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Abteilung / Zentrum / Institut:
Prof. Dr. Gernot Zissel
Dr. Kerstin Höhne
Christel Heine
Alexander Hupert
Natalie Anasiewicz
Cordula Huber
Sonja Maria Lutsch
Maximilian Munschies
Patrick Oeller
Katharina Reisgys
Roland Schmidt-Wolf

The research group “Diffuse Parenchymal Lung Diseases” (DLPD) focusses on the research on
Sarcoidosis and Idiopathic Pulmonary Fibrosis (IPF)


SARCOIDOSIS is a highly heterogeneous disease in clinical presentation, clinical severity as well as in disease manifestation. As far back as 1953, Löfgren and co-workers have already shown that there is a benign form of sarcoidosis with an acute onset, bihilar lymphadenopathy, and bilateral arthritis, which was named after its discoverer. Chest-X-ray is abnormal in 95 % of the sarcoidosis patients and the lung is affected in more than 90% of cases, however, extra-pulmonary sarcoidosis and chronic courses requiring prolonged treatment are quite common. Frequently affected organs are liver, heart, central nervous system, muscle, and skin. The relevance of extra-pulmonary disease can be seen by the fact that many of sudden heart death in young and middle-aged adults is due to unrecognized heart manifestation. In addition, neuro-sarcoidosis frequently causes permanent palsy of cranial and peripheral nerves, recently reviewed in.
For research purposes we established a new sarcoidosis clinical activity classification system (SCAC) which is based on the clinical onset and progress of the disease and results in six rough phenotype classes. It reflects more precisely the clinical outcome of sarcoidosis and has been field-tested. In our ongoing study on Genotype-Phenotype-Relationships in Sarcoidosis (GenPhenReSa) funded by the German Research Foundation first results show an association of SCA-classes with susceptibility gene variants. An association study employing deep genotyping with more than 200 traits is under progress in a cohort of 2031 patients followed over 4 years for phenotyping.
We hypothesize that different clinical courses such as spontaneous remission and corticosteroid-resistant disease are based on a specific genetic background in sarcoidosis and the other granulomatous disorders of interest. To elucidate the nature of these genetic factors, we performed the first and several more genome-wide association studies (GWAS) in sarcoidosis identifying butyrophilin-like 2 (BTNL2) as the first susceptibility gene for sarcoidosis on chromosome 6 that was independent of the known association with HLA-DR. Since this initial work, additional susceptibility loci have been discovered, including gender- and course-specific findings.
Current projects in sarcoidosis research of our group focus on the potential role of such susceptibility loci in the pathophysiology of sarcoidosis. Currently we investigate the role of OS9, MARCH9 and RAB23 in the pathophysiology of sarcoidosis and their impact in immunological processes. Additional markers have to be elucidated in future.

PULMONARY FIBROSIS summarizes a heterogeneous group of interstitial lung diseases accompanied by various degrees of inflammation and fibrosis resulting in the damage of the lung parenchyma. Recently, the subgroup of idiopathic interstitial pneumonias (IIP) has been classified into seven different syndromes. The most frequent of these conditions are idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP) and cryptogenic organizing pneumonia (COP). The etiology of these diseases has remained elusive and the molecular mechanisms driving their pathogenesis are poorly understood.
Idiopathic pulmonary fibrosis is the most common form of these IIPs and it presents as a chronic progressive disease characterized by areas of abnormal fibroblasts accumulation, the so-called fibroblast-foci. IPF is an insidious, rapidly progressive disease with a median survival time of approximately three years following diagnosis and a 5-year survival rate of 20-40 %. Fibroblasts and contractile myofibroblasts are important effector cells in fibrosis producing excess of extra-cellular matrix like collagen, which leads to progressive dyspnea. The recently approved drug pirfendidone prevents progression in about 20 % of the patients for about a year, thus, there is still no effective therapy available to stop the progress of IPF.
We found that alveolar macrophages from patients with pulmonary fibrosis release the CC-chemokine CCL18 in increased amounts. In addition, serum levels of CCL18 are predictors of the clinical course in IPF. Most importantly, CCL18 is not only a biomarker; but it is directly involved in the pathogenesis of pulmonary fibrosis as it induces collagen and alpha-smooth muscle actin in fibroblasts and epithelial-to-mesenchymal transition in epithelial cells. However, these activities are dependent on the expression of putative CCL18-receptors. Currently we are investigating the role of the putative CCL18 receptors CCR6 and GPER. Interestingly, current results point to an anticyclical pathway induction by targeting these receptors by CCL18.
We also found CCL18 in high concentrations in sera from patients suffering from LUNG CANCER and found a correlation of CCL18 serum levels with survival time. Thus, we are also interested in the role of CCL18 in cancer pathogenesis and its application as a biomarker in NSCLC.



Optimierung des Beryllium Lymphozyten-Proliferationstests

Die chronische Berylliose (engl. chronic beryllium disease (CBD) ist eine arbeitsmedizinische Erkrankung, die klinisch nicht von der Sarkoidose zu unterscheiden ist. Diese Unterscheidung ist aber relevant, da die Sarkoidose eine schicksalhafte Erkrankung darstellt, während die CBD durch das Einatmen von Beryllium-haltigen Stäuben, in der Regel am Arbeitsplatz, hervorgerufen wird und somit arbeitsmedizinisch relevant ist. Neben der Abklärung einer glaubhaften Berylliumexposition ist der Nachweis der Beryllium-Sensibilisierung ein eminent wichtiger Bestandteil der Diagnose. Der Nachweis der Beryllium-Sensibilisierung erfolgt standardmäßig durch den sog. Beryllium-Lymphozyten-Proiferationstest (BeLPT). Bei diesem Test werden isolierte Lymphozyten mit Berylliumsalzen in verschiedenen Konzentrationen versetzt und nach bestimmten Zeitabständen wird die Proliferationsrate der Zellen im Vergleich mit unstimulierten Zellen gemessen. Diese Messung erfolgt in der Regel durch den Einbau von Brom-desoxyuridin in die DNA der proliferienden Zellen, das dann mittels Antikörper gemessen werden kann.
Der BeLPT ist der einzige Test, der zum Nachweis der CBD zugelassen ist. Gleichzeitig ist er durch die vielen notwendigen Schritte im Testablauf aufwändig und fehleranfällig. Hier ist eine Optimierung angebracht. So könnte man sich andere Be-Detektionssysteme (DELFIA), andere Nachweissysteme der Proliferation (CFSE, Ki67) vorstellen oder gar zu anderen Readoutsystemen wie z.B. dem IFNg Freisetzungstest übergehen.
Diese Optimierungen sind bei der extremen Seltenheit der CBD nicht zu leisten. Allerdings gibt es auch eine Sensibilisierung gegen Zirkonium, die man bei ca. 30-40% der bisher von uns untersuchten Probanden eine nachweisen kann. Diese Sensibilisierung wird wahrscheinlich durch Zr-haltige Antitranspirantien hervorgerufen, hat aber keinerlei Krankheitswert. Diese Zr-Sensibilisierung lässt sich aber nutzen, um den BeLPT zu optimieren. Mit dem Nachweis derZr- Sensibilisierung soll in hier angebotenen Doktorarbeit die oben beschriebenen Methoden auf ihre Tauglichkeit und dem sicheren Nachweis der Sensibilisierung geprüft und verglichen werden.
Beginn und Dauer nach Absprache.
Prof. Dr. Gernot Zissel
0761-270 74360


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