Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med

Immunology and Inflammation Program, Garvan Institute of Medical Research, Darlinghurst 2010, Australia.
Journal of Experimental Medicine (Impact Factor: 12.52). 08/2008; 205(7):1551-7. DOI: 10.1084/jem.20080218
Source: PubMed


Hyper-immunoglobulin E syndrome (HIES) is a primary immune deficiency characterized by abnormal and devastating susceptibility to a narrow spectrum of infections, most commonly Staphylococcus aureus and Candida albicans. Recent investigations have identified mutations in STAT3 in the majority of HIES patients studied. Despite the identification of the genetic cause of HIES, the mechanisms underlying the pathological features of this disease remain to be elucidated. Here, we demonstrate a failure of CD4+ T cells harboring heterozygous STAT3 mutations to generate interleukin 17-secreting (i.e., T helper [Th]17) cells in vivo and in vitro due to a failure to express sufficient levels of the Th17-specific transcriptional regulator retinoid-related orphan receptor t. Because Th17 cells are enriched for cells with specificities against fungal antigens, our results may explain the pattern of infection susceptibility characteristic of patients with HIES. Furthermore, they underscore the importance of Th17 responses in normal host defense against the common pathogens S. aureus and C. albicans.

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    • "Such findings have implications for diagnostic efforts and advancing our understanding of disease pathophysiology. For example, the finding that mutations in STAT3 (which transduces signals from IL-6, a canonical Th17 cytokine) can lead to hyper-IgE syndrome (HIES) led to the discovery that this subset of HIES patients fail to generate Th17 cells, potentially accounting for their susceptibility to fungal infection (Ma et al., 2008). There are also therapeutic implications; for instance, the discovery that SGK1 regulates Th17 cell differentiation led to the hypothesis that increased dietary salt intake may contribute to increased risk of autoimmune disease (Kleinewietfeld et al., 2013). "
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    ABSTRACT: The balance between Th17 and T regulatory (Treg) cells critically modulates immune homeostasis, with an inadequate Treg response contributing to inflammatory disease. Using an unbiased chemical biology approach, we identified a novel role for the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A in regulating this balance. Inhibition of DYRK1A enhances Treg differentiation and impairs Th17 differentiation without affecting known pathways of Treg/Th17 differentiation. Thus, DYRK1A represents a novel mechanistic node at the branch point between commitment to either Treg or Th17 lineages. Importantly, both Treg cells generated using the DYRK1A inhibitor harmine and direct administration of harmine itself potently attenuate inflammation in multiple experimental models of systemic autoimmunity and mucosal inflammation. Our results identify DYRK1A as a physiologically relevant regulator of Treg cell differentiation and suggest a broader role for other DYRK family members in immune homeostasis. These results are discussed in the context of human diseases associated with dysregulated DYRK activity.
    Full-text · Article · May 2015 · eLife Sciences
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    • "Information about its role in human sepsis is scarce [14]. TH17 cells contribute to host defense against extracellular bacteria, such as Staphylococcus aureus and Klebsiella pneumoniae as well as fungi [50, 51]. In humans, TH17 lymphocyte count on day 1 and after 6 days in survivors with severe sepsis was higher than that in nonsurvivors [52]. "
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    ABSTRACT: Sepsis is a systemic inflammatory response syndrome due to infection. The incidence rate is estimated to be up to 19 million cases worldwide per year and the number of cases is rising. Infection triggers a complex and prolonged host response, in which both the innate and adaptive immune response are involved. The disturbance of immune system cells plays a key role in the induction of abnormal levels of immunoregulatory molecules. Furthermore, the involvement of effector immune system cells also impairs the host response to the infective agents and tissue damage. Recently, postmortem studies of patients who died of sepsis have provided important insights into why septic patients die and showed an extensive depletion of CD4 and CD8 lymphocytes and they found that circulating blood cells showed similar findings. Thus, the knowledge of the characterization of circulating lymphocyte abnormalities is relevant for the understanding of the sepsis pathophysiology. In addition, monitoring the immune response in sepsis, including circulating lymphocyte subsets count, appears to be potential biomarker for predicting the clinical outcome of the patient. This paper analyzes the lymphocyte involvement and dysfunction found in patients with sepsis and new opportunities to prevent sepsis and guide therapeutic intervention have been revealed.
    Full-text · Article · Aug 2014 · BioMed Research International
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    • "These findings result from the balance between the Th17 and Th2 pathways, where the Th17 pathway inhibits the Th2 pathway and IgE production. Patients have relapsing Candida albicans and Staphylococcus aureus infection in the skin and lungs [61]. "
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    ABSTRACT: Human Th17 pro-inflammatory cells are currently defined as cells that produce IL-17A and F, tumor necrosis factor (TNF)-α, IL-6, IL-21, IL-22 and IL-23. Recently discovered related molecules are forming a family of cytokines, the IL-17 family, IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F. The associated receptors for the IL-17 family identified are IL-17R, IL-17RH1, IL-17RL (receptor like), IL-17RD and IL-17RE. This review introduces the roles of IL-17 and Th17 cells in human autoimmune diseases. Studies have shown that T cells with inflammatory effects on epithelial, endothelial and fibroblast cells express IL-17. Th17 cells are supposed to be involved in various autoimmune diseases, such as rheumatoid arthritis, psoriasis, multiple sclerosis, and inflammatory bowel diseases. Base on the biologic functions and regulation, IL-17 has regulatory roles in host defense and chronic inflammation which result in tissue damage and autoimmunity. So the IL-17 links links innate and adaptive immunity and has both beneficial and pathological effects on the immune system. This paper will focus on the possible roles of IL-17 in autoimmune diseases, a fundamental player in immune regulation.
    Full-text · Article · Aug 2014 · Postepy Dermatologii I Alergologii
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