Hammad, Hamida

Lambrecht, Bart

English

Bart N. Lambrecht

Hamida Hammad

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New England Journal of Medicine

Asthma and Coagulation

Ghent University Academic Bibliography

clinical implications of basic researchT h e  n e w  e ngl a nd  j o u r na l  o f  m e dic i n eElizabeth G. Phimister, Ph.D., Editorn engl j med 369;20 nejm.org november 14, 20131964Asthma and CoagulationBart N. Lambrecht, M.D., Ph.D., and Hamida Hammad, Ph.D.Asthma is characterized by chronic inflammation of the airways, contraction of smooth muscle, overproduction of mucus, and remodeling of the airway wall. In many forms of asthma, there is an accumulation of eosinophils, which predicts a good response to inhaled glucocorticoids. Eosino-philic inflammation is controlled by type 2 help-er T (Th2) lymphocytes of the adaptive immune system, which make interleukin-4, interleukin-5, and interleukin-13 in response to the presentation of an allergen by dendritic cells in the airway. However, many features of asthma can also be controlled by type 2 innate lymphoid cells, which cannot specifically recognize allergens but do produce interleukin-5 and interleukin-13 when stimulated by cytokines made by lung epithelial cells and macrophages.Although immune cells control all the fea-tures of asthma, it is unclear why and how they react to allergens. Most organisms that express allergens, such as pollinating plants, house-dust mites, cockroaches, and environmental fungi, are not intrinsically pathogenic to the host. How-ever, some proteins or lipids of these organisms trigger pattern-recognition receptors of the mam-malian immune system. For example, the house-dust mite is known to carry at least 20 allergens that can induce IgE responses in humans. In mice, the development of an asthmalike condi-tion triggered by house-dust mites depends on the expression of toll-like receptor 4 (TLR4) on airway epithelial cells.1 Although many allergens contain lipopolysaccharide, which can potentially bind and activate TLR4, it is also possible that TLR4 is triggered by endogenous danger signals that are released on exposure to allergens.Some allergens have proteolytic activity and trigger protease-activated receptors on barrier epi-thelial cells and dendritic cells, but until the re-cent publication of an article by Millien et al.,2 there was no known link between protease al-lergens and TLR4 signaling. Millien et al. found that TLR4 has a critical role in the allergic re-sponse to fungal proteases, such as those derived from environmental aspergillus species.Colonization by aspergillus is frequently found in patients with severe asthma, and it causes allergic bronchopulmonary aspergillosis, a syn-drome characterized by eosinophilic pulmonary infiltrates, high production of IgE, and central bronchiectasis. Millien and colleagues found that the development of airway inflammation, mucus hypersecretion, and bronchial hyperreactivity in response to the inhalation of an aspergillus pro-tease depends on TLR4 and its downstream adaptor molecules (Fig. 1). As compared with wild-type control mice, TLR4-deficient mice, on exposure to aspergillus protease, showed a paltry recruitment of type 2 innate lymphoid cells (de-spite normal numbers of Th2 cells) and a reduc-tion in asthmalike features.Millien et al. also found that the activation of TLR4 in wild-type mice by a fungal protease was indirect and required the presence of a serum factor. While trying to identify the responsible Figure 1 (facing page). Fibrinogen Cleavage Products in Asthma.When fungal spores or proteases from aspergillus are inhaled, they can trigger the activation of dendritic cells that cause the development of type 2 helper T (Th2) immunity in the draining lymph nodes. Th2 lympho-cytes then return to the lungs to cause mild eosino-philia and mucus production by goblet cells. Millien and colleagues2 found that fungal proteases subse-quently cleave fibrinogen into fibrin and fibrinogen cleavage products (FCPs). The FCPs trigger the toll-like receptor 4 (TLR4) on epithelial cells to cause the recruit-ment of type 2 innate lymphoid cells (ILC2s), which further boost airway eosinophilia and mucus produc-tion. The fibrin assembles with mucus to form plugs that can obstruct the airways. At the same time, TLR4 triggering by FCPs causes macrophages to inhibit fun-gal growth. This system in which a molecule involved in coagulation activates TLR4 is reminiscent of the way Toll is activated by Spätzle in fruit flies.The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITEIT GENT on November 18, 2013. For personal use only. No other uses without permission.  Copyright © 2013 Massachusetts Medical Society. All rights reserved. n engl j med 369;20 nejm.org november 14, 2013 1965Clinical Implications of Basic ResearchProtease-activated receptorAsthmalike featuresGoblet-cell metaplasiaAirway hyperresponsivenessFibrin mucus plugsGoblet cellDendritic cellAntigen uptakeby dendritic cellActivation of ILC2sTLR4 TLR4Interleukin-13Phagocytosis and fungistasisInterleukin-5 Interleukin-5MacrophageAspergillus conidiaFCPsInterleukin-33Interleukin-25Development of airway eosinophiliaThrombinFibrinogenFibrinogenFCPsFibrinFibrinAirway mucus from goblet cellsProteaseProteaseActivation of Th2 cellsTLR4-independent initiation phase TLR4-dependent amplification phaseLymph nodeSmooth muscleAirway lumenLung epitheliumBlood vesselActivation of coagulation cascade1Phimister10/29/13AUTHOR PLEASE NOTE:Figure has been redrawn and type has been resetPlease check carefullyAuthorFig #TitleMEDEArtistIssue dateCOLOR FIGUREDraft 5Lambrecht N Koscal11/14/13Asthma meets coagulation through TLR4LaurencotThe New England Journal of Medicine Downloaded from nejm.org at UNIVERSITEIT GENT on November 18, 2013. For personal use only. No other uses without permission.  Copyright © 2013 Massachusetts Medical Society. All rights reserved. n engl j med 369;20 nejm.org november 14, 20131966Clinical Implications of Basic Researchserum component, the authors considered how toll-like receptors were discovered in the model organism drosophila. Mutations in the genes Toll and Spätzle caused fruit flies to be colonized by Aspergillus fumigatus.3 The Toll ligand pro-Spätzle is activated by a serine protease — a mechanism that also underlies the activation of coagulogen, a clotting factor of the horseshoe crab, an inver-tebrate that has changed little over the past 400 million years.4 Millien et al. found that, similarly, fungal proteases cleave the serum factor fibrin-ogen, thus causing clot formation and releasing fibrinogen cleavage products that can activate TLR4. The activation of TLR4 by fibrinogen cleav-age products subsequently triggers antifungal immunity and fungistasis of aspergillus conidia grown on alveolar macrophages, just as it does in drosophila.Thrombin, the classic activator of coagulation, also generates fibrinogen cleavage products from fibrinogen, thus triggering TLR4. The thrombin inhibitor hirudin was able to suppress aspergil-lus-driven asthmalike changes in mice, but it also suppressed asthmalike changes driven by the model antigen ovalbumin, which has no pro-tease activity.2 Allergen challenge in humans and mice is generally accompanied by the extravasa-tion of plasma, platelet aggregation, and activa-tion of the coagulation cascade in the lung inter-stitium and bronchoalveolar compartment, with elevations of tissue factor, thrombin, and fibrin-ogen, which explains how fibrinogen cleavage products can be generated with most allergens.5Millien et al. found that activation of the co-agulation cascade by endogenous or allergen-derived proteases is an important factor in driv-ing asthmalike changes in mice by means of TLR4 signaling. Additional research is required to evaluate whether this finding can be trans-lated into clinical applications. The fibrinogen cleavage products need to be defined more pre-cisely before drug candidates can be screened. It remains to be determined whether fibrinogen cleavage products are present in the affected air-ways of persons with asthma. Although Millien et al. were able to suppress aspergillus-induced asthmalike changes by blocking the generation of fibrinogen cleavage products, it is notable that trials of inhaled (low-molecular-weight) heparin in the context of allergen-challenge studies in-volving humans have yielded various effects. Given the heterogeneous nature of the disease, it is conceivable that a subset of patients with asthma may one day benefit from antithrombotic medications.Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.From the VIB Inflammation Research Center and Department of Respiratory Medicine, Ghent University, Ghent, Belgium.1. Hammad H, Chieppa M, Perros F, Willart MA, Germain RN, Lambrecht BN. House dust mite allergen induces asthma via Toll-like receptor 4 triggering of airway structural cells. Nat Med 2009;15:410-6.2. Millien VO, Lu W, Shaw J, et al. Cleavage of fibrinogen by proteinases elicits allergic responses through Toll-like receptor 4. Science 2013;341:792-6.3. Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA. The dorsoventral regulatory gene cassette spätzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 1996;86:973-83.4. Arnot CJ, Gay NJ, Gangloff M. Molecular mechanism that induces activation of Spätzle, the ligand for the Drosophila Toll receptor. J Biol Chem 2010;285:19502-9.5. de Boer JD, Majoor CJ, van ’t Veer C, Bel EH, van der Poll T. Asthma and coagulation. Blood 2012;119:3236-44.DOI: 10.1056/NEJMcibr1311045Copyright © 2013 Massachusetts Medical Society.apply for jobs at the nejm careercenterPhysicians registered at the NEJM CareerCenter can apply for jobs electronically.  A personal account created when you register allows you to apply for positions,  using your own cover letter and CV, and keep track of your job-application history. Visit NEJMjobs.org for more information. The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITEIT GENT on November 18, 2013. For personal use only. No other uses without permission.  Copyright © 2013 Massachusetts Medical Society. All rights reserved. 

Asthma and coagulation

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Asthma and coagulation

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