Dendritic cells (DCs) are pivotal in determining the class of an adaptive immune response. However, the molecular mechanisms within DCs that determine this decision-making process are unknown. Here, we demonstrate that distinct Toll-like receptor (TLR) ligands instruct human DCs to induce distinct Th cell responses by differentially modulating mitogen-activated protein kinase signaling. Thus, Escherichia coli LPS and flagellin, which trigger TLR4 and TLR5, respectively, instruct DCs to stimulate Th1 responses via IL-12p70 production, which depends on the phosphorylation of p38 and c-Jun N-terminal kinase 1/2. In contrast, the TLR2 agonist, Pam3cys, and the Th2 stimulus, schistosome egg Ags: 1) barely induce IL-12p70; 2) stimulate sustained duration and magnitude of extracellular signal-regulated kinase 1/2 phosphorylation, which results in stabilization of the transcription factor c-Fos, a suppressor of IL-12; and 3) yield a Th2 bias. Thus, distinct TLR agonists differentially modulate extracellular signal-regulated kinase signaling, c-Fos activity, and cytokine responses in DCs to stimulate different Th responses.

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The pathogenesis of Schistosoma mansoni infection is largely determined by host T-cell mediated immuneSchistosomiasis is a debilitating parasitic disease affecting about 200 million people in 70 countries in the world and is caused by one of the three different species of Schistosoma: S. mansoni, S. haematobium, and S. japonicum. The major pathology of these parasitic infections is associated with a host delayed type hypersensitivity reaction to parasitic egg and egg products. Granulomatous inflammation is a cellular hypersensitivity reaction mediated by egg antigen-specific, MHC class II-restricted, TCR αβ expressing, CD4 + T helper cells (Iacomini et al. 1995). Patients infected with S. mansoni mount cellular and humoral immune responses to soluble egg antigens derived from crude homogenates of eggs. Thus, the end result of host responses to schistosome eggs in the liver is advanced portal fibrosis with dense deposits of collagens in greatly expanded portal tracts (El-Zayadi 2004). The immune reaction produced by the body against the schistosomal infection is a double-weaponed arm. Unfortunately, the harmful weapon is the longest and the most powerful. That is the immune reaction against the schistosomal egg causing the schistosomal granuloma. The other weapon of the immune system that should be lengthened and empowered is the protective immune response against infection, egg production and/or the granuloma formation. Many researchers have been doing their best to get the suitable agent that can stimulate the maximal, specific immune response against schistosomiasis (Goes & Hirsch 1996).Considerable efforts have been exerted to determine which S. mansoni antigens induce and elicit T cell-mediated responses and granuloma formation (Goes & Hirsch 1996). Several laboratories have isolated various antigens from crude soluble egg anigens (SEA) and soluble worm antigens (SWAP), and investigated their role in serology, blastogenic reactions, and granuloma responses to SEA (Bahia-Oliveira et al. 1997). These studies revealed a variety of biologically active antigenic moeities derived from S. mansoni antigen preparations (Goes & Hirsch 1996). One antigen, Smp40 (major egg antigen p40), has been described as highly immunogenic in humans and has been cloned and sequenced (Cao et al. 1993). The Smp40 peptide has 354 amino acid residues and shares homologies with the family of heat shock proteins and α-crystallins. There is evidence that α-crystallins act as chaperone for other important egg antigens released during the migra- tion phase of the eggs in the hepatic system (Nene et al. 1986). The immune response to Smp40 and Smp40 overlapping peptides can be studied in the cellular proliferation assays with the addition of either anti-interleukin (IL)-10 or IL-2 to overcome anergy. In the last decade, substantial resources have been invested to identify, characterize, and purify various schistosome antigens for the purpose of designing and testing potential vaccines. In fact, elucidation of egg antigens has received much les...

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The prostaglandins (PG) are known to regulate immune cell function(s) and participate in the progression of both acute and chronic inflammatory reactions. Using an in vitro model of Schistosoma mansoni egg-induced hypersensitivity granulomas, we have delineated the role of immune complexes (IC) in the induction and release of PG and their inhibitory effects on granuloma development. The hypersensitivity-type granuloma reaction to soluble egg antigen (SEA) was examined using a model of in vitro granuloma formation. Our results show that granuloma formation was dramatically suppressed by the addition to the granuloma cultures of IC, PGE1, PGE2, while PGF2 alpha had no significant effect. The inhibition of the PG function was achieved by the introduction of anti-PG antibodies that blocked suppression of granuloma formation. It appears in this model system that IC may inhibit the activity of granuloma formation by stimulating the monocyte-macrophage lineage to release inhibitory mediators. Our results suggest that the prostaglandins E series may be important in the generation and maintenance of suppression of the granulomatous inflammatory response to S. mansoni egg antigens.