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• W2897762503 abstract "This review highlights advances in mechanisms of allergic disease, particularly type 2 innate lymphoid cells, TH2 lymphocytes, B cells, dendritic cells, microbiome and barrier function, eosinophils, and mast cells. During the last year, considerable progress has been made in the further characterization of type 2 inflammation controlled by both adaptive (TH2) and type 2 innate lymphoid effector cells. New pathways of lymphocyte activation, trafficking, and recruitment and effector cell mechanisms have been discovered. The plasticity of lymphocyte effector cell responses is another area in which major progress has been achieved. Accumulating evidence will influence both our understanding of allergic disease and our efforts for allergy prevention and treatment. This review highlights advances in mechanisms of allergic disease, particularly type 2 innate lymphoid cells, TH2 lymphocytes, B cells, dendritic cells, microbiome and barrier function, eosinophils, and mast cells. During the last year, considerable progress has been made in the further characterization of type 2 inflammation controlled by both adaptive (TH2) and type 2 innate lymphoid effector cells. New pathways of lymphocyte activation, trafficking, and recruitment and effector cell mechanisms have been discovered. The plasticity of lymphocyte effector cell responses is another area in which major progress has been achieved. Accumulating evidence will influence both our understanding of allergic disease and our efforts for allergy prevention and treatment. This review highlights advances in mechanisms of type 2 innate lymphoid cells (ILC2s), CD4+ TH2 lymphocytes, regulatory T (Treg) cells, B cells, dendritic cells (DCs), allergic inflammatory cells (mast cells [MCs], basophils, and eosinophils), macrophages, neutrophils and natural killer (NK) cells, airway epithelial and other structural cells, stem cells, the inflammasome, the microbiome, and genetic and epigenetic mechanisms. The review focuses on articles that have been published in the Journal of Allergy and Clinical Immunology since 2017 while also referring to key recent findings and trends covered elsewhere. Airway remodeling shows age-dependent clinical manifestations, and these are largely mechanistically undefined. The wingless/integrase (Wnt) pathway, which comprises 19 secreted glycoproteins in human subjects and mice, has been recently implicated in asthma pathogenesis.1Reuter S. Beckert H. Taube C. Take the Wnt out of the inflammatory sails. Modulatory effects of Wnt in airway diseases.Lab Invest. 2016; 96: 177-185Crossref PubMed Scopus (29) Google Scholar, 2Trischler J. Shiomi T. Turner D.L. Sklepkiewicz P.L. Goldklang M.P. Tanaka K.F. et al.Immune modulation of the T cell response in asthma through Wnt10b.Am J Respir Cell Mol Biol. 2016; 54: 584-593Crossref PubMed Scopus (21) Google Scholar Wnt5a is essential for lung development and expressed in the epithelial and mesenchymal compartment in the neonatal lung3Bozyk P.D. Popova A.P. Bentley J.K. Goldsmith A.M. Linn M.J. Weiss D.J. et al.Mesenchymal stromal cells from neonatal tracheal aspirates demonstrate a pattern of lung-specific gene expression.Stem Cells Dev. 2011; 20: 1995-2007Crossref PubMed Scopus (37) Google Scholar, 4Li C. Xiao J. Hormi K. Borok Z. Minoo P. Wnt5a participates in distal lung morphogenesis.Dev Biol. 2002; 248: 68-81Crossref PubMed Scopus (247) Google Scholar and has been implicated in airway remodeling in asthmatic patients.5Kumawat K. Gosens R. WNT-5A. Signaling and functions in health and disease.Cell Mol Life Sci. 2016; 73: 567-587Crossref PubMed Scopus (107) Google Scholar, 6Kumawat K. Menzen M.H. Bos I.S.T. Baarsma H.A. Borger P. Roth M. et al.Noncanonical WNT-5A signaling regulates TGF-β-induced extracellular matrix production by airway smooth muscle cells.FASEB J. 2013; 27: 1631-1643Crossref PubMed Scopus (89) Google Scholar, 7Kumawat K. Menzen M.H. Slegtenhorst R.M. Halayko A.J. Schmidt M. Gosens R. TGF-β-activated kinase 1 (TAK1) signaling regulates TGF-β-induced WNT-5A expression in airway smooth muscle cells via Sp1 and β-catenin.PLoS One. 2014; 9: e94801Crossref PubMed Scopus (33) Google Scholar Dietz et al8Dietz K. de Los Reyes Jiménez M. Gollwitzer E.S. Chaker A.M. Zissler U.M. Rådmark O.P. et al.Age dictates a steroid-resistant cascade of Wnt5a, transglutaminase 2, and leukotrienes in inflamed airways.J Allergy Clin Immunol. 2017; 139: 1343-1354.e6Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar demonstrated age-related differences in leukotriene (LT) and Wnt pathways during early- and late-onset allergic airway inflammation in mice. Moreover, the investigators identified a steroid-resistant cascade of Wnt5a, transglutaminase (Tgm2), and LTs, which might represent a therapeutic target for airway inflammation and remodeling.8Dietz K. de Los Reyes Jiménez M. Gollwitzer E.S. Chaker A.M. Zissler U.M. Rådmark O.P. et al.Age dictates a steroid-resistant cascade of Wnt5a, transglutaminase 2, and leukotrienes in inflamed airways.J Allergy Clin Immunol. 2017; 139: 1343-1354.e6Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar In another study authors found constitutive increased expression of protein arginine methyltranferase 1 in human asthmatic airway smooth muscle cells that is caused by low micro-RNA (miR)–19a expression.9Sun Q. Liu L. Wang H. Mandal J. Khan P. Hostettler K.E. et al.Constitutive high expression of protein arginine methyltransferase 1 in asthmatic airway smooth muscle cells is caused by reduced microRNA-19a expression and leads to enhanced remodeling.J Allergy Clin Immunol. 2017; 140: 510-524.e3Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Enhanced protein arginine methyltranferase 1 expression leads to induction of airway remodeling (extracellular matrix deposition, proliferation and migration of airway smooth muscle cells, and α–smooth muscle actin production) in asthmatic patients through extracellular signal-regulated kinase 1/2, mitogen-activated protein kinase, and signal transducer and activator of signaling 1 signaling.9Sun Q. Liu L. Wang H. Mandal J. Khan P. Hostettler K.E. et al.Constitutive high expression of protein arginine methyltransferase 1 in asthmatic airway smooth muscle cells is caused by reduced microRNA-19a expression and leads to enhanced remodeling.J Allergy Clin Immunol. 2017; 140: 510-524.e3Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Another interesting finding in the field comes from an article highlighting neutrophils as a major source of oncostatin M production in human subjects.10Pothoven K.L. Norton J.E. Suh L.A. Carter R.G. Harris K.E. Biyasheva A. et al.Neutrophils are a major source of the epithelial barrier disrupting cytokine oncostatin M in patients with mucosal airways disease.J Allergy Clin Immunol. 2017; 139: 1966-1978.e9Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar Oncostatin M has been previously associated with disruption of the barrier function in differentiated airway epithelium. In an article by Qiao et al,11Qiao Y. Tam J.K.C. Tan S.S.L. Tai Y.K. Chin C.Y. Stewart A.G. et al.CD151, a laminin receptor showing increased expression in asthmatic patients, contributes to airway hyperresponsiveness through calcium signaling.J Allergy Clin Immunol. 2017; 139: 82-92.e5Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar CD151 was depicted to complex newly synthesized influenza A viral proteins with host nuclear export proteins and stabilize microtubule complexes. These are key processes necessary for the polarized trafficking of viral progeny to the host plasma membrane for assembly. This site is not targeted by current therapy and can be exploited in the future to attenuate influenza A virus infection severity. In a recent study the remote effects of a strictly enteric helminth infection with Heligmosomoides polygyrus on respiratory syncytial virus infection was investigated.12McFarlane A.J. McSorley H.J. Davidson D.J. Fitch P.M. Errington C. Mackenzie K.J. et al.Enteric helminth-induced type I interferon signaling protects against pulmonary virus infection through interaction with the microbiota.J Allergy Clin Immunol. 2017; 140: 1068-1078.e6Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar The authors developed a coinfection murine model and showed attenuated disease and pulmonary inflammation, as well as viral load, when mice were first infected with the helminth. Protective effects were mediated through type I interferon upregulation, whereas adaptive immune responses, including TH2 responses, were not essential. Reduced gut microbiota diversity and low mucosal total IgA levels in infancy have been associated with allergy development. Recently, Dzidic et al13Dzidic M. Abrahamsson T.R. Artacho A. Björkstén B. Collado M.C. Mira A. et al.Aberrant IgA responses to the gut microbiota during infancy precede asthma and allergy development.J Allergy Clin Immunol. 2017; 139: 1017-1025.e14Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar showed that a low and aberrant (in terms of bacterial targets and recognition patterns) IgA responsiveness to the gut microbiota during infancy precedes asthma and allergy development. These findings possibly indicate an impaired mucosal barrier function among allergic children. Bruton tyrosine kinase (BTK) was shown to be a critical regulator of NLRP3 inflammasome activation, and its ablation led to reduced IL-1β processing and secretion in response to stimuli, such as leucocidin toxin.14Liu X. Pichulik T. Wolz O.-O. Dang T.-M. Stutz A. Dillen C. et al.Human NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activity is regulated by and potentially targetable through Bruton tyrosine kinase.J Allergy Clin Immunol. 2017; 140: 1054-1067.e10Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar Because BTK mutations cause the genetic immunodeficiency X-linked agammaglobulinemia, it has been suggested that X-linked agammaglobulinemia can be attributed to genetic inflammasome deficiency and that NLRP3 inflammasome-linked inflammation could be pharmacologically targeted through BTK.14Liu X. Pichulik T. Wolz O.-O. Dang T.-M. Stutz A. Dillen C. et al.Human NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome activity is regulated by and potentially targetable through Bruton tyrosine kinase.J Allergy Clin Immunol. 2017; 140: 1054-1067.e10Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar Blau syndrome, or early-onset sarcoidosis, is a juvenile-onset systemic granulomatosis associated with a mutation in nucleotide-binding oligomerization domain 2 (NOD2). Takada et al15Takada S. Kambe N. Kawasaki Y. Niwa A. Honda-Ozaki F. Kobayashi K. et al.Pluripotent stem cell models of Blau syndrome reveal an IFN-γ-dependent inflammatory response in macrophages.J Allergy Clin Immunol. 2018; 141: 339-349.e11Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar established Blau syndrome–specific induced pluripotent stem cell (iPSC) lines. The disease-associated NOD2 mutation of iPSCs was corrected by using the CRISPR-Cas9 system to specifically evaluate the in vitro phenotype of iPSC-derived cells. The investigators also inserted the same NOD2 mutation into a control iPSC line. These isogenic iPSCs were then differentiated into monocytic cell lineages. Data from Takada et al show that Blau syndrome or early-onset sarcoidosis is mediated through IFN-γ–induced ligand–independent autoinflammation. This is characterized by nuclear factor κB activation and proinflammatory cytokine production. Autoantibodies to cytokines have been described in various pathologies, including autoimmune diseases with or without susceptibility to infections, chronic inflammatory disorders, and cancer.16Browne S.K. Holland S.M. Anticytokine autoantibodies in infectious diseases. Pathogenesis and mechanisms.Lancet Infect Dis. 2010; 10: 875-885Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar In a study by Spohn et al,17Spohn G. Arenas-Ramirez N. Bouchaud G. Boyman O. Endogenous polyclonal anti-IL-1 antibody responses potentiate IL-1 activity during pathogenic inflammation.J Allergy Clin Immunol. 2017; 139: 1957-1965.e3Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar endogenous polyclonal anti-cytokine antibody responses were shown to be able to enhance IL-1β activity in patients with inflammatory and autoimmune diseases.17Spohn G. Arenas-Ramirez N. Bouchaud G. Boyman O. Endogenous polyclonal anti-IL-1 antibody responses potentiate IL-1 activity during pathogenic inflammation.J Allergy Clin Immunol. 2017; 139: 1957-1965.e3Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar The enhanced morbidity was demonstrated by an inflammatory bowel disease and an inflammatory arthritis murine model, which were immunized with 2 different IL-1β variants. During recent times, considerable discussion has focused on a subset of tissue-resident NK cells that are distinct from conventional NK cells and preferentially distribute in nonlymphoid tissues (Table I).18Peng H. Tian Z. Diversity of tissue-resident NK cells.Semin Immunol. 2017; 31: 3-10Crossref PubMed Scopus (69) Google Scholar, 19Male V. Liver-resident NK cells. The human factor.Trends Immunol. 2017; 38: 307-309Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Another recent finding is memory response of NK cells, which can be divided into antigen-specific and antigen-independent cells and can be observed in both infectious and noninfectious settings.20Geary C.D. Sun J.C. Memory responses of natural killer cells.Semin Immunol. 2017; 31: 11-19Crossref PubMed Scopus (54) Google Scholar However, a series of questions remain unanswered, such as the influence of functional heterogeneity in effector NK cell pool on memory development, as well as epigenetic determinants, additional receptors, and ligands in the same context. Moreover, it is unknown whether memory NK cells become tissue resident–like T-cell subsets and whether they provide heterologous clinical benefits.Table IRecent Journal advances concerning NK cells•The majority of human lung NK cells are made up of highly differentiated hypofunctional CD69−CD56dim NK cells and move dynamically to blood.•A novel human NK subpopulation was identified, which is fully mature, expresses high PD-1 levels, and has a low proliferative rate and impaired antitumor activity. The latter can be restored after antibody-mediated disruption of PD-1/programmed death ligand interaction.•Defective NK activity might underlie herpes simplex virus 1–induced severe skin lesions in patients with eczema herpeticum. Open table in a new tab In a study by Marquardt et al,21Marquardt N. Kekäläinen E. Chen P. Kvedaraite E. Wilson J.N. Ivarsson M.A. et al.Human lung natural killer cells are predominantly comprised of highly differentiated hypofunctional CD69-CD56dim cells.J Allergy Clin Immunol. 2017; 139: 1321-1330.e4Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar the vast majority of NK cells in human lungs were made up of highly differentiated hypofunctional CD69−CD56dim NK cells. The majority of lung NK cells in the same study were suggested to move dynamically to blood rather than remaining as tissue-resident CD69+ NK cells. Pesce et al22Pesce S. Greppi M. Tabellini G. Rampinelli F. Parolini S. Olive D. et al.Identification of a subset of human natural killer cells expressing high levels of programmed death 1. A phenotypic and functional characterization.J Allergy Clin Immunol. 2017; 139: 335-346.e3Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar identified and characterized a population of novel human NK cells that express high levels of programmed death 1 (PD-1), are phenotypically fully mature, and are increased in patients with ovarian cancer. These cells exhibited low proliferative rates in response to cytokines and impaired antitumor activity that can be partially restored by antibody-mediated disruption of PD-1/programmed death ligand interaction.22Pesce S. Greppi M. Tabellini G. Rampinelli F. Parolini S. Olive D. et al.Identification of a subset of human natural killer cells expressing high levels of programmed death 1. A phenotypic and functional characterization.J Allergy Clin Immunol. 2017; 139: 335-346.e3Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar In a mouse model of eczema herpeticum with an impaired skin barrier, a critical role of defective NK activities was demonstrated for the development of herpes simplex virus 1–induced severe skin lesions.23Kawakami Y. Ando T. Lee J.-R. Kim G. Kawakami Y. Nakasaki T. et al.Defective natural killer cell activity in a mouse model of eczema herpeticum.J Allergy Clin Immunol. 2017; 139: 997-1006.e10Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar Increased numbers of MCs at sites of inflammation might be a driving mechanism, a bystander effect, or a host-driven compensatory mechanism to control and terminate disease. Some of the open questions in the field include identification of the activators of MCs in nonallergic diseases, as well as of the mediators involved in the different effects that MCs have in different responses (Fig 1, B).24Siebenhaar F. Redegeld F.A. Bischoff S.C. Gibbs B.F. Maurer M. Mast cells as drivers of disease and therapeutic targets.Trends Immunol. 2018; 39: 151-162Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar Bone marrow–derived cultured MCs and peritoneal cell–derived MCs were recently shown to produce substantially different releasates on IgE activation in mice.25Shubin N.J. Glukhova V.A. Clauson M. Truong P. Abrink M. Pejler G. et al.Proteome analysis of mast cell releasates reveals a role for chymase in the regulation of coagulation factor XIIIA levels via proteolytic degradation.J Allergy Clin Immunol. 2017; 139: 323-334Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Moreover, the same study showed that the protease content of MCs shapes the proteome of the releasate and that chymase regulates the transglutaminase coagulation factor XIIIA through proteolytic degradation. IL-33 was shown to potentiate IgE-mediated MC responses by both increasing the numbers of degranulating and chemokine-producing cells and enhancing the magnitude of responses of individual MCs.26Joulia R. L'Faqihi F.-E. Valitutti S. Espinosa E. IL-33 fine tunes mast cell degranulation and chemokine production at the single-cell level.J Allergy Clin Immunol. 2017; 140: 497-509.e10Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar The same study showed that in the absence of IL-33 pretreatment, human MCs demonstrated an all-or-none response after FcεRI triggering (ie, a direct correlation between the number of degranulating MCs and the strength of FcεRI stimulation with a constant magnitude of response). Lotfi-Emran et al27Lotfi-Emran S. Ward B.R. Le Q.T. Pozez A.L. Manjili M.H. Woodfolk J.A. et al.Human mast cells present antigen to autologous CD4+ T cells.J Allergy Clin Immunol. 2018; 141: 311-321.e10Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar used in situ–matured primary human MCs and matched CD4+ T cells to assess the ability of the former to act as antigen-presenting cells. Their results showed that IFN-γ primes human MCs to activate T cells through a superantigen and to present CMV to TH1 cells, co-opting MC secretory granules for antigen processing and presentation. The described MC degranulation increases surface delivery of HLA class II/peptide and thus promotes stimulation of T-cell proliferation. Recently, the role of pyruvate dehydrogenase (PDH) in MC function was investigated, and the authors showed that PDH is essential for immunologically mediated MC degranulation.28Sharkia I. Hadad Erlich T. Landolina N. Assayag M. Motzik A. Rachmin I. et al.Pyruvate dehydrogenase has a major role in mast cell function, and its activity is regulated by mitochondrial microphthalmia transcription factor.J Allergy Clin Immunol. 2017; 140: 204-214.e8Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Microphthalmia transcription factor is partially located in the mitochondria and interacts with PDH, regulating its activity in a manner that depends on the PDH phosphorylation status. These findings render PDH a new target for manipulating allergic disease. In patients with food allergy, Notch signaling has been highlighted as a novel therapeutic target because pharmacologic inhibition suppressed food antigen–induced intestinal mucosal mast cell (MMC) hyperplasia.29Honjo A. Nakano N. Yamazaki S. Hara M. Uchida K. Kitaura J. et al.Pharmacologic inhibition of Notch signaling suppresses food antigen-induced mucosal mast cell hyperplasia.J Allergy Clin Immunol. 2017; 139: 987-996.e10Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar This in turn led to alleviation of allergic diarrhea and systemic anaphylaxis in a mouse model of experimental food allergy. Furthermore, Notch signaling was shown to induce MMC differentiation through upregulation of gene expression characteristic of MMCs in the presence of IL-3. Burton et al30Burton O.T. Stranks A.J. Tamayo J.M. Koleoglou K.J. Schwartz L.B. Oettgen H.C. A humanized mouse model of anaphylactic peanut allergy.J Allergy Clin Immunol. 2017; 139: 314-322.e9Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar have developed a humanized mouse model of anaphylactic peanut allergy with engraftment of human hematopoietic stem cells in nonobese diabetic mice with severe combined immunodeficiency lacking the cytokine receptor common gamma chain (γc−/−) and carrying a human stem cell factor transgene. These mice showed robust engraftment with T cells, B cells, and MCs in their tissues and mounted specific antibody responses, including peanut-specific IgE. Most importantly, they exhibited MC-mediated systemic anaphylaxis when challenged enterally with peanut, and this was inhibited by anti-IgE (omalizumab) treatment. Sialic acid-binding immunoglobulin-like lectin (Siglec) 8 is a protein on the surfaces of eosinophils, MCs, and basophils. Siglec-8 was found to be endocytosed by these cells and localized in the lysosomal compartment.31O'Sullivan J.A. Carroll D.J. Cao Y. Salicru A.N. Bochner B.S. Leveraging Siglec-8 endocytic mechanisms to kill human eosinophils and malignant mast cells.J Allergy Clin Immunol. 2018; 141: 1774-1785.e7Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Furthermore, targeting saporin to Siglec-8 caused extensive cell death, thus offering a pathway that can be leveraged to kill eosinophils and malignant MCs (Fig 1, A).31O'Sullivan J.A. Carroll D.J. Cao Y. Salicru A.N. Bochner B.S. Leveraging Siglec-8 endocytic mechanisms to kill human eosinophils and malignant mast cells.J Allergy Clin Immunol. 2018; 141: 1774-1785.e7Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar Release of eosinophil cytotoxic granule proteins results through several different mechanisms, one of which is cytolysis, which is associated with release of intact granules, so-called clusters of free eosinophil granules. A recent study aimed at elucidating the molecular mechanism of eosinophil cytolysis and showed that adhesion-induced cytolysis is mediated through receptor-interacting protein kinase 3-mixed lineage kinase-like-dependent necroptosis. Triggering cytolysis is counterregulated by an induction of autophagy in eosinophils (Fig 1, A).32Radonjic-Hoesli S. Wang X. de Graauw E. Stoeckle C. Styp-Rekowska B. Hlushchuk R. et al.Adhesion-induced eosinophil cytolysis requires the receptor-interacting protein kinase 3 (RIPK3)-mixed lineage kinase-like (MLKL) signaling pathway, which is counterregulated by autophagy.J Allergy Clin Immunol. 2017; 140: 1632-1642Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Mannose receptor (MRC1/CD206) mediates allergic sensitization and asthma to multiple glycoallergens, including cockroach. In a study by Zhou et al,33Zhou Y. Do D.C. Ishmael F.T. Squadrito M.L. Tang H.M. Tang H.L. et al.Mannose receptor modulates macrophage polarization and allergic inflammation through miR-511-3p.J Allergy Clin Immunol. 2018; 141: 350-364.e8Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar MRC1-mediated limitation of allergic inflammation was investigated, and the authors showed a decreased cockroach allergen uptake by Mrc1−/− lung macrophages. This resulted in exacerbated lung inflammation in Mrc1−/− mice, with increased levels of cockroach allergen–specific IgE and TH2/TH17 cytokines in a cockroach allergen-induced mouse model. Mrc1−/− macrophages showed low levels of miR-511-3 and an M1 phenotype in contrast to overexpression of miR-511-3p that was associated with an M2 phenotype of macrophages. Expression of prostaglandin D2 (PGD2) synthase and its product PGD2 were significantly downregulated by miR-511-3p, and plasma levels of the latter were significantly lower in human asthmatic patients compared with nonasthmatic subjects. Over the last years, a strong body of evidence indicates the importance of the cross-talk between antigen-presenting DCs and structural cell–derived signals in terms of allergic sensitization and disease initiation and persistence. On allergen stimulation, epithelial cells create a specific inflammatory microenvironment that instructs DCs to initiate the immune response. Furthermore, it is becoming increasingly evident that DCs are key inducers of peripheral tolerance and that their tolerogenic functions can be directed and enhanced by in vivo–targeted delivery of defined T-cell antigens. How specific tolerogenic mechanisms mediated by DCs in steady state can be used to suppress ongoing autoimmune processes under proinflammatory conditions remains to be seen.34Iberg C.A. Jones A. Hawiger D. Dendritic cells as inducers of peripheral tolerance.Trends Immunol. 2017; 38: 793-804Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar DCs conditioned by activin A–induced Treg cells lead to the generation of an immunoregulatory circuit involving tolerogenic DCs and forkhead box P3 (FoxP3)+ Treg cells, which ultimately protect from experimental asthma.35Semitekolou M. Morianos I. Banos A. Konstantopoulos D. Adamou-Tzani M. Sparwasser T. et al.Dendritic cells conditioned by activin A-induced regulatory T cells exhibit enhanced tolerogenic properties and protect against experimental asthma.J Allergy Clin Immunol. 2018; 141: 671-684.e7Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar PD-1/programmed death ligand 1 signaling pathways were essential in activin A–induced Treg cell potentiation of tolerogenic DCs. Exposure to inhalant allergens through the skin often precedes allergic inflammation in the lung. In a study by Deckers et al,36Deckers J. Sichien D. Plantinga M. van Moorleghem J. Vanheerswynghels M. Hoste E. et al.Epicutaneous sensitization to house dust mite allergen requires interferon regulatory factor 4-dependent dermal dendritic cells.J Allergy Clin Immunol. 2017; 140: 1364-1377.e2Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar the investigators applied house dust mite (HDM) epicutaneously, and this led to TH2 sensitization and eosinophilic airway inflammation on intranasal HDM challenge. Skin sensitization could occur without prior skin damage or HDM enzymatic activation but was facilitated by applying the allergen under an occlusive tape. Importantly, interferon regulatory factor 4–dependent dermal type 2 conventional DCs and not epidermal Langerhans cells were identified as the central players in HDM sensitization through the skin. In an experimental Bet v 1 sensitization model, mice were vaccinated with a flagellin-allergen fusion protein (rFlaA:Bet v 1) containing the Toll-like receptor (TLR) 5 ligand flagellin A from Listeria monocytogenes and the birch pollen allergen Bet v 1.37Schülke S. Fiedler A.-H. Junker A.-C. Flaczyk A. Wolfheimer S. Wangorsch A. et al.Critical role of mammalian target of rapamycin for IL-10 dendritic cell induction by a flagellin A conjugate in preventing allergic sensitization.J Allergy Clin Immunol. 2018; 141: 1786-1798.e11Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar Vaccination suppressed TH2 responses from CD4+ T cells and prevented allergic sensitization. In addition, rFlaA:Bet v 1 activated the mammalian target of rapamycin, with a subsequent increase in the metabolic activity of stimulated myeloid DCs. rFlaA:Bet v 1–mediated IL-10 but not proinflammatory cytokine secretion was inhibited by rapamycin in myeloid DCs. In another study tumor progression locus 2 deficiency in mice led to exacerbated HDM-induced allergic airway inflammation.38Kannan Y. Li Y. Coomes S.M. Okoye I.S. Pelly V.S. Sriskantharajah S. et al.Tumor progression locus 2 reduces severe allergic airway inflammation by inhibiting Ccl24 production in dendritic cells.J Allergy Clin Immunol. 2017; 139: 655-666.e7Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar The investigators showed that tumor progression locus 2 inhibited CCL24 expression in lung DCs, which in turn prevented exaggerated airway eosinophilia and inflammation. Bacterial cowshed isolates have been previously shown to be allergy protective in mice. Stein et al39Stein K. Brand S. Jenckel A. Sigmund A. Chen Z.J. Kirschning C.J. et al.Endosomal recognition of Lactococcus lactis G121 and its RNA by dendritic cells is key to its allergy-protective effects.J Allergy Clin Immunol. 2017; 139: 667-678.e5Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar demonstrated that bacterial RNA of Lactococcus lactis G121 mediates protection against experimental asth" @default.
• W2897762503 created "2018-10-26" @default.
• W2897762503 creator A5053003825 @default.
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• W2897762503 date "2018-12-01" @default.
• W2897762503 modified "2023-09-26" @default.
• W2897762503 title "Advances in mechanisms of allergic disease in 2017" @default.
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• W2897762503 doi "https://doi.org/10.1016/j.jaci.2018.09.027" @default.
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