International Journal of Molecular Sciences Editorial From the Allergic Cascade to the Epithelium-Driven Disease: The Long Road of Bronchial Asthma Christian Domingo 1,2, * and Rosa M. Mirapeix 3 1 Servei de Pneumologia, Hospital Parc Taulí de Sabadell, 08208 Sabadell, Spain 2 Departament de Medicina, Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, Spain 3 Departament de Ciències Morfològiques, Universitat Autònoma de Barcelona (UAB), 08193 Barcelona, Spain * Correspondence: cdomingo@tauli.cat In medicine, much of the progress made is due to the emergence of new drugs. We learn the underlying mechanisms behind the modification or inhibition of certain pathways, as well as what occurs due to the lack of intervention. A clear example is the evolution in the knowledge of the pathophysiology of bronchial asthma. In the second half of the last century, the boundaries of the traditional classification of allergic and non-allergic asthma were expanded [1]. Coinciding with the advent of immunotherapy, researchers revealed how the so-called allergy cascade was set in motion, that is, all the reactions that began with the activation of dendritic cells or antigen-presenting cells (APC). The presence of allergens, antigens that favour the production and release of immunoglobulin E (IgE) into the environment by plasma cells, promotes the activation of the Th2 pathway. The Th2 pathway requires the differentiation of Th0 lymphocytes (naïve T cells) into Th2 lymphocytes. This pathway can generate IgE against each allergen to which these antibodies become sensitised, hence called adaptive immunity (i.e., the production of the type of antibody “adapts” to the different allergens with which the individual has been in contact) [2]. Since the cell initiating the reaction is the Th2 lymphocyte, it is also called the Th2 pathway. Immunotherapy modifies the immune response and diverts it to the Th1 pathway instead of the Th2 pathway (as occurs in allergies) through its effect on regulatory T cells. Subsequently, the first of several drugs called biologics (thus named because they were Citation: Domingo, C.; Mirapeix, originally derived from live Chinese hamster cells), or monoclonal antibodies (mAbs), was R.M. From the Allergic Cascade to marketed. The first of these blocked IgE, thus acting again on the Th2 pathway. Allergen- the Epithelium-Driven Disease: The sensitised, IgE-producing patients with clinical symptoms as a consequence of allergen Long Road of Bronchial Asthma. Int. exposure were referred to as patients with allergic phenotypes [3,4]. J. Mol. Sci. 2023, 24, 2716. https:// Posteriorly, it became known that during this Th2 process, other molecules known doi.org/10.3390/ijms24032716 as interleukins (IL5, IL4, and IL13), were released into the environment [5]. It has been Received: 13 January 2023 confirmed that the presence of these interleukins favours respectively the synthesis, matura- Revised: 25 January 2023 tion, and recruitment of eosinophils; the activation of the Th2 pathway and the blocking of Accepted: 29 January 2023 VCAM-1 expression; and finally, the activation of INOs, the enzyme that favours the release Published: 1 February 2023 of the exhaled fraction of nitric oxide (FENO). The presence of these molecules increases in certain pathological situations and are, therefore, markers of disease (biomarkers). Like IgE, these interleukins, as well as eosinophils, were initially observed in the Th2 pathway, but later, it was noted that after blocking IgE and downregulating the Th2 pathway, they Copyright: © 2023 by the authors. continued to be present. At that time, it was documented that the activation of other cells, Licensee MDPI, Basel, Switzerland. such as type 2 innate lymphoid cells (ILC2) and natural killer T cells (NKT cells), also led This article is an open access article distributed under the terms and to an increase in the same ILs as well as eosinophils. It was, therefore, revealed that the conditions of the Creative Commons production of these ILs might occur as a consequence of the activation of more than one Attribution (CC BY) license (https:// pathway. ILC2 and NKT cells are cells of the so-called innate immune system and respond creativecommons.org/licenses/by/ in the same way regardless of the noxa; thus, there is no “adaptive response” to the type of 4.0/). trigger. Patients with elevated eosinophil levels were defined as those with eosinophilic Int. J. Mol. Sci. 2023, 24, 2716. https://doi.org/10.3390/ijms24032716 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2023, 24, 2716 2 of 3 phenotypes. Since immunological factors are not dichotomous, there is a third group of patients Int. J. Mol. Sci. 2023, 24, x FOR PEER REVIEW who have biomarkers of both pathways. Patients with elevated biomarkers 2 of 3 (allergic and/or eosinophilic phenotype) caused by the activation of Th2 lymphocytes and/or ILC2 were considered as those with T2 inflammation and by exclusion, all other patients with asthma those withwho did not have eosinophilic a T2 phenotype phenotypes. were considered Since immunological factors to are have notnon-T2 asthma. dichotomous, More recently, it has been observed that the activation there is a third group of patients who have biomarkers of both pathways. Patients with of innate immunity is produced by other elevated molecules, biomarkers namely (allergic TSLP, and/or IL33, andphenotype) eosinophilic IL25 [5,6].causedWithout by thediscussing activationthe of charac- teristics Th2 of eachand/or lymphocytes of these ILC2molecules in detail, were considered it waswith as those observed that they and T2 inflammation appear by ex-as a result of damage clusion, to the all other bronchial patients ciliated with asthma who epithelium, did not have which, in these were a T2 phenotype circumstances, considered releases tothese have non-T2 molecules asthma. into the environment. Since they represent an alarm signal indicating More recently, epithelial damageit(epithelial has been observed that thethe cell disruption, activation of innate appearance immunity is space, of intercellular pro- loss of duced cilia, by theother molecules, thickness namely TSLP, of basement IL33, andand membrane, IL25in[5,6]. Without general, lossdiscussing the char- of the barrier function of acteristics of each ofthey the epithelium), these molecules are in detail,These called alarmins. it was alarmins observed that theyactivate directly appear as thea result cells of innate ofimmunity. damage toBlocking the bronchialthemciliated with aepithelium, new anti-TSLP which, in thesehas antibody circumstances, shown thatreleases these alarmins, these molecules into the environment. Since they represent an alarm signal indicating ep- especially TSLP, exert control over the activity of antigen-presenting cells. Disease control ithelial damage (epithelial cell disruption, the appearance of intercellular space, loss of is, therefore, exerted by the bronchial ciliated epithelium, which releases alarmins into the cilia, the thickness of basement membrane, and in general, loss of the barrier function of environment when it is damaged. T2 asthma (and perhaps non-T2 asthma) then becomes the epithelium), they are called alarmins. These alarmins directly activate the cells of in- an epithelium-driven nate immunity. Blockingdisease. them withAs mentioned a new anti-TSLPabove, antibody anti-alarmin has mAbs shown are thatcurrently these being developed. It should be kept in mind, however, that in immunology, alarmins, especially TSLP, exert control over the activity of antigen-presenting cells. Dis- and in the human body in general, there are always regulatory mechanisms ease control is, therefore, exerted by the bronchial ciliated epithelium, which releasesthat exert functions antagonistic to physiological alarmins ones in an attempt into the environment when to it achieve is damaged. homeostasis. T2 asthma When(andwe administer perhaps non-T2 a mAb, we are modifying asthma) the phenotype then becomes of the individual, an epithelium-driven disease. and Asthis causes their mentioned above, body to try to maintain anti-alarmin the lost mAbs balance by are currently activating being developed. other pathways. It should be kept An in example mind, however,is the that activation in immu- of the Th2 pathway nology, andbyin allergens, the humanthrough already-sensitised body in general, there are always B cells that express regulatory IgE on their mechanisms that surface. exert functions Although thisantagonistic allergic pathway to physiological is stoppedones at thein an attempt level of APCs,to achieve homeostasis. the possibility exists that it When may we administerby be activated a mAb, we are modifying the activation of a lower theloop. phenotype FigureofA1 theillustrates individual, and pathways. these this causes In their thisbody brieftoaccount, try to maintain we describedthe lostthebalance by activating evolution other pathways.of of our understanding Anbronchial example asthma.isOwing the activation of the Th2 pathway to the emergence of various bydrugs allergens, withthrough already-sensitised immunoregulatory effects,B we have cells movedthat from express theIgE on their surface. now-distant concept Although this allergic of the “allergic pathway cascade” to is stopped that at the of epithelial-driven level of APCs, the possibility exists disease. We shall see what the future holds. that it may be activated by the activation of a lower loop. Figure A1 illustrates these pathways. In this brief account, we described the evolution of our understanding of bronchial Author Contributions: Both authors contributed equally to the manuscript. All authors have read asthma. Owing to the emergence of various drugs with immunoregulatory effects, we and agreed to the published version of the manuscript. have moved from the now-distant concept of the “allergic cascade” to that of epithelial- Conflicts driven of Interest: disease. We shallThe seeauthors declare what the noholds. future conflict of interest. Appendix Appendix AA Figure A1. This figure shows the disruption of the ciliated bronchial epithelium that favours the Figure A1. This figure shows the disruption of the ciliated bronchial epithelium that favours the release release ofof alarmins. alarmins. Alarmins, Alarmins, in turn, in turn, activate, activate, below below the epithelium, the epithelium, the innate the innate immunity immunity responsible respon- for the initial production and release of the three interleukins (IL5, sible for the initial production and release of the three interleukins (IL5, IL4, and IL13) which contribute IL13) which con- to tribute to the definition of the T2 inflammation. On the left upper side, the arrow shows the regula- the definition of the T2 inflammation. On the left upper side, the arrow shows the regulatory effect of tory TSLPeffect onof TSLP onimmunity adaptive adaptive immunity (partially(partially modified modified from Domingo from Domingo C.; Drugs C.; Drugs 2017 [5]). 2017 [5]). Int. J. Mol. Sci. 2023, 24, 2716 3 of 3 References 1. Domingo, C.; Pacheco, A.; Hinojosa, M.; Bosque, M. The Relevance of IgE in the Pathogenesis of Allergy: The Effect of an Anti-IgE Drug in Asthma and Other Diseases. Recent Pat. Inflamm. Allergy Drug Discov. 2007, 1, 151–164. 2. Palomares, O.; Sánchez-Ramón, S.; Dávila, I.; Prieto, L.; Pérez de Llano, L.; Lleonart, M.; Domingo, C.; Nieto, A. DivergEnt: How IgE Axis Contributes to the Continuum of Allergic Asthma and Anti-IgE Therapies. Int. J. Mol. Sci. 2017, 18, 1328. [CrossRef] [PubMed] 3. Domingo, C. Omalizumab for severe asthma: Efficacy beyond the atopic patient? Drugs 2014, 74, 521–533. [CrossRef] [PubMed] 4. Domingo, C.; Pomares, X.; Navarro, A.; Rudi, N.; Sogo, A.; Dávila, I.; Mirapeix, R.M. Omalizumab Is Equally Effective in Persistent Allergic Oral Corticosteroid-Dependent Asthma Caused by Either Seasonal or Perennial Allergens: A Pilot Study. Int. J. Mol. Sci. 2017, 18, 521. [CrossRef] [PubMed] 5. Domingo, C. Overlapping Effects of New Monoclonal Antibodies for Severe Asthma. Drugs. 2017, 77, 1769–1787. [CrossRef] [PubMed] 6. Menzies-Gow, A.; Colice, G.; Griffiths, J.M.; Almqvist, G.; Ponnarambil, S.; Kaur, P.; Ruberto, G.; Bowen, K.; Hellqvist, Å.; Mo, M.; et al. NAVIGATOR: A phase 3 multicentre, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy and safety of tezepelumab in adults and adolescents with severe, uncontrolled asthma. Respir Res. 2020, 21, 266. [CrossRef] [PubMed] Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.