© 2007 The Authors 241 Journal compilation © 2007 Blackwell Publishing Ltd Parasite Immunology , 2007, 29, 241–249 DOI: 10.1111/j.1365-3024.2007.00939.x Blackwell Publishing Ltd ORIGINAL ARTICLE Immune responses in chronic schistosomiasis Early responses associated with chronic pathology in murine schistosomiasis C. B. CÊTRE-SOSSAH, 1 M. A. MONTESANO, 2 G. L. FREEMAN, Jr., 3 M. T. WILLARD, 4 D. G. COLLEY 5 & W. E. SECOR Division of Parasitic Diseases, Centers for Disease Control and Prevention, Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA, USA SUMMARY Inbred male CBA/J mice infected with Schistosoma mansoni develop either hypersplenomegaly syndrome (HSS) or moderate splenomegaly syndrome (MSS) by 20 weeks of infection. Pathologically and immunologically, MSS and HSS closely parallel the intestinal and hepatosplenic clinical forms of schistosomiasis in humans, respectively. By 6 weeks after infec- tion, mice that eventually will become MSS develop T cell- stimulatory, cross-reactive idiotypes (CRI) while HSS mice never produce CRI. Because presence of CRI is useful to predict degree of chronic pathology, we used this measure to investigate what other early immunological events occurred in animals destined to develop severe morbidity. At 8 weeks of infection, there was a strong inverse correlation between CRI and splenomegaly, egg counts, and liver hydroxyproline. Similarly, phorbol myristate acetate (PMA)- and ionomycin-stimulated intracellular cytokine expression of IL-4, IL-5, and GM-CSF in splenic CD4 + T cells was inversely correlated with serum CRI and directly correlated with spleen size. In contrast, spleen cell intracellular TNF-α and peritoneal cell production of nitric oxide demonstrated positive correlations with CRI and inverse correlations with measures of morbidity. Surpris- ingly, IL-10 and IFN-γ were not correlated with CRI levels. These studies link chronic pathology to certain immunological responses during the acute phase of schistosomiasis. Keywords cytokines, idiotypes, mice, schistosomiasis, splenomegaly INTRODUCTION Most persons with chronic Schistosoma mansoni infections may suffer a variety of subtle morbidities, but do not develop severe hepatosplenic disease (1). Patients with this ‘intestinal’ form of schistosomiasis experience fatigue and only occa- sional gastrointestinal discomfort and anaemia despite the continued presence of adult schistosome worms in the mesenteric vasculature. In contrast, a relatively small proportion of infected individuals progress to develop the severe hepatosplenic form of the disease, which is characterized by hepatosplenomegaly, periportal fibrosis, portal hypertension, ascites, esophageal varices, collateral circulation, haematemesis, and, if untreated, death (2). The factors that determine whether an individual develops the intestinal or hepatosplenic form of chronic schistosomiasis are poorly understood, but many studies have implicated a role for immunoregulatory mechanisms in this process (3–6). Investigation of this hypothesis has been limited by the absence of an animal model that predictably develops such a spectrum of disease. Over the last several years, we have studied inbred male CBA/ J mice with chronic S. mansoni infections that develop one of two distinct pathophysiological syndromes by 20 weeks of infection: hypersplenomegaly syndrome (HSS) or moderate splenomegaly syndrome (MSS) (7,8). MSS and HSS remark- ably parallel the intestinal and hepatosplenic clinical forms, respectively, observed in human schistosomiasis. HSS affects approximately 20% of these mice and presents with massive splenomegaly, ascites, thymic atrophy, severe anaemia, and cachexia. The remaining majority of mice develop only moder- ate splenomegaly. Histopathological features of HSS include Correspondence: W. Evan Secor, Division of Parasitic Diseases, Centers for Disease Control and Prevention, 4770 Buford Highway, NE, MS-F13, Atlanta, GA 30341-3724, USA (e-mail: was4@cdc.gov). 1 Current Address: Virology Unit, CIRAD-EMVT, Campus International de Baillarguet, TA 30/G, 34398 Montpellier Cedex 5, France. 2 Current Address: Division of Laboratory Science, National Center for Environmental Health, Centers for Disease Control and Prevention, 4770 Buford Highway, NE, Atlanta, GA 30341, USA. 3 Deceased. 4 Current Address: Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. 5 Current Address: Center for Tropical and Emerging Global Diseases, 145 Coverdell Center, University of Georgia, Athens, GA 30602, USA. Received: 30 November 2006 Accepted for publication: 1 December 2006