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The cellular protein shredder is impaired by cigarette smoke and in COPD patients
Scientists at Helmholtz Zentrum München, together with an international team and colleagues from the University Hospital of the University Munich (LMU) and the German Center for Lung Research (DZL), have shown for the first time that cigarette smoke reduces the activity of the immunoproteasome*. In addition, patients with chronic obstructive pulmonary disease (COPD) display reduced immunoproteasome levels. This might contribute to the COPD patients' increased susceptibility to airway infections, as recently published in the 'American Journal of Respiratory and Critical Care Medicine'.
The immunoproteasome is a defined structure in mammalian cells that is specialized to degrade protein molecules that are foreign to the cell, such as upon virus infection. Its function is comparable to a cellular shredder. Protein shreds (peptides) are then presented to the immune system on the outside of the cell to evoke a specific immune response against the virus-infected cell. A research team headed by PD Dr. Silke Meiners from the Institute of Lung Biology and Disease (iLBD) / Comprehensive Pneumology Center (CPC) at the Helmholtz Zentrum München has now discovered that smoking crucially impairs this protective response of the immune system.
"We observed that cigarette smoke reduces the activity of the immunoproteasome in human cells," explains first author Ilona Kammerl. "As a result, the presentation of the degraded protein shreds to the immune system does not function properly and thus weakens the specific immune response." Importantly, lungs of COPD patients displayed reduced immunoproteasome activity.
"COPD patients frequently experience acute worsening of pulmonary function (“exacerbations”) during a viral infection, and often do not completely recover from these. This suggests that the specific immune response to viral pathogens is reduced in COPD patients. Our data provide the first indications that this is due to cigarette smoke-induced reductions in immunoproteasome activity," emphasizes study leader Silke Meiners. Cigarette smoke is a primary risk factor for COPD.
Use as biomarker conceivable
The scientists now want to investigate whether lower immunoproteasome activity can serve as a biomarker for increased susceptibility to viral infections in COPD. Further studies should clarify whether changes in immunoproteasome levels are detectable in blood cells and this is associated with increased susceptibility to airway infections.
The immunoproteasome could also be suitable as a therapeutic target structure. "A targeted increase of immunoproteasome activity would be advantageous to elicit a more efficient immune response to virus infections in COPD patients and thus counteract a decline in pulmonary function," explains Prof. Dr. Oliver Eickelberg, Vice-Director in the DZL, chairman of the CPC, and director of the iLBD.
The Immunoproteasom* is a cylinder-shaped protein complex that degrades protein structures, particular those that originate from proteins foreign to the cells, such as from virus particles, into smaller parts. These are then presented to the immune system at the cell surface in order to sensitize it for these foreign structures and virus infected cells.
Kammerl, I.E. et al. (2016). Impairment of immunoproteasome function by cigarette smoke and in COPD, American Journal of Respiratory and Critical Care Medicine
Link to publication
As German Research Center for Environmental Health, Helmholtz Zentrum München pursues the goal of developing personalized medical approaches for the prevention and therapy of major common diseases such as diabetes mellitus and lung diseases. To achieve this, it investigates the interaction of genetics, environmental factors and lifestyle. The Helmholtz Zentrum München has about 2,300 staff members and is headquartered in Neuherberg in the north of Munich. Helmholtz Zentrum München is a member of the Helmholtz Association, a community of 18 scientific-technical and medical-biological research centers with a total of about 37,000 staff members.
The Comprehensive Pneumoloy Center (CPC) is a joint research project of the Helmholtz Zentrum München, the Ludwig-Maximilians-Universität with its University Hospital and the Asklepios Fachkliniken München-Gauting. The CPC's objective is to conduct research on chronic lung diseases in order to develop new diagnosis and therapy strategies. The CPC maintains a focus on experimental pneumology with the investigation of cellular, molecular and immunological mechanisms involved in lung diseases. The CPC is one of five sites of the German Center for Lung Research (Deutsches Zentrum für Lungenforschung, DZL).
The German Center for Lung Research (DZL) pools German expertise in the field of pulmonology research and clinical pulmonology. The association’s head office is in Giessen. The aim of the DZL is to find answers to open questions in research into lung diseases by adopting an innovative, integrated approach and thus to make a sizeable contribution to improving the prevention, diagnosis and individualized treatment of lung disease and to ensure optimum patient care.
Scientific contact :
PD Dr. Silke Meiners, Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Comprehensive Pneumology Center, Max-Lebsche Platz 31, 81377 Munich– Phone: +49 89 3187 4673 - E-mail: silke.meinersnoSp@firstname.lastname@example.org