Sandrine Marquet

Severe Hepatic Fibrosis in Schistosoma mansoni Infection Is Controlled by a Major Locus That Is Closely Linked to the Interferon-γ Receptor Gene

Lethal disease due to hepatic periportal fibrosis occurs in 2%-10% of subjects infected by Schistosoma mansoni in endemic regions such as Sudan. It is unknown why few infected individuals present with severe disease, and inherited factors may play a role in fibrosis development. Schistosoma mansoni infection levels have been shown to be controlled by a locus that maps to chromosome 5q31-q33. To investigate the genetic control of severe hepatic fibrosis (assessed by ultrasound examination) causing portal hypertension, a segregation analysis was performed in 65 Sudanese pedigrees from the same village. Results provide evidence for a codominant major gene, with.16 as the estimated allele A frequency predisposing to advanced periportal fibrosis. For AA males, AA females, and Aa males a 50% penetrance is reached after, respectively, 9, 14, and 19 years of residency in the area, whereas for other subjects the penetrance remains <.02 after 20 years of exposure. Linkage analysis performed in four candidate regions shows that this major locus maps to chromosome 6q22-q23 and that it is closely linked (multipoint LOD score 3.12) to the IFN-gammaR1 gene encoding the receptor of the strongly antifibrogenic cytokine interferon-gamma. These results show that infection levels and advanced hepatic fibrosis in human schistosomiasis are controlled by distinct loci; they suggest that polymorphisms within the IFN-gammaR1 gene could determine severe hepatic disease due to S. mansoni infection and that the IFN-gammaR1 gene is a strong candidate for the control of abnormal fibrosis observed in other diseases.

Interleukin-13 in the skin and interferon-gamma in the liver are key players in immune protection in human schistosomiasis.

Summary:u2002 Immunity against schistosomes includes anti‐infection immunity, which is mainly active against invading larvae in the skin, and anti‐disease immunity, which controls abnormal fibrosis in tissues invaded by schistosome eggs. Anti‐infection immunity is T‐helper 2 (Th2) cell‐dependent and is controlled by a major genetic locus that is located near the Th2 cytokine locus on chromosome 5q31‐q33. Mutations in the gene encoding interleukin (IL)‐13 that decrease or increase IL‐13 production account, at least in part, for that genetic control. In contrast, protection against hepatic fibrosis is dependent on interferon (IFN)‐γ and is controlled by a major genetic locus that is located on 6q23, near the gene encoding the IFN‐γ receptor β chain. Mutations that modulate IFN‐γ gene transcription are associated with different susceptibility to disease. These data indicate that IL‐13 in the skin and IFN‐γ in the liver are key players in protective immunity against schistosomes. These roles relate to the high anti‐fibrogenic activities of IFN‐γ and to the unique ability of IL‐13 in Th2 priming in the skin and in the mobilization of eosinophils in tissues. The coexistence of strong IFN‐γ and IL‐13‐mediated immune responses in the same subject may involve the compartmentalization of the anti‐schistosome immune response between the skin and the liver.

Evidence That Interferon-γ Plays a Protective Role during Cerebral Malaria

BACKGROUND The pathogenic mechanisms of cerebral malaria (CM) are unclear but are thought to involve cytokine-mediated inflammation enhanced by parasite sequestration in the brain microcirculation. The role that interferon (IFN)-gamma could play that would enhance inflammation but also reduce parasitemia is unclear. METHODS Plasma IFN-gamma concentrations were measured by enzyme-linked immunosorbent assay in 96 children with CM and 40 children with uncomplicated malaria (UM) who had been recruited from Gabriel Toure Hospital (Bamako, Mali). We investigated the relationship between IFN- gamma concentrations and disease by nonparametric analysis. Polymorphisms in IFNG were characterized by restriction enzyme analysis or size-determination electrophoresis. Associations between polymorphisms and CM were evaluated by the family-based association test on 240 families. RESULTS During episodes of malaria, IFN-gamma concentrations were lower in children with CM than in children with UM (P = .007). IFNG-183T (P = .009) and IFNG-183G/T (P = .013) were found to be less frequent than expected in children with CM. A trend toward association was also observed between IFNG(CA)14/(CA)14 (P = .073) and CM. The IFNG-183G/T and IFNG(CA)14/(CA)14 genotypes were more frequent in children with UM than in children with CM (odds ratio, 0.30 and 0.34, respectively). CONCLUSIONS The low plasma IFN- gamma concentrations in children with CM and the associations between a reduced risk of CM and (1) the IFNG-183T allele (which increases gene transcription) and (2) the IFNG-183G/T genotype are consistent with the concept that IFN-gamma protects against CM.

A functional promoter variant in IL12B predisposes to cerebral malaria

The role of the Th1 pathway in the pathogenesis of severe malaria is unclear. We recently reported that a polymorphism with increasing IFNG transcription is associated with protection against cerebral malaria (CM). Interleukin-12 is required for Th1 cell differentiation, which is characterized by the production of interferon-gamma. We investigated 21 markers in IL12-related genes, including IL12A and IL12B encoding the two IL-12 (IL12p70) subunits, IL12p35 and IL12p40. We performed a family-based association study using a total sample set of 240 nuclear families. The IL12Bpro polymorphism was associated with susceptibility to CM. The CTCTAA allele and the GC/CTCTAA genotype are over-transmitted to children with CM (P = 0.0002 and 0.00002, respectively). We estimated the odds ratio to be 2.11 for risk of CM in heterozygous children [(95% confidence interval, 1.49-2.99); P < 0.0001]. Although the CTCTAA allele had a dominant effect on CM susceptibility, this effect is much stronger in heterozygous children, consistent with the functional effects of this allele in a heterozygous form. Heterozygosity for this polymorphism has been associated with reduced expression of the gene encoding IL12p40 and a low level of IL12p70 production. These results, together with the findings from immunological studies of low interferon-gamma and IL-12 levels in CM, support a protective role for the Th1 pathway in CM.

Gene Expression Analysis Reveals Genes Common to Cerebral Malaria and Neurodegenerative Disorders

Cerebral malaria, a reversible encephalopathy affecting young children, is a medical emergency requiring urgent clinical assessment and treatment. We performed a whole-transcriptomic analysis of blood samples from Malian children with cerebral or uncomplicated malaria. We focused on transcripts from pathways for which dysfunction has been associated with neurodegenerative disorders. We found that SNCA, SIAH2, UBB, HSPA1A, TUBB2A, and PINK1 were upregulated (fold-increases, ≥2.6), whereas UBD and PSMC5 were downregulated (fold-decreases, ≤4.39) in children with cerebral malaria, compared with those with uncomplicated malaria. These findings provide the first evidence for pathogenic mechanisms common to human cerebral malaria and neurodegenerative disorders.

Susceptibilité génétique aux infections parasitaires humaines: étude de la bilharziose

Une etude familiale effectuee dans une population exposee aux schistosomes montre que la resistance humaine a la bilharziose est sous le controle dun gene majeur et quun polymorphisme au niveau de ce locus explique en grande partie les differences de susceptibilite a linfection. Des etudes dassociation effectuees sur des sujets exposes aux parasites a lorigine du paludisme et de la leishmaniose indiquent egalement un controle genetique de la susceptibilite humaine a ces infections et aux pathologies qui leur sont associees.