No Evidence for a Major Effect of Tumor Necrosis Factor Alpha Gene Polymorphisms in Periportal Fibrosis Caused by Schistosoma mansoni Infection

Carole Moukoko Eboumbou (1) , Nasureldin El Wali (2) , O. K. Saeed (3) , Qurashi Mohamed-Ali (2) , Jean Gaudart (4, 5) , Alain Dessein (1) , Christophe Chevillard (1)

1 GIMP - Génétique et immunologie des maladies parasitaires
2 University of Gezira
3 LMSP - Laboratoire de Mécanique des Systèmes et des Procédés
4 AMU - Aix Marseille Université
5 SESSTIM - U912 INSERM - Aix Marseille Univ - IRD - Sciences Economiques et Sociales de la Santé & Traitement de l'Information Médicale

Hepatic periportal fibrosis (PPF), associated with portal hypertension, is a major pathological consequence of infections with Schistosoma mansoni and Schistosoma japonicum. Indeed, affected subjects may die from portal hypertension. Previous studies have indicated that tumor necrosis factor alpha (TNF-␣) may aggravate fibrosis. We therefore investigated whether PPF was associated with certain polymorphisms of the TNF-␣ gene. Four polymorphisms (TNF-␣ ؊376 G/A, ؊308 G/A, ؊238 G/A, and ؉488 G/A) were investigated in two Sudanese populations living in an area in which S. mansoni is endemic. These polymorphisms were analyzed for 105 Sudanese subjects with various grades of PPF, from mild to advanced; all subjects were from two neighboring villages (Taweela and Umzukra). They were then analyzed for 70 subjects with advanced liver disease and for 345 matched controls from the Gezira region. We found no evidence of associations between these four polymorphisms and PPF in both of these studies. Thus, these four polymorphisms, two of which (TNF-␣ ؊376 and ؊308) were found to increase TNF-␣ gene transcription, are unlikely to have a major effect on PPF progression in these populations. However, this result does not exclude the possibility that these polymorphisms have a minor effect on PPF development. Schistosomiasis is a serious public health problem affecting over 200 million people in developing countries (15, 41). Most of the infections occurring in areas where schistosomes are endemic are asymptomatic. However, 5 to 15% of infected individuals develop severe disease with Symmers fibrosis. Schistosomes (Schistosoma mansoni) produce several hundred eggs per day, and a proportion of these eggs are trapped in hepatic tissues and in presinusoidal venules. There, they induce a granulomatous inflammation that leads, in certain subjects , to the accumulation of scar tissue in the periportal spaces. Periportal fibrosis (PPF) causes venous obstruction and portal blood hypertension and contributes to the development of splenomegaly. Severely affected patients develop esopha-geal varices, ascites, and cachexia, resulting in death in the absence of treatment. Fibrosis, which involves stellate (Ito) cells derived from fibroblasts, results from an imbalance between the positive and negative regulatory mechanisms controlling the production and degradation of extracellular matrix proteins (ECMP). The production of collagen and ECMP is stimulated by a variety of cytokines and growth factors (inter-leukin-1 [IL-1], IL-4, IL-13, tumor necrosis factor alpha [TNF-␣]), monocyte chemotactic protein 1, platelet-derived growth factors, and transforming growth factor ␤), which stimulate fibroblast differentiation and the production of ECMP by fi-broblasts, Kupffer cells, and endothelial cells (14, 16, 22, 30). Other cytokines, such as alpha interferon (IFN-␣) and IFN-␥,

Domaines: Santé; Maladies infectieuses; Parasitologie; Santé publique et épidémiologie; Applications [stat.AP]

Carole Moukoko Eboumbou, Nasureldin El Wali, O. K. Saeed, Qurashi Mohamed-Ali, Jean Gaudart, et al.. No Evidence for a Major Effect of Tumor Necrosis Factor Alpha Gene Polymorphisms in Periportal Fibrosis Caused by Schistosoma mansoni Infection. Infection and Immunity, 2003, 71 (10), pp.5456-5460. ⟨10.1128/IAI.71.10.5456–5460.2003⟩. ⟨hal-01211756⟩