Autosomal Dominant STAT3 Deficiency and Hyper-IgE Syndrome

Chandesris, Marie-Olivia; Melki, Isabelle; Natividad, Angels; Puel, Anne; Fieschi, Claire; Liu, Yi; Thumerelle, C.; Oksenhendler, Éric; Boutboul, David; Thomas, Caroline; Hoarau, C.; Lebranchu, Yvon; Stéphan, Jean-Louis; Cazorla, Céline; Aladjidi, Nathalie; Micheau, M; Tron, Fran cois; Baruchel, André; Barlogis, Vincent; Palenzuela, Gilles; Mathey, C.; Dominique, S.; Body, Gérard; Munzer, Martine; Fouyssac, Fanny; Jaussaud, R.; Bader-Meunier, Brigitte; Mahlaoui, Nizar; Blanche, Stéphane; Debré, Marianne; Bourgeois, M. Le; Gandemer, Virginie; Lambert, Nathalie; Grandin, Virginie; Ndaga, Stéphanie; Jacques, Corinne; Harre, Chantal; Forveille, Monique; Alyanakian, Marie‐Alexandra; Durandy, Anne; Bodemer, Christine; Suarez, Félipe; Hermine, Olivier; Lortholary, Olivier; Casanova, Jean‐Laurent; Fischer, Alain; Pïcard, Capucine

doi:10.1097/md.0b013e31825f95b9

Cited by 283 publications

(180 citation statements)

References 72 publications

(141 reference statements)

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“…On rare occasion, EBV lymphomas have been described in AD-HIES patients. However, in a recent cohort of 60 AD-HIES patients, 7% developed lymphomas, none associated with EBV (43). Whether deficiency of STAT3 in these patients may impact clinical outcomes of EBV infection also remains a question.…”

Section: Discussionmentioning

confidence: 99%

B Lymphocytes from Patients with a Hypomorphic Mutation inSTAT3Resist Epstein-Barr Virus-Driven Cell Proliferation

Koganti

Paz

Freeman

et al. 2014

J Virol

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E pstein-Barr virus (EBV) is an oncovirus that infects B cells and epithelial cells (1-3). EBV establishes lifelong latency in memory B lymphocytes; periodic activation into the lytic cycle can lead to asymptomatic shedding of virus in saliva. Upon infection of primary B cells, EBV must first drive cell proliferation in order to establish latency (3). Latency contributes to viral persistence. Although most of mankind is persistently infected with EBV, only a small fraction develops EBV-related cancers of B and epithelial cells (3,4). While this propensity for development of cancer, particularly posttransplant lymphoproliferative disorders, is prominently associated with loss of EBV-directed T cell immunity (3,5,6), the pathogenesis of other forms of EBV-cancers, such as endemic Burkitt lymphoma and nasopharyngeal cell carcinoma, is more complex. Not surprisingly, the contribution of host cellular proteins toward EBV-driven cell proliferation and potentially to EBV-related diseases is important (3, 7-9). Most of our understanding of the involvement of cellular proteins and mechanisms that may contribute to pathogenesis derives from investigations on downstream effects of EBV latent membrane proteins and the nuclear antigens (7,8). Such studies have included new infection of B cells in culture, examination of EBV-derived B cell lines (lymphoblastoid cell lines [LCL]), and expression of individual viral proteins in culture. We are interested in understanding whether EBV can manipulate the host during the early stages of infection, possibly even before viral latency proteins are expressed.Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that is well known for its prosurvival and proproliferative functions (10-13). STAT3 is also constitutively active in many human cancers, including EBV-related cancers (11,(13)(14)(15). While STAT3 can be transcriptionally induced by the EBV oncoprotein LMP1 in already transformed B cells (16), whether STAT3 contributes to cell proliferation early after infection of primary B cells with EBV has not been investigated. Anecdotally, we have observed that B cells from patients with autosomal dominant hyper-IgE syndrome (AD-HIES or Job's syndrome) are difficult to transform with EBV. Patients with AD-HIES have a heterozygous dominant negative mutation in their STAT3 gene that renders the majority of cellular STAT3 nonfunctional despite normal levels of STAT3 protein (17). Such patients have a rare primary immunodeficiency characterized by eczema, skin and lung infections, extremely elevated serum IgE, and a variety of skeletal, connective tissue, and vascular abnormalities (18). In the setting of EBV infection in culture, we have observed that LCL from AD-HIES patients are slower to emerge than those from healthy subjects, but sometimes LCL cannot be generated even after repeated attempts, suggesting that there are inherent differences between B cells derived from AD-HIES patients and those from healthy subjects. Also of importance, studies have demonst...

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Section: Discussionmentioning

confidence: 99%

B Lymphocytes from Patients with a Hypomorphic Mutation inSTAT3Resist Epstein-Barr Virus-Driven Cell Proliferation

Koganti

Paz

Freeman

et al. 2014

J Virol

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“…Several studies have demonstrated the role of interleukin-17A (IL-17A) in clearance of pneumococcal carriage in mice (8,9). The increased incidence of pneumococcal sinopulmonary infections in patients with Job's disease (10), now understood to be due to a genetic defect in the STAT3 transcription factor which is essential for differentiation of IL-17-producing T H 17 cells (11), points to the importance of this effector cytokine in humans as a mechanism of protection against mucosal pneumococcal infections.…”

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confidence: 99%

Toll-Like Receptor 2-Dependent Protection against Pneumococcal Carriage by Immunization with Lipidated Pneumococcal Proteins

et al. 2014

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bInfections with Streptococcus pneumoniae cause substantial morbidity and mortality, particularly in children in developing nations. Polysaccharide-conjugate vaccines provide protection against both invasive disease and colonization, but their use in developing countries is limited by restricted serotype coverage and expense of manufacture. Using proteomic screens, we recently identified several antigens that protected mice from pneumococcal colonization in a CD4؉ T cell-and interleukin-17A (IL-17A)-dependent manner. Since several of these proteins are lipidated, we hypothesized that their immunogenicity and impact on colonization are in part due to activation of Toll-like receptor 2 (TLR2), a receptor for lipoproteins. Here we show that lipidated versions of the antigens elicited significantly higher activation of both human embryonic kidney cells engineered to express TLR2 (HEK-TLR2) and wild-type (WT) murine macrophages than nonlipidated mutant antigens. Lipoprotein-stimulated secretion of proinflammatory cytokines was ϳ10؋ to ϳ100؋ lower in murine TLR2-deficient macrophages than in WT macrophages. Subcutaneous immunization of C57BL/6 mice with protein subunit vaccines containing one or two of these lipoproteins or protein fusion constructs bearing N-terminal lipid adducts elicited a robust IL-17A response and a significant reduction in colonization compared with immunization with alum alone. In contrast, immunization of Tlr2 ؊/؊ mice elicited no detectable IL-17A response and no protection against pneumococcal colonization. These experiments suggest that the lipid moieties enhance the immunogenicity and protective efficacy of pneumococcal T H 17 antigens through activation of TLR2. Thus, triggering TLR2 with an antigen-specific protein subunit formulation is a possible strategy for the development of a serotype-independent pneumococcal vaccine that would reduce pneumococcal carriage.

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“…HIES is due to defects in Janus activated kinase/signal transducer and activator of transcription (JAK-STAT)-mediated cytokine signals, including interleukin (IL)-6 and IL-23 [8][9][10][11][12][13] .…”

Section: Discussionmentioning

confidence: 99%

Right-sided endocarditis in an adult patient with hyperimmunoglobulin-E syndrome successfully treated with high-dose daptomycin

Gounari

Skourtis

Panagos

et al. 2014

CRIM

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Autosomal Dominant STAT3 Deficiency and Hyper-IgE Syndrome

Cited by 283 publications

References 72 publications

B Lymphocytes from Patients with a Hypomorphic Mutation inSTAT3Resist Epstein-Barr Virus-Driven Cell Proliferation

B Lymphocytes from Patients with a Hypomorphic Mutation inSTAT3Resist Epstein-Barr Virus-Driven Cell Proliferation

Toll-Like Receptor 2-Dependent Protection against Pneumococcal Carriage by Immunization with Lipidated Pneumococcal Proteins

Right-sided endocarditis in an adult patient with hyperimmunoglobulin-E syndrome successfully treated with high-dose daptomycin

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