The basic immunology of asthma

In many asthmatics, chronic airway inflammation is driven by IL-4-, IL-5-, and IL-13-producing Th2 cells or ILC2s. Type 2 cytokines promote hallmark features of the disease such as eosinophilia, mucus hypersecretion, bronchial hyperresponsiveness (BHR), IgE production, susceptibility to exacerbations. However, only half asthmatics have this “type 2-high” signature, 2-low” asthma more associated with obesity, presence neutrophils, unresponsiveness corticosteroids, mainstay therapy. Here, we review underlying immunological basis various endotypes discussing results obtained from animal studies well generated in clinical targeting specific immune pathways. Asthma a inflammatory airways leading cough, wheeze, shortness breath, chest tightness. symptoms are airways, which triggers processes remodeling wall, (BHR, tendency smooth muscle react non-specific stimuli cold air. often starts at young age (childhood-onset asthma), but some patients can develop later life (late-onset asthma). Childhood-onset late-onset differ ways. Late-onset severe less allergy than childhood-onset asthma. children, atopy, lower-lung function, respiratory-tract infections especially rhinovirus, represent major risk factors for persistence Whether present asthmatic children drives pathogenicity respiratory viruses whether frequent viral set stage still not understood. Because so central pathogenesis, it surprising that primary goal treatment has been achieve control avoid future Unsupervised clustering methodology look course revealed heterogeneous disease, reflected patient-specific differences onset, factors, degrees severity, comorbidity, response (Wu et al., 2019Wu W. Bang S. Bleecker E.R. Castro M. Denlinger L. Erzurum S.C. Fahy J.V. Fitzpatrick A.M. Gaston B.M. Hastie A.T. al.Multiview Cluster Analysis Identifies Variable Corticosteroid Response Phenotypes Severe Asthma.Am. J. Respir. Crit. Care Med. 2019; 199: 1358-1367Crossref PubMed Scopus (35) Google Scholar). We also realize now all reversible obstruction, persistent obstruction caused airway-wall plugging seen one biggest unmet medical needs care (Dunican 2018Dunican E.M. Elicker Gierada D.S. Nagle S.K. Schiebler M.L. Newell J.D. Raymond W.W. Lachowicz-Scroggins M.E. Di Maio Hoffman E.A. al.National Heart Lung Blood Institute (NHLBI) Research Program (SARP)Mucus plugs linked eosinophilia airflow obstruction.J. Clin. Invest. 2018; 128: 997-1009Crossref (126) Historically, two main forms identified: allergic nonallergic asthma, turned out be an oversimplification. Allergic tends begin childhood T helper (Th2) cell responses, other conditions atopic dermatitis rhinitis. This form induced early encounters environmental allergens house dust mite (HDM), pollen, cockroach, dander when new, e.g., occupational allergen, encountered. Upon recognizing allergens, allergen-specific produce type (interleukin [IL]-4, IL-5, IL-9, IL-13), lead accumulation high numbers eosinophils overproduction, synthesis immunoglobulin E (IgE) B cells, detected serum through positive skin-prick test. Although mechanisms protective behind sensitization understood extensively modeled mice (reviewed Lambrecht Hammad, 2017Lambrecht B.N. Hammad H. The immunology epidemic hygiene hypothesis.Nat. Immunol. 2017; 18: 1076-1083Crossref (142) Scholar), why localizes persists into adulthood, clear. Disease onset coincides, however, very crucial period system lung structural development childhood. Lifelong homeostasis immune-mediated diseases shaped during neonatal period. Therefore, alterations environment “window opportunity” could changes organ behavior, persist long after initial trigger gone (de Kleer 2016de I.M. Kool de Bruijn M.J. Willart van Moorleghem Schuijs Plantinga Beyaert R. Hams E. Fallon P.G. al.Perinatal Activation Interleukin-33 Pathway Promotes Immunity Developing Lung.Immunity. 2016; 45: 1285-1298Abstract Full Text PDF Scholar; Saglani 2018Saglani Gregory L.G. Manghera A.K. Branchett W.J. Uwadiae F. Entwistle L.J. Oliver R.A. Vasiliou J.E. Sherburn Lui al.Inception early-life allergen-induced reliant on IL-13+CD4+ cells.Sci. 3: eaan4128Crossref (2) contrast non-allergic usually late common females obese (Pakkasela 2020Pakkasela Ilmarinen P. Honkamäki Tuomisto L.E. Andersén Piirilä Hisinger-Mölkänen Sovijärvi A. Backman Lundbäck B. al.Age-specific incidence asthma.BMC Pulm. 2020; 20: 9Crossref (5) sometimes difficult treat. phenotypes were classified non-Th2 aging, smoking. Th2-associated accompanied recurrent rhinosinusitis nasal polyps (CRSwNP) sensitivity aspirin eosinophil (Bachert 2020Bachert C. Marple Schlosser R.J. Hopkins Schleimer R.P. Bröker Laidlaw T. Song Adult rhinosinusitis.Nat. Rev. Dis. Primers. 6: 86Crossref (4) As diseases, clinicians division just last years, classification evolved 2-high -ultra-high (essentially eosinophilic; see Figure 1) 2-low (non-eosinophilic, neutrophilic, metabolic; 2; Peters 2019Peters M.C. Ringel Dyjack N. Herrin Woodruff Rios O’Connor Seibold M.A. A transcriptomic method determine dysfunction T2-high T2-low asthma.Am. 465-477Crossref (41) Endotypes defined pathophysiological mechanisms, might direct responsiveness therapies inhaled corticosteroids biologicals (Fahy, 2015Fahy asthma--present most, absent many.Nat. 2015; 15: 57-65Crossref (576) Lötvall 2011Lötvall Akdis C.A. Bacharier L.B. Bjermer Casale T.B. Custovic Lemanske Jr., R.F. Wardlaw A.J. Wenzel S.E. Greenberger P.A. endotypes: new approach entities within syndrome.J. Allergy 2011; 127: 355-360Abstract (758) 2019Lambrecht Cytokines Asthma.Immunity. 50: 975-991Abstract (138) such, endotype orchestrated IL-4, IL-13, ultra-type reflecting (Figure 1). complex no biomarkers identified far. generally includes 2).Figure 2Schematic our current understanding asthmaShow full captionType characterized lack biomarkers, and/or corticosteroids. Different broad range severity identified.View Large Image ViewerDownload Hi-res image Download (PPT) identified. review, will focus endotypes, highlighting articles where authors imply causality rigorous experimentation. discuss molecular pathways unraveled great detail particular using molecule-specific biologics. feature reduction diameter airways. narrowing mediated infiltration activation dendritic (DCs), eosinophils, lymphocytes, innate lymphoid (ILCs), mast cells. interplay between these types neighboring epithelial leads BHR which, most cases, use bronchodilators. does always normalize following patients, long-lasting smaller explain fixed addition, including (which consists hyperplasia, goblet metaplasia, exaggerated subepithelial collagen deposition), contribute greatly pathogenesis Our role (ECs) advanced years. Nowadays, ECs considered physical barrier body outside world recognized immunologically active orchestrate responses external triggers. altered loss tight junction proteins keep them together, increased permeability. Allergens HDM endowed enzymatic activities, able cleave intercellular junctions cell-cell contacts (Wan 1999Wan Winton H.L. Soeller Tovey Gruenert D.C. Thompson P.J. Stewart G.A. Taylor G.W. Garrod D.R. Cannell M.B. Robinson Der p 1 facilitates transepithelial allergen delivery disruption junctions.J. 1999; 104: 123-133Crossref Epithelial damage actually correlates (Papi 2018Papi Brightling Pedersen Reddel H.K. Asthma.Lancet. 391: 783-800Abstract (350) Moreover, EC functions (Carsin 2016Carsin Mazenq Ilstad Dubus J.C. Chanez Gras D. Bronchial epithelium children: key player asthma.Eur. 25: 158-169Crossref (21) idea may way initiation life. express myriad pattern recognition receptors toll-like (TLRs), nucleotide-binding oligomerization do-main (NOD)-like (NLRs), C-type lectin (CLRs), retinoic acid-inducible gene (RIG)-I-like (RLRs), protease-activated receptors, purinergic receptors. These allow respond variety producing chemokines 3). mice, exposure production IL-1?, granulocyte-macrophage colony-stimulating factor (GM-CSF) (Willart 2012Willart Deswarte K. Pouliot Braun Interleukin-1? controls via release GM-CSF IL-33.J. Exp. 2012; 209: 1505-1517Crossref (267) macrophage colony stimulating (M-CSF) (Moon 2018Moon H.G. Kim S.J. Jeong J.J. Han S.S. Jarjour N.N. Lee Abboud-Werner S.L. Chung Choi H.S. Natarajan V. al.Airway Cell-Derived Colony Stimulating Factor-1 Allergen Sensitization.Immunity. 49: 275-287.e5Abstract (20) transforming growth ? (TGF-?) (Denney 2015Denney Byrne Shea T.J. Buckley J.S. Pease Herledan G.M. Walker S.A. Lloyd C.M. Pulmonary Cytokine TGF-?1 Is Critical Cofactor Enhanced Innate Lymphoid Cell Function.Immunity. 43: 945-958Abstract Scholar) ECs, best-studied epithelial-derived context IL-33, thymic stromal lymphopoietin (TSLP), IL-25. “alarmins” produced HDM, Aspergillus fumigatus, cat protein Feld1, mainly TLR4/Myd88-dependent manner (Cayrol 2018Cayrol Duval Schmitt Roga Camus Stella Burlet-Schiltz O. Gonzalez-de-Peredo Girard J.P. Environmental induce proteolytic maturation IL-33.Nat. 19: 375-385Crossref (100) 2009Hammad Chieppa Perros Germain R.N. House induces Toll-like receptor 4 triggering cells.Nat. 2009; 410-416Crossref (781) All establishment murine models eosinophilic (Lambrecht humans, exact contribution alarmins assess, certainly they different IL-33 IL1RL1, encoding ST2, among highly replicated loci (Moffatt 2010Moffatt M.F. Gut I.G. Demenais Strachan D.P. Bouzigon Heath von Mutius Farrall Lathrop Cookson W.O.C.M. GABRIEL ConsortiumA large-scale, consortium-based genomewide association study asthma.N. Engl. 2010; 363: 1211-1221Crossref (1289) bronchoalveolar lavages (Li 2018Li Y. Wang Lv Z. Li Chen Huang Corrigan C.J. Ying Elevated Expression TSLP Airways Human Asthmatics Vivo: Potential Biomarker Refractory Disease.J. 200: 2253-2262Crossref (57) Patients levels higher ST2 expression blood suptum compared non-eosinophilic (Gasiuniene 2019Gasiuniene Janulaityte I. Zemeckiene Barkauskiene Sitkauskiene interleukin-33 asthma.Scand. 89: e12724Crossref (6) IL-25 transcripts elevated had greater hyperresponsiveness, IgE, thickening, signature genes (Cheng 2014Cheng Xue Yi Shi Zhang Huo X. Bonser L.R. Zhao Xu Erle D.J. Zhen G. interleukin-25 mediator Th2-high, corticosteroid-responsive 2014; 190: 639-648Crossref (111) mRNA mucosa (Ying 2005Ying Ratoff Meng Q. Mallett Cousins T.H. Thymic Th2-attracting severity.J. 2005; 174: 8183-8190Crossref (625) It was shown ILC2 longevity responsible their resistance corticoid (Kabata 2013Kabata Moro Fukunaga Suzuki Miyata Masaki Betsuyaku Koyasu Asano corticosteroid natural inflammation.Nat. Commun. 2013; 4: 2675Crossref classically cytokine, correlate neutrophilic (Mitchell 2018Mitchell P.D. Salter Oliveria El-Gammal Tworek Smith S.G. Sehmi Gauvreau Apos P.M.O. Its Receptor Inhaled Challenge Asthmatics.Int. Arch. 176: 133-142Crossref (16) mode action comes models. Indeed, absence cytokine signaling failed immunity allergens. participate ability activate number involved basophils (Chan 2019Chan B.C.L. Lam C.W.K. Tam L.S. Wong C.K. IL33: Roles Inflammation Therapeutic Perspectives.Front. 10: 364Crossref (36) ILC2s DCs (Roan 2019Roan Obata-Ninomiya Ziegler S.F. cell-derived cytokines: alarm.J. 129: 1441-1451Crossref (69) lungs organs attributed subset conventional (conventional cDC2s) require IRF4 (Deckers 2017Deckers Sichien Van Vanheerswynghels Hoste Malissen Dombrowicz Guilliams De Bosscher al.Epicutaneous requires interferon regulatory 4-dependent dermal cells.J. 140: 1364-1377.e2Abstract Several cytokines, TSLP, GM-CSF, target SIRP?+CD11b+ cDC2s differentiation 2020Moon M.K. Kang Harijith Ren Christman J.W. Ackerman Park G.Y. Colony-stimulating its potential therapeutic targets asthma.Allergy. 75: 357-369Crossref (3) On contrary, bona fide XCR1+CD103+ cDC1s monocyte-derived even protect Th1-associated IL-12 inhibit (Conejero 2017Conejero Khouili Martínez-Cano Izquierdo H.M. Brandi Sancho CD103+ restrain production.JCI Insight. (Published online May 17, 2017)https://doi.org/10.1172/jci.insight.90420Crossref (23) To proper immunity, exposed need migrate tissue draining lymph nodes, process potentially controlled ILC2-derived IL-13 I (IFN) (Halim 2014Halim T.Y. Steer Mathä Gold Martinez-Gonzalez McNagny K.M. McKenzie A.N. Takei Group critical adaptive cell-mediated inflammation.Immunity. 40: 425-435Abstract (561) Webb 2017Webb L.M. Lundie Borger J.G. Brown Connor Cartwright Dougall Wilbers R.H. Cook P.C. Jackson-Jones L.H. al.Type required (Th) induction cells.EMBO 36: 2404-2418Crossref (31) question IFN, normally anti-microbial remains unclear. Results lab that, Th2-inducing helminths, IFN peculiar hybrid characteristics (IRF8 expression) (CD64 (Bosteels 2020Bosteels Neyt Helden Debeuf Prijck Bosteels Vandamme Martens al.Inflammatory cDCs Acquire Features Macrophages Orchestrate Respiratory Virus Infection.Immunity. 52: 1039-1056.e9Abstract (45) clarified, since experimental data clearly identify CD64– CD64+ driver important ongoing both humans mice. lung, CD1c-expressing found high-affinity Fc?RI, suggesting inflammation, related (Dutertre 2019Dutertre Becht Irac Khalilnezhad Narang Ng P.Y. den Hoogen L.L. Leong J.Y. al.Single-Cell Mononuclear Phagocytes Reveals Subset-Defining Markers Circulating Inflammatory Dendritic Cells.Immunity. 51: 573-589.e8Abstract (78) Naessens 2020Naessens Morias Hamrud Gehrmann U. Budida Mattsson Baker Skogberg Israelsson Thörn al.Human Conventional Cells Neogenesis Chronic Obstructive Disease.Am. 202: 535-548Crossref difficulty obtaining samples made functional difficult. recent study, sputum used proxy compartment, Siebold group CD11b+IRF4+CD103– expressing (TSLPR) 2-associated (Peters finding therefore provides rationale CD11b+ maintain cDC2 addressed. experiments depletion CD11c+ challenge suppressed (van Rijt 2005van Jung Kleinjan Vos Duez Hoogsteden H.C. vivo abrogates characteristic asthma.J. 201: 981-991Crossref (492) Despite yielding results, caveat strategy affects subsets DCs. DC addressed cell-specific strategies, purifying gene-expression profiles. Using latter strategy, DCs, accumulate challenge, attraction good promoting 2013Plantinga Branco-Madeira Toussaint Vanhoutte Killeen al.Conventional CD11b(+) initiate allergen.Immunity. 38: 322-335Abstract (526) paper proposed drivers repeated (Yi 2018Yi Zhai Niu Zhu Liu Jing K