Th2 Cytokines Are Associated with Persistent Hepatic Fibrosis in HumanSchistosoma japonicumInfection

Abstract

We conducted a prospective cohort study in Leyte, the Philippines, among 611 Schistosoma japonicum-infected participants 7-30 years old, all of whom were treated with praziquantel at baseline. To detect hepatic fibrosis, abdominal ultrasound was performed at baseline and 12 months after treatment. Stool for assessment of S. japonicum infection was collected at baseline and at 3, 6, 9, and 12 months after treatment. Cytokines (interleukin [IL]-4, IL-5, IL-10, IL-13, tumor necrosis factor- alpha , and interferon- gamma ) produced by peripheral-blood mononuclear cells in response to soluble worm antigen preparation (SWAP), soluble egg antigen (SEA), and control medium were measured once 4 weeks after treatment. IL-4 to SWAP and IL-10 to both SWAP and SEA were associated with the presence of baseline fibrosis after adjustment for potential confounding variables (P<.03, for all). In participants with fibrosis at baseline, IL-4 to SWAP and IL-5 and IL-13 to both SWAP and SEA were associated with persistent fibrosis at 12 months after treatment (P<.05, for all). Males showed consistently stronger T helper 2 (Th2) cytokine responses to both SWAP and SEA than did females (P<.02, for all). These results suggest an independent role for Th2-biased cytokine responses to S. japonicum antigens in persistent hepatic fibrosis and indicate that Th2 cytokines may contribute to the male-biased prevalence of fibrosis.

Age-Stratified Profiles of Serum IL-6, IL-10, and TNF-α Cytokines Among Kenyan Children with Schistosoma haematobium, Plasmodium falciparum, and Other Chronic Parasitic Co-Infections

“…The unforeseen lack of association between schistosomiasis-associated morbidities (anemia, wasting, and stunting) and pro-inflammatory cytokines previously seen in other endemic settings 5,18,19 might be explained by the intrinsic plasma level variability of cytokine levels when compared with laboratory responses seen in antigen T-cell-stimulating assays performed in other studies. [18][19][20] Co-infections could have also played an important role. For example, interactions across the immune responses to co-infecting parasites have been suggested in studies in Mali, where immune responses to acute malaria were blunted in children co-infected with urogenital schistosomiasis whose baseline production of IL-6, IL-4, IL-10, and interferon (INF)-γ was initially high.…”

“…18 Elevated pro-inflammatory TNF-α is associated with hepatic fibrosis in a S. mansoniendemic area in Uganda and S. japonicum-endemic settings in the Philippines and China. 6,20,27 Parasite-induced inflammation is thought to be part of the causal pathway of undernutrition and anemia. 5,6,9 Our results, however, did not show any association between IL-6 or TNF-α and the wasting, stunting, or anemia in this group of children.…”

Use of Ultrasonography to Evaluate Schistosoma japonicum-Related Morbidity in Children, Sichuan Province, China, 2000–2007

“…To identify abnormal measures, height-adjusted standards were published by Li and others 22 in 2004. These references have been used in research studies, 34 but they are not routinely used in Chinese hospitals and in the field where ultrasonographers use standard adult cutoffs for children. To our knowledge, this is the first documented study that compares both standards using community-based data from Chinese children living in a S. japoni cum -endemic area.…”

Maternal Infection with Schistosoma japonicum Induces a Profibrotic Response in Neonates

“…Chronic schistosomiasis is known to elicit production of Th2 cytokines, and this Th2 signature has been associated with the development of fibrosis in both human populations and animal models (5)(6)(7). In our earlier studies, stimulation of peripheral blood mononuclear cells (PBMCs) from S. japonicum-infected, nonpregnant individuals with schistosome soluble egg antigens (SEA) caused increased production of the Th2 cytokines interleukin 4 (IL-4) and IL-13, which were associated with increased risk of persistent fibrosis 12 months posttreatment (5).…”

“…In our earlier studies, stimulation of peripheral blood mononuclear cells (PBMCs) from S. japonicum-infected, nonpregnant individuals with schistosome soluble egg antigens (SEA) caused increased production of the Th2 cytokines interleukin 4 (IL-4) and IL-13, which were associated with increased risk of persistent fibrosis 12 months posttreatment (5). A number of other Th2 cytokines, profibrotic growth factors, and mediators of extracellular matrix (ECM) accumulation contribute to the development of fibrosis, including transforming growth factor ␤1 (TGF-␤1), thrombin, monocyte chemotactic protein 1 (MCP-1), and connective tissue growth factor (CTGF) (8).…”