Human schistosomiasis mansoni: immune responses during acute and chronic phases of the infection.

Schistosoma mansoni infection may occur either as an acute infection in individuals who have recently visited an endemic area, with no previous contact with the parasite, or as a lasting chronic disease, if not interrupted by specific chemotherapy. The acute phase is characterized by symptoms such as fever, cough, diarrhea, anorexia, and arthralgias in combination with leukocytosis and eosinophilia, and a high cellular immune response to schistosome antigens especially those from the parasite's eggs. In the chronic phase, most patients living in endemic areas are asymptomatic, and their immune responses to egg antigens are modulated. A few develop periportal fibrosis of the liver, which may result in the hepatosplenic form of the disease. The humoral response (IgG, IgM and IgE) in acute patients to egg and worm antigens does not differ from the chronic phase. However, a high level of IgG and IgM antibodies to KLH were detected in acute patients. Acute patients express a considerably higher in vitro cellular responsiveness than do chronic patients, especially to egg antigens. They present a mixed profile of Th1 and Th2 cytokines. Ultrasound examinations of endemic population reveal a high heterogeneity between the patients as regards the presence and intensity of periportal fibrosis. Most patients are asymptomatic and their immune responses to schistosoma egg antigens (SEA) are modulated. In contrast, a high percentage of patients with incipient fibrosis (early stage of hepatosplenic) responded strongly to SEA. Patients with advanced hepatosplenic disease were likely to be non-responders to SEA. Most of the chronic patients presented a Th2 profile with low production of interferon-gamma (IFN-gamma). The intensity of infection favors the production of interleukin (IL)-10. After adjusting for age, sex, and intensity of infection, a strong correlation was observed between the production of IL-13 and the degree of fibrosis. Chronic asymptomatic patients and those with incipient fibrosis expressed very high levels of heterogeneity of their antibody responses. IgG response to soluble worm antigen preparation (SWAP) was distinct and significantly higher in hepatosplenic patients than in those asymptomatic or with incipient fibrosis. Levels of IgG4 to SEA were significantly higher in sera from patients with incipient fibrosis as compared to uninfected and hepatosplenic groups. Polyclonal idiotypic antibodies and their fragments F(ab')2, directly stimulate in culture T cells of schistosomiasis patients in presence of IL-1. Polyclonal idiotypic antibodies are able to modulate in vitro granuloma formation around SEA-polyacrylamide. The importance of idiotypes for protection or pathology in schistosomiasis is still not clear.

Cytokines, chemokine receptors, CD4+CD25HIGH+ T-cells and clinical forms of human schistosomiasis.

Previous studies have demonstrated that distinct immune response profiles can be correlated with the development/maintenance of different clinical forms of human schistosomiasis. We have previously shown that individuals with the more severe clinical forms of the disease such as those presenting different levels of fibrosis or with the hepatosplenic (HS) clinical form of the disease show significantly different immune response when compared with those with the intestinal clinical form (INT). To better understand the immune mechanisms associated with the clinical form of the schistosomiasis, in this study, we present the results of the evaluation, at a single cell level, of the cytokine patterns as well as the chemokine receptors expression by T-cell subsets after in vitro short-term stimulation with soluble egg antigens as well as the ex vivo frequency analysis of putative regulatory CD4+CD25HIGH+ T-cell subset in the peripheral blood mononuclear cells. We observed an increase on IL-4+, IL-5+ and IL-10+ cells both in the CD4+ and CD8+ lymphocytes in INT and a significant decrease on the number of IL-4+, IL-5+ and IL-10+ T-lymphocytes for HS. However, patients with detectable fibrosis presented decrease on IL-10+ (both CD4+ and CD8+ lymphocytes) and basal levels of IL-4 and IL-5. These data suggested that although INT group is under the influence of an effective immunoregulated immune response, mainly due to the high percentage of IL-10+ cells, it presents a mixed type (Type1/Type-2) immune profile. Moreover, the chemokine receptors expression demonstrated that CXCR3 and CXCR4 by CD4+ T-cells in INT may dictate the selective profile of IL-10 associated with the immunomodulatory events in human schistosomiasis. Additionally, the ex vivo analysis also suggests that higher levels of CD4+CD25HIGH+ T-cells may play a role in controlling morbidity in chronic human schistosomiasis. Taken together, these data suggest a major role of IL-10-producing CXCR4+ CD4+ T-cell subset for the asymptomatic outcome of the disease.

High expression of co-stimulatory and adhesion molecules are observed on eosinophils during human Schistosoma mansoni infection

Herein we have focused attention on major phenotypic features of peripheral blood eosinophils from chronic Schistosoma mansoni-infected patients. For this purpose, detailed immunophenotypic profiles of a range of cell surface markers were performed, including activation markers (CD23/CD69/CD25/HLA-DR), co-stimulatory molecules (CD28/CD80/CD86), chemokine receptors (CXCR1/CXCR2/CCR3/CCR5) besides L-selectin-CD62L and adhesion molecules (CD18/CD54). Our major findings pointed out increased frequency of CD23+-cells, besides decreased percentages of CD69+-eosinophils, suggesting a chronic activation status with low frequency of early activated eosinophils in chronic S. mansoni-infected patients (INT) in comparison to non-infected individuals (NI). Moreover, a dichotomic expression of beta-chemokine receptors was observed during human schistosomiasis mansoni with higher CCR5 and lower levels of CCR3 observed between groups. Enhanced expression of co-stimulatory receptors (CD28/CD86) and adhesion molecules (CD54/CD18), besides striking lower frequency of L-selectin+ were reported for eosinophils from INT group as compared to NI. Interestingly, the frequency of CD62L+-eosinophils and a range of cell activation related molecules pointed out an opposite pattern of association in NI and INT, where only INT patients that display lower frequency of CD62L+-eosinophils (first CD62L tertile) kept the unusual relationship between the expression of L-selectin and the CD23 activation marker. These findings suggest that distinct dynamic of activation markers expressed by eosinophils may occur during chronic S. mansoni infection.

High expression of co-stimulatory and adhesion molecules are observed on eosinophils during human Schistosoma mansoni infection.

Herein we have focused attention on major phenotypic features of peripheral blood eosinophils from chronic Schistosoma mansoni-infected patients. For this purpose, detailed immunophenotypic profiles of a range of cell surface markers were performed, including activation markers (CD23/CD69/CD25/HLA-DR), co-stimulatory molecules (CD28/CD80/CD86), chemokine receptors (CXCR1/CXCR2/CCR3/CCR5) besides L-selectin-CD62L and adhesion molecules (CD18/CD54). Our major findings pointed out increased frequency of CD23+-cells, besides decreased percentages of CD69+-eosinophils, suggesting a chronic activation status with low frequency of early activated eosinophils in chronic S. mansoni-infected patients (INT) in comparison to non-infected individuals (NI). Moreover, a dichotomic expression of beta-chemokine receptors was observed during human schistosomiasis mansoni with higher CCR5 and lower levels of CCR3 observed between groups. Enhanced expression of co-stimulatory receptors (CD28/CD86) and adhesion molecules (CD54/CD18), besides striking lower frequency of L-selectin+ were reported for eosinophils from INT group as compared to NI. Interestingly, the frequency of CD62L+-eosinophils and a range of cell activation related molecules pointed out an opposite pattern of association in NI and INT, where only INT patients that display lower frequency of CD62L+-eosinophils (first CD62L tertile) kept the unusual relationship between the expression of L-selectin and the CD23 activation marker. These findings suggest that distinct dynamic of activation markers expressed by eosinophils may occur during chronic S. mansoni infection.