How are airborne allergens remembered by the immune system?

The reason patients with asthma and allergic diseases have recurrent and persistent respiratory symptoms in response to environmental exposure to allergens or certain infectious agents is not fully understood. Immune responses are divided into 2 arms: innate and adaptive immunity. In general, innate immunity reacts rapidly but less specifically to pathogens, whereas adaptive immunity is slower to develop but more specific and builds up immunologic memory. Immunologic memory that is mediated by gene recombination and clonal expansion is a unique feature of adaptive immunity. However, innate immunity might also demonstrate memory responses even though it may use different and less specific mechanisms. For example, invertebrates (eg, mosquitos and bumble bees) and plants, which do not have adaptive immune systems, generate memory responses to reinfection with the same pathogens.1Netea M.G. Joosten L.A. Latz E. Mills K.H. Natoli G. Stunnenberg H.G. et al.Trained immunity: a program of innate immune memory in health and disease.Science. 2016; 352aaf1098Crossref Scopus (1196) Google Scholar In animal models, an infection or vaccination with certain microbial products (eg, BCG, Candida albicans, LPS, and β-glucan) can protect against infections independent of adaptive immunity.1Netea M.G. Joosten L.A. Latz E. Mills K.H. Natoli G. Stunnenberg H.G. et al.Trained immunity: a program of innate immune memory in health and disease.Science. 2016; 352aaf1098Crossref Scopus (1196) Google Scholar In humans, BCG vaccination in newborn children provides protection not only against tuberculosis but also against respiratory viruses and sepsis induced by other pathogens.2Benn C.S. Netea M.G. Selin L.K. Aaby P. A small jab - a big effect: nonspecific immunomodulation by vaccines.Trends Immunol. 2013; 34: 431-439Abstract Full Text Full Text PDF PubMed Scopus (332) Google Scholar These previous findings suggest the presence of immunologic memory in innate immunity. The concept of “trained immunity” has recently been proposed to define a long-term adaptation of innate immunity to previous exposure to microbes or their products or a de facto innate immune memory.1Netea M.G. Joosten L.A. Latz E. Mills K.H. Natoli G. Stunnenberg H.G. et al.Trained immunity: a program of innate immune memory in health and disease.Science. 2016; 352aaf1098Crossref Scopus (1196) Google Scholar,3Netea M.G. Domínguez-Andrés J. Barreiro L.B. Chavakis T. Divangahi M. Fuchs E. et al.Defining trained immunity and its role in health and disease.Nat Rev Immunol. 2020; 20: 375-388Crossref PubMed Scopus (632) Google Scholar From the disease perspective, trained immunity is beneficial, as it improves the host’s defense against subsequent infection from pathogens. However, it could also be detrimental and result in overly active immune responses or chronic inflammation. In asthma and allergic diseases, adaptive immune cells mediate immunologic memory to allergens by producing antigen-specific TH2 cell–type CD4+ T cells and IgE antibodies. In the current issue of the Journal of Allergy and Clinical Immunology, Lechner et al demonstrate that innate immune cells, specifically macrophages, remember previous exposure to house dust mite (HDM) allergens.4Lechner A. Henkel F. Hartung F. Bohnacker S. Alessandrini F. Gubernatorova E.O. et al.Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma.J Allergy Clin Immunol. 2022; 149: 2078-2090Abstract Full Text Full Text PDF Scopus (3) Google Scholar Expression of mRNA encoding chemokines and cytokines increased when human monocyte-derived macrophages were exposed to HDM extract in vitro. Although most mRNAs returned to baseline levels after a 5-day resting period, the levels of CCL17 and IL6 mRNAs remained elevated. When macrophages were re-exposed to HDM extract, the levels of CCL17, IL-6, and cysteinyl leukotrienes increased dramatically beyond the levels achieved during the initial exposure to HDM, suggesting that macrophages are “trained” to produce a large quantity of proinflammatory mediators by previous exposure to HDM. Although these HDM-exposed (or HDM-trained) and rechallenged macrophages produced a large amount of prostaglandin E2 (PGE2), macrophages from mice deficient in PGE2 receptor produced less CCL17, suggesting that autocrine PGE2 may explain the increased production of CCL17. Furthermore, blocking TNF-α during the training period or deficiency of TNF-α in myeloid cells inhibited production of CCL17 and PGE2 following re-exposure to HDM, suggesting that autocrine TNF-α also plays a central role in the amplification event cascade. These results were recapitulated in macrophages generated from monocytes from patients with HDM sensitivity and asthma or myeloid progenitors in the bone marrow of mice previously exposed to HDM.4Lechner A. Henkel F. Hartung F. Bohnacker S. Alessandrini F. Gubernatorova E.O. et al.Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma.J Allergy Clin Immunol. 2022; 149: 2078-2090Abstract Full Text Full Text PDF Scopus (3) Google Scholar Taken together, these results suggest that the training state is maintained during monocyte and macrophage differentiation. Thus, component(s) in HDM extract activate and likely train macrophages to produce high amounts of CCL17, IL-6, and cysteinyl leukotrienes following re-exposure to HDM through the TNF-α and PGE2 pathways (Fig 1). Such immunologic memory or trained immunity of macrophages may facilitate recruitment of TH2 cells and promote airway inflammation during repeated airborne exposure to allergens. Lechner et al further investigated the molecular mechanisms.4Lechner A. Henkel F. Hartung F. Bohnacker S. Alessandrini F. Gubernatorova E.O. et al.Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma.J Allergy Clin Immunol. 2022; 149: 2078-2090Abstract Full Text Full Text PDF Scopus (3) Google Scholar The memory in adaptive immunity is mediated by gene recombination and clonal expansion of T cells and B cells. Although the molecular mechanisms of trained immunity are not fully understood, multiple regulatory events are likely involved, including changes in chromatin organization, DNA methylation, transcription of long noncoding RNAs, and metabolic reprogramming.3Netea M.G. Domínguez-Andrés J. Barreiro L.B. Chavakis T. Divangahi M. Fuchs E. et al.Defining trained immunity and its role in health and disease.Nat Rev Immunol. 2020; 20: 375-388Crossref PubMed Scopus (632) Google Scholar Most of the proinflammatory gene loci are repressed in a cell at a steady state,5Smale S.T. Tarakhovsky A. Natoli G. Chromatin contributions to the regulation of innate immunity.Annu Rev Immunol. 2014; 32: 489-511Crossref PubMed Scopus (118) Google Scholar whereas epigenetic changes, including histone 3 lysine 27 acetylation (H3K27ac) and histone 3 lysine 4 methylation (H3K4me1 and H3K4me3), mark an open configuration of chromatin in trained myeloid cells.3Netea M.G. Domínguez-Andrés J. Barreiro L.B. Chavakis T. Divangahi M. Fuchs E. et al.Defining trained immunity and its role in health and disease.Nat Rev Immunol. 2020; 20: 375-388Crossref PubMed Scopus (632) Google Scholar,6Saeed S. Quintin J. Kerstens H.H. Rao N.A. Aghajanirefah A. Matarese F. et al.Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity.Science. 2014; 3451251086Crossref Scopus (887) Google Scholar Metabolites regulate the activities of the enzymes that produce these epigenetic changes; for example, the tricarboxylic acid cycle metabolite fumarate and α-ketoglutarate regulate the activities of KDM5 histone demethylases and H3K27 demethylase JMJD3, respectively.7Donohoe D.R. Bultman S.J. Metaboloepigenetics: interrelationships between energy metabolism and epigenetic control of gene expression.J Cell Physiol. 2012; 227: 3169-3177Crossref PubMed Scopus (163) Google Scholar Lechner et al found less abundant H3K4 or H3K9 methylation in HDM-trained macrophages.4Lechner A. Henkel F. Hartung F. Bohnacker S. Alessandrini F. Gubernatorova E.O. et al.Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma.J Allergy Clin Immunol. 2022; 149: 2078-2090Abstract Full Text Full Text PDF Scopus (3) Google Scholar Furthermore, bone marrow–derived macrophages from HDM-exposed mice secreted more amino acids to the extracellular milieu than resting macrophages did, and they produced high amounts of the histone demethylase modulator 2-hydroxyglutamate. Supplementation with exogenous 2-hydroxyglutamate promoted macrophage production of CCL17 and PGE2, suggesting that metabolic reprogramming and epigenetic modification are likely involved in the immunologic phenotypes of HDM-trained macrophages (Fig 1). The study by Lechner et al4Lechner A. Henkel F. Hartung F. Bohnacker S. Alessandrini F. Gubernatorova E.O. et al.Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma.J Allergy Clin Immunol. 2022; 149: 2078-2090Abstract Full Text Full Text PDF Scopus (3) Google Scholar elegantly integrated in vitro tissue culture, in vivo mouse models, and human specimens to provide evidence for trained immunity in promoting proinflammatory functions of macrophages previously exposed to allergens. However, several questions remain. First, how long will the immunologic memory of macrophages last? In the study by Lechner et al, macrophages were rested for 5 or 7 days after the initial exposure to HDM, but immunologic memory of T cells and B cells typically lasts for months or years. Importantly, TNF-α signaling of macrophage progenitors in the bone marrow was altered by airborne exposure to HDM,4Lechner A. Henkel F. Hartung F. Bohnacker S. Alessandrini F. Gubernatorova E.O. et al.Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma.J Allergy Clin Immunol. 2022; 149: 2078-2090Abstract Full Text Full Text PDF Scopus (3) Google Scholar so these progenitors may provide weeks or months of memory as they proliferate and supply peripheral tissues. The second question is related to the pathologic significance of macrophage memory, considering the redundancy of the immune system. For example, CCL17 is produced by macrophages, monocytes, and dendritic cells. Therefore, macrophages may be just a fraction of the entire pool of proinflammatory mediators. Moreover, airway pathology may not be altered significantly in the absence of macrophage memory. However, macrophages may play a pivotal role considering their unique anatomic localizations in mucosal tissues as well as rapid and robust production of cytokines and/or chemokines. Finally, the specificity of HDM-induced macrophage memory is unknown. Future studies are needed to determine whether macrophages trained by HDM show enhanced inflammatory responses to heterogenous allergens, such as those from fungi and pollens. If this is true, innate immune memory may provide a model to explain the clinical manifestation of patients who are reactive to many allergens. More studies are necessary to understand the biologic and pathologic roles for memory macrophages. In summary, the article by Lechner et al4Lechner A. Henkel F. Hartung F. Bohnacker S. Alessandrini F. Gubernatorova E.O. et al.Macrophages acquire a TNF-dependent inflammatory memory in allergic asthma.J Allergy Clin Immunol. 2022; 149: 2078-2090Abstract Full Text Full Text PDF Scopus (3) Google Scholar provides a major advance by bringing the novel concept of trained immunity or innate immune memory to the fields of asthma and allergic diseases. As was previously shown, group 2 innate lymphoid cells from mice exposed to a protease papain, Aspergillus allergens, or IL-33 responded more vigorously to secondary challenge with IL-33 or papain even after a resting period of several months.8Martinez-Gonzalez I. Mathä L. Steer C.A. Ghaedi M. Poon G.F. Takei F. Allergen-experienced group 2 innate lymphoid cells acquire memory-like properties and enhance allergic lung inflammation.Immunity. 2016; 45: 198-208Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar In addition, airway epithelial stem cells from patients with chronic rhinosinusitis retain intrinsic memory of previous exposure to IL-4 and IL-13, which may contribute to basal cell hyperplasia and mucosal barrier dysfunction.9Ordovas-Montanes J. Dwyer D.F. Nyquist S.K. Buchheit K.M. Vukovic M. Deb C. et al.Allergic inflammatory memory in human respiratory epithelial progenitor cells.Nature. 2018; 560: 649-654Crossref PubMed Scopus (185) Google Scholar Skin epithelial stem cells maintain accessibility to stress response genes including inflammasome components for 6 months after primary exposure to chemical proinflammatory agents.10Naik S. Larsen S.B. Gomez N.C. Alaverdyan K. Sendoel A. Yuan S. et al.Inflammatory memory sensitizes skin epithelial stem cells to tissue damage.Nature. 2017; 550: 475-480Crossref PubMed Scopus (261) Google Scholar Therefore, various innate immune cells and stromal cells likely have the capacity to remember previous incidents of inflammation or exposure to microbial products. In the future, it will be important to examine the interactions between cells in innate immune memory and those in conventional memory responses. One might expect a synergistic interaction to promote inflammation and immunopathology, or alternatively, a regulatory interaction to harness inflammation and regain immune and tissue homeostasis. Further studies on trained immunity will provide opportunities to better understand the immunologic mechanisms of asthma and allergic diseases and to develop new strategies to treat them. Macrophages acquire a TNF-dependent inflammatory memory in allergic asthmaJournal of Allergy and Clinical ImmunologyVol. 149Issue 6PreviewInfectious agents can reprogram or “train” macrophages and their progenitors to respond more readily to subsequent insults. However, whether such an inflammatory memory exists in type 2 inflammatory conditions such as allergic asthma was not known. Full-Text PDF Open Access