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Address reprint requests to Dr. Maryland, Chicago, Illinois Oxford Academic. Google Scholar. Janice Lyon Kluskens, M.
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Marluce Bibbo, M. Cite Citation. Permissions Icon Permissions. Abstract The relative increase in endometrial adenocarcinoma in women has increased the need for more objective criteria in the distinction of hyperplastic and neoplastic endometrium. Issue Section:. You do not currently have access to this article. Download all figures. Sign in. You could not be signed in. Sign In Forgot password? Mutations affecting the calcium-dependent fucose- or mannose-binding site prevented the expression of CDa. However, nearby surfaces involving residues analogous to Y and L of CDa influence the specificity of CLR-glycan interactions 56 , This strongly suggests that the specific recognition of a schistosome-derived ligand by CDa is required to initiate proinflammatory signaling pathways Figure 1.
Hypothetical model of CDa binding Lewis X. The Lewis X trisaccharide blue is predicted to bind CDa tan.
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Side chains involved in calcium or sugar binding are shown. Calcium ions are shown in green; side chain oxygen and nitrogen atoms are shown in red and blue, respectively. In this model of CDa, R, and D are oriented toward the ligand-binding site. To clarify the nature of the schistosome-derived ligand s that triggers CDa-dependent signals we generated recombinant CDa chimeras via a tandem affinity purification tag placed at the amino-terminus of the full-length receptor.
Using this recombinant protein, we were able to screen a glycan library for the first time. Although no overwhelming candidates were identified, there was a trend toward the recognition of multi-antennary glycan structures containing Lewis-related antigens, consistent with the properties of the DC-SIGN receptor family.
This directs the acetylation of p65, which enhances the activity of p65 and enables p65 to antagonize non-canonical RelB signaling 44 , It remains to be seen whether the murine homologs of DC-SIGN are capable of directing Th2-promoting events when presented with fucosylated ligands, or whether the murine CD family members have evolved fixed, specialized, proinflammatory functions.
Figure 2. CDa synergizes with Dectinrelated receptors to drive the pro-inflammatory cytokine responses triggered by live schistosome eggs. Schistosome egg ligands interact with Dectin-2, Mincle, and CDa.
Our recent work suggests that variable function of DC-SIGN may not need to be dictated by the recognition of distinct ligands but may instead be determined by the combinatorial detection of ligands by additional receptors. In particular, we confirmed that the pattern-recognition receptor Dectin-2 plays a role in the detection of schistosome-derived glycans and revealed that synergy between CDa and Dectin-2 maximizes the proinflammatory cytokine responses initiated by live schistosome eggs 37 , Dectin-2 is a member of a group of CLRs that includes Mincle, Dectin-3, and the dendritic cell activating receptors, Dcar1 and Dcar2 Infection with schistosomes can result in clinical syndromes of dissimilar severity.
In the experimental model, with genetically inbred mouse strains, identical parasite loads and similar infection protocols, disease heterogeneity is largely based on the predominant activation of pro- vs. Here we have described the synergistic crosstalk of egg antigen-sensing CLRs CDa with Dectin-2 and Mincle, and analyzed how the interaction of their respective signaling pathways results in the activation of pathogenic Th17 cell responses and the consequent development of severe egg-induced immunopathology.
The broader implication of our findings is the knowledge that receptors can collaborate with one another to shape immunopathological responses in a combinatorial fashion and that their signaling pathways can be individually targeted for the purpose of ameliorating disease.
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All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Human schistosomiasis. Lancet — Hotez PJ, Fenwick A. Schistosomiasis in Africa: an emerging tragedy in our new global health decade.
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Variation of hepatic fibrosis and granuloma size among mouse strains infected with Schistosoma mansoni. Am J Trop Med Hyg. Differential antigen recognition by T cell populations from strains of mice developing polar forms of granulomatous inflammation in response to eggs of Schistosoma mansoni. Eur J Immunol. PLoS Pathog. Induction and regulation of pathogenic Th17 cell responses in schistosomiasis. Semin Immunopathol. Genetic control of severe egg-induced immunopathology and IL production in murine schistosomiasis.
J Immunol. Downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J Exp Med. Exacerbated egg-induced immunopathology in murine Schistosoma mansoni infection is primarily mediated by IL and restrained by IFN-gamma. Alternative macrophage activation is essential for survival during schistosomiasis and downmodulates T helper 1 responses and immunopathology. Immunity — Delayed hypersensitivity-type granuloma formation and dermal reaction induced and elicited by a soluble factor isolated from Schistosoma mansoni eggs.
Proteomic analysis of Schistosoma mansoni egg secretions.
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Mol Biochem Parasitol. Omega-1, a glycoprotein secreted by Schistosoma mansoni eggs, drives Th2 responses.
Molecular characterisation of kappa-5, a major antigenic glycoprotein from Schistosoma mansoni eggs. Expansion of CD4 T cells expressing a highly restricted TCR structure specific for a single parasite epitope correlates with high pathology in murine schistosomiasis. Exp Parasitol.
The roles of ILA in inflammatory immune responses and host defense against pathogens. Immunol Rev. Understanding the ILIL immune pathway. Trends Immunol. T H cells in the circle of immunity and autoimmunity. Nat Immunol.