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Eur Respir J 2011; 38: 500–501 DOI: 10.1183/09031936.00103211 CopyrightßERS 2011

EDITORIAL Immune system dysregulation in chronic

B.J. Marsland*,#,M.Ko¨nigshoff", S. Saglani+ and O. Eickelberg"

hronic lung (CLDs), including chronic obstruc- blocking and/or neutralising them alone was insufficient to tive pulmonary disease (COPD), , lung , substantially ameliorate or prevent asthma. In a keynote pre- C interstitial lung disease and pulmonary hypertension, sentation, Prof. Stephen Holgate (University of Southampton, present a significant and rising problem. CLDs Southampton, UK) highlighted the airway as a central develop at the interface between genetic susceptibilities and determinant for the development and of asthma, as environmental aspects, and arecurrentlythesecondleading opposed to Th2 responses per se.Notably,large-scaleapproaches, cause of death worldwide. Thus far, of only limited such as genome wide association studies (GWAS), have recently effect exist for CLDs; the search for novel and effective therapeutic uncovered disease-relevant in asthma, which are associated strategies has been at the centre of recent major research efforts. with airway epithelial cell function rather than Th2 responses. As part of the pathogenesis of many CLDs, ill-defined lung Indeed, key components of the allergic disease might be genes injuries and failed repair mechanisms ultimately lead to per- associated with maintenance of the epithelial barrier integrity (e.g. turbed lung architecture that is incompatible with normal tight junctions), innate or epithelial growth factors. At respiratory function. In particular, the immunological mechan- its core, the chronicity of asthma may thus be due to defective isms that initiate and maintain CLD remain to be fully unravelled. epithelial cell responses, integrity and repair, compounded by inappropriate inflammatory responses against innocuous envir- The mission of the European Respiratory Society (ERS) is to onmental . With this in mind, the most effective anti- alleviate suffering from respiratory disease and promote lung asthma therapies of the future may be those targeting pathways health through research, knowledge sharing, and medical and associated with epithelial cell layer integrity and repair. public education. In support of this mission, the ERS holds an annual Lung Science Conference (LSC), which brings together Prof. Sebastian Johnston (Imperial College London, London, leading basic scientists with physician scientists and clinicians UK) highlighted data revealing that production of on distinct topics that are of relevance to respiratory . was impaired during rhinovirus-induced exacerbations of asthma. Importantly, these data suggest the use of interferons In April 2011, world-leading scientists and clinicians met at the as a candidate new for asthma exacerbations. Following ninth LSC in Estoril, Portugal, to share their latest discoveries the line of key cellular players in asthma, Prof. Clare Lloyd and to work towards identifying the cellular and molecular (Imperial College London) presented evidence for the impor- pathways that underlie the development of CLDs. The meeting tance of IL-17 in cd T-cell responses during asthma. highlighted major novel findings in immune system (dys)func- tion in the major CLDs, as outlined in detail below. Some of the presentations discussed can be found in the E-Resources on the EARLY ORIGINS OF CLDs ERS website (at http://www.ers-education.org/pages/default. There is growing evidence that events in the first years of can aspx?id52556). influence susceptibility to disease. Prof. Patrick Holt (Telethon Institute for Child Health Research, Perth, Australia) outlined CURRENT STATUS OF ASTHMA RESEARCH: ATOPY that early respiratory are one of the strongest AND THE EPITHELIUM associations with the development of asthma. Prof. Holt argued The incidence of asthma has been steadily increasing in recent that a central determinant of increased persistent asthma is the decades and intensive research has particularly focused upon concurrent exposure to allergens and viral . Support for the role of T-helper cell (Th) type 2 responses and therapies this perspective is found in mouse models of disease, which designed to neutralise the activity of Th2-associated , have shown that concurrent viral infections can break tolerance such as (IL)-4, IL-5 and IL-13. Disappointing results of aero-allergens or indeed enhance their presentation to Th2 from clinical trials have suggested that, although these cells cells by increasing and migration. and cytokines were strongly associated with allergic disease, In recent work by the laboratory of Prof. Charles Mackay (Monash University, Melbourne, Australia), a link between diet *Service de Pneumologie, Centre Hospitalier Universitaire Vaudois and #Faculty of and and was attributed to the cellular receptors GPR41 Medicine, University of Lausanne Vaudois Lausanne, Lausanne, Switzerland. "Comprehensive and 43. These G--coupled receptors recognise short- Pneumology Center, Ludwig-Maximilians-University, University Hospital Grosshadern, and chain fatty (SCFA), microbial gastrointestinal-derived Helmholtz Zentrum Mu¨nchen, Munich, Germany. +Respiratory Paediatrics, Royal Brompton metabolites of fibre. Mice lacking these receptors on their cells, Hospital, Imperial College London, London, UK. which are unable to respond to SCFA, exhibit an exaggerated CORRESPONDENCE: O. Eickelberg, Comprehensive Pneumology Center, Ludwig Maximilians disease development in models of arthritis, colitis and allergic University Munich, University Hospital Grosshadern, and Helmholtz Zentrum Mu¨nchen, Max- airway inflammation. Removing the (in axenic/ Lebsche-Platz 31, 81377 Mu¨nchen, Germany. E-mail: [email protected] germ-free mice) and consequently reducing the circulating

500 VOLUME 38 NUMBER 3 EUROPEAN RESPIRATORY JOURNAL B. MARSLAND ET AL. EDITORIAL: CHRONIC LUNG DISEASES

levels of SCFA exaggerated disease development, while in- at controlling inflammation in general, they are ineffective in creasing the levels of SCFA by administration of exogenous certain cases of COPD, as from COPD patients can SCFA-suppressed disease. These findings strongly link dietary be insensitive to . The exact role of macrophages intake with inflammation and it is tempting to speculate that in COPD needs to be clarified; specifically, whether macro- diets high in fibre may be protective against chronic inflamma- phages are acting as instigators of disease or maintainers of tion. Moreover, changes in diet in the Western world might chronicity, or whether they are simply trying to clear up the underlie the trend in increasing incidence of and damage. over recent decades. are another major cell type associated with COPD. It appears clear that there will be multiple pathways through In particular, (NE) has been shown to which early childhood events could impact upon the develop- influence cigarette smoke-induced emphysema. At the 2011 ment of lung inflammation. Prof. Troy Randall (University of LSC, Prof. Steven Shapiro (University of Pittsburgh, Pittsburgh, Rochester Medical Center, Rochester, NY, USA) presented late- PA, USA) presented that mice deficient in NE also exhibited breaking data, indicating that there is a window of development decreased recruitment. The role of neutrophils and in neonatal mice, in which there is an increased propensity NE might in fact be less related to the direct protease activity towards the development of inducible broncho-associated damaging the lung , and more related to the need for NE lymphoid tissue (iBALT). Specifically, administration of lipo- for neutrophil migration into tissues and recruitment of polysaccharide (LPS) to the of mice within the first weeks alternate cell types, such as . The balance between of birth led to an IL-17-dependent increase in iBALT, which, neutrophil and recruitment, clearance and effector strikingly, was maintained at a high level through adulthood. function, remains at the core of COPD pathogenesis. The presence of iBALT indicates that adaptive immune responses in the lung might develop locally or more rapidly Lung fibrosis is regulated by several cytokines, following inhalation; such enhanced formation due to and growth factors. Transforming -b is a potent early childhood exposures could act to shape inflammation later pro-fibrotic mediator and is involved in IL-17A production by in life. Whether such local responses would be protective (by . In his presentation, Prof. Thomas Wynn (National enhancing the response against viral infection, for example) or Institute of Allergy and Infectious Diseases, Bethesda, MD, could in fact sustain allergic responses or tissue damage, USA) discussed the impact of IL-17A-driven inflammation remains to be seen. within the development of bleomycin-induced fibrosis, while pointing out that IL-13 is critically involved in Schistosoma MECHANISMS UNDERLYING COPD AND FIBROSIS mansoni-driven fibrosis. IL-17A is a key mediator of bleomycin- Accurate detection of the early stages of COPD/emphysema induced fibrosis driven by transforming growth factor-b, as well has proven difficult. Employing cutting-edge pathological as IL-1b. Importantly, he highlighted that these distinct immune techniques, Prof. James Hogg and colleagues (University of responses may be critical to the nature of the remodelling British Columbia, Vancouver, BC, Canada) have made sub- processes and crucial to the identification of specific therapeutic stantial contributions to our understanding of this disease. strategies. Indeed, detailed examination of COPD lung tissue indicates that a narrowing and destruction of the terminal Ultimately, many CLD may be relieved if we understood how bronchioles (small airway remodelling and fibrosis) precedes to regenerate normal lung tissue in the adult human, perhaps emphysema formation. Prof. Hogg’s data also indicate that through tissue-engineering approaches or stem cell biology. macrophages, rather than neutrophils, were predominantly In this respect, Prof. Marc Humbert (INSERM, Paris, France) present in emphysematous tissues; whether this provides clues has highlighted c-kit-positive cells as putative progenitor cells to the critical cells involved in the maintenance of chronicity, homing to the perivascular compartment in pulmonary arterial tissue damage or repair remains to be elucidated. hypertension, possibly contributing to the vascular remodel- ling process characteristic of this condition. Unquestionably, macrophages are strongly linked with COPD, as discussed by Prof. Peter Barnes (Imperial College London). It will be this focus on lung that we will highlight Indeed, there is a 5–10-fold increase in the number of macro- during the 10th LSC in 2012. Therefore, we invite you to join us phages in the airways and parenchyma of COPD patients, which for the ‘‘Rebuilding a diseased lung: repair and regeneration’’ increases in line with the severity of emphysema. Data indicates LSC, from March 30 to April 1, 2012, in Estoril, Portugal. that macrophages isolated from COPD patients release higher levels of inflammatory mediators, such as chemokines, cytokines STATEMENT OF INTEREST and proteases, whilst having a reduced capacity to phagocytose A statement of interest for O. Eickelberg can be found at www.erj. particles. Moreover, although corticosteroids are highly effective ersjournals.com/site/misc/statements.xhtml

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