Brusselle, Guy

Demedts, Ingel

Joos, Guy

Ghent University Academic Bibliography

CorrespondenceDendritic Cell Maturity and ObstructiveAirway DiseaseTo the Editor:We read with interest the article by Demedts and colleagues, whoevaluated, by immunohistochemistry, the increased infiltrationof small airways by dendritic cells (DCs) in chronic obstructivepulmonary disease (COPD) (1). In asthma, we have reported adecrease in the number of mature DCs (mDCs) in endobronchialbiopsies of current smokers by comparisonwith never-smokers (2).Also, we have unpublished data showing that the bronchialmucosaof patients with COPD has fewer mDCs than normal healthynonsmoker controls and that current smokers have significantlyfewer sputummDCsthanex-smokerswithorwithoutCOPD.Whatmight be a possible explanation for these apparent differences?The identification of the distinct immunophenotypes of DCsdepends on the method applied. Fluorescence activated cell sorter(FACS)analysisof cells isolated from lungdigests,bronchoalveolarlavage fluid, or sputum allows identification of Langerhans’ cells(LCs), myeloid DCs types 1 and 2, and plasmacytoid DCs, anddistinguishes between mDCs and immature DCs (iDCs). In tissue,immunohistochemistry can identify LCs (CD1a1, Langerin1) andmDCs(CD831),butotherDCphenotypesarenotdetectedreliablyin paraffin wax–embedded material. Demedts and colleaguesapplied an antibody directed against Langerin and thus provideinteresting data on the increased numbers of LCs, an importantsubset of DCs, but their article does not address changes in thenumbers of mDCs. Moreover, the LCs that stained positively forLangerin were most likely immature, as Langerin expression isdown-regulated upon maturation.Interestingly, cigarette smoke has been shown in vitro tosuppress DC maturation (3), and incubation of LPS-maturedDCs with sputum from patients with COPD decreases expres-sion of costimulatory molecules on mDCs and inhibits DCmaturation (4). Thus, DC maturation is likely attenuated inhealthy smokers and in smokers with obstructive airway disease.The reciprocal of this may be an increase in the numbers ofiDCs reported by Demedts and coworkers (1).Finally, decreasedDCmaturationmay shift theCD41/CD81T-cell ratio in the lungs toward CD81 cells, as the time requiredfor DCs to launch the proliferative program for CD81 is less thanthat required for CD41 cells (5). As the proliferative capacity ofCD81 cells is greater than that of CD41 cells, the latter are moresusceptible to the effects of reduced DC maturation (6). Thehypothesis that cigarette smoke–induced reduction of DCmatura-tion is associated with development of the ‘‘abnormal’’ or exagger-ated inflammation associated with smokers and COPD, or toresistanceof asthmatic smokers to steroid therapy, shouldbe tested.Conflict of Interest Statement: M.T. has no financial relationship with a commer-cial entity that has an interest in the subject of this manuscript. P.K.J. has beenreimbursed by GlaxoSmithKline (GSK), AstraZeneca, and Merck, Sharp & Dohme(Merck) for attending several conferences and has participated as a paid speakerin scientific meetings or courses organized and financed by GSK, AstraZeneca,Merck, and Boehringer Ingelheim; he has served as a consultant to GSK andNovartis, and in the last 3 years has held research grants from GSK, Merck, andAstraZeneca.MARIA TSOUMAKIDOUPETER K. JEFFERYImperial College LondonandRoyal Brompton HospitalLondon, United KingdomReferences1. Demedts IK, Bracke KR, Pottelberge GV, Testelmans D, Verleden GM,Vermassen FE, Joos GF, Brusselle GG. Accumulation of dendriticcells and increased CCL20 levels in the airways of patients with chronicobstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:998–1005.2. Tsoumakidou M, Elston W, Zhu J, Wang Z, Gamble E, Siafakas NM,Barnes NC, Jeffery PK. Cigarette smoking alters bronchial mucosalimmunity in asthma. Am J Respir Crit Care Med 2007;175:919–925.3. Vassallo R, Tamada K, Lau JS, Kroening PR, Chen L. Cigarette smokeextract suppresses human dendritic cell function leading to preferentialinduction of Th-2 priming. J Immunol 2005;175:2684–2691.4. Roghanian A, Drost EM, MacNee W, Howie SE, Sallenave J. Inflamma-tory lung secretions inhibit dendritic cell maturation and function vianeutrophil elastase. Am J Respir Crit Care Med 2006;174:1189–1198.5. van Stipdonk MJ, Hardenberg G, Bijker MS, Lemmens EE, Droin NM,Green DR, Schoenberger SP. Dynamic programming of CD81 Tlymphocyte responses. Nat Immunol 2003;4:361–365.6. Seder RA, Ahmed R. Similarities and differences in CD41 and CD81effector and memory T cell generation. Nat Immunol 2003;4:835–842.From the Authors:We read with great interest the letter by Tsoumakidou andJeffery regarding our article on the accumulation of dendriticcells (DCs) in the small airways of patients with chronicobstructive pulmonary disease (COPD) (1). They suggest thatDC maturation is attenuated in healthy smokers and in smokerswith obstructive airway disease. This hypothesis surely deservesfurther attention, but our data do not allow confirmation of thisstatement.When comparing data from different studies, several meth-odological issues need to be kept in mind. First, the site of sam-pling might differ. Findings in large airways are not necessarilythe same as in small airways. Second, the study populationmight be quite different in one study compared with another.The effects of cigarette smoke on DC maturation might bedifferent in asthmatics when compared with patients with COPDor healthy controls. Third, differences in the use of markers tostudy DCs are of great importance. Both CD1a and Langerin aremarkers for immature DCs. In the study by Tsoumakidou andcolleagues, there was no effect of cigarette smoking on thenumber of CD1a1DCs in bronchial epithelium (2), findings thatare consistent with our data obtained in patients with COPD.CD83 is often used as a marker for mature DCs, but severalgroups reported the expression of CD83 on B lymphocytes andLangerhans’ cells (3). Immunohistochemical studies using CD83as a single marker to identify mature DCs should be interpretedwith caution. CD208may be a bettermarker to studymatureDCsby immunohistochemistry (4).There are currently no data that allow a conclusion on theeffect of cigarette smoke on DC maturation in small airways ofpatients with COPD. Future cross-sectional studies should beundertaken to investigate the effect of cigarette smoking onboth immature and mature DC numbers in healthy controls,patients with COPD, and asthmatics. The subjects in thesestudies should be carefully matched regarding age, severity ofdisease, site of sampling, and treatment. Finally, it would beespecially useful to start longitudinal studies in which the numberof DCs could be evaluated before and after quitting smoking.While this is not possible on tissue sections from surgical speci-mens, it should be possible to perform these studies using serialbronchial biopsies.Conflict of Interest Statement: None of the authors has a financial relationshipwith a commercial entity that has an interest in the subject of this manuscript.INGEL K. DEMEDTSGUY F. JOOSGUY G. BRUSSELLEGhent University HospitalGhent, BelgiumReferences1. Demedts IK, Bracke KR, Pottelberge GV, Testelmans D, Verleden GM,Vermassen FE, Joos GF, Brusselle GG. Accumulation of dendriticcells and increased CCL20 levels in the airways of patients with chronicobstructive pulmonary disease. Am J Respir Crit Care Med 2007;175:998–1005.2. Tsoumakidou M, Elston W, Zhu J, Wang Z, Gamble E, Siafakas NM,Barnes NC, Jeffery PK. Cigarette smoking alters bronchial mucosalimmunity in asthma. Am J Respir Crit Care Med 2007;175:919–925.3. Zhou LJ, Schwarting R, Smith HM, Tedder TF. A novel cell-surfacemolecule expressed by human interdigitating reticulum cells, Langer-hans cells, and activated lymphocytes is a new member of the Igsuperfamily. J Immunol 1992;149:735–742.4. de Saint-Vis B, Vincent J, Vandenabeele S, Vanbervliet B, Pin JJ, it-Yahia S, Patel S, Mattei MG, Banchereau J, Zurawski S, et al. A novellysosome-associated membrane glycoprotein, DC-LAMP, inducedupon DC maturation, is transiently expressed in MHC class IIcompartment. Immunity 1998;9:325–336.Is Giant Cell Interstitial Pneumonitis Synonymouswith Hard Metal Lung Disease?To the Editor:The large case series of hard metal disease described byMoriyamiand colleagues in their article provides an important source ofclinico-pathologic data pertaining to a rare, but important inter-stitial lung disease (1). The implications of the authors’ reportedobservations from an immunological perspective were highlightedin the erudite editorial by Nemery andAbraham in the same issue(2). There were, however, important epidemiologic inferences tobe drawn from this report that are also worthy of comment.The authors used electron probe microanalysis to assess theelemental content in lung biopsy material from 85 patients withinterstitial lung disease ‘‘suspected to be of environmental oroccupational origin.’’ Although 23 of the 85 biopsies studied(27%) manifest pathologic findings of giant cell interstitialpneumonitis (GIP), the basis for study inclusion (i.e., etiologicalsuspicion of an occupational disease) is not elucidated and mayvery well have included such histology as one criterion. Thiswould be a reasonable approach, given that GIP has come to betreated as a pathologic finding wholly attributable to hard metalor related cobalt-containing exposures. Indeed, this was thestated rationale for ‘‘delisting’’ GIP as an ‘‘idiopathic’’ pneumo-nia in the 2002 American Thoracic Society/European Respira-tory Society (ATS/ERS) statement on the classification ofidiopathic interstitial pneumonias (3).In that light, the further epidemiologic observation of Mor-iyama and colleagues is all the more intriguing: of the 23 patientswith GIP, 2 (8.7%) had no occupational history of exposure (onewas a schoolteacher) and no tungsten or cobalt detectable byprobe analysis. A recent case report from India of an officesweeper with GIP but no suspect history also raises the questionas towhether sporadic cases of this condition occur that cannot beequated with hard metal lung disease (4). There certainly havebeen cases of GIP in which an occupational history was atypical,but where metals analysis indicated likely occult cobalt exposure(5). Conversely, a thorough metal analysis can be negative, butnonetheless the occupational or environmental history may behighly suspect, as in the case of a 15-year-old with GIP both ofwhose parents had occupational exposure to hard metal (6).Nemery and Abraham argue cogently that we need to fill in ourknowledge gaps about hardmetal lung disease (2).Until we do so,it may have been premature to banish GIP from the schema of‘‘idiopathic interstitial pneumonias,’’ as was done in the ATS/ERS statement (3).Conflict of Interest Statement: P.D.B. has no financial relationship with a com-mercial entity that has an interest in the subject of this manuscript.PAUL D. BLANCUniversity of California, San FranciscoSan Francisco, CaliforniaReferences1. Moriyama H, Kobayashi M, Takada T, Shimizu T, Terada M, Narita J-I,Maruyuma M, Watanabe K, Suzuki E, Gejyo F. Two-dimensionalanalysis of elements and mononuclear cells in hard metal lung disease.Am J Respir Crit Care Med 2007;176:70–77.2. Nemery B, Abraham JL. Hard metal lung disease: still hard to under-stand. Am J Respir Crit Care Med 2007;176:2–3.3. American Thoracic Society. American Thoracic Society/European Res-piratory Society international multidisciplinary consensus classificationof the idiopathic interstitial pneumonias. Am J Respir Crit Care Med2002;165:277–304.4. Menon B, Sharma A, Kripalani J, Jain S. Giant cell interstitial pneumoniain a 60-year-old female without hard metal disease. Respiration(Herrlisheim) 2006;73:833–835.5. Choi JW, Lee KS, Chung MP, Han J, Chung MJ, Park JS. Giant cellinterstitial pneumonia: high-resolution CT and pathologic findings infour adult patients. Am J Radiol 2005;184:268–272.6. Kakugawa T, Mukae H, Nagata T, Ishii H, Kaida H, Hayashi T, SuematsuT, Kadota J-I, Kohno S. Giant cell interstitial pneumonia in a 15-year-old boy. Intern Med 2002;41:1007–1012.From the Authors:We appreciate Dr. Blanc’s comments on our article (1). Wescreened 85 biopsies; tungsten was detected in surgical biopsiesfrom 17 patients and in transbronchial biopsies (TBBs) fromthree additional patients. Three TBBs were excluded from ourstudy because the pathologists could not make an accuratepathologic diagnosis due to the small size of the TBB. A TBBfrom an office sweeper without an exposure history was patho-logically diagnosed as giant cell interstitial pneumonia (GIP)(2), but we did not include TBB cases. Even though pathologistsfind giant cells when screening biopsies, they should be carefulin making a final diagnosis of GIP, because giant cells are foundin other diseases such as viral pneumonia, especially pneumoniadue to measles, and sarcoidosis.We applied an improved technique for element analysis oftissue sections using an electron probe microanalyzer (EPMA)with a wavelength dispersive spectrometer (WDS) (1). Thistechnique has about 10 times higher sensitivity than EPMA withan energy dispersive spectrometer and enabled us to detecttungsten in lung tissue in which the element was not found by theother method (unpublished data; Reference 3). We found twobiopsies exhibiting featuresofGIPwithneither tungstennor cobaltdetected in the lung tissuebyEPMA-WDSnoraworkinghistory inthe hard metal industry. Finally, 2 (10.5%) of 19 surgical lungbiopsies were thought to be ‘‘idiopathic’’ GIP in our case series.In addition to EPMA, atomic absorption spectrometry, plasmaoptical emission mass spectrometry, and ionic coupled plasmaemission spectrometry have been used to detect tungsten andcobalt in lung tissue (2, 4, 5).All of these techniques aremethods todetect elements in dissolved tissue solution. Using these methods,one cannot see the relationship between elements and the charac-teristic lesions ofGIP, including centrilobular fibrosis andgiant cellaccumulation within alveolar space; thus, some GIP diagnosed ashard metal lung disease might actually be ‘‘idiopathic’’ GIP.834 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 176 2007

Dendritic cell maturity and obstructive airway disease

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Dendritic cell maturity and obstructive airway disease

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Ghent University Academic Bibliography