Schistosomes are parasitic helminths that cause chronic infections in over 200 million people in tropical and sub-tropical areas around the world. Glycoproteins from the eggs of the parasite... Show moreSchistosomes are parasitic helminths that cause chronic infections in over 200 million people in tropical and sub-tropical areas around the world. Glycoproteins from the eggs of the parasite Schistosoma mansoni induce various immune responses in the human host, including T-cell modulation and granuloma formation. Three major, immunogenic egg glycoproteins have been identified; omega-1, IPSE/_1 and kappa-5. The studies in this thesis have unraveled structural and molecular details of the interaction between these three glycoproteins and innate immune cells of the host. Firstly, we have studied the structural details of the N-glycans expressed on these three glycoproteins. Most notably, omega-1 and IPSE/_1 carry diantennary N-glycans which mainly display Lewis X motifs, while kappa-5 expresses triantennary N-glycans with LDN motifs. Then, we have investigated the interaction of the egg glycoproteins with C-type lectin receptors on antigen-presenting immune cells. We show that specific glycan motifs on the egg glycoproteins determine differential binding to these lectin receptors. Finally, we have investigated functional effects of omega-1 and kappa-5. We show that the Th2-modulating capacity of omega-1 is dependent on both glycan-lectin interactions as well as its RNase activity. We found that kappa-5 contains granuloma-inducing properties, which are partly mediated by its LDN motifs. Show less
Parasitic worms of the genus, Schistosoma, infect millions of people mainly in the tropics and can cause serious morbidity. Human schistosoma infection is often associated with strong T helper 2... Show moreParasitic worms of the genus, Schistosoma, infect millions of people mainly in the tropics and can cause serious morbidity. Human schistosoma infection is often associated with strong T helper 2 polarized immune responses as well as immunehyporesponsiveness. Dendritic cells play a central role in sensing of pathogens and generation of appropriate immune responses against these pathogens. This thesis describes that human schistosoma infection suppresses phenotype and T cell polarizing capacity of dendritic cells present in blood of these subjects. Furthermore, in vitro studies identified molecular markers in dendritic cells that can be used to predict whether these cells will induce T helper 1 or 2 responses following exposure to Th1-polarizing bacterial extracts or Th2- skewing lipids derived from schistosoma worms. Finally, the identification of the major Th2-polarizing component secreted by schistosoma eggs and the molecular mechanisms through which this factor instructs dendritic cells to drive this response is described. Taken together, these studies provide new insights in the molecular interplay between dendritic cells and schistosomes and as such in the cellular and molecular mechanisms behind shaping of T helper 2 immune responses and/or immunehyporesponsiveness observed during these parasitic worm infections. Show less
Multiple Sclerosis is a degenerative disease of the central nervous system (CNS), involving autoimmunity against myelin, resulting in demyelination and paralysis. Antigen-specific immunotherapy may... Show moreMultiple Sclerosis is a degenerative disease of the central nervous system (CNS), involving autoimmunity against myelin, resulting in demyelination and paralysis. Antigen-specific immunotherapy may reduce this pathological autoimmunity, without disturbing normal immune function. This could be achieved by targeting of myelin antigens towards C-type lectin receptors (CLR) that recognize carbohydrate structures and are expressed on immune cells, because targeting of CLR under steady state conditions can suppress immunity in an antigen-specific way. In vitro studies showed that mannosylation of peptides results in internalization via the mannose receptor. In this study we observed, that immunization with mannosylated peptide does not induce disease in EAE, a model for Multiple Sclerosis. Instead, antigen-specific tolerance was induced; CNS inflammation was absent and DTH responses were impaired. Using transfer of TCR transgenic T cells in vivo we visualized that immunization with mannosylated peptide enhanced antigen presentation and induced vigorous expansion of T cells. However, T cells showed reduced blast formation and did not transfer EAE, despite normal production of inflammatory cytokines and chemokines. Lymphocytes accumulated in the lymph node of tolerized mice, which was counteracted by injection of Pertussis Toxin. Established EAE or ongoing DTH responses were ameliorated after mannosylated peptide treatment. In conclusion, mannosylated myelin peptide induced tolerance to EAE due to incomplete differentiation of encephalitogenic T cells and can be used to treat ongoing autoimmunity. Therefore, mannosylated antigens may represent a novel therapeutic approach for antigen-specific modulation of autoreactive T cells in vivo. Show less
