Emerging Role of HMGB1 in the Pathogenesis of Schistosomiasis Liver Fibrosis.

In chronic schistosomiasis, liver fibrosis is linked to portal hypertension, which is a condition associated with high mortality and morbidity. High mobility group box 1 (HMGB1) was originally described as a nuclear protein that functions as a structural co-factor in transcriptional regulation. However, HMGB1 can also be secreted into the extracellular milieu under appropriate signal stimulation. Extracellular HMGB1 acts as a multifunctional cytokine that contributes to infection, injury, inflammation, and immune responses by binding to specific cell-surface receptors. HMGB1 is involved in fibrotic diseases. From a clinical perspective, HMGB1 inhibition may represent a promising therapeutic approach for treating tissue fibrosis. In this study, we demonstrate elevated levels of HMGB1 in the sera in experimental mice or in patients with schistosomiasis. Using immunohistochemistry, we demonstrated that HMGB1 trafficking in the hepatocytes of mice suffering from acute schistosomiasis was inhibited by Glycyrrhizin, a well-known HMGB1 direct inhibitor, as well as by DIC, a novel and potential anti-HMGB1 compound. HMGB1 inhibition led to significant downregulation of IL-6, IL4, IL-5, IL-13, IL-17A, which are involved in the exacerbation of the immune response and liver fibrogenesis. Importantly, infected mice that were treated with DIC or GZR to inhibit HMGB1 pro-inflammatory activity showed a significant increase in survival and a reduction of over 50% in the area of liver fibrosis. Taken together, our findings indicate that HMGB1 is a key mediator of schistosomotic granuloma formation and liver fibrosis and may represent an outstanding target for the treatment of schistosomiasis.

Testing the vestibular evoked myogenic potential (VEMP) to identify subclinical neurological alterations in different phases of human T-lymphotropic virus type 1 infection.

BACKGROUND CONTEXT: The diagnosis of human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is based on clinical signs and the confirmation of HTLV-1 infection in the central nervous system. Electrophysiological tests may facilitate an earlier diagnosis of spinal cord involvement. Vestibular evoked myogenic potential (VEMP) testing evaluates the vestibulospinal tract, which is correlated with the motor tract; the target of damage by HAM/TSP. PURPOSE: This study examines the subclinical neurological alterations related to HTLV-1 infection in individuals with asymptomatic HTLV-1 infections, possible HAM/TSP, and confirmed HAM/TSP. STUDY DESIGN: Vestibular evoked myogenic potential testing was performed at the beginning of the study and repeated every 6 months for 18 months. Ninety volunteers were selected for the study: 30 were HTLV-1 seronegative (the control group) and 60 were HTLV-1 seropositive (of these, 18 were asymptomatic, 25 had possible HAM/TSP, and 17 had confirmed HAM/TSP). The VEMP response was classified as normal or abnormal (latency prolongation or no response). A change in the VEMP response from normal to abnormal was the event of interest. To perform a survival analysis, the subjects with normal VEMP responses at the first assessment were selected. METHODS: The results were analyzed blindly. Vestibular evoked myogenic potential was measured using short tone bursts as acoustic stimuli (1 kHz, 118 dBHL, a rise-fall of 1 millisecond, and a plateau of 2 milliseconds). The stimulation rate was 5 Hz, and the analysis time for each response was 60 milliseconds; each trial averaged 200 responses. RESULTS: The mean age of the subjects in the control group was 38 ± 11 years (median 35), and 13 (43%) were men. In the study group, the mean age was 51 ± 12 years (median 53), and 12 (20%) were men. An analysis of the survival curve indicated that the median time for a change in VEMP response from normal to abnormal was 18 months, which is in agreement with the slow progression of HTLV-1-associated neurologic disease. The survival analysis showed that the change in VEMP response was significantly different between the asymptomatic and HAM/TSP groups (p=.02). CONCLUSIONS: Vestibular evoked myogenic potential testing was useful for monitoring the development of HAM/TSP in HTLV-1-infected individuals.

Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni.

BACKGROUND: Schistosomiasis mansoni is a major cause of portal fibrosis and portal hypertension. The Hedgehog pathway regulates fibrogenic repair in some types of liver injury. AIMS: Determine if Hedgehog pathway activation occurs during fibrosis progression in schistosomiasis and to determine if macrophage-related mechanisms are involved. METHODS: Immunohistochemistry was used to characterize the cells that generate and respond to Hedgehog ligands in 28 liver biopsies from patients with different grades of schistosomiasis fibrosis staged by ultrasound. Cultured macrophages (RAW264.7 and primary rat Kupffer cells) and primary rat liver sinusoidal endothelial cells (LSEC) were treated with schistosome egg antigen (SEA) and evaluated using qRT-PCR. Inhibition of the Hedgehog pathway was used to investigate its role in alternative activation of macrophages (M2) and vascular tube formation. RESULTS: Patients with schistosomiasis expressed more ligands (Shh and Ihh) and target genes (Patched and Gli2) than healthy individuals. Activated LSEC and myofibroblasts were Hedgehog responsive [Gli2(+)] and accumulated in parallel with fibrosis stage (P < 0.05). Double IHC for Ihh/CD68 showed that Ihh(+) cells were macrophages. In vitro studies demonstrated that SEA-stimulated macrophages to express Ihh and Shh mRNA (P < 0.05). Conditioned media from such macrophages induced luciferase production by Shh-LightII cells (P < 0.001) and Hedgehog inhibitors blocked this effect (P < 0.001). SEA-treated macrophages also up-regulated their own expression of M2 markers, and Hh pathway inhibitors abrogated this response (P < 0.01). Inhibition of the Hedgehog pathway in LSEC blocked SEA-induced migration and tube formation. CONCLUSION: SEA stimulates liver macrophages to produce Hh ligands, which promote alternative activation of macrophages, fibrogenesis and vascular remodelling in schistosomiasis.

Neuroschistosomiasis mansoni: literature review and guidelines.

BACKGROUND: Schistosomiasis is a tropical disease caused by worms of the genus Schistosoma. It is endemic in the Caribbean Islands, the middle east, eastern Asia, South America, and Africa. In nonendemic areas, physicians should be aware of this condition in travelers returning from endemic areas and in immigrants. The main disease-causing species are Schistosoma haematobium, Schistosoma mansoni, and Schistosoma japonicum. Neuroschistosomiasis is an ectopic form of the disease that is mainly associated with S. japonicum infection. Involvement of the central nervous system (CNS) in S. mansoni infection is neglected and underestimated. Neuroschistosomiasis mansoni can be classified into cerebral, spinal, and encephalomyelitic forms in the course of an acute or chronic infection. REVIEW SUMMARY: We review the CNS involvement by S. mansoni infection with an emphasis on life cycle, epidemiology, pathophysiology and immunology, clinical manifestations, diagnostic criteria, differential diagnosis, current treatment guidelines, and prognosis. CONCLUSIONS: Although an underreported CNS infection, found mainly in underdeveloped countries, neuroschistosomiasis mansoni still causes significant incapacity and morbidity. Hence, neurologists should become familiar with this infection worldwide and include it in the differential diagnosis of CNS involvement in travelers returning from endemic areas and in immigrants.

Early right cardiac dysfunction in patients with schistosomiasis mansoni.

BACKGROUND: Pulmonary hypertension (PH) is a complication of schistosomiasis mansoni (SM), mainly in the hepatosplenic form. However, its prevalence is not well established. We evaluated the usefulness of Doppler echocardiographic indexes to detect right heart dysfunction in SM. METHODS: A total of 83 patients divided into two groups were studied: Group 1: 44 patients with hepatosplenic SM, and Group 2: 39 patients with hepatointestinal SM who served as controls. All patients underwent a Doppler echocardiogram. Right ventricular end-diastolic area (RVEDA), the peak systolic tricuspid annular tissue velocity (S'), right ventricular index of myocardial performance (RVIMP) and right atrial area (RAA) were measured in all patients. Tricuspid regurgitation peak velocity (TR) was measured and the pressure gradient (TG) was obtained. RESULTS: The prevalence of patients with elevated systolic pulmonary artery pressure at echocardiography was 31% in hepatosplenic patients, while no patient with the hepatointestinal form presented PH. Patients with hepatosplenic SM had larger RVEDA (10.0 ± 2.8 vs. 8.5 ± 1.8 cm(2) /m, P = 0.006) and RAA (9.39 [8.3-11.0] vs. 7.7 [6.9-8.4 cm(2) /m], P < 0.001). There was correlation between TG and RVIMP (r = 0.58; P < 0.001) and between TG and RAA (r = 0.36; P = 0.03) in Group 1. CONCLUSION: Larger RAA and RVEDA were found in patients with hepatosplenic SM, when compared to patients with the hepatointestinal form, which may suggest early impairment of RV function in patients with hepatosplenic SM.

Schistosoma mansoni: magnetic resonance analysis of liver fibrosis according to WHO patterns for ultrasound assessment of schistosomiasis-related morbidity.

For the last two decades, ultrasound (US) has been considered a surrogate for the gold standard in the evaluation of liver fibrosis in schistosomiasis. The use of magnetic resonance imaging (MRI) is not yet standardised for diagnosing and grading liver schistosomal fibrosis. The aim of this paper was to analyse MRI using an adaptation of World Health Organization (WHO) patterns for US assessment of schistosomiasis-related morbidity. US and MRI were independently performed in 60 patients (42.1 +/- 13.4 years old), including 37 men and 23 women with schistosomiasis. Liver involvement appraised by US and MRI was classified according to the WHO protocol from patterns A-F. Agreement between image methods was evaluated by kappa index (k). The correlation between US and MRI was poor using WHO patterns [k = 0.14; confidence interval (CI) 0.02; 0.26]. Even after grouping image patterns as "A-D", "Dc-E" and "Ec-F", the correlation between US and MRI remained weak (k = 0.39; CI 0.21; 0.58). The magnetic resonance adaptation used in our study did not confirm US classification of WHO patterns for liver fibrosis.

Schistosoma mansoni: magnetic resonance analysis of liver fibrosis according to WHO patterns for ultrasound assessment of schistosomiasis-related morbidity

For the last two decades, ultrasound (US) has been considered a surrogate for the gold standard in the evaluation of liver fibrosis in schistosomiasis. The use of magnetic resonance imaging (MRI) is not yet standardised for diagnosing and grading liver schistosomal fibrosis. The aim of this paper was to analyse MRI using an adaptation of World Health Organization (WHO) patterns for US assessment of schistosomiasis-related morbidity. US and MRI were independently performed in 60 patients (42.1 ± 13.4 years old), including 37 men and 23 women with schistosomiasis. Liver involvement appraised by US and MRI was classified according to the WHO protocol from patterns A-F. Agreement between image methods was evaluated by kappa index (k). The correlation between US and MRI was poor using WHO patterns [k = 0.14; confidence interval (CI) 0.02; 0.26]. Even after grouping image patterns as "A-D", "Dc-E" and "Ec-F", the correlation between US and MRI remained weak (k = 0.39; CI 0.21; 0.58). The magnetic resonance adaptation used in our study did not confirm US classification of WHO patterns for liver fibrosis.

Disagreement between ultrasound and magnetic resonance imaging in the identification of schistosomal periportal fibrosis

Abdominal ultrasound (US) has been widely used in the evaluation of patients with schistosomiasis mansoni. It represents an important indirect method of diagnosis and classification of the disease, and it has also been used as a tool in the evaluation of therapeutic response and regression of fibrosis. We describe the case of a man in whom US showed solid evidence of schistosomal periportal fibrosis and magnetic resonance imaging revealed that periportal signal alteration corresponded to adipose tissue which entered the liver togheter with the portal vein.

The role of chemokines in Schistosoma mansoni infection: insights from human disease and murine models

Chemokines are a superfamily of low-molecular-weight cytokines that were initially described for their chemoattractant activity. It is now clear chemokines have several other activities that modulate immune processes. More than 50 chemokines ligands and at least 19 receptors have been described to date. Depending on the number of N-terminal cysteine residues, chemokines are grouped in the subfamilies CXC, CC, C or CX3C. A growing body of evidence suggests a role for chemokines in the pathogenesis of several inflammatory diseases. Our studies involving mice and humans infected with Schistosoma mansoni suggest an important role of the chemokine CCL3 and its receptors (CCR1 and CCR5) in the pathogenesis of severe schistosomiasis. We suggest that the differential activation of CCR1 or CCR5 during the course of schistosomiasis may dictate the outcome of the disease.

Disagreement between ultrasound and magnetic resonance imaging in the identification of schistosomal periportal fibrosis.

Abdominal ultrasound (US) has been widely used in the evaluation of patients with schistosomiasis mansoni. It represents an important indirect method of diagnosis and classification of the disease, and it has also been used as a tool in the evaluation of therapeutic response and regression of fibrosis. We describe the case of a man in whom US showed solid evidence of schistosomal periportal fibrosis and magnetic resonance imaging revealed that periportal signal alteration corresponded to adipose tissue which entered the liver together with the portal vein.

The role of chemokines in Schistosoma mansoni infection: insights from human disease and murine models.

Chemokines are a superfamily of low-molecular-weight cytokines that were initially described for their chemoattractant activity. It is now clear chemokines have several other activities that modulate immune processes. More than 50 chemokines ligands and at least 19 receptors have been described to date. Depending on the number of N-terminal cysteine residues, chemokines are grouped in the subfamilies CXC, CC, C or CX3C. A growing body of evidence suggests a role for chemokines in the pathogenesis of several inflammatory diseases. Our studies involving mice and humans infected with Schistosoma mansoni suggest an important role of the chemokine CCL3 and its receptors (CCR1 and CCR5) in the pathogenesis of severe schistosomiasis. We suggest that the differential activation of CCR1 or CCR5 during the course of schistosomiasis may dictate the outcome of the disease.

Treatment of schistosomal myeloradiculopathy with praziquantel and corticosteroids and evaluation by magnetic resonance imaging: a longitudinal study.

BACKGROUND: The best treatment for schistosomal myeloradiculopathy (SMR) remains undefined. There is also no longitudinal study to estimate the value of magnetic resonance imaging (MRI) in the diagnosis and follow-up of this disease. METHODS: Patients with the following presentation were considered for study: lumbar and/or lower limb pain; lower limb weakness; anesthesia, hypoesthesia, or paresthesia; bladder and/or intestinal dysfunction; and sexual impotence. Sixteen patients with SMR were treated with oral praziquantel (50 mg/kg in a single dose) and methylprednisolone (15 mg/kg/day intravenously for 5 days) followed by prednisone (1 mg/kg/day orally for 6 months). Clinical outcome was prospectively evaluated in months 2 and 6 of treatment. RESULTS: Image alterations were detected by MRI at diagnosis for all patients, and normalization or improvement was reported at the end of treatment. There was statistically significant clinical melioration at both the second and sixth months of therapy for most neurological alterations. However, the best clinical outcome was achieved when the steroid was given for >2 months. CONCLUSIONS: Treatment with praziquantel associated with corticosteroids was successful in all cases. MRI proved to be a good method for the diagnosis of SMR and helpful in the evaluation of response to treatment.

Color and genomic ancestry in Brazilians.

This work was undertaken to ascertain to what degree the physical appearance of a Brazilian individual was predictive of genomic African ancestry. Using a panel of 10 population-specific alleles, we assigned to each person an African ancestry index (AAI). The procedure was able to tell apart, with no overlaps, 20 males from northern Portugal from 20 males from São Tomé Island on the west coast of Africa. We also tested 10 Brazilian Amerindians and observed that their AAI values fell in the same range as the Europeans. Finally, we studied two different Brazilian population samples. The first consisted of 173 individuals from a rural Southeastern community, clinically classified according to their Color (white, black, or intermediate) with a multivariate evaluation based on skin pigmentation in the medial part of the arm, hair color and texture, and the shape of the nose and lips. In contrast to the clear-cut results with the African and European samples, our results showed large variances and extensive overlaps among the three Color categories. We next embarked on a study of 200 unrelated Brazilian white males who originated from cosmopolitan centers of the four major geographic regions of the country. The results showed AAI values intermediate between Europeans and Africans, even in southern Brazil, a region predominantly peopled by European immigrants. Our data suggest that in Brazil, at an individual level, color, as determined by physical evaluation, is a poor predictor of genomic African ancestry, estimated by molecular markers.

Role of immune complexes from patients with different clinical forms of Schistosomiasis in the modulation of in vitro granuloma reaction

Schistosomiasis is a disease whose pathology is strongly related to the granulomatous reaction formed around parasite eggs trapped in host tissues. Studies have shown that the chronic intestinal form (INT) of the infection is associated with a variety of immunoregulatory mechanisms which lead to a diminished granulomatous reaction. Using an in vitro model of granuloma reaction, we show that immune complexes (IC) isolated from sera of INT patients are able to reduce granulomatous reaction developed by peripheral blood mononuclear cells (PBMC) from acute (AC), INT and hepatosplenic (HE) patients to soluble egg antigen (SEA)-conjugated polyacrylamide beads (PB-SEA). This inhibitory activity is also observed in cell proliferation assay of PBMC from INT and HE patients stimulated with SEA and adult worm antigen (SWAP). Furthermore, IC isolated from sera of patients with different clinical forms of the disease are also able to suppress INT patients PBMC reactivity. Therefore, our results show that circulating IC present in sera of patients with different clinical forms of schistosomiasis may down-regulate PBMC reactivity to parasite antigens resulting in a diminished granuloma reaction to parasite eggs.