CD209a Expression on Dendritic Cells Is Critical for the Development of Pathogenic Th17 Cell Responses in Murine Schistosomiasis

Ponichtera, Holly; Shainheit, Mara G.; Liu, Beiyun C.; Raychowdhury, Raktima; Larkin, Bridget; Russo, Joanne M.; Salantes, D. Brenda; Lai, Chao‐Qiang; Parnell, Laurence D.; Yun, Tae Jin; Cheong, Cheolho; Bunnell, Stephen C.; Hacohen, Nir; Stadecker, Miguel J.

doi:10.4049/jimmunol.1400121

Cited by 34 publications

(50 citation statements)

References 68 publications

(98 reference statements)

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“…The eggs deposited by schistosome parasites are potent inducers of type 2 cytokines [57] but severe hepatic granulomatous pathology in response to the eggs is due to a pathogenic Th17 response, which is largely dependent on the expression of CD209a by dendritic cells [58]. The expression of CD209a is highly upregulated in response to IL-4 or IL-13 [38,59,60], suggesting the potential for a amplification of IL-17 responses by type 2 cytokines.…”

Section: Il-17 and Type 2 Cytokinesmentioning

confidence: 98%

IL-17 and neutrophils: unexpected players in the type 2 immune response

Allen¹,

Sutherland²,

Rückerl³

2015

Current Opinion in Immunology

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The study of immunity to helminth infection has been central to understanding the function of type 2 cytokines and their targets. Although type 2 cytokines are considered anti-inflammatory and promote tissue repair, they also contribute to allergy and fibrosis. Here, we utilise data from helminth infection models, to illustrate that IL-17 and neutrophils, typically associated with pro-inflammatory responses, are intimately linked with type 2 immunity. Neutrophils work with IL-4Rα-activated macrophages to control incoming larvae but this comes at a cost of enhanced tissue damage. Chitinase like proteins (CLPs) bridge these diverse outcomes, inducing both protective IL-17 and reparative Th2 responses. Dysregulation of CLPs, IL-17 and neutrophils likely contribute to disease severity and pathology associated with type 2 immunity.

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Section: Il-17 and Type 2 Cytokinesmentioning

confidence: 98%

IL-17 and neutrophils: unexpected players in the type 2 immune response

Allen¹,

Sutherland²,

Rückerl³

2015

Current Opinion in Immunology

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“…116 Conversely, IL-4 and IL-13 may amplify Th17 responses by up-regulating CD209a expression on dendritic cells. 117 When the type 2 response fails to fully suppress the IL-17 response, or further promotes it, excessive tissue damage can occur. Understanding what regulates the IL-17eIL-4/13 feedback loops will provide invaluable insight into situations in which IL-17 exacerbates type 2 inflammation.…”

Section: Neurogenic Inflammationmentioning

confidence: 99%

Endotypes of allergic diseases and asthma: An important step in building blocks for the future of precision medicine

Agache

Akdiş

2016

Allergology International

161

140

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Discoveries from basic science research in the last decade have brought significant progress in knowledge of pathophysiologic processes of allergic diseases, with a compelling impact on understanding of the natural history, risk prediction, treatment selection or mechanism-specific prevention strategies. The view of the pathophysiology of allergic diseases developed from a mechanistic approach, with a focus on symptoms and organ function, to the recognition of a complex network of immunological pathways. Several subtypes of inflammation and complex immune-regulatory networks and the reasons for their failure are now described, that open the way for the development of new diagnostic tools and innovative targeted-treatments. An endotype is a subtype of a disease condition, which is defined by a distinct pathophysiological mechanism, whereas a disease phenotype defines any observable characteristic of a disease without any implication of a mechanism. Another key word linked to disease endotyping is biomarker that is measured and evaluated to examine any biological or pathogenic processes, including response to a therapeutic intervention. These three keywords will be discussed more and more in the future with the upcoming efforts to revolutionize patient care in the direction of precision medicine and precision health. The understanding of disease endotypes based on pathophysiological principles and their validation across clinically meaningful outcomes in asthma, allergic rhinitis, chronic rhinosinusitis, atopic dermatitis and food allergy will be crucial for the success of precision medicine as a new approach to patient management.

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“…Although genetically determined differences in schistosome egg-induced immunopathology among inbred mouse strains have been documented (Cheever et al, 1987), the molecular mechanisms underlying such heterogeneous responses remain to be fully understood. In a previous gene profiling analysis of DCs from high-(CBA) versus low-pathology (BL/6) mice, we found striking differences in the baseline expression of C-type lectin receptors (CLRs), which are a broad family of pattern recognition receptors (PRRs) capable of binding to glycan residues, such as those typically present on schistosome eggs, in a calcium-dependent manner (Ponichtera et al, 2014). In particular, CD209a (SIGNR5) expression was 18-fold higher in CBA versus BL/6 DCs (Ponichtera et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

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SUMMARY The immunopathology caused by schistosome helminths varies greatly in humans and among mouse strains. A severe form of parasite egg-induced hepatic granulomatous inflammation, seen in CBA mice, is driven by Th17 cells stimulated by IL-1β and IL-23 produced by dendritic cells that express CD209a (SIGNR5), a C-type lectin receptor (CLR) related to human DC-SIGN. Here, we show that CD209a-deficient CBA mice display decreased Th17 responses and are protected from severe immunopathology. In vitro, CD209a augments the egg-induced IL-1β and IL-23 production initiated by the related CLRs Dectin-2 and Mincle. While Dectin-2 and Mincle trigger an FcRγ-dependent signaling cascade that involves the tyrosine kinase Syk and the trimolecular Card9-Bcl10-Malt1 complex, CD209a promotes the sustained activation of Raf-1. Our findings demonstrate that CD209a drives severe Th17 cell-mediated immunopathology in a helminthic disease based on synergy between DC-SIGN- and Dectin-2-related CLRs.

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CD209a Expression on Dendritic Cells Is Critical for the Development of Pathogenic Th17 Cell Responses in Murine Schistosomiasis

Cited by 34 publications

References 68 publications

IL-17 and neutrophils: unexpected players in the type 2 immune response

IL-17 and neutrophils: unexpected players in the type 2 immune response

Endotypes of allergic diseases and asthma: An important step in building blocks for the future of precision medicine

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

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