IL-4 and reactive oxygen species are elevated in Egyptian patients affected with schistosomal liver disease.

UNLABELLED: Schistosomiasis is a chronic liver disease that is endemic in rural areas of Egypt. Some patients may acquire infection and develop minimal complications while others may develop severe complications and progress to portal hypertension and cirrhosis especially if co-infected with hepatitis C virus (HCV). The reasons for this are poorly understood. Previous studies suggested an independent role for Th2-biased cytokine responses to schistosomal antigens in persistent hepatic fibrosis and development of complications. Studies in murine schistosomiasis demonstrated that the development of fibrosis requires the production of the profibrotic cytokines such as IL-4. On the other hand, previous studies have suggested that reactive oxygen species may play an important role in schistosomal granuloma formation and disease progression AIM: To investigate the status of the profibrotic IL-4 cytokine, oxidative stress (as indicated by thiobarbituric acid reactive substances), the antioxidants enzymes catalase and red blood cells glutathione content in a cohort of Egyptian patients affected with schistosomal hepatic disease and or hepatitis C infection. MATERIALS AND METHODS: The current study included four groups: patients with isolated HCV infection (HCV), comprised of 22 patients aged (mean +/- SD) 51.3 +/- 4.7 years; patients with HCV and schistosomal hepatic fibrosis (SHF) (Co-infected patients), comprised of 22 patients aged 49.6 +/- 4.0 years, patients with pure chronic schistosomiasis comprised of 22 patients with chronic schistosomiasis aged 53.7 +/- 5.6 years and a control group, comprised of 22 control subjects aged 48.5 +/- 5.4 years. Thiobarbituric acid reactive substances (TBARS), Catalase activity and red blood cells glutathione contents were determined using chemical methods while plasma IL-4 was determined using a commercially available ELISA kit. RESULTS: A significant reduction in erythrocyte catalase activity in patients with isolated HCV infection, isolated SHF and those co-infected with SHF and HCV compared with the control group was found (P < 0.05). A similar pattern was found regarding erythrocyte glutathione content. Conversely TBARS level were significantly increased in patients with HCV, SHF and mixed groups compared with the control group (P < 0.05). Plasma IL-4-values were significantly increased in the three groups compared to the control subjects group. Furthermore, plasma IL-4 was significantly higher in patients with isolated SHF and those with SHF + HCV compared to the HCV alone patient group. Plasma IL-4 also correlated positively with portal vein diameter in SHF and SHF . HCV groups. (r = 0.54 and P < 0.05). Furthermore when all patients were analysed collectively, there was a positive correlation between plasma IL-4 and right lobe of the liver and plasma TBARS concentration. CONCLUSION: Schistosomal infection triggers a Th2 type immune response as indicated by the high plasma IL-4. It also triggers an increase in reactive oxygen species levels. These effects especially IL-4 lead to more reduction in the level of antioxidants enzymes (that may be already compromised in malnourished schistosomal patients) with the resultant disease progression and development of complications.

In Egyptians, a mutation in the lymphotoxin-alpha gene may increase susceptibility to hepatitis C virus but not that to schistosomal infection.

In Egypt, human schistosomiasis is a chronic endemic disease that can produce portal hypertension and occasionally death. Curiously, most Egyptian cases of the disease are complicated by co-infection with hepatitis C virus (HCV), the co-infection generally resulting in more severe liver disease than seen in those only infected with HCV. The high frequency of co-infection may be the result of transmission of the virus during parental schistosomal therapy or schistosomiasis-related surgery but it also seems possible that certain individuals are particularly susceptible to both schistosome and HCV infection. Lymphotoxin-alpha (LTalpha) participates in inflammatory responses, and single-nucleotide polymorphisms (SNP) in the human LTalpha gene have recently been found to have profound effects on individual susceptibility to various diseases, including some of those caused by parasitic infection. The possibility that the SNP that create an NcoI restriction site in the gene are associated with increased susceptibility to schistosomal and/or HCV infection has now been investigated in the Egyptian city of Alexandria. The subjects investigated were 22 patients infected only with HCV, 44 cases of schistosomal hepatic fibrosis (SHF) who were either co-infected with HCV (22) or HCV-free (22), and 22 apparently healthy, schistosome-free and HCV-free controls. When each of these subjects was tested for the NcoI polymorphism in their LTalpha gene, by PCR-RFLP, those with isolated HCV infection and those co-infected with Schistosoma and HCV (but not those infected with Schistosoma alone) were found significantly more likely to carry the mutation than the control subjects (P<0.05). When the cases of SHF were pooled together (irrespective of HCV-infection status), they were not found significantly more likely to have the mutation than the controls. At least in Egypt, therefore, the LTalpha mutation may have a role in susceptibility to HCV infection (and the subsequent development of clinical manifestations) but appears to have little if any effect on susceptibility to schistosome infection. Larger studies are now needed to confirm these results.