recent studies have shown that Tfh and Th9 cells might also promote liver granulomas and fibrogenesis in the murine schistosomiasis. Thus, during infection, T-cell subsets undergo complicated cross-talk with antigen presenting cells that then defines their various roles in the local microenvironment for regulating the pathological progression of schistosomiasis. This current review summarizes a vast body of literature to elucidate the contribution of T lymphocytes and their associated cytokines in the immunopathology of schistosomiasis.

A rare cause of granulomatous hepatitis: Tularemia

Tularemia is a zoonotic infection caused by Francisella tularensis. Tularemia has several clinical form in humans, including ulceroglandular, pneumonic, oropharyngeal, oculoglandular, and systemic (typhoidal). Tularemia may develop granulomatous and suppurative lesions, especially in the affected regional lymph nodes and various organs. Patients with hepatic involvement typically have elevated transaminase levels, hepatomegaly and rarely jaundice. Histologically, there are typically suppurative microabscesses with occasional surrounding macrophages. Rarely, hepatic granuloma can develop due to tularemia. We present a case of an 8 year-old male residing in a rural village in Turkey, who came to our hospital after having intermittent fever for four months and right upper abdominal pain for two months. Liver had a nodular appearance in liver imaging and liver biopsy were consistent with granulomatous hepatitis. The microagglutination test was positive for tularemia in the patient who was investigated for granulomatous hepatitis etiology. Symptoms and signs improved with tularemia treatment. We present a rare case of hepatic involvement of tularemia in a child. Clinicians should be suspicious of and evaluate for typhoidal tularemia in patients who present with prolonged fever and non-specific systemic symptoms, potentially with associated abdominal pain.

Türkiye'de Hepatik Granülomlarin Prevalansı ve Etiyolojisi: Bir Sistematik Derleme

Objective: Hepatic granulomas (HGs) are seen in 2- 4% of liver biopsies and the etiology is heterogeneous including liver involvement in systemic immunologic disorders and infectious diseases, primary hepatic diseases, drug hepatotoxicity, foreign bodies, and reaction to neoplastic disease. Common etiologies are primary biliary cholangitis (PBC) and sarcoidosis in the Western world, while infections especially tuberculosis (TB) preclude in the Eastern countries. In Turkey, HGs have been reported in 2-5% of liver biopsies and the etiology includes both infections and non-infectious diseases. In this review, we aimed to determine the prevalence and etiology of HGs in Turkey. Material and Methods: A search of Pubmed, Scopus and Science Citation Index and national databses (including Tübitak Ulakbim, Türkmedline, and Türk Atıf Dizini) was done and 60 reports were reached. Four studies from Turkey dedicated to describe the rate of HGs and their etiology were determined. Results: The rate of HGs is 2.27% (208/9164). Infections as a group (TB, hydatid disease, HCV, brucellosis, fascioliasis, typhoid fever, fungal infection, HBV, actinomycosis, yersiniosis, leishmaniasis, and infectious mononucleosis) were the etiology in 38.4%. PBC was the leading etiology, followed by sarcoidosis, TB, and hydatid disease. Beside the dedicated HG series, 11 series from Turkey included cases with HGs and 45 papers described 52 case reports with HGs. Conclusion: HGs are seen in 2.3% of the liver biopsies in Turkey. The infections still represent the leading etiology and among them, TB appears the commonest one. When the cases are evaluated individually, PBC is the leading etiology. Infections are followed by PBC and sarcoidosis, which are main two etiologies of HGs in the world. The local and regional epidemiology of certain infectious diseases, particularly TB determines the etiologic distribution of HGs.

Preventive CTLA-4-Ig Treatment Reduces Hepatic Egg Load and Hepatic Fibrosis in Schistosoma mansoni-Infected Mice.

Background Hepatic fibrosis and granuloma formation as a consequence of tissue entrapped eggs produced by female schistosomes characterize the pathology of Schistosoma mansoni infection. We have previously shown that single-sex infection with female schistosomes mitigates hepatic fibrosis after secondary infection. This was associated with an increased expression of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), known as a negative regulator of T cell activation. Based on these findings, we hypothesized that administration of agonistic CTLA-4-Ig (Belatacept) is capable to prevent and/or treat hepatic fibrosis during schistosomiasis. Methods Mice were infected with 50 S. mansoni cercariae and CTLA-4-Ig, or appropriated control-Ig was administered for 4 weeks. Preventive treatment started 4 weeks after infection, before onset of egg production, and therapeutic treatment started 8 weeks after infection when hepatic fibrosis was already established. Results When given early after infection, livers of CTLA-4-Ig-treated mice showed significantly reduced collagen deposition and decreased expression of profibrotic genes in comparison to controls. In addition, administration of CTLA-4-Ig suppressed the inflammatory T cell response in infected mice. If therapy was started at a later time point when fibrogenesis was initiated, CTLA-4-Ig had no impact on hepatic fibrosis. Conclusion We could demonstrate that an early preventive administration of CTLA-4-Ig suppresses effector T cell function and therefore ameliorates liver fibrosis. CTLA-4-Ig administration after onset of egg production fails to treat hepatic fibrosis.

Modelling approaches to predict and evaluate schistosomiasis immunization utilizing SEA loaded on chitosan nanoparticles via liver tissue differentiation and angiogenesis

Background: Anti-schistosome vaccination is a necessary approach to minimize the hepatic vascular changes that lead to hepatic pathological consequences. Objective: To assess the prophylactic impact of soluble egg antigen (SEA) loaded on chitosan nanoparticles (ChNPs) on hepatic vascular and pathological consequences in experimental schistosomiasis. Material and Methods: Seventy male Swiss albino mice were classified into 7 groups; each of 10. G1: Non-infected control; G2: Infected control group; G3: Injected by ChNPs then infected subcutaneously (SC) with S. mansoni cercaria; G4: Injected by Freund’s Complete Adjuvant (FCA) then infected; G5: Injected by crude schistosomal egg antigen (SEA) combined with FCA (SEA-FCA) then infected; G6: Injected by SEA loaded on ChNPs (SEA-ChNPs) then infected; G7: Injected by both SEA-FCA + SEA-ChNPs then infected. Evaluation was done by parasitological, histopathological and immunohistochemical studies in murine models challenged by Schistosoma mansoni infection. Results: SEA-ChNPs was more successful in reducing stools and liver egg counts, hepatic granulomas number and size, improving hepatic architecture and vasculature, minimizing hepatic fibrosis, enhancing angiogenesis constructive impact, ameliorating adverse effects during fibrogenesis and remodeling of hepatic tissue by fibrosis degradation than SEA-FCA. Conclusion: ChNPs potentiated the protective and immune impact of SEA as proved by parasitological, histopathological and immunohistochemical assays; and confirmed its specific, marked, supportive and constructive effects on hepatic angiogenesis

AMELIORATIVE EFFECT OF CALOTROPIS PROCERA AND/OR PRAZIQUANTEL ON SCHISTOSOMA MANSONI INFECTED MICE

Seventy albino mice were infected with~ 80 S. mansoni cercariae and were classified into: GI: infected non-treated group, GII: treated with C. procera alcoholic extract after infection (therapeutic), GIII: treated with C. procera aqueous extract after infection (therapeutic), GIV: treated with C. procera alcoholic extract before infection (prophylactic alcoholic), GV: treated with C. procera aqueous extract before infection (prophylactic aqueous), GVI: treated with praziquantel, treated group with praziquantel combined with aqueous extract of C. procera and G.VII: infected and treated with half dose of Praziquantel combined with aqueous plant extract. Seven weeks post infection, all mice were autopsied, and livers and ilea were parasitological examined (Tissue egg load) and histological assessments (Number & size of hepatic granulomas). Schistosomes recovered from all groups were processed to calculate total worm burdens. The results showed that mice treated with C. procera alcoholic and aqueous extracts showed more significant reduction in total worm burden (43.7% & 46.4%), total egg tissue load (60% & 50.7%) and number of hepatic granuloma (45.9% & 55.5%) than mice in prophylactic aqueous or alcoholic groups (38.3% & 36%, 27.2% & 44%, 25.6% & 39%, respectively). Female wormsrecovered from mice of aqueous or alcoholic treated groups showed less fecundity than those recovered from mice of prophylactic groups (1475±181 & 2821±200, corresponding to 3674±1447 & 3023±709, respectively). Mice treated with praziquantel or treated with praziquantel combined with C. procera aqueous extract showed the highest reduction in total tissue egg load (86.4% & 97.4%, respectively). Mice treated with praziquantel combined with C. procera aqueous extract showed higher reduction in total egg tissue (97.4%), number and size of hepatic granuloma (72.3% & 31.4%) than those treated with praziquantel (86.4%, 55.5% &10.8%, respectively).