No association of IL2, IL4, IL6, TNF, and IFNG gene polymorphisms was found with Taenia solium human infection or neurocysticercosis severity in a family-based study.

Neurocysticercosis (NC) is caused by the establishment of the metacestode stage of Taenia solium in the human central nervous system. A great heterogeneity in the susceptibility to the infection and to the disease has been reported. While the factors involved in this heterogeneity are not completely understood, clearly different immune-inflammatory profiles have been associated to each condition. This study evaluated the association of cytokine single nucleotide polymorphisms (SNPs) with susceptibility to infection and disease severity in NC patients. Blood samples from 92 NC cases and their parents (trios) were genotyped for SNPs in five cytokines relevant for the immune response: IL4 (-589C/T), IL6 (-174C/G), IFNG (+874T/A), TNF (-238G/A), and IL2 (-330G/T). Specific DNA fragments were amplified by the polymerase chain reaction, using the 5'-nuclease Taqman assay on a 7500 platform, allowing the detection of the polymorphism genotypes. No association between the polymorphisms evaluated neither with susceptibility to infection nor with disease severity was found, although previous studies reported variations in the levels of these cytokines among different NC clinical pictures. These results, nevertheless, add new elements to our understanding of the complex pathogenic mechanisms involved in susceptibility to infection by T. solium cysticerci and the severity of the ensuing disease.

[Acute arterial thrombosis in a context of hyperhomocysteinemia: Case report and literature review]. / Thrombose artérielle aiguë dans un contexte d'hyperhomocystéinémie : à propos d'un cas et revue de la littérature.

INTRODUCTION: Hyperhomocysteinemia is a biological marker that could be identified in the venous thrombotic events and rarely during acute arterial thrombotic events. The consequences can be serious. Effective diagnostic strategy is needed to optimize the management. CASE REPORT: Following bariatric surgery, a 40-year-old patient was admitted with an acute encephalopathy associated with peripheral lower limb arterial ischemia. The diagnostic work-up identified a major hyperhomocysteinemia whose causes were several. Surgical treatment and anticoagulation was associated with vitamins and trace elements supplementation. Correcting deficiencies allowed delirium and hyperhomocysteinemia improvement. Once treatment established, the patient did not present a recurrent thrombotic episode. CONCLUSION: Major hyperhomocysteinemia seems to be associated with an increased risk of acute arterial thrombosis. This marker might be considered in nutritional deficiency situations with appropriate support on the vascular, metabolic and nutrition level.

Genetic analysis of human predisposition to hepatosplenic disease caused by schistosomes reveals the crucial role of connective tissue growth factor in rapid progression to severe hepatic fibrosis.

Schistosome worms inhabit mammalian mesenteric veins. Their eggs cause chronic inflammation, which progresses to periportal fibrosis in 5 to 30% of cases, increasing portal blood pressure and leading to esophageal varices. Episodes of bleeding cause hepatic necrosis and may ultimately lead to hepatic failure and the death of the patient. Schistosome infections can also cause pulmonary hypertension and heart failure. The mechanisms of fibrogenesis and fibrolysis are beginning to be unraveled, but it remains unclear why disease occurs only in certain subjects, as also observed for other types of chronic liver inflammation, as in hepatitis C or B. We summarize here the results that showed that fibrosis progression is determined by a genetic locus on chromosome 6. The CCN2 gene at this locus, encodes CTGF that is a crucial regulator of fibrosis. Two groups of CCN2 polymorphisms independently modulate the progression of hepatic fibrosis. These results were obtained in an Asian population, but were extended to humans living in Africa and South America and are presently tested in liver fibrosis of other etiological origins.

A STAT6 gene polymorphism is associated with high infection levels in urinary schistosomiasis.

Th2-mediated immunity is critical for human defence against schistosome, and susceptibility to infection is controlled by a major genetic locus, mapped on the 5q31-q33 region comprising the genes IL4, IL5 and IL13. We have reported an association between the rs1800925 polymorphism in the IL13 promoter and infection levels in a Dogon population (693 subjects in Ségué and 148 in Boul), where Schistosoma haematobium is endemic. In the same population, we investigated whether other polymorphisms in genes involved in type 2 cytokine immune response could affect susceptibility to schistosome infection. By logistic regression analysis, we found an association between a single-nucleotide polymorphism (SNP) in the STAT6 gene (rs324013) and infection levels (P=0.04). We confirmed this association in analyses restricted to subjects under 20 years age and living in Boul, the village with the highest levels of infection (P=0.005). We detected an additive effect of the rs324013 and rs1800925 polymorphisms (P=0.011). These SNPs were not strongly correlated with any other tested markers surrounding the two genes. Furthermore, electrophoretic mobility shift assay has shown that both polymorphisms affect transcription factor binding. These results are consistent with the Th2 cytokine pathway enhancing resistance to schistosome infection in humans.

[Interleukin 13 and interleukin 13 receptor involvement in systemic sclerosis]. / Implication de l'interleukine 13 et de son récepteur dans la sclérodermie systémique.

PURPOSE: Interleukin 13 is an immunoregulatory cytokine predominantly secreted by activated Th2 cells. It has similar functions with interleukin 4 and they share a common receptor. However, unlike interleukin 4, l'interleukin 13 does not appear to be important in the initial differentiation of CD4 T into Th2-type cells, but rather appears to be necessary in the effector phase of inflammation and fibrosis. This cytokine has been involved in recent works in allergic inflammation and in some fibrotic diseases leading to a scientific interest to analysis the role of interleukin 13 in systemic sclerosis (scleroderma). MAIN POINTS: Systemic sclerosis is an autoimmune disease characterized by vascular alteration and skin and visceral fibrosis. A genetic background associated with susceptibility is supposed. Knowing the profibrogenic properties of interleukin 13, we asked if polymorphisms located in interleukin 13 and interleukin 13 receptor genes could be associated with systemic sclerosis. We observed significant associations between IL13 and IL13RA2 gene polymorphisms and the disease, particularly the cutaneous diffuse form of the disease. PERSPECTIVES AND PROJECTS: Results concerning the involvement of interleukin 13 pathway in systemic sclerosis need to be confirmed on another larger population. Functional studies will be done to explain the effect of these associations. We feel that IL13/IL13R pathway is interesting as immunomodulation with the interleukin 13 receptor inhibitor is possible in therapy.

Identification of a novel G245R polymorphism in the IL-2 receptor beta membrane proximal domain associated with human visceral leishmaniasis.

Binding of the interleukin-2 (IL-2) to the IL-2 receptor (IL-2R) triggers a series of intracellular events culminating in lymphocyte proliferation and differentiation. We report here the identification of a novel G245R polymorphism in the membrane proximal domain of the IL-2 receptor beta chain (IL-2Rbeta). Present at a frequency of 7.2%, the IL-2-Rbeta G245R was identified in a population of Eastern Sudan exposed to a severe outbreak of visceral leishmaniasis (VL), a disease associated with a marked depression of T-cell antigen-specific responses. The location of the G245R polymorphism next to the box1/box2 proximal cytokine receptor homology segment and suggestive genetic association with the development of disease (P=0.043), suggest that it may affect Janus kinase (JAK) association and impair growth signal transduction. However, additional genetic association with a synonymous single nucleotide polymorphism (IL2RB+8777T) suggests that other variations of IL2RB or nearby genes participate in the highly significant linkage with VL at 22q12 previously reported for this population.

An epidemiological study of familial neurocysticercosis in an endemic Mexican community.

Neurocysticercosis (NC) caused by Taenia solium is a frequent parasitic disease of the central nervous system. It is highly endemic in many developing countries, where many people are exposed but few become infected. Here, the relevance of age, gender, and genetic and exposure factors on NC susceptibility was studied in 649 inhabitants of a rural community of Mexico. Endemicity was confirmed by the high prevalence of pig cysticercosis (32.8%) and human seroprevalence (43.8%). Human NC cases were diagnosed by computerised tomography scans. A questionnaire to evaluate risk factors was applied and familial relationships between participants were registered. An overall NC frequency of 9.1% (59/649) was found. NC frequency increased with age but did not associate with gender. Most NC cases were asymptomatic. None of the evaluated risk factors were associated with NC. No familial aggregation was detected when studying all cases, although a significant relationship between mother and child in cases with multiple parasites was found. These findings point to the fact that human NC in high exposure conditions is not simply related to exposure factors and they do not support the participation of a major gene in single-cyst NC. Rather, our results point to a complex interaction of genetic and environmental factors involved in NC.

[Genetic factors predisposing to fibrosis in systemic sclerosis]. / Facteurs de prédisposition génétiques à la fibrose au cours de la sclérodermie systémique.

PURPOSE: Physiopathology of systemic sclerosis includes autoimmunity factors, endothelial lesions and abnormal fibrotic process which characterizes this disease in the field of systemic autoimmune disorders. Genetic factors of susceptibility are showed by possibility of familial forms of the disease, Choctaw American Indians homogenous population with high disease prevalence of systemic sclerosis and experimental animal models. KEY POINTS: We propose a review of the articles published to date in the literature concerning genetical analysis of genes coding for factors potentially involved in the fibrotic process of systemic sclerosis. This includes cytokines (TNF-alpha, interleukin-1, chemokines), growth factors (TGF-beta), extracellular matrix proteins (collagen, fibrillin, fibronectine) and agents acting on vascular tone (angiotensin-converting enzyme and NO synthase). PERSPECTIVES: Identification of genetic factors involved in the susceptibility to fibrosis of systemic sclerosis would lead to a better understanding of physiopathological mechanisms of this disease and to therapeutic targets using immunomodulation with drugs, such as already performed in rheumatoid arthritis.

Contrasting cellular responses in Schistosoma haematobium infected and exposed individuals from areas of high and low transmission in Zimbabwe.

The study compared cytokine profiles of individuals from two areas with different transmission patterns for Schistosoma haematobium. One area was a high transmission (HT) while the other was a low transmission (LT) area for S. haematobium. Observations on cellular immune responses were made on stimulated peripheral blood mononuclear cells (PBMC), which were collected pre-treatment, then at 12 and 18 months post treatment. Stimulation was with schistosome worm and egg antigens and a mitogen, phaetohaemaglutinin (PHA). Observations were made on PBMC proliferation and the profiles of cytokine produced over a 5-day incubation period. The two distinct areas showed significant differences on both levels of proliferation and cytokine production for all the measured classes (IL-4, IL-5, IL-10 and IFN-gamma). PBMC from individuals from the LT area had high levels of proliferation but low cytokine production to both antigen stimulants while PBMC from individuals from the HT area showed low levels of proliferation but high cytokine production levels. Prior to treatment, individuals not excreting schistosome ova in the HT area had higher levels of proliferation to the stimulants, than the infected individuals. However, after treatment re-infected individuals showed high levels of proliferation. Before treatment, both infected and uninfected groups showed low and similar ratios, respectively, of IL-4:IFN-gamma, IL-5:IFN-gamma and IL-10:IFN-gamma, while IFN-gamma was high in the infected individuals. After treatment the non re-infected had higher levels of IL-4, IL-5 and IL-10, with the infected having high levels of IFN-gamma. Th1-like response dominated during infection with the Th2-like responses dominating post treatment and in uninfected individuals. The results indicated that the cytokine balance determines, in part, susceptibility or resistance to S. haematobium infection.

Genetic control of visceral leishmaniasis in a Sudanese population: candidate gene testing indicates a linkage to the NRAMP1 region.

There is some evidence showing that genetic factors are involved in human susceptibility to parasitic diseases such as schistosomiasis and malaria. Studies have shown that the Nramp1 and H-2 genes are implicated in the control of Leishmania donovani infection in mice. We sought genetic loci involved in the control of susceptibility to visceral disease caused by L. donovani in humans. We studied 37 families with at least two affected sibs living in a village in eastern Sudan, where an outbreak of visceral leishmaniasis occurred between 1995 and 2000. The genetic markers located in five chromosomal regions containing candidate genes were typed: 2q35 (NRAMP1), 5q31-q33 (Th2 cytokine cluster), 6p21 (HLA/TNF-alpha), 6q23 (INFGRI) and 12q15 (INF-gamma). Linkage (multipoint lod-score=1.08; P=0.01) was observed for the 5'(CA) repeat polymorphism in the NRAMP1 promoter. This suggests that genetic variations of this gene affect susceptibility to visceral leishmaniasis in this population.

High prevalence of calcified silent neurocysticercosis in a rural village of Mexico.

Human neurocysticercosis (NC) is a parasitic disease caused by TAENIA SOLIUM when its larvae lodge in the central nervous system. NC prevalence estimates are obscured by the variable and often asymptomatic clinical picture. While infection depends on exposure, severity is possibly related with various host factors (immunity, genes and gender). This epidemiological study of cranial CT scans in an endemic rural community found that 9.1% of apparently healthy subjects had calcified lesions and were completely asymptomatic. Silent NC cases did not correlate with the exposure factors tested but showed family aggregation and higher rates of positive serology. Thus, NC prevalence may be higher than currently considered and host-related factors appear to be involved in infection and pathogenesis.

Antileishmanial antibodies in an outbreak of visceral leishmaniasis in eastern Sudan: high antibody responses occur in resistant subjects and are not predictive of disease.

A 3-year longitudinal survey was carried out from 1998 to 2000 in a village in eastern Sudan where a visceral leishmaniasis (VL) outbreak occurred. Leishmania-specific antibodies were analysed by enzyme-linked immunosorbent assay and immunoblotting. Immunoblot analysis detected antibodies to Leishmania in 80% of the healthy subjects and half of them harboured high immunoglobulin (Ig) G antibody levels, similar to those of VL patients. These antibodies belonged to the IgG1 and IgG3 subclasses but neither their respective levels nor the immunoblot recognition patterns were predictive of VL. During this epidemic, a large proportion of subjects had a high antileishmanial antibody response, indicating that they were infected by Leishmania though most of them remained healthy during the whole study period. These results obtained in the context of an outbreak contrast with those obtained from studies performed in endemic areas characterized by lower parasite transmission levels. Furthermore, the clinical and serological follow-up of our study subjects showed that VL occurred mainly in subjects who had been serologically positive for 5-24 months rather than resulting from primo infection by the parasite.

Five-year impact of repeated praziquantel treatment on subclinical morbidity due to Schistosoma japonicum in China.

We report the 5-year impact (1996-2001) of repeated praziquantel chemotherapy on subclinical morbidity related to Schistosoma japonicum infection. We repeated stool examinations and hepatosplenic ultrasonography in a cohort of 120 individuals living on an island with endemic infection in Dongting Lake, China. Prevalence of schistosome infection fell by 43% and intensity (geometric mean eggs per gram) declined by 80% over the 5 years. However, transmission persisted at a dangerously high rate of 13% per year for re-infection or new infection in the cohort. The prevalence of left-lobe enlargement and dilated portal vein fell significantly (P < 0.01) to about half initial levels although a few patients progressed during the study period. At study endpoint, infection was nearly twice as common if the portal vein was dilated (23% versus 13%, respectively), but this association was not statistically significant (P > 0.05). However, endpoint infection was even more strongly associated with left-lobe enlargement (57% versus 15%, P < 0.01). The proportions of subjects with improved parenchymal and periportal fibrosis were much higher than the proportions of subjects that progressed (P < 0.05). Reduction of prevalence and intensity of infection, and improvement of subclinical morbidity, were benefits of repeated treatments. Further research is needed to understand why some patients developed fibrosis despite substantial reductions in egg counts and to evaluate the functional importance of residual subclinical morbidity after chemotherapy-based control in the lake and marshland area of China.

The sandfly fauna in the visceral-leishmaniasis focus of Gedaref, in the Atbara-River area of eastern Sudan.

Visceral leishmaniasis (VL) is an acute public-health problem in Sudan. Between 1997 and 2000, four, brief entomological surveys were carried out in Barbar El Fugarra, a village in the state of Gedaref, in the Atbara-River area of eastern Sudan. Between 1996 and 1999, 658 cases of VL occurred among the village's population of about 4000. CDC miniature light-traps set inside and outside human dwellings were used to collect a total of 12,745 sandflies, including five species of the genus Phlebotomus and 19 of Sergentomyia. Phlebotomus papatasi and P. orientalis made up 7% and 5% of the collected sandflies, respectively. Seasonal variation was observed in the numbers of P. orientalis, P. papatasi, S. schwetzi and S. magna caught. Almost all (88%) of the sandflies collected were caught inside houses or granaries and there appeared to be particularly large indoor populations of P. orientalis, P. papatasi, S. schwetzi, S. magna and S. clydei. Phlebotomus orientalis could be responsible for the indoor transmission of the parasites causing the local VL, between humans and between humans and local dogs (which have been found infected by some of the Leishmania zymodemes found in humans). The co-occurrence in this focus of P. papatasi and Arvicanthis niloticus, which are known vectors and reservoir hosts, respectively, of L. major, indicates the possibility that outbreaks of human cutaneous leishmaniasis might occur in the area.

Description of three new polymorphisms in the intronic and 3'UTR regions of the human interferon gamma gene.

Interferon-gamma (IFN-gamma) is a key regulator of the development and functions of the immune system. In particular, this cytokine plays a major role in immune defense against infections by various human pathogens and polymorphisms in the IFN-gamma gene, including the transcription regulatory region, and might affect host resistance to infectious agents such as schistosomes. In this study on the genetics of human schistosomiasis we uncovered three new single nucleotide polymorphisms in the IFN-gamma genes. Two polymorphisms are located in the third intron and the third is in the 3'UTR region of this gene: an A to G transition at position +2109 from the transcription start and two G to A transitions at positions +3810 and +5134. In a SUDANESE population living in an endemic area of malaria and schistosomiasis, the allelic frequenciesare: 0.85 (+2109A), 0.15 (+2109G), 0.92 (+3810G), 0.08 (+3810A), (+5134G) and 0.04 (+5134A).

Two new polymorphisms in the human interferon gamma (IFN-gamma) promoter.

Two new single-nucleotide polymorphisms are described within the human interferon gamma (IFN-gamma) promoter in a Sudanese population. One is a G to T transition at position -183 from the transcription start. The other is a A to G transition at position -155. Allelic frequency analysis indicated frequencies of 0.927 (G) and 0.073 (T) at position -183 and 0.977 (A) and 0.023 (G) at position -155. These two polymorphisms have not been detected in the Centre d'Etude du Polymorphisme Humain (CEPH) reference population. The polymorphism -183(G-->T) may alter the AP-1 binding domain and the regulation of transcription. The polymorphism -155(A-->G) is located close to the nuclear factor-activated T-cell site (NFAT site) (-168 TAAAGGAAA-160) and may affect the stability of this region.

T cell clones from Schistosoma haematobium infected and exposed individuals lacking distinct cytokine profiles for Th1/Th2 polarisation.

T cell clones were derived from peripheral blood mononuclear cells of Schistosoma haematobium infected and uninfected individuals living in an endemic area. The clones were stimulated with S. haematobium worm and egg antigens and purified protein derivative. Attempts were made to classify the T cell clones according to production of the cytokines IL-4, IL-5 and IFN-gamma. All the T cell clones derived were observed to produce cytokines used as markers for the classification of Th1/Th2 subsets. However, the 'signature' cytokines marking each subset were produced at different levels. The classification depended on the dominating cytokine type, which was having either Th0/1 or Th0/2 subsets. The results indicated that no distinct cytokine profiles for polarisation of Th1/Th2 subsets were detected in these S. haematobium infected humans. The balance in the profiles of cytokines marking each subset were related to infection and re-infection status after treatment with praziquantel. In the present study, as judged by the changes in infection status with time, the T cell responses appeared to be less stable and more dynamic, suggesting that small quantitative changes in the balance of the cytokines response could result in either susceptibility or resistant to S. haematobium infection.

T cell clones from Schistosoma haematobium infected and exposed individuals lacking distinct cytokine profiles for Th1/Th2 polarisation

T cell clones were derived from peripheral blood mononuclear cells of Schistosoma haematobium infected and uninfected individuals living in an endemic area. The clones were stimulated with S. haematobium worm and egg antigens and purified protein derivative. Attempts were made to classify the T cell clones according to production of the cytokines IL-4, IL-5 and IFN-gamma. All the T cell clones derived were observed to produce cytokines used as markers for the classification of Th1/Th2 subsets. However, the 'signature' cytokines marking each subset were produced at different levels. The classification depended on the dominating cytokine type, which was having either Th0/1 or Th0/2 subsets. The results indicated that no distinct cytokine profiles for polarisation of Th1/Th2 subsets were detected in these S. haematobium infected humans. The balance in the profiles of cytokines marking each subset were related to infection and re-infection status after treatment with praziquantel. In the present study, as judged by the changes in infection status with time, the T cell responses appeared to be less stable and more dynamic, suggesting that small quantitative changes in the balance of the cytokines response could result in either susceptibility or resistant to S. haematobium infection