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• W129386045 abstract "Asthma is a type-I allergic airway disease characterized by Th2 cells and IgE. Episodes of bronchial inflammation, eosinophilic in nature and promoting bronchoconstriction, may become chronic and lead to persistent respiratory symptoms and irreversible structural airway changes. Representative mostly of mild to moderate asthma, this clinical definition fails to account for the atypical and often more severe phenotype found in a considerable proportion of asthmatics who have increased neutrophil cell counts in the airways as a distinguishing trait. Neutrophilic inflammation is a hallmark of another type of allergic airway pathology, hypersensitivity pneumonitis. Considered as an immune counterpart of asthma, hypersensitivity pneumonitis is a prototypical type-III allergic inflammatory reaction involving the alveoli and lung interstitium, steered by Th1 cells and IgG and, in its chronic form, accompanied by fibrosis. Although pathologically very different and commonly approached as separate disorders, as discussed in this review, clinical studies as well as data from animal models reveal undeniable parallels between both airway diseases. Danger signaling elicited by the allergenic agent or by accompanying microbial patterns emerges as critical in enabling immune sensitization and in determining the type of sensitization and ensuing allergic disease. On this basis, we propose that asthma allergens cause severe noneosinophilic asthma because of sensitization in the presence of hypersensitivity pneumonitis-promoting danger signaling. Asthma is a type-I allergic airway disease characterized by Th2 cells and IgE. Episodes of bronchial inflammation, eosinophilic in nature and promoting bronchoconstriction, may become chronic and lead to persistent respiratory symptoms and irreversible structural airway changes. Representative mostly of mild to moderate asthma, this clinical definition fails to account for the atypical and often more severe phenotype found in a considerable proportion of asthmatics who have increased neutrophil cell counts in the airways as a distinguishing trait. Neutrophilic inflammation is a hallmark of another type of allergic airway pathology, hypersensitivity pneumonitis. Considered as an immune counterpart of asthma, hypersensitivity pneumonitis is a prototypical type-III allergic inflammatory reaction involving the alveoli and lung interstitium, steered by Th1 cells and IgG and, in its chronic form, accompanied by fibrosis. Although pathologically very different and commonly approached as separate disorders, as discussed in this review, clinical studies as well as data from animal models reveal undeniable parallels between both airway diseases. Danger signaling elicited by the allergenic agent or by accompanying microbial patterns emerges as critical in enabling immune sensitization and in determining the type of sensitization and ensuing allergic disease. On this basis, we propose that asthma allergens cause severe noneosinophilic asthma because of sensitization in the presence of hypersensitivity pneumonitis-promoting danger signaling. Conventionally, asthma is defined as a type-I allergic airway disease mediated by Th2 cells and IgE and characterized by bronchial inflammation that is eosinophilic in nature. In a considerable number of patients, the chronic inflammation and ensuing airway remodeling can result in persistence of symptoms and decreased lung function. However, the conventional definition of asthma and its emphasis on eosinophilia in the context of a Th2-biased immune response does not explain all clinical observations.1Wills-Karp M Santeliz J Karp CL The germless theory of allergic disease: revisiting the hygiene hypothesis.Nat Rev Immunol. 2001; 1: 69-75Crossref PubMed Scopus (662) Google Scholar, 2Herrick CA Bottomly K To respond or not to respond: T cells in allergic asthma.Nat Rev Immunol. 2003; 3: 405-412Crossref PubMed Scopus (300) Google Scholar For example, neutrophilic infiltration is observed during severe acute asthma attacks and in severe persistent asthma. Furthermore, severe chronic asthma frequently also includes an additional Th1 component and even alveolitis. The etiology underlying severe asthma is not well understood and treatment of severe asthmatics is often resistant to conventional asthma anti-inflammatory treatment. This renders noneosinophilic or mixed neutrophilic/eosinophilic severe asthma enigmatic as well as an important challenge to the medical and immunological community. Allergic alveolitis and allergen-specific CD4+ T-cell responsiveness polarized toward Th1 are features also observed in a dissimilar type of allergic disease, namely hypersensitivity pneumonitis (HP). Similarly to asthma, HP is a pathological response of the airways to airborne antigen that, however, is driven by Th1 cells and IgG. Chronic HP can ultimately lead to lung fibrosis and respiratory insufficiency. This review starts from the proposition that the identification of shared and inflammation type-specific mechanisms at work in the onset and pathology of either allergic disease, (severe) asthma or HP, might help to better comprehend at least some aspects of severe asthma. We review the main pathological features observed in mild to moderate asthmatics and commonly associated with conventional asthma phenotypes. From here, we discuss how mouse models have contributed to unravel the immunological basis and pathogenesis of mild asthma. Special emphasis is put on the nature of asthma-eliciting allergens and the dependence of their experimental counterparts on accompanying adjuvants to generate the danger signals necessary for raising Th2-biased sensitization. Reminding us that mouse asthma as such does not exist, the shortcomings of mouse models to mimic characteristic features of especially chronic and severe asthma are discussed in the last part of this section. In the next section devoted to HP, comparison with asthma illustrates prominent differences in pathology and immunology and highlights the crucial role of the origin of the sensitizing antigen, the nature of the danger signaling elicited at the time of antigen encounter, and genetic predisposition. From these differences and similarities we propose in the final section of the review that noneosinophilic or mixed neutrophilic/eosinophilic severe asthma may represent a separate pathology that results from an accidental HP-like sensitization by asthma-characteristic allergens that are generally associated with mild to moderate eosinophilic asthma. Furthermore, we discuss experimental data from mouse models that support this proposition. Persistent mild asthma is characterized by chronic inflammation of the airways that is mostly eosinophilic in nature. The airways of patients with mild asthma have an increased sensitivity and responsiveness to inhaled allergen and often to nonspecific irritants such as cold air, cigarette smoke, perfume, and others. This results in variable and episodic bronchoconstriction with increased mucus production, cough, wheezing, and dyspnea3Tattersfield AE Knox AJ Britton JR Hall IP Asthma.Lancet. 2002; 360: 1313-1322Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar [see also the Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2007. Available from http://www.ginasthma.com/download.asp?intId=309, p 2, last accessed September 15, 2008]. Genetic factors such as predisposition toward the development of atopy, and environmental factors such as viral infection, intensity, and frequency of exposure to airborne allergens, occupational exposures, and overall hygiene, seem to cooperate through still ill-defined mechanisms to initiate allergic sensitization and to control the further evolution to asthma as well as its severity.1Wills-Karp M Santeliz J Karp CL The germless theory of allergic disease: revisiting the hygiene hypothesis.Nat Rev Immunol. 2001; 1: 69-75Crossref PubMed Scopus (662) Google Scholar, 4Kleeberger SR Peden D Gene-environment interactions in asthma and other respiratory diseases.Annu Rev Med. 2005; 56: 383-400Crossref PubMed Scopus (94) Google Scholar, 5Bossé Y Hudson TJ Toward a comprehensive set of asthma susceptibility genes.Annu Rev Med. 2007; 58: 171-184Crossref PubMed Scopus (63) Google Scholar As illustrated in Figure 1, eosinophils along with mast cells, Th2 lymphocytes, dendritic cells (DCs), and macrophages as well as structural cells such as airway smooth muscle, mucous glands, and lung epithelium are the main cellular protagonists in the inflamed airways of patients with mild to moderate asthma.6Busse WW Lemanske Jr, RF Asthma.N Engl J Med. 2001; 344: 350-362Crossref PubMed Scopus (1709) Google Scholar From an immunological viewpoint, the allergic sensitization and resulting inflammation are interpreted as a breakdown of immune tolerance toward environmental antigens. Although these antigens as such are not associated with infectious microbial organisms, they do evoke a futile immunological response in sensitive individuals. As a result, allergen-specific Th2 cells and IgE are generated and on encountering the allergen initiate the complex cascade illustrated in Figure 1 that ultimately leads to the type-I allergic reaction. Although everyone is exposed to numerous indoor and outdoor allergens such as house dust mites, pollen, and pets, the normal outcome of such exposures in nonatopic individuals is immunological tolerance.7Hoyne GF Tan K Corsin-Jimenez M Wahl K Stewart M Howie SE Lamb JR Immunological tolerance to inhaled antigen.Am J Respir Crit Care Med. 2000; 162: S169-S174Crossref PubMed Scopus (36) Google Scholar, 8Eisenbarth SC Piggott DA Huleatt JW Visintin I Herrick CA Bottomly K Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen.J Exp Med. 2002; 196: 1645-1651Crossref PubMed Scopus (989) Google Scholar Regulatory T cell (Treg) and DC subsets are central in controlling tolerance versus sensitization and in determining the nature of subsequent immune responses. Specifically, myeloid DCs have been shown to be responsible for Th2-skewed sensitization against inhaled allergen. In contrast, plasmacytoid DCs promote tolerogenic responses and protect the airways against allergic inflammation.9de Heer HJ Hammad H Soullie T Hijdra D Vos N Willart MA Hoogsteden HC Lambrecht BN Essential role of lung plasmacytoid dendritic cells in preventing asthmatic reactions to harmless inhaled antigen.J Exp Med. 2004; 200: 89-98Crossref PubMed Scopus (670) Google Scholar, 10van Rijt LS Lambrecht BN Dendritic cells in asthma: a function beyond sensitization.Clin Exp Allergy. 2005; 35: 1125-1134Crossref PubMed Scopus (71) Google Scholar Both DC subsets are highly flexible, and co-existing environmental danger-associated molecular patterns (DAMPs) may trigger danger signaling that shifts this balance from immune tolerance toward Th2-skewed immunity. In mice, contact with allergen alone is not sufficient to circumvent inherent tolerance mechanisms without the support of immune potentiators. Most often a biphasic protocol is applied in which systemic administration of antigen in the presence of a Th2-skewing adjuvant (generally aluminum hydroxide salts; alum) is followed by secondary exposure(s) to aerosolized antigen. Alum, the archetypical adjuvant, is used not only in most mouse asthma models but also in human vaccines. Lacking conserved pathogen-associated molecular patterns (PAMPs), alum does not require Toll-like receptor (TLR) signaling for its adjuvant activity.11Gavin AL Hoebe K Duong B Ota T Martin C Beutler B Nemazee D Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling.Science. 2006; 314: 1936-1938Crossref PubMed Scopus (484) Google Scholar Instead, intraperitoneal injection of alum has been shown to induce the release of uric acid.12Kool M Soullie T van Nimwegen M Willart MA Muskens F Jung S Hoogsteden HC Hammad H Lambrecht BN Alum adjuvant boosts adaptive immunity by inducing uric acid and activating inflammatory dendritic cells.J Exp Med. 2008; 205: 869-882Crossref PubMed Scopus (752) Google Scholar Acting as endogenous DAMP, uric acid proved to be responsible for the recruitment of monocytes into the peritoneal cavity and their subsequent conversion into inflammatory DCs that drive Th2 cell responses. Also, the Nalp3 inflammasome has been identified as a crucial mediator of the Th2-stimulatory activity of alum.13Eisenbarth SC Colegio OR O'Connor W Sutterwala FS Flavell RA Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminum adjuvants.Nature. 2008; 453: 1122-1126Crossref PubMed Scopus (1196) Google Scholar Nalp3 is an intracellular protein component belonging to the Nod-like receptor arm of the innate immune system that, similar to TLRs, senses both nonself and endogenous DAMPs. Thus, the induction of uric acid by alum and a Nalp3-dependent activation of innate inflammatory pathways seem to be at the basis of the Th2-skewed adjuvant activity of the inorganic alum salt. Low-level contamination of experimental allergens such as ovalbumin (OA) with lipopolysaccharide14Watanabe J Miyazaki Y Zimmerman GA Albertine KH McIntyre TM Endotoxin contamination of ovalbumin suppresses murine immunologic responses and development of airway hyper-reactivity.J Biol Chem. 2003; 278: 42361-42368Crossref PubMed Scopus (96) Google Scholar or other PAMPs may also elicit signals that promote allergic sensitization. This is supported by the fact that inhalation of endotoxin-free OA induces tolerance instead of sensitization, and the fact that sensitization by conventional, endotoxin-contaminated, OA preparations requires the functional lipopolysaccharide-cognitive receptor, TLR-4.8Eisenbarth SC Piggott DA Huleatt JW Visintin I Herrick CA Bottomly K Lipopolysaccharide-enhanced, toll-like receptor 4-dependent T helper cell type 2 responses to inhaled antigen.J Exp Med. 2002; 196: 1645-1651Crossref PubMed Scopus (989) Google Scholar Interestingly, other allergens used for mouse models such as pollens, house dust mite, ragweed, molds, and cockroach proteins do not require adjuvant (alum) support for inducing sensitization. These real-life allergens differ from the inert model allergen, OA, by their intrinsic enzymatic activity, which triggers danger signaling. Likewise in humans, exogenous enzymes such as proteases from molds and mites as well as industry-related proteases, cellulases, and lipases have allergenic characteristics.15Reed CE Kita H The role of protease activation of inflammation in allergic respiratory diseases.J Allergy Clin Immunol. 2004; 114: 997-1008Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar, 16Brant A Hole A Cannon J Helm J Swales C Welch J Taylor AN Cullinan P Occupational asthma caused by cellulase and lipase in the detergent industry.Occup Environ Med. 2004; 61: 793-795Crossref PubMed Scopus (32) Google Scholar, 17Baur X Enzymes as occupational and environmental respiratory sensitisers.Int Arch Occup Environ Health. 2005; 78: 279-286Crossref PubMed Scopus (30) Google Scholar, 18Hammad H Lambrecht BN Dendritic cells and epithelial cells: linking innate and adaptive immunity in asthma.Nat Rev Immunol. 2008; 8: 193-204Crossref PubMed Scopus (508) Google Scholar, 19Radauer C Bublin M Wagner S Mari A Breiteneder H Allergens are distributed into few protein families and possess a restricted number of biochemical functions.J Allergy Clin Immunol. 2008; 121: 847-852Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar Environmental pollutants such as cigarette smoke may further increase the allergenic properties of antigens: mice inhaling OA together with cigarette smoke exhibit high OA-specific IgE levels (representative of atopy) and distinct eosinophil- and mucus cell-enriched airway inflammation on airway challenge with nebulized OA.20Moerloose KB Robays LJ Maes T Brusselle GG Tournoy KG Joos GF Cigarette smoke exposure facilitates allergic sensitization in mice.Respir Res. 2006; 7: 49Crossref PubMed Scopus (69) Google Scholar This observation could provide a mechanistic basis for the notion that smoking is a risk factor for asthma development.21Siroux V Pin I Oryszczyn MP Le Moual N Kauffmann F Relationships of active smoking to asthma and asthma severity in the EGEA study. Epidemiological study on the genetics and environment of asthma.Eur Respir J. 2000; 15: 470-477Crossref PubMed Scopus (322) Google Scholar Although signals leading to Th2 reactivity can be endogenous in nature, induced by chemical or enzymatically active substances, their role in the development of atopy and asthma is complex and dependent on both the genetic background and immune conditioning of the individual by environmental PAMPs. Thus, the timing of allergen exposure during one's lifetime, along with the frequency and intensity of exposure, play a crucial role in the establishment of tolerance or sensitization and the development of asthma.22Steerenberg PA Van Amsterdam JG Vandebriel RJ Vos JG Van Bree L Van Loveren H Environmental and lifestyle factors may act in concert to increase the prevalence of respiratory allergy including asthma.Clin Exp Allergy. 1999; 29: 1303-1308Crossref PubMed Scopus (30) Google Scholar, 23Platts-Mills TA Asthma severity and prevalence: an ongoing interaction between exposure, hygiene, and lifestyle.PLoS Med. 2005; 2: e34Crossref PubMed Scopus (31) Google Scholar The presumed impact on atopy of immune conditioning by prior microbial exposures is translated in the hygiene hypothesis postulating that reduced exposure to bacteria, viruses, and parasites in early childhood facilitates atopic sensitization,1Wills-Karp M Santeliz J Karp CL The germless theory of allergic disease: revisiting the hygiene hypothesis.Nat Rev Immunol. 2001; 1: 69-75Crossref PubMed Scopus (662) Google Scholar, 24von Mutius E Allergies, infections and the hygiene hypothesis—the epidemiological evidence.Immunobiology. 2007; 212: 433-439Crossref PubMed Scopus (216) Google Scholar probably because of a diminished induction of regulatory T cells.25Lee JH Yu HH Wang LC Yang YH Lin YT Chiang BL The levels of CD4+CD25+ regulatory T cells in paediatric patients with allergic rhinitis and bronchial asthma.Clin Exp Immunol. 2007; 148: 53-63Crossref PubMed Scopus (161) Google Scholar Inversely, frequent stimulation of the innate immune system by environmental PAMPs such as lipopolysaccharide or by contact with livestock may diminish the risk of developing allergic sensitization. This so-called farming effect is suggested by several population studies in rural areas of Europe.26von Mutius E Asthma and allergies in rural areas of Europe.Proc Am Thorac Soc. 2007; 4: 212-216Crossref PubMed Scopus (84) Google Scholar Also studies in mice demonstrated a protection against systemic OA sensitization by prior lipopolysaccharide inhalation.27Tulić MK Wale JL Holt PG Sly PD Modification of the inflammatory response to allergen challenge after exposure to bacterial lipopolysaccharide.Am J Respir Cell Mol Biol. 2000; 22: 604-612Crossref PubMed Scopus (246) Google Scholar Additionally, gene linkage studies showed a correlation between gene polymorphisms related to the innate immune system, the response to endotoxin exposure and infections, and allergic disease.28Koppelman GH Gene by environment interaction in asthma.Curr Allergy Asthma Rep. 2006; 6: 103-111Crossref PubMed Scopus (58) Google Scholar, 29Simpson A John SL Jury F Niven R Woodcock A Ollier WE Custovic A Endotoxin exposure, CD14, and allergic disease: an interaction between genes and the environment.Am J Respir Crit Care Med. 2006; 174: 386-392Crossref PubMed Scopus (255) Google Scholar, 30Holgate ST Yang Y Haitchi HM Powell RM Holloway JW Yoshisue H Pang YY Cakebread J Davies DE The genetics of asthma: ADAM33 as an example of a susceptibility gene.Proc Am Thorac Soc. 2006; 3: 440-443Crossref PubMed Scopus (77) Google Scholar, 31Holgate ST Davies DE Powell RM Howarth PH Haitchi HM Holloway JW Local genetic and environmental factors in asthma disease pathogenesis: chronicity and persistence mechanisms.Eur Respir J. 2007; 29: 793-803Crossref PubMed Scopus (112) Google Scholar Here, the effects may be age-specific as was reported for the influence on atopy of a specific CD14 polymorphism that was apparent during mid childhood but no longer at early adulthood.32O'Donnell AR Toelle BG Marks GB Hayden CM Laing IA Peat JK Goldblatt J Le Souef PN Age-specific relationship between CD14 and atopy in a cohort assessed from age 8 to 25 years.Am J Respir Crit Care Med. 2004; 169: 615-622Crossref PubMed Google Scholar Repeated episodes of allergen exposure and subsequent inflammatory responses can eventually lead to a worsening of the asthmatic phenotype because of a state of chronic inflammation. This condition may result in persistent respiratory symptoms and a permanent decrease in lung function, with the airways becoming increasingly sensitive and reactive not only to specific allergens, but also to environmental stimuli such as cigarette smoke, cold air, or fog. This nonspecific airway hyperreactivity may be at least partly attributed to structural alterations in the airways observed in chronic or severe asthma: mucus gland hyperplasia, airway smooth muscle hypertrophy, epithelial shedding, and subepithelial thickening of the basement membrane (subepithelial fibrosis), together called airway remodeling.33Bousquet J Jeffery PK Busse WW Johnson M Vignola AM Asthma. From bronchoconstriction to airways inflammation and remodeling.Am J Respir Crit Care Med. 2000; 161: 1720-1745Crossref PubMed Scopus (1560) Google Scholar, 34Jeffery PK Remodeling in asthma and chronic obstructive lung disease.Am J Respir Crit Care Med. 2001; 164: S28-S38Crossref PubMed Scopus (773) Google Scholar, 35Mauad T Bel EH Sterk PJ Asthma therapy and airway remodeling.J Allergy Clin Immunol. 2007; 120: 997-1009Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar In contrast to the long-term allergen exposure of patients, most mouse models of asthma involve relatively short-term allergen exposures of up to 10 days. Although experimentally convenient, these short-term models are likely to be driven by immune and inflammatory mechanisms quite distinct from those involved in mild and severe persistent asthma that have chronic inflammation as a hallmark. In mice, prolonged exposure protocols lead to highly divergent outcomes. Generally, down-regulation of inflammatory responses is observed along with the establishment of a long-lasting tolerant state,36Yiamouyiannis CA Schramm CM Puddington L Stengel P Baradaran-Hosseini E Wolyniec WW Whiteley HE Thrall RS Shifts in lung lymphocyte profiles correlate with the sequential development of acute allergic and chronic tolerant stages in a murine asthma model.Am J Pathol. 1999; 154: 1911-1921Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 37Van Hove CL Maes T Joos GF Tournoy KG Prolonged inhaled allergen exposure can induce persistent tolerance.Am J Respir Cell Mol Biol. 2007; 36: 573-584Crossref PubMed Scopus (89) Google Scholar in fact quite similar to the response of nonasthmatic individuals. Interestingly, other studies on prolonged OA aerosol exposure, given three times a week for 6 weeks, showed consistent evidence for airway remodeling but with inflammation varying from low level38Sakai K Yokoyama A Kohno N Hamada H Hiwada K Prolonged antigen exposure ameliorates airway inflammation but not remodeling in a mouse model of bronchial asthma.Int Arch Allergy Immunol. 2001; 126: 126-134Crossref PubMed Scopus (63) Google Scholar to moderate sustained eosinophilic airway inflammation and hyperreactivity.39McMillan SJ Lloyd CM Prolonged allergen challenge in mice leads to persistent airway remodelling.Clin Exp Allergy. 2004; 34: 497-507Crossref PubMed Scopus (188) Google Scholar This dissociation of remodeling from inflammation in chronicity models indicates that once initiated, these pathological features are not necessarily intertwined, as also observed in paucigranulocytic asthma patients.40Holgate ST Pathogenesis of asthma.Clin Exp Allergy. 2008; 38: 872-897Crossref PubMed Scopus (550) Google Scholar Genetic factors are also determinants in the establishment of chronic asthma-like features in mouse models. Using a protocol of tightly controlled, low-level exposure to OA aerosol throughout a period of 8 weeks, BALB/c mice developed inflammatory features much like chronic asthma: intraepithelial presence of eosinophils, chronic inflammation in the lamina propria, airway remodeling and hyperreactivity, and no alveolitis. Strikingly, no significant airway hyperreactivity or airway lesions were observed when this protocol was applied to C57BL/6 mice,41Kumar RK Foster PS Modeling allergic asthma in mice: pitfalls and opportunities.Am J Respir Cell Mol Biol. 2002; 27: 267-272Crossref PubMed Scopus (182) Google Scholar although these mice are often used in regular, short-term models of asthma. Other studies too have underscored the importance of strain specificity and route of exposure in the outcome of chronic asthma models. One study showed that in A/J, BALB/c, C57BL/6, and C3H/HeJ mice, repeated inhalational exposure to OA initially promotes a characteristic eosinophilic airway inflammation in the first weeks, but ultimately leads in all strains to antigenic tolerance42Shinagawa K Kojima M Mouse model of airway remodeling: strain differences.Am J Respir Crit Care Med. 2003; 168: 959-967Crossref PubMed Scopus (182) Google Scholar as was also reported by others.36Yiamouyiannis CA Schramm CM Puddington L Stengel P Baradaran-Hosseini E Wolyniec WW Whiteley HE Thrall RS Shifts in lung lymphocyte profiles correlate with the sequential development of acute allergic and chronic tolerant stages in a murine asthma model.Am J Pathol. 1999; 154: 1911-1921Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 37Van Hove CL Maes T Joos GF Tournoy KG Prolonged inhaled allergen exposure can induce persistent tolerance.Am J Respir Cell Mol Biol. 2007; 36: 573-584Crossref PubMed Scopus (89) Google Scholar In contrast, intranasal antigen exposure in A/J mice resulted in continuous eosinophilic airway inflammation and, after 12 weeks of antigen exposure, in airway remodeling. Strikingly, both eosinophilic inflammation and remodeling were less prominent in BALB/c mice and absent in C57BL/6 and C3H/HeJ mice. These observations illustrate how genetic predisposition and route of exposure may co-operate to overcome inherent anti-inflammatory and tolerance mechanisms, thus leading to a condition much like that observed in chronic asthma. The observed strain differences clearly do not follow the Th1-Th2 paradigm because both Th1-biased C57BL/6 mice and Th2-biased BALB/c mice developed tolerance to the instilled antigen after an initial inflammatory episode. It seems that other factors besides genetic factors dictating Th2 reactivity and atopy determine the propensity for progression to chronic disease and irreversible histological changes in the lungs. One such factor may be granulocyte-macrophage colony-stimulating factor (GM-CSF). In chronically exposed antigen-tolerant BALB/c mice, eosinophilic inflammation was fully restored after instillation of recombinant GM-CSF.43Swirski FK Sajic D Robbins CS Gajewska BU Jordana M Stampfli MR Chronic exposure to innocuous antigen in sensitized mice leads to suppressed airway eosinophilia that is reversed by granulocyte macrophage colony-stimulating factor.J Immunol. 2002; 169: 3499-3506PubMed Google Scholar Inversely, GM-CSF-deficient mice showed reduced eosinophil numbers despite unaltered atopy, Th2 reactivity, and airway hyperreactivity.44Su YC Rolph MS Hansbro NG Mackay CR Sewell WA Granulocyte-macrophage colony-stimulating factor is required for bronchial eosinophilia in a murine model of allergic airway inflammation.J Immunol. 2008; 180: 2600-2607Crossref PubMed Scopus (36) Google Scholar When considering asthma, at least in its early stages, as a Th2 cell-mediated eosinophilic inflammation of the airways, HP (extrinsic allergic alveolitis) may be considered as its counterpart both from an immunological and pathological point of view. The inflammatory process in the acute phase of HP characteristically features a nonatopic neutrophilic inflammation of the respiratory bronchioles, alveoli, and interstitial tissue of the lungs.45Yi ES Hypersensitivity pneumonitis.Crit Rev Clin Lab Sci. 2002; 39: 581-629Crossref PubMed Scopus (44) Google Scholar, 46McSharry C Anderson K Bourke SJ Boyd G Takes your breath away—the immunology of allergic alveolitis.Clin Exp Immunol. 2002; 128: 3-9Crossref PubMed Scopus (52) Google Scholar, 47Lacasse Y Selman M Costabel U Dalphin JC Ando M Morell F Erkinjuntti-Pekkanen R Muller N Colby TV Schuyler M Cormier Y Clinical diagnosis of hypersensitivity pneumonitis.Am J Respir Crit Care Med. 2003; 168: 952-958Crossref PubMed Scopus (501) Google Scholar, 48Mohr LC Hypersensitivity pneumonitis.Curr Opin Pulm Med. 2004; 10: 401-411Crossref PubMed Scopus (120) Google Scholar Similarly to asthma, the pathology is induced by repeated exposure to airborne agents in individuals previously sensitized to specific agents via the pulmonary mucosa, and manifests itself in acute, subacute, or chronic forms.48Mohr LC Hypersensitivity pneumonitis.Curr Opin Pulm Med. 2004; 10: 401-411Crossref PubMed Scopus (120) Google Scholar, 49Ismail T McSharry C Boyd G Extrinsic allergic alveolitis.Respirology. 2006; 11: 262-268Crossref PubMed Scopus (37) Google Scholar However, in contrast to asthma, the causative agents are small organic particles, often of microbial origin, or volatile reactive chemicals, and the resulting pathology is clearly of a different nature. 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• W129386045 title "Where Asthma and Hypersensitivity Pneumonitis Meet and Differ" @default.
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