Sensory neurons promote immune homeostasis in the lung

Cell, Год журнала: 2023, Номер 187(1), С. 44 - 61.e17

Опубликована: Дек. 21, 2023

Cytokines employ downstream Janus kinases (JAKs) to promote chronic inflammatory diseases. JAK1-dependent type 2 cytokines drive allergic inflammation, and patients with JAK1 gain-of-function (GoF) variants develop atopic dermatitis (AD) asthma. To explore tissue-specific functions, we inserted a human GoF variant (JAK1GoF) into mice observed the development of spontaneous AD-like skin disease but unexpected resistance lung inflammation when JAK1GoF expression was restricted stroma. We identified previously unrecognized role for in vagal sensory neurons suppressing airway inflammation. Additionally, Calcb/CGRPβ dependent on vagus nerve, CGRPβ suppressed group innate lymphoid cell function Our findings reveal evolutionarily conserved distinct functions across tissues. This biology raises possibility that therapeutic JAK inhibitors may be further optimized efficacy enhance precision medicine future.

Язык: Английский

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Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee

Опубликована: Апрель 15, 2025

This report provides an updated classification of inborn errors immunity (IEIs) involving 508 different genes and 17 phenocopies. Of these, we 67 novel monogenic defects 2 phenocopies due to neutralizing anti-cytokine autoantibodies or somatic mutations, which either have been discovered since the previous update (published June 2022) were reported earlier but recently confirmed and/or expanded. The new additions made after rigorous review genetic descriptions IEIs by International Union Immunological Societies (IUIS) Expert Committee using criteria established define IEI. Although similar pathogenic variants in one gene, terms both classes mutation (missense, nonsense, etc.) impact on protein function, can result a spectrum phenotypic manifestations, they are herein classified according most consistently phenotype. In addition, because single gene recognizable diseases gain loss such cases their clinical manifestations as distinct entry same table depending associated will serve valuable resource for immunologists geneticists involved molecular diagnosis individuals with heritable acquired immunological disorders. Moreover, expect this also all disciplines medicine, patients may be first seen rheumatologists, hematologists, allergists, dermatologists, neurologists, gastroenterologists, pulmonologists, upon presenting features. Finally, expanding known related causes human immune requires dissection underlying cellular mechanisms, reveals fundamental requirements specific genes, pathways, processes, even cell types. Such knowledge not only contribute improved patient management pave way development implementation therapies that target cause—rather than symptoms—of these conditions.

Язык: Английский

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Human immunity

Опубликована: Фев. 26, 2025

Due to the burden of infectious diseases, human life expectancy at birth remained about 20–25 years until end 19th century, implying that host defense—which operates individual level, and only poorly that—is barely sufficient population level. Microbes preceded us by three billion evolve much more rapidly. Moreover, protective immunity has been selected evolutionary cost allergy, autoinflammation, autoimmunity. It is therefore no exaggeration predict almost all humans carry inborn errors immunity, with insufficient or excessive responses some environmental triggers, otherwise. Thanks remarkable power its concepts recent progress in methods, genetics finally made it possible investigate mechanisms molecular cellular levels. Human provide countless opportunities analyze derailments natural conditions, an unprecedented scale, are thus a unique asset from both biological medical perspectives. Hence, Journal Immunity.

Язык: Английский

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JAKs and STATs from a Clinical Perspective: Loss-of-Function Mutations, Gain-of-Function Mutations, and Their Multidimensional Consequences

Journal of Clinical Immunology, Год журнала: 2023, Номер 43(6), С. 1326 - 1359

Опубликована: Май 4, 2023

The JAK/STAT signaling pathway plays a key role in cytokine and is involved development, immunity, tumorigenesis for nearly any cell. At first glance, the appears to be straightforward. However, on closer examination, factors influencing activity, such as diversity, receptor profile, overlapping JAK STAT specificity among non-redundant functions of complexes, positive regulators (e.g., cooperating transcription factors), negative SOCS, PIAS, PTP), demonstrate complexity pathway's architecture, which can quickly disturbed by mutations. has been, still is, subject basic research offers an enormous potential development new methods personalized medicine thus translation molecular into clinical practice beyond use inhibitors. Gain-of-function loss-of-function mutations three immunologically particularly relevant signal transducers STAT1, STAT3, STAT6 well JAK1 JAK3 present themselves through individual phenotypic pictures. established, traditional paradigm leading immunodeficiency gain-of-function mutation autoimmunity breaks down more differentiated picture disease patterns evolve. This review intended provide overview these specific syndromes from perspective summarize current findings pathomechanism, symptoms, immunological features, therapeutic options STAT6, JAK1, diseases.

Язык: Английский

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Neuroimmune interplay during type 2 inflammation: Symptoms, mechanisms, and therapeutic targets in atopic diseases

Journal of Allergy and Clinical Immunology, Год журнала: 2023, Номер 153(4), С. 879 - 893

Опубликована: Авг. 25, 2023

Type 2 inflammation is characterized by overexpression and heightened activity of type cytokines, mediators, cells that drive neuroimmune activation sensitization to previously subthreshold stimuli. The consequences altered differ tissue disease; they include skin inflammation, pruritogens, itch amplification in atopic dermatitis prurigo nodularis; airway and/or hyperresponsiveness, loss expiratory volume, airflow obstruction increased mucus production asthma; sense smell chronic rhinosinusitis with nasal polyps; dysphagia eosinophilic esophagitis. We describe the interactions underlie various sensory autonomic pathologies inflammatory diseases present recent advances targeted treatment approaches reduce its associated symptoms these diseases. Further research needed better understand mechanisms chronic, sustained related inflammation. immunity a specialized, evolutionarily conserved arm immune system combats ectoparasitic endoparasitic helminths, expels toxins, promotes repair.1Gandhi N.A. Bennett B.L. Graham N.M.H. Pirozzi G. Stahl N. Yancopoulos G.D. Targeting key proximal drivers disease.Nat Rev Drug Discov. 2016; 15: 35-50Crossref PubMed Scopus (392) Google Scholar, 2Gandhi N.M. Commonality IL-4/IL-13 pathway diseases.Expert Clin Immunol. 2017; 13: 425-437Crossref (276) 3Kopp E.B. Agaronyan K. Licona-Limon I. Nish S.A. Medzhitov R. Modes response initiation.Immunity. 2023; 56: 667-694Abstract Full Text PDF (1) 4Molofsky A.B. Locksley R.M. ins outs innate adaptive immunity.Immunity. 704-722Abstract (0) Scholar When epithelial barrier breached, alarmin cytokines (eg, thymic stromal lymphopoietin [TSLP], IL-25, IL-33) activate tissue-resident (such as mast cells, dendritic group lymphoid [ILC2s]) while simultaneously recruiting granulocytes, including eosinophils basophils. Collectively, orchestrate polarized through histamine, other mediators neutralize expel parasitic helminths toxins repair turnover, remodeling, fibrosis. Although processes are protective intended restore homeostasis, setting allergy continuous stress become pathologic, resulting variety Mechanical reflexes such scratching, constriction, coughing, sneezing, gastrointestinal motility also protect surfaces triggered direct neurons, often concert input target organs. 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Boguniewicz Sher adolescents uncontrolled trial.JAMA 156: 44-56Crossref (254) 25Paller Wollenberg Arkwright P.D. children 6 11 years old placebo-controlled 83: 1282-1293Abstract (174) 26Paller ages months younger than randomised, double-blind, 400: 908-919Abstract 27Wollenberg Worm Lynde Lacour J.P. al.Tralokinumab for results 52-week, multicentre, (ECZTRA ECZTRA 2).Br 437-449Crossref (214) 28Wollenberg Howell M.D. Silverberg Kell Ranade al.Treatment tralokinumab, anti-IL-13 mAb.J. Clin. 143: 135-141Abstract (252) 29Gutermuth Pink A.E. Soldbro Bjerregård Øland Weidinger Tralokinumab plus inadequate intolerance ciclosporin A: trial 7).Br 186: 440-452Crossref (26) 30Silverberg Toth Alexis A.F. Elewski B.E. trial.Br 450-463Crossref (133) 31Simpson Carsten Flohr Eichenfield L.F. Sofen Taïeb lebrikizumab (an antibody) inadequately controlled corticosteroids: II (TREBLE).J 2018; 78: 863-871.e11Abstract (239) 32Guttman-Yassky Armstrong A.W. Drew lebrikizumab, high-affinity interleukin 13 inhibitor, dermatitis. A 2b 411-420Crossref 33Silverberg Irvine A.D. Stein Gold 388: 1080-1091Crossref (16) 34Silverberg Pinter Pulka Poulin Bouaziz al.Phase 2B study nemolizumab pruritus.J 145: 173-182Abstract (159) 35Kabashima Matsumura Komazaki Kawashima Nemolizumab JP01 JP02 Study Group. agents (AD) provide improvement signs up 68 weeks: III, long-term studies.Br 642-651Crossref 36Ständer Legat F.J. Paul Narbutt al.Trial nodularis.N 382: 706-716Crossref (144) 37Kamata Tada Optimal use Jak inhibitors biologics on basis current evidence.JID Innov. 3100195Abstract 38Bieber Kabashima al.Atopic pathomechanisms lessons learned novel systemic therapeutic options.JEADV. 36: 1432-1449Google 39Lee K.P. Plante Korte J.E. Elston D.M. Oral Janus kinase systematic review meta-analysis.Skin Health Dis. 3: e133Crossref 40Rodriguez-Roy Ficheux A.-S. Misery Brenaut Efficacy treatments pruritus: literature meta-analysis.Front 91079323Google 41Huang I.-H. Chung W.-H. Wu P.-C. C.-B. JAK-STAT pathogenesis An updated review.Front 131068260Crossref (12) 42Haas Capellino Phan N.Q. Böhm Luger T.A. Straub R.H. al.Low density sympathetic nerve fibers relative substance P-positive lesional nodularis.J 2010; 58: 193-197Abstract (73) 43Liang Reimert C.M. CGRP-immunoreactive nodularis—an exploration neurogenic 2000; 27: 359-366Crossref (62) 44Williams K.A. Huang A.H. Belzberg Kwatra S.G. Prurigo management.J 1567-1575Abstract 45Molina F.A. Burrows N.P. Jones R.R. Terenghi Polak J.M. Increased neuropeptides nodular prurigo: quantitative immunohistochemical analysis.Br 1992; 127: 344-351Crossref 46Kabata Artis Neuro-immune crosstalk Invest. 129: 1475-1482Crossref (88) 47Teresiak-Mikołajczak Czarnecka-Operacz Jenerowicz Silny Neurogenic markers process relation severity pruritus.Postepy Alergol. 30: 286-292Crossref (33) 48Yang T.B. B.S. 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Zhang Lee Van Dyken al.Pulmonary neuroendocrine amplify asthma 360eaan8546Crossref (228) 64Hara Jha M.K. Mattoo Nash Khan Orengo al.Interleukin 4 directly olfactory induces mice.J 151: AB128Abstract 65Rouyar Classe Gorski Bock Le-Guern Roche al.Type 2/Th2-driven impairs neurogenesis model.Allergy. 74: 549-559Crossref (14) 66Backaert Steelant Hellings P.W. Talavera Gerven TRiP roles transient potential cation channels upper inflammation.Curr Asthma Rep. 21: 20Crossref 67Li Jiang Shen al.Sneezing reflex mediated peptidergic nose brainstem.Cell. 3762-3773Abstract (23) 68Samivel D.W. Son H.R. role CD4+ cell-mediated rhinitis.Oncotarget. 2015; 7: 148-160Crossref 69Yu Chang Yu Capsaicin-sensitive vagal afferent nerve-mediated interoceptive signals esophagus.Molecules. 26: 3929Crossref (3) 70O'Shea K.M. Aceves S.S. Dellon E.S. Pathophysiology esophagitis.Gastroenterology. 154: 333-345Abstract 71Akiho Ihara Motomura Nakamura Cytokine-induced alterations disorders.World Gastrointest Pathophysiol. 2011; 2: 72-81Crossref 72Hu Liu al.Increased acid responsiveness guinea pig esophagitis.Am Physiol Liver 307: G149-G157Crossref (21) 73Zhang Shoda Arva N.C. Chehade Collins M.H. al.Mast cell-pain connection esophagitis.Allergy. 77: 1895-1899Crossref (8) Scholar).Table INeuroimmune affecting AD, PN, CRSwNP, EoEConditionSymptomsNeuroimmune interactionsType profileADPruritus•Colocalization cells7Kulka Scholar,8Liang Scholar•Type OSM promote pruritogen sensitization9Sonkoly Scholar•Neuropeptide proinflammatory basophils)7Kulka Scholar,10Tominaga Scholar•Scratching causes alarmins IL-33), which can act neurons9Sonkoly Scholar,11Garcovich Scholar,14Liu Scholar•Some express receptors IL-13, IL-31, TRPA1, TRPV118Oetjen Scholar,19Cevikbas Scholar•Reducing reduces itch20Blauvelt

Язык: Английский

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The ins and outs of innate and adaptive type 2 immunity

Immunity, Год журнала: 2023, Номер 56(4), С. 704 - 722

Опубликована: Апрель 1, 2023

Type 2 immunity is orchestrated by a canonical group of cytokines primarily produced innate lymphoid cells, 2, and their adaptive counterparts, CD4

Язык: Английский

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Human germline gain-of-function in STAT6: from severe allergic disease to lymphoma and beyond

Trends in Immunology, Год журнала: 2024, Номер 45(2), С. 138 - 153

Опубликована: Янв. 21, 2024

Язык: Английский

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Mechanisms and therapeutic prospect of the JAK-STAT signaling pathway in liver cancer

Molecular and Cellular Biochemistry, Год журнала: 2024, Номер 480(1), С. 1 - 17

Опубликована: Март 22, 2024

Язык: Английский

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The Microbe, the Infection Enigma, and the Host

Annual Review of Microbiology, Год журнала: 2024, Номер 78(1), С. 103 - 124

Опубликована: Июль 10, 2024

Human infectious diseases are unique in that the discovery of their environmental trigger, microbe, was sufficient to drive development extraordinarily effective principles and tools for prevention or cure. This medical prowess has outpaced, perhaps even hindered, scientific progress equal magnitude biological understanding diseases. Indeed, hope kindled by germ theory disease rapidly subdued infection enigma, need a host solution, when it realized most individuals infected with agents continue do well. The root causes death unhappy few remained unclear. While canonical approaches vitro (cellular microbiology), vivo (animal models), natura (clinical studies) analyzed consequences considered be cause disease, cells, tissues, organisms seen as uniform host, alternative searched preexisting particularly human genetic immunological determinants populations diverse trigger microbe.

Язык: Английский

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Inborn errors of immunity with atopic phenotypes in the allergy and immunology clinic: a practical review

Current Opinion in Allergy and Clinical Immunology, Год журнала: 2025, Номер unknown

Опубликована: Фев. 12, 2025

Purpose of review Inborn errors immunity with atopic phenotypes (IEIwA) are a subgroup IEI that may present severe and/or multiple clinical manifestations. Because their specific management and prognosis, it is important to distinguish IEIwA from multifactorial allergic diseases. We aimed the main manifestations associated summarize available data regarding precision medicine approach for these conditions. Recent findings include more than 50 monogenic disorders marked by different immune dysregulation mechanisms such as alterations in cytokine signaling, T cell receptor function, mast activation, skin barrier integrity. A critical role diagnosis played advanced genetic testing. Emerging treatments targeted monoclonal antibodies small molecules, whereas hematopoietic stem transplantation (HSCT) still valid option some be curative also on Summary The recognition accurate crucial timely appropriate therapeutic intervention. should suspected according presence ‘red flags’ at evaluation stage, early-onset atopy, recurrent/atypical infections, autoimmunity. diagnostic confirmation requires Precision approaches like biological therapies HSCT seem provide promising results. It worth noting translational research field currently paving way thorough understanding molecular bases common

Язык: Английский

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