Diminished allergic disease in patients with STAT3 mutations reveals a role for STAT3 signaling in mast cell degranulation.
Andrea M. Siegel,Kelly D. Stone,Glenn Cruse,Monica G. Lawrence,Ana Olivera,Mi-Yeon Jung,John S. Barber,Alexandra F. Freeman,Steven M. Holland,Michelle O'Brien,Nina Jones,Laura Wisch,Heidi H. Kong,Avanti Desai,Orly N. Farber,Alasdair M. Gilfillan,Juan Rivera,Joshua D. Milner +17 more
TLDR
This study serves as an example for how mutations in specific atopic pathways can lead to discrete allergic phenotypes, encompassing increased risk of some phenotypes but a relative protection from others.Abstract:
Background Severe atopic conditions associated with elevated serum IgE are heterogeneous with few known causes. Nearly every patient with autosomal-dominant hyper-IgE syndrome (AD-HIES) due to signal transducer and activator of transcription 3 (STAT3) mutations has a history of eczematous dermatitis and elevated IgE; however, clinical atopy has never been systematically studied. Objective Understanding of genetic determinants of allergic disease may lead to novel therapies in controlling allergic disease. Methods We conducted clinical evaluation of the rates of food allergies and anaphylaxis in patients with AD-HIES, a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis, and healthy volunteers with no history of atopy. Morphine skin prick testing, ImmunoCAP assays for allergen-specific IgE, and basophil activation were measured. A model of systemic anaphylaxis was studied in transgenic mice carrying an AD-HIES mutation. STAT3 was silenced in LAD2 and primary human mast cells to study the role of STAT3 in signaling and degranulation after IgE cross-linking. Results Food allergies and anaphylaxis were markedly diminished in patients with AD-HIES compared with a cohort of patients with no STAT3 mutation but with similar histories of elevated IgE and atopic dermatitis. Morphine skin prick testing and basophil activation were diminished in patients with AD-HIES, whereas mice carrying an AD-HIES mutation were hyporesponsive to systemic anaphylaxis models. Rapid mast cell STAT3 serine727 phosphorylation was noted after IgE cross-linking, and inhibition of STAT3 signaling in mast cells lead to impaired FceRI-mediated proximal and distal signaling, as well as reduced degranulation. Conclusion This study serves as an example for how mutations in specific atopic pathways can lead to discrete allergic phenotypes, encompassing increased risk of some phenotypes but a relative protection from others.read more
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Journal ArticleDOI
STAT3 signaling in immunity.
TL;DR: Information on the numerous and distinct biological actions of STAT3 is summarized, and recent discoveries are highlighted, with a specific focus on STAT3 function in the immune and hematopoietic systems.
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The pathophysiology of anaphylaxis
TL;DR: Current understanding of the immunopathogenesis and pathophysiology of anaphylaxis is described, focusing on the roles of IgE and IgG antibodies, immune effector cells, and mediators thought to contribute to examples of the disorder.
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Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.
Asbjørg Stray-Pedersen,Hanne Sørmo Sorte,Pubudu S. Samarakoon,Tomasz Gambin,Tomasz Gambin,Ivan K. Chinn,Zeynep Coban Akdemir,Hans Christian Erichsen,Lisa R. Forbes,Shen Gu,Bo Yuan,Shalini N. Jhangiani,Donna M. Muzny,Olaug K. Rødningen,Ying Sheng,Sarah K. Nicholas,Lenora M. Noroski,Filiz O. Seeborg,Carla M. Davis,Debra Canter,Emily M. Mace,Timothy J. Vece,Carl E. Allen,Harshal Abhyankar,Philip M. Boone,Christine R. Beck,Wojciech Wiszniewski,Børre Fevang,Pål Aukrust,Geir E. Tjønnfjord,Tobias Gedde-Dahl,Henrik Hjorth-Hansen,Ingunn Dybedal,Ingvild Nordøy,Silje F. Jørgensen,Tore G. Abrahamsen,Torstein Øverland,Anne Grete Bechensteen,Vegard Skogen,Liv T. N. Osnes,Mari Ann Kulseth,Trine Prescott,Cecilie F. Rustad,Ketil Heimdal,John W. Belmont,Nicholas L. Rider,Javier Chinen,Tram N. Cao,Eric A. Smith,María Soledad Caldirola,Liliana Bezrodnik,Saul Oswaldo Lugo Reyes,Francisco Javier Espinosa Rosales,Nina Denisse Guerrero-Cursaru,Luis A. Pedroza,Cecilia Poli,Cecilia Poli,José Luis Franco,Claudia Milena Trujillo Vargas,Juan Carlos Aldave Becerra,Nicola A.M. Wright,Thomas B. Issekutz,Andrew C. Issekutz,Jordan K. Abbott,Jason W. Caldwell,Diana K. Bayer,Alice Y. Chan,Alessandro Aiuti,Caterina Cancrini,Eva Holmberg,Christina E. West,Magnus K. O. Burstedt,Ender Karaca,Gozde Yesil,Gozde Yesil,Hasibe Artac,Yavuz Bayram,Mehmed M. Atik,Mohammad K. Eldomery,Mohammad S. Ehlayel,Stephen Jolles,Berit Flatø,Alison A. Bertuch,I. Celine Hanson,Victor Wei Zhang,Lee-Jun C. Wong,Jianhong Hu,Magdalena Walkiewicz,Yaping Yang,Christine M. Eng,Eric Boerwinkle,Eric Boerwinkle,Richard A. Gibbs,William T. Shearer,Robert Lyle,Jordan S. Orange,James R. Lupski +96 more
TL;DR: This high‐throughput genomic approach enabled detection of disease‐related variants in unexpected genes; permitted detection of low‐grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.
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Autosomal recessive phosphoglucomutase 3 (PGM3) mutations link glycosylation defects to atopy, immune deficiency, autoimmunity, and neurocognitive impairment
Yu Zhang,Xiaomin Yu,Mie Ichikawa,Jonathan J. Lyons,Shrimati Datta,Ian T. Lamborn,Huie Jing,Emily S. Kim,Matthew Biancalana,Lynne A. Wolfe,Thomas DiMaggio,Helen F. Matthews,Sarah M. Kranick,Kelly D. Stone,Steven M. Holland,Daniel S. Reich,Jason D. Hughes,Huseyin Mehmet,Joshua J McElwee,Alexandra F. Freeman,Hudson H. Freeze,Helen C. Su,Joshua D. Milner +22 more
TL;DR: In this paper, the authors defined a genetic syndrome of severe atopy, increased serum IgE levels, immune deficiency, autoimmunity, and motor and neurocognitive impairment.
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Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution
TL;DR: A comprehensive understanding of JAK/STAT3 signaling in normal development, and in adaptive and maladaptive responses to stress, is essential for the continued development of safe and effective therapies that target this signaling pathway.
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