CD209a Synergizes with Dectin-2 and Mincle to Drive Severe Th17 Cell-Mediated Schistosome Egg-Induced Immunopathology

Morales, Yoelkys; Miller, Emily A.; Jaramillo, Luis D.; Ponichtera, Holly; Wuethrich, Marcel; Cheong, Cheolho; Seminario, Maria Cristina; Russo, Joanne M.; Bunnell, Stephen C.; Stadecker, Miguel J.

doi:10.1016/j.celrep.2018.01.001

Cited by 27 publications

(53 citation statements)

References 44 publications

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“…Still, fucosylated Lewis x antigen, a known hDC-SIGN ligand, mediated suppression and tolerance to transplantation through mDC-SIGN + monocyte-derived macrophages ( 35 ). In addition, a recent study on mDC-SIGN functioning during schistosome egg infection revealed the capacity of mDC-SIGN to signal via Raf-1 depending on its carbohydrate recognition domain and affect DC functioning ( 36 ). Therefore, studies aimed at investigating DC-SIGN functioning in vivo that rely on recognition of specific glycan structures should take the ligand-binding specificity into consideration, as well as the capacity of mDC-SIGN to affect intracellular signaling.…”

Section: Discussionmentioning

confidence: 99%

Mouse DC-SIGN/CD209a as Target for Antigen Delivery and Adaptive Immunity

et al. 2018

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The efficacy of vaccination studies aimed at targeting antigens to human DC-SIGN (hDC-SIGN) have been notoriously difficult to study in vivo, as eight dendritic cell-specific intercellular adhesion molecule-3 grabbing non-integrin (DC-SIGN) homologs have been described in mice. CD209a/SIGNR5 has been coined as the mouse DC-SIGN (mDC-SIGN) ortholog, based on its expression and location in the genome. Nonetheless, which properties of hDC-SIGN are covered by mDC-SIGN is poorly investigated. One of the most important functions of DC-SIGN is the induction of adaptive immunity. As such, the aim of this study is to determine the capability of mDC-SIGN to induce adaptive immune responses. Here, we show that mDC-SIGN is expressed on GM-CSF cultured bone marrow-derived dendritic cells (BMDCs) and macrophages. However, mDC-SIGN is an internalizing receptor which, unlike hDC-SIGN, quickly resurfaces after internalization. Binding of OVA-coupled anti-mDC-SIGN antibody by BMDCs leads to quick internalization, processing, and presentation to antigen-specific CD8+ and CD4+ T cells, which can be boosted using the TLR4 ligand, monophosphoryl lipid A. In the homeostatic condition, mDC-SIGN is mostly expressed on myeloid cells in the skin and spleen. A subcutaneous injection of fluorescent anti-mDC-SIGN reveals specific targeting to mDC-SIGN+ skin dendritic cells (DCs) and monocyte-derived DCs in situ. A subcutaneous vaccination strategy containing OVA-coupled anti-mDC-SIGN antibody generated antigen-specific polyfunctional CD8+ T cell and CD4+ T cell responses and a strong isotype-switched OVA-specific antibody response in vivo. We conclude that mDC-SIGN shows partly overlapping similarities to hDC-SIGN and that targeting mDC-SIGN provides a valuable approach to investigate the immunological function of DC-SIGN in vivo.

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Section: Discussionmentioning

confidence: 99%

Mouse DC-SIGN/CD209a as Target for Antigen Delivery and Adaptive Immunity

et al. 2018

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“…Rather, it is dependent on ω1 RNase activity in addition to its native glycosylation, enabling the molecule to bind to the mannose receptor on dendritic cells and be internalized ( 49 , 50 ). It is noteworthy that both α1 and ω1 within SEA are glycoproteins, with many functional activities of such egg molecules being glycan dependent, requiring interactions with selected C-type lectin receptors on immune cells ( 51 – 54 ).…”

Section: Differences In Granulomatous Inflammation Of Liver and Intesmentioning

confidence: 99%

Schistosoma “Eggs-Iting” the Host: Granuloma Formation and Egg Excretion

2018

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Schistosomiasis is a major cause of morbidity in humans invoked by chronic infection with parasitic trematodes of the genus Schistosoma. Schistosomes have a complex life-cycle involving infections of an aquatic snail intermediate host and a definitive mammalian host. In humans, adult male and female worms lie within the vasculature. Here, they propagate and eggs are laid. These eggs must then be released from the host to continue the life cycle. Schistosoma mansoni and Schistosoma japonicum reside in the mesenteric circulation of the intestines with egg excreted in the feces. In contrast, S. haematobium are present in the venus plexus of the bladder, expelling eggs in the urine. In an impressive case of exploitation of the host immune system, this process of Schistosome “eggs-iting” the host is immune dependent. In this article, we review the formation of the egg granuloma and explore how S. mansoni eggs laid in vasculature must usurp immunity to induce regulated inflammation, to facilitate extravasation through the intestinal wall and to be expelled in the feces. We highlight the roles of immune cell populations, stromal factors, and egg secretions in the process of egg excretion to provide a comprehensive overview of the current state of knowledge regarding a vastly unexplored mechanism.

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“…In addition, CD209a (C-type lectin receptor), expressed on DCs, also proved to be essential for the development of Th17 cell responses in murine schistosomiasis (61, 69). CD209a-deficient CBA mice had decreased Th17 responses and developed reduced egg-induced liver immunopathology (69,70). Clinical studies also demonstrated the positive correlation between the percentage of Th17 cells and bladder pathology in S. haematobium-infected children (62).…”

Section: Th17/il-17 Exacerbate the Egg-induced Liver Immunopathologymentioning

confidence: 99%

T Lymphocyte-Mediated Liver Immunopathology of Schistosomiasis

et al. 2020

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The parasitic worms, Schistosoma mansoni and Schistosoma japonicum, reside in the mesenteric veins, where they release eggs that induce a dramatic granulomatous response in the liver and intestines. Subsequently, infection may further develop into significant fibrosis and portal hypertension. Over the past several years, uncovering the mechanism of immunopathology in schistosomiasis has become a major research objective. It is known that T lymphocytes, especially CD4 + T cells, are essential for immune responses against Schistosoma species. However, obtaining a clear understanding of how T lymphocytes regulate the pathological process is proving to be a daunting challenge. To date, CD4 + T cell subsets have been classified into several distinct T helper (Th) phenotypes including Th1, Th2, Th17, T follicular helper cells (Tfh), Th9, and regulatory T cells (Tregs). In the case of schistosomiasis, the granulomatous inflammation and the chronic liver pathology are critically regulated by the Th1/Th2 responses. Animal studies suggest that there is a moderate Th1 response to parasite antigens during the acute stage, but then, egg-derived antigens induce a sustained and dominant Th2 response that mediates granuloma formation and liver fibrosis. In addition, the newly discovered Th17 cells also play a critical role in the hepatic immunopathology of schistosomiasis. Within the liver, Tregs are recruited to hepatic granulomas and exert an immunosuppressive role to limit the granulomatous inflammation and fibrosis. Moreover, recent studies have shown that Tfh and Th9 cells might also promote liver granulomas and fibrogenesis in the murine schistosomiasis. Thus, during infection, T-cell subsets undergo complicated cross-talk with antigen presenting cells that then defines their various roles in the local microenvironment for regulating the pathological progression of schistosomiasis. This current review summarizes a vast body of literature to elucidate the contribution of T lymphocytes and their associated cytokines in the immunopathology of schistosomiasis.

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CD209a Synergizes with Dectin-2 and Mincle to Drive Severe Th17 Cell-Mediated Schistosome Egg-Induced Immunopathology

Cited by 27 publications

References 44 publications

Mouse DC-SIGN/CD209a as Target for Antigen Delivery and Adaptive Immunity

Mouse DC-SIGN/CD209a as Target for Antigen Delivery and Adaptive Immunity

Schistosoma “Eggs-Iting” the Host: Granuloma Formation and Egg Excretion

T Lymphocyte-Mediated Liver Immunopathology of Schistosomiasis

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