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HINTERGRUND: In der NAKO Gesundheitsstudie liegen die Daten zu selbstberichteten Krebserkrankungen der ersten Hälfte der Teilnehmenden vor. ZIEL: Beschreibung der Methoden zur Erfassung selbstberichteter Krebserkrankungen und Tumorlokalisationen in der NAKO und Darstellung erster Ergebnisse. MATERIAL UND METHODEN: In einem computergestützten, standardisierten persönlichen Interview wurden 101.787 Teilnehmende (54.526 Frauen, 47.261 Männer) gefragt, ob bei ihnen jemals eine Krebserkrankung (bösartiger Tumor einschließlich in situ) ärztlich diagnostiziert wurde und wie viele Krebserkrankungen sie hatten. Anhand einer Liste wurde die Tumorlokalisation erfragt. Absolute und relative Häufigkeiten von Selbstangaben zu Krebserkrankungen insgesamt und einzelnen Tumorlokalisationen wurden berechnet und mit krebsregisterbasierten Daten verglichen. ERGEBNISSE: Eine ärztlich diagnostizierte Krebserkrankung wurde von 9,4 % der Frauen und 7,0 % der Männer berichtet. Von den Personen, die eine Krebserkrankung berichteten, gaben 88,3 % der Teilnehmenden an, nur eine Krebserkrankung gehabt zu haben. Bei Frauen war die häufigste bösartige Krebserkrankung Brustkrebs, gefolgt von Gebärmutterhalskrebs und malignem Melanom, bei Männern Prostatakrebs, gefolgt von malignem Melanom und Darmkrebs. Beim Vergleich der Krebserkrankungen, die von 45- bis 74-jährigen NAKO-Teilnehmenden in den letzten fünf Jahren berichtet wurden, mit krebsregisterbasierten 5‑Jahres-Prävalenzen wurden für die meisten Tumorlokalisationen in der NAKO niedrigere relative Häufigkeiten beobachtet. Vergleichsweise häufiger traten das maligne Melanom sowie Gebärmutterhalskrebs und Leberkrebs bei Frauen und Harnblasenkrebs und Brustkrebs bei Männern auf. DISKUSSION: Die NAKO ist eine reichhaltige Datenbasis für die zukünftige Untersuchung inzidenter Krebserkrankungen. BACKGROUND: In the German National Cohort (NAKO Gesundheitsstudie), the largest prospective cohort study in Germany, data on self-reported cancer diagnoses are now available for the first half of participants. OBJECTIVES: Description of the methods to assess self-reported cancer diagnoses and type of cancer in the NAKO and presentation of first results. MATERIAL AND METHODS: In a computer-assisted, standardized personal interview, 101,787 participants (54,526 women, 47,261 men) were asked whether they had ever been diagnosed with cancer (malignant tumors including in situ) by a physician and how many cancer diagnoses they had. The type of cancer was classified with a list. Absolute and relative frequencies of self-reported cancer diagnoses and types of cancer were calculated and compared with cancer registry data. RESULTS: A physician-diagnosed cancer was reported by 9.4% of women and 7.0% of men. Of the participants who reported a cancer diagnosis, 88.3% reported to have had only one cancer diagnosis. In women, the most frequent malignancies were breast cancer, cervical cancer, and melanoma. In men, the most frequent malignancies were prostate cancer, melanoma, and colorectal cancer. Comparing the frequencies of cancer diagnoses reported by 45- to 74-year-old NAKO participants within the last five years to cancer registry-based 5‑year prevalences, most types of cancer were less frequent in the NAKO, with the exception of melanoma in men and women, cervical cancer and liver cancer in women, and bladder cancer and breast cancer in men. CONCLUSIONS: The NAKO is a rich data basis for future investigations of incident cancer.

BACKGROUND: Numerous studies have reported an increase in mental disorders during the COVID-19 pandemic, but the exact reasons for this development are not well understood. In this study we investigate whether pandemic-related occupational and financial changes (e.g., reduced working hours, working from home, financial losses) were associated with increased symptoms of depression and anxiety compared with the situation before the pandemic. METHODS: We analyzed data from the German National Cohort (NAKO) Study. Between May and November 2020, 161 849 study participants answered questions on their mental state and social circumstances. Their responses were compared with data from the baseline survey before the pandemic (2014–2019). Linear fixed-effects models were used to determine whether individual changes in the severity of symptoms of depression (PHQ-9) or anxiety (GAD-7) were associated with occupational/ financial changes (controlling for various covariates). RESULTS: The prevalence of moderate or severe symptoms of depression and anxiety increased by 2.4% and 1.5%, respectively, during the COVID-19 pandemic compared with the preceding years. The mean severity of the symptoms rose slightly. A pronounced increase in symptoms was observed among those who became unemployed during the pandemic (+ 1.16 points on the depression scale, 95% confidence interval [0.91; 1.41], range 0–27). Increases were also seen for reduced working hours with no short-time allowance, increased working hours, working from home, insecurity regarding employment, and financial strain. The deterioration in mental health was largely statistically explained by the occupational and financial changes investigated in the model. CONCLUSION: Depressive symptoms and anxiety disorders increased slightly in the study population during the first year of the COVID-19 pandemic. Occupational and financial difficulties were an essential contributory factor. These strains should be taken into account both in the care of individual patients and in the planning of targeted prevention measures.

Die korperliche Aktivitat stellt ein komplexes Verhalten dar, dessen valide und reliable Erfassung in gros angelegten populationsbasierten Studien mit besonderen Herausforderungen einhergeht. In der bundesweiten NAKO Gesundheitsstudie liegen zur Halbzeit der Basiserhebung die Daten zur korperlichen Aktivitat fur 100.000 Teilnehmende vor. Beschreibung der Erfassung der korperlichen Aktivitat und Prasentation erster deskriptiver Ergebnisse. Das multimodale Erhebungskonzept bestand aus zwei Fragebogen, dem Questionnaire on Annual Physical Activity Pattern (QUAP) und dem Global Physical Activity Questionnaire (GPAQ), einem computerbasierten Erinnerungsprotokoll der vergangenen 24 h (cpar24) und einer 7‑Tage-Akzelerometrie (Actigraph GT3X/+; Fa. ActiGraph, Pensacola, FL, USA). Fur die einzelnen Erhebungsmodule lagen auswertbare Datensatze in unterschiedlicher Zahl vor (QUAP: n = 16.372; GPAQ: n = 90.900; cpar24: n = 23.989; Akzelerometrie: n = 35.218). Die Analysen der einzelnen Module ergaben unterschiedliche Durchschnittswerte fur die moderate oder intensive korperliche Gesamtaktivitat der Teilnehmenden: Bei Frauen wurden 75–216 min/Tag gemessen, bei Mannern 73–224 min/Tag. Personen der Altersgruppe 20–39 Jahre verbrachten 66–200 min/Tag in moderater oder intensiver korperlicher Gesamtaktivitat, wahrend Personen der Altersgruppe 40–69 Jahre 78–244 min/Tag aufwendeten. Erste modulubergreifende Analysen der korperlichen Aktivitat in der NAKO zeigen den Nutzen komplementar eingesetzter Erhebungsmethoden. Die umfangreichen Daten stellen eine wertvolle Ressource fur die Charakterisierung der Zusammenhange zwischen korperlicher Aktivitat und Krankheitspravention dar, die in der Zukunft erfolgen soll.

The behavior of a cell depends on how its adhesion molecules interact with the cellular microenvironment. Hemidesmosomal collagen XVII essentially contributes to cell adhesion and modulates keratinocyte directionality and proliferation during skin regeneration, however only little is known about the involved interactions. Here, we used keratinocytes from patients with junctional epidermolysis bullosa with late onset, which exclusively produce a collagen XVII mutant with the p.R1303Q mutation within its extracellular C-terminus. Although this mutant was normally expressed and targeted to the membrane and the expression of integrins α3β1, α6β4 and of laminin-332 was unchanged, the keratinocytes were less adhesive, showed migratory defects and decreased clonogenic growth. Since the p.R1303Q substitution is located within the predicted laminin-332 binding site of collagen XVII, we anticipated an altered collagen XVII-laminin-332 interaction. Indeed, the pR1303Q collagen XVII ectodomain showed decreased binding capability to laminin-332 and was less co-localized with pericellular laminin-332 molecules in cell culture. Thus, aberrant collagen XVII-laminin-332 interaction results in reduced cell adhesion, destabilized cell motility and decreased clonogenicity, which in turn lead to blister formation, delayed wound healing and skin atrophy.

Asthma is one of the most common chronic diseases in both children and adults. Asthma first occurring in adulthood (adult-onset asthma, AOA) is associated with poorer prognosis compared to childhood-onset asthma (COA), which urgently calls for more research in this area. The aim of this work was to analyze the data on asthma collected in the German National Cohort and compare it with the German Health Interview and Examination Survey for Adults (DEGS), in particular regarding AOA.Our analysis was based on the dataset of the main questionnaire at mid-term of the German National Cohort baseline examination, comprising 101,723 participants. Variables considered in the analyses were self-reported diagnosis of asthma, age at first diagnosis, asthma treatment in the past 12 months, age, and sex.In the midterm dataset, 8.7% of women and 7.0% of men in the German National Cohort reported that they had ever been diagnosed with asthma. Approximately one third of participants with asthma received their initial diagnosis before their 18th birthday. COA affected 2.2% of women and 2.8% of men, whereas AOA affected 6.5% of women and 4.2% of men. During the previous 12 months, 33% of COA cases and 60% of AOA cases were medically treated.The proportion of persons affected by asthma in the German National Cohort, as well as observed patterns regarding age and gender, corresponds to other data sources such as DEGS. However, in our analysis, the proportion of individuals with AOA was higher than described in the literature. The increase in cumulative asthma diagnoses with age is markedly steeper in younger participants, indicating a rising trend over time.HINTERGRUND: Asthma bronchiale stellt über alle Bildungsschichten hinweg eine der häufigsten chronischen Erkrankungen im Kindes- und Erwachsenenalter dar. Im Erwachsenenalter erstmals auftretendes Asthma (Adult-onset Asthma, AOA) ist im Vergleich zu Childhood-onset Asthma (COA) mit einer schlechteren Prognose assoziiert, was verstärkte Untersuchungen in diesem Bereich erfordert. Ziel der Arbeit war es, Häufigkeiten und das Alter bei Erstdiagnose aus Selbstangaben zu Asthma bei Erwachsenen in der NAKO Gesundheitsstudie darzustellen und mit Daten der Studie zur Gesundheit Erwachsener in Deutschland (DEGS) zu vergleichen.Unsere Analyse beruht auf einem Datensatz zur Halbzeit der NAKO-Basiserhebung mit 101.284 Personen. Verwendete Variablen waren die Selbstangabe zum jemals ärztlich diagnostizierten Asthma, Alter bei Erstdiagnose, Behandlung in den letzten 12 Monaten, Alter und Geschlecht.Laut Datenbasis zur Halbzeit berichteten in der NAKO 8,7 % der Frauen und 7,0 % der Männer, dass bei ihnen jemals Asthma diagnostiziert wurde. Etwa bei einem Drittel der Teilnehmenden mit Asthma wurde die Diagnose bereits im Kindes‑/Jugendalter (18 Jahre) gestellt. Dabei waren 2,2 % der Frauen und 2,8 % der Männer von COA betroffen und 6,5 % der Frauen und 4,2 % der Männer von AOA. In den vorangegangenen 12 Monaten gaben 33 % der COA-Fälle und 60 % der AOA-Fälle an, ärztlich behandelt worden zu sein.Die Häufigkeit von Asthma in der NAKO Gesundheitsstudie in Abhängigkeit von Alter und Geschlecht entspricht weitgehend den Daten aus anderen Studien wie DEGS. Allerdings ist der AOA-Anteil höher als in der Literatur beschrieben. Der Anstieg der kumulativen Asthmadiagnosen ist bei den jüngeren Geburtsjahrgängen deutlich steiler, was für eine Zunahme über die Zeit spricht.

In healthy skin, epidermis and dermis are anchored together at the dermal-epidermal junction (DEJ), a specialized basement membrane pivotal for skin integrity and function. However, increased inflammation in the DEJ is associated with the disruption and separation of this junction and sub-epidermal blistering. Granzyme B (GzmB) is a serine protease secreted by immune cells. Dysregulated inflammation may lead to increased GzmB accumulation and proteolysis in the extracellular milieu. Although elevated GzmB is observed at the level of the DEJ in inflammatory and blistering skin conditions, the present study is the first to explore GzmB in the context of DEJ degradation in autoimmune sub-epidermal blistering. In the present study, GzmB induced separation of the DEJ in healthy human skin. Subsequently, α6/β4 integrin, collagen VII, and collagen XVII were identified as extracellular substrates for GzmB through western blot, and specific cleavage sites were identified by mass spectrometry. In human bullous pemphigoid, dermatitis herpetiformis, and epidermolysis bullosa acquisita, GzmB was elevated at the DEJ when compared to healthy samples, while α6/β4 integrin, collagen VII, and collagen XVII were reduced or absent in the area of blistering. In summary, our results suggest that regardless of the initial causation of sub-epidermal blistering, GzmB activity is a common final pathway that could be amenable to a single targeted treatment approach.

In epidemiologic studies, standardised measurement of socio-demographic and employment-related factors is becoming increasingly important, as variables such as gender, age, education or employment status are factors influencing health and disease risks.The article gives an overview of the scientific background and assessment of socio-demographic factors in the German National Cohort Study. In addition, the distribution of individual characteristics in the cohort as well as relationships with health-related measures are presented by way of example.The analysis is based on the data of the first half of the baseline survey (n = 101,724). On this basis, we present the distribution of key socio-demographic characteristics and analyse relationships with exemplary selected health indicators (body mass index, self-reported health) to assess the validity of socio-demographic data measurements.On average, study participants were 52.0 years old (SD = 12.4). Of the participants, 53.6% were women, 54.3% had high education, 60.1% were married and 72% were employed while 3.4% were unemployed. Well-established correlations between socio-demographic factors and health could be reproduced with the German National Cohort data. For example, low education, old age and unemployment were associated with an increased prevalence of obesity and poor self-reported health.The German National Cohort provides a comprehensive measurement of socio-demographic characteristics. Combined with a wide range of health data and the longitudinal measurements available in the future, this opens up new opportunities for health science and social epidemiological research in Germany.

High levels of adiposity in the population have a major impact on various diseases, but previous epidemiologic studies have largely been restricted to simple anthropometric measures such as the body mass index (BMI), an imperfect predictor of disease risk. There is a critical need for the use of improved measures of relative weight and body composition in large-scale, population-based research.The current article presents initial descriptive results of body composition and fat distribution based on the midterm baseline dataset of the German National Cohort, which included 101,817 participants who were examined in 18 study centers in Germany between March 2014 and March 2017. The anthropometric measures encompassed body weight, height, waist and hip circumference, bioelectrical impedance analysis (BIA), sonography of abdominal adipose tissue, 3D-body scanning, and magnetic resonance imaging.BMI analyses showed that 46.2% of men and 29.7% of women were overweight and 23.5% of men and 21.2% of women were obese. On average, women in almost all age groups demonstrated more subcutaneous adipose tissue layer thickness than men. The mean values of visceral adipose tissue layer thickness, on the other hand, were higher among men than among women in all age groups and increased continuously across age groups in both sexes.The comprehensive assessment of body composition and fat distribution provides novel future opportunities for detailed epidemiologic analyses of overweight and adiposity in relation to the development of chronic diseases.

HINTERGRUND: Muskuloskelettale Symptome und Erkrankungen sind in der Bevölkerung sehr weit verbreitet und verursachen hohe Kosten in Gesundheitswesen und Volkswirtschaft. ZIEL DER ARBEIT: Die Häufigkeit muskuloskelettaler Symptome und Erkrankungen aus den Bereichen Rückenschmerzen, Osteoporose, Arthrose und Arthritis wurde auf Basis von Daten der bevölkerungsbasierten NAKO Gesundheitsstudie beschrieben. MATERIAL UND METHODEN: Die Daten wurden in der ersten Hälfte der NAKO-Basiserhebung von März 2014 bis März 2017 bei Erwachsenen im Alter von 20–75 Jahren erhoben. In die Analysen gingen Daten von 101.779 Interviewteilnehmenden sowie von 9370 Teilnehmenden aus zwei klinischen Untersuchungen ein. Mittels der klinischen Handuntersuchung wurden tastbar geschwollene Gelenke sowie auf Druck schmerzhafte Gelenke identifiziert. Die Winkelstuhluntersuchung lieferte Daten zu Ruheschmerzen am Knie- und Hüftgelenk. Häufigkeiten wurden auf die deutsche Standardbevölkerung 2011 gewichtet. ERGEBNISSE: In den Selbstberichten der Teilnehmenden im Interview wurden am häufigsten jemals diagnostizierte andauernde Rückenschmerzen (22,5 %) und Arthrosen (20,6 %) angegeben, seltener Osteoporose (2,9 %) und rheumatoide Arthritis (1,9 %). In der Handuntersuchung wurden bei 6,0 % Schmerzen an mindestens einem Fingergelenk festgestellt. Laut Winkelstuhluntersuchung waren 8,2 % von einem Ruheschmerz in mindestens einem Knie betroffen sowie 5,1 % an der Hüfte. Frauen berichteten insgesamt häufiger muskuloskelettale Erkrankungen und Symptome als Männer, der Anteil Betroffener nahm mit dem Alter deutlich zu. DISKUSSION: Die Ergebnisse belegen die große Verbreitung vieler muskuloskelettaler Erkrankungen. Die berichtete Beschwerdelast ist mit Ergebnissen aus früheren bevölkerungsbezogenen Erhebungen vergleichbar. BACKGROUND: Musculoskeletal diseases and symptoms are very common in the general population. They lead to high healthcare costs and pose a significant burden to the national economy. OBJECTIVES: Based on data from the population-based German National Cohort (GNC), frequencies of musculoskeletal symptoms and diseases are reported, including back pain, osteoporosis, osteoarthritis, and arthritis. MATERIAL AND METHODS: Data were collected from March 2014 to March 2017 in adults aged 20–75 years during the first half of the baseline survey of the GNC. The sample comprised 101,779 interviewed subjects, including 9370 subjects who underwent clinical musculoskeletal examinations. The interview included questions about specific musculoskeletal disorders. A clinical examination of the hand provided information about palpable swollen joints and pressure-sensitive joints. Resting pain of the knees and hips was also assessed by a clinical examination. Frequencies were standardized to the German standard population of the year 2011. RESULTS: Having ever been diagnosed with recurrent back pain (22.5%) or osteoarthritis (20.6%) were the most common complaints reported in the interview; osteoporosis (2.9%) and rheumatoid arthritis (1.9%) were stated more seldom. According to the hand examination, 6.0% of all participants experienced pain in at least one finger joint. Resting pain was present in at least one knee among 8.2% and in at least one hip among 5.1% of the participants as assessed during the clinical examination. Women were more likely to report musculoskeletal disorders and symptoms than men. The proportion of adults affected by musculoskeletal diseases increased strongly with age. CONCLUSION: Musculoskeletal disorders and symptoms occur frequently. The burden of complaints and diagnoses is comparable to previous population-based surveys.

BACKGROUND: The German National Cohort (NAKO) is an interdisciplinary health study aimed at elucidating causes for common chronic diseases and detecting their preclinical stages. This article provides an overview of design, methods, participation in the examinations, and their quality assurance based on the midterm baseline dataset (MBD) of the recruitment. METHODS: More than 200,000 women and men aged 20–69 years derived from random samples of the German general population were recruited in 18 study centers (2014–2019). The data collection comprised physical examinations, standardized interviews and questionnaires, and the collection of biomedical samples for all participants (level 1). At least 20% of all participants received additional in-depth examinations (level 2), and 30,000 received whole-body magnet resonance imaging (MRI). Additional information will be collected through secondary data sources such as medical registries, health insurances, and pension funds. This overview is based on the MBD, which included 101,839 participants, of whom 11,371 received an MRI. RESULTS: The mean response proportion was 18%. The participation in the examinations was high with most of the modules performed by over 95%. Among MRI participants, 96% completed all 12 MRI sequences. More than 90% of the participants agreed to the use of complementary secondary and registry data. DISCUSSION: Individuals selected for the NAKO were willing to participate in all examinations despite the time-consuming program. The NAKO provides a central resource for population-based epidemiologic research and will contribute to developing innovative strategies for prevention, screening and prediction of chronic diseases. HINTERGRUND: Die NAKO Gesundheitsstudie ist ein bundesweites interdisziplinäres Forschungsvorhaben mit dem Ziel, die Ursachen für chronische Krankheiten und deren vorklinische Stadien zu untersuchen. Der Artikel gibt einen Überblick über das Studiendesign, die Methoden, die Teilnahme an den Untersuchungen und ihre Qualitätssicherung zur Halbzeit der Basiserhebung. METHODEN: Für die Basiserhebung wurden mehr als 200.000 Frauen und Männer im Alter von 20–69 Jahren aus Zufallsstichproben der Allgemeinbevölkerung in 18 Studienzentren rekrutiert (2014–2019). Die Basiserhebung beinhaltet Untersuchungen, Befragungen und Biomaterialien für alle Teilnehmerinnen und Teilnehmer (Level 1), ein erweitertes Programm für mindestens 20 % (Level 2) und eine Magnetresonanztomografie (MRT) für 30.000 Teilnehmerinnen und Teilnehmer. Sekundär- und Registerdaten werden über Krankheitsregister, Kranken- und Rentenversicherungen erhoben. Die Auswertung bezieht die Datenbasis zur Halbzeit der Basiserhebung mit 101.839 Teilnehmerinnen und Teilnehmern ein, davon 11.371 mit einer MRT-Untersuchung. ERGEBNISSE: Die mittlere Responsequote zur Halbzeit betrug insgesamt 18 %. Die Teilnahme an den Untersuchungen lag überwiegend bei mehr als 95 %. Bei 96 % der MRT-Teilnehmerinnen und Teilnehmer konnten alle 12 MRT-Sequenzen vollständig durchgeführt werden. Der Erschließung und wissenschaftlichen Nutzung ergänzender Sekundär- und Registerdaten stimmten mehr als 90 % der Teilnehmerinnen und Teilnehmer zu. DISKUSSION: Die Bereitschaft, möglichst alle Untersuchungsmodule durchzuführen, war trotz des zeitlichen Aufwandes außerordentlich hoch. Dadurch wird die NAKO zu einer zentralen Ressource für die epidemiologische Forschung in Deutschland. Sie wird es ermöglichen, neue Strategien zur Früherkennung, Vorhersage und Primärprävention chronischer Krankheiten zu entwickeln.

Übergewicht und Adipositas sind bedeutende Risikofaktoren für verschiedene Erkrankungen. Als Maß zu ihrer Bestimmung wurde in früheren Studien meist nur der Body-Mass-Index (BMI) verwendet. Der BMI ist allerdings ein Marker, der den Einfluss auf das Krankheitsrisiko nur unzureichend erfasst. In groß angelegten, bevölkerungsbasierten Studien besteht daher ein vordringlicher Bedarf, verbesserte Messmethoden der Körperzusammensetzung und -fettverteilung einzusetzen. Der vorliegende Beitrag stellt die in der NAKO (Nationale Kohorte) Gesundheitsstudie eingesetzten Messverfahren zur Beschreibung von Körperzusammensetzung und -fettverteilung und die ersten deskriptiven Ergebnisse vor. Diese beziehen sich auf die Daten zur Halbzeit der Basiserhebung, welche 101.817 Teilnehmende einschließt, die in 18 Studienzentren in Deutschland zwischen März 2014 und März 2017 untersucht worden sind. Die anthropometrischen Messungen umfassten Körpergewicht, Körpergröße und -umfänge, bioelektrische Impedanzanalyse (BIA), Sonographie des Abdominalfettes, 3‑D-Bodyscanner und Magnetresonanztomographie. Die Analyse des BMI zeigte, dass 46,2 % der Männer sowie 29,7 % der Frauen übergewichtig und 23,5 % der Männer und 21,2 % der Frauen adipös waren. Frauen wiesen im Mittel in fast allen Altersgruppen eine höhere Schichtdicke an subkutanem Fettgewebe auf als Männer. Die mittlere Schichtdicke des viszeralen Fettgewebes lag hingegen bei den Männern in allen Altersgruppen über den Werten der Frauen und stieg bei beiden Geschlechtern über die Altersgruppen kontinuierlich an. Die umfassenden Daten über die Körperfettverteilung und -zusammensetzung ermöglichen es zukünftig, den Einfluss von Übergewicht und Adipositas auf die Entstehung von chronischen Erkrankungen im Detail zu analysieren. High levels of adiposity in the population have a major impact on various diseases, but previous epidemiologic studies have largely been restricted to simple anthropometric measures such as the body mass index (BMI), an imperfect predictor of disease risk. There is a critical need for the use of improved measures of relative weight and body composition in large-scale, population-based research. The current article presents initial descriptive results of body composition and fat distribution based on the midterm baseline dataset of the German National Cohort, which included 101,817 participants who were examined in 18 study centers in Germany between March 2014 and March 2017. The anthropometric measures encompassed body weight, height, waist and hip circumference, bioelectrical impedance analysis (BIA), sonography of abdominal adipose tissue, 3D-body scanning, and magnetic resonance imaging. BMI analyses showed that 46.2% of men and 29.7% of women were overweight and 23.5% of men and 21.2% of women were obese. On average, women in almost all age groups demonstrated more subcutaneous adipose tissue layer thickness than men. The mean values of visceral adipose tissue layer thickness, on the other hand, were higher among men than among women in all age groups and increased continuously across age groups in both sexes. The comprehensive assessment of body composition and fat distribution provides novel future opportunities for detailed epidemiologic analyses of overweight and adiposity in relation to the development of chronic diseases.

BACKGROUND: In epidemiologic studies, standardised measurement of socio-demographic and employment-related factors is becoming increasingly important, as variables such as gender, age, education or employment status are factors influencing health and disease risks. AIMS: The article gives an overview of the scientific background and assessment of socio-demographic factors in the German National Cohort Study. In addition, the distribution of individual characteristics in the cohort as well as relationships with health-related measures are presented by way of example. MATERIAL AND METHODS: The analysis is based on the data of the first half of the baseline survey (n = 101,724). On this basis, we present the distribution of key socio-demographic characteristics and analyse relationships with exemplary selected health indicators (body mass index, self-reported health) to assess the validity of socio-demographic data measurements. RESULTS: On average, study participants were 52.0 years old (SD = 12.4). Of the participants, 53.6% were women, 54.3% had high education, 60.1% were married and 72% were employed while 3.4% were unemployed. Well-established correlations between socio-demographic factors and health could be reproduced with the German National Cohort data. For example, low education, old age and unemployment were associated with an increased prevalence of obesity and poor self-reported health. DISCUSSION: The German National Cohort provides a comprehensive measurement of socio-demographic characteristics. Combined with a wide range of health data and the longitudinal measurements available in the future, this opens up new opportunities for health science and social epidemiological research in Germany. HINTERGRUND: In epidemiologischen Studien ist die standardisierte Erfassung soziodemografischer Merkmale von hoher Bedeutung, da Variablen wie Geschlecht, Alter, Bildung oder Erwerbsstatus wichtige Einflussfaktoren auf Gesundheitschancen und Krankheitsrisiken darstellen. In der NAKO Gesundheitsstudie werden zentrale Faktoren aus diesem Themenbereich berücksichtigt. ZIEL DER ARBEIT: Der Beitrag gibt einen Überblick über den wissenschaftlichen Hintergrund und die konkrete Erhebung soziodemografischer Angaben in der NAKO. Zudem werden die Verteilung einzelner Merkmale sowie Zusammenhänge mit gesundheitsassoziierten Maßen exemplarisch vorgestellt. MATERIAL UND METHODEN: Anhand der Daten zur Halbzeit der Basiserhebung (n = 101.724) wurde die Verteilung soziodemografischer Merkmale dargestellt und Zusammenhänge mit beispielhaft ausgewählten Gesundheitsindikatoren (Body-Mass-Index, selbst berichtete Gesundheit) analysiert, um die Validität der Messung soziodemografischer Angaben zu beurteilen. ERGEBNISSE: Das mittlere Alter der Teilnehmenden lag bei 52,0 Jahren (SD = 12,4). 53,6 % der Teilnehmenden waren Frauen, 54,3 % hatten einen hohen Bildungsabschluss, 60,1 % waren verheiratet zusammenlebend, 72,0 % erwerbstätig und 3,4 % erwerbslos. Bekannte Zusammenhänge zwischen Soziodemografie und Gesundheit konnten reproduziert werden. So waren niedrige Bildung, hohes Alter und Erwerbslosigkeit mit einer erhöhten Häufigkeit von Adipositas und schlechter selbst berichteter Gesundheit assoziiert. DISKUSSION: Die NAKO Gesundheitsstudie erhebt viele soziodemografische Merkmale. In Kombination mit der Fülle an Gesundheitsdaten und dem Längsschnittdesign ergeben sich so neue Möglichkeiten für die gesundheitswissenschaftliche und sozialepidemiologische Forschung in Deutschland.

BACKGROUND: Caries and periodontitis are highly prevalent worldwide. Because detailed data on these oral diseases were collected within the framework of the German National Cohort (GNC), associations between oral and systemic diseases and conditions can be investigated. OBJECTIVES: The study protocol for the oral examination was designed to ensure a comprehensive collection of dental findings by trained non-dental staff within a limited examination time. At the mid-term of the GNC baseline examination, a first quality evaluation was performed to check the plausibility of results and to propose measures to improve the data quality. MATERIALS AND METHODS: A dental interview, saliva sampling and oral diagnostics were conducted. As part of the level‑1 examination, the number of teeth and prostheses were recorded. As part of the level‑2 examination, detailed periodontal, cariological and functional aspects were examined. All examinations were conducted by trained non-dental personnel. Parameters were checked for plausibility and variable distributions were descriptively analysed. RESULTS: Analyses included data of 57,967 interview participants, 56,913 level‑1 participants and 6295 level‑2 participants. Percentages of missing values for individual clinical parameters assessed in level 1 and level 2 ranged between 0.02 and 3.9%. Results showed a plausible distribution of the data; rarely, implausible values were observed, e.g. for measurements of horizontal and vertical overbite (overjet and overbite). Intra-class correlation coefficients indicated differences in individual parameters between regional clusters, study centres and across different examiners. CONCLUSIONS: The results confirm the feasibility of the study protocol by non-dental personnel and its successful integration into the GNC’s overall assessment program. However, rigorous dental support of the study centres is required for quality management. HINTERGRUND:Karies und Parodontitis sind weltweit hoch prävalente Erkrankungen. Durch ihre Erfassung im Rahmen der NAKO Gesundheitsstudie können Assoziationen zwischen oralen und systemischen Erkrankungen untersucht werden. FRAGESTELLUNG: In einer ersten Qualitätsanalyse zur Halbzeit der NAKO-Basiserhebung wird die Plausibilität der zahnmedizinischen Ergebnisse überprüft. Es werden Maßnahmen zur Verbesserung der Datenqualität vorgeschlagen. MATERIAL UND METHODEN: Ein zahnmedizinisches Interview, eine Speichelprobengewinnung und eine Befunderhebung wurden durchgeführt. Im Rahmen der Level-1-Untersuchung wurden Zahn- und Prothesenanzahl erfasst. In der Level-2-Untersuchung wurden detaillierte parodontologische, kariologische und funktionelle Befunde erhoben. Alle Untersuchungen wurden von geschultem nichtzahnmedizinischen Personal durchgeführt. Es wurden Plausibilitätsprüfungen durchgeführt sowie Verteilungen deskriptiv dargestellt. ERGEBNISSE: In die Analysen gingen Daten von 57.967 Interviewteilnehmer*innen, 56.913 Level-1- und 6295 Level-2-Teilnehmer*innen ein. Der Anteil fehlender Werte lag für die einzelnen Parameter der Level-1- und Level-2-Untersuchungen zwischen 0,02 % und 3,9 %. Die Parameter zeigten eine plausible Verteilung; vereinzelt wurden unplausible Werte beobachtet, z. B. beim horizontalen und vertikalen Überbiss (Overjet und Overbite). Anhand der Intraklassenkorrelationskoeffizienten wurden für die einzelnen Parameter Unterschiede zwischen regionalen Clustern, den Studienzentren und verschiedenen Untersucher*innen nachgewiesen. DISKUSSION: Die bisherigen Ergebnisse bestätigten die Umsetzbarkeit des Studienprotokolls durch nichtzahnmedizinisches Personal und die erfolgreiche Integration in das Untersuchungsprogramm der NAKO Gesundheitsstudie. Die Studienzentren benötigen eine intensive zahnmedizinische Betreuung für das Qualitätsmanagement.

BACKGROUND: Infectious diseases continue to play an important role for disease perception, health-economic considerations and public health in Germany. In recent years, infectious diseases have been linked to the development of non-communicable diseases. Analyses of the German National Cohort (GNC) may provide deeper insights into this issue and pave the way for new targeted approaches in disease prevention. OBJECTIVES: The aim was to describe the tools used to assess infectious diseases and to present initial data on infectious disease frequencies, as well as to relate the GNC assessment tools to data collection methods in other studies in Germany. METHODS: As part of the baseline examination, questions regarding infectious diseases were administered using both an interview and a self-administered touchscreen questionnaire. Data from the initial 101,787 GNC participants were analysed. RESULTS: In the interview, 0.2% (HIV/AIDS) to 8.6% (shingles) of respondents reported ever having a medical diagnosis of shingles, postherpetic neuralgia (in cases where shingles was reported), hepatitis B/C, HIV/AIDS, tuberculosis or sepsis if treated in hospital. In the questionnaire, 12% (cystitis) to 81% (upper respiratory tract infections) of respondents reported having experienced at least one occurrence of upper or lower respiratory tract infections, gastrointestinal infections, cystitis or fever within the past 12 months. OUTLOOK: The cross-sectional analyses of data and tools presented here – for example on determinants of susceptibility to self-reported infections – can be anticipated from the year 2021 onward. Beyond that, more extensive research into infectious disease epidemiology will follow, particularly once analyses of GNC biological materials have been performed. HINTERGRUND: Infektionen spielen für das Krankheitsempfinden, für gesundheitsökonomische Überlegungen sowie Public Health in Deutschland weiterhin eine wichtige Rolle. Sie wurden in den letzten Jahren außerdem mit der Entstehung von nichtübertragbaren Erkrankungen in Zusammenhang gebracht. Die NAKO Gesundheitsstudie kann Erkenntnisse auf diesem Gebiet vertiefen und damit zielgenaueren präventiven Ansätzen den Weg bereiten. ZIEL: Die infektionsbezogenen Erhebungsinstrumente sollen beschrieben und in Bezug zu Erhebungsarten anderer deutscher Studien gesetzt werden. Zudem werden erste Daten zur Häufigkeit von Infektionskrankheiten berichtet. METHODEN: Fragen zu Infektionskrankheiten wurden in der NAKO-Basiserhebung sowohl im Interview als auch im Selbstausfüllerfragebogen (Touchscreen) gestellt. Es wurden die Daten der ersten 101.787 Teilnehmenden ausgewertet. ERGEBNISSE: Das Auftreten von Herpes Zoster (HZ), Post-Zoster-Neuralgie (bei Angabe von HZ), Hepatitis B/C, HIV/Aids und Tuberkulose im Sinne einer ärztlichen Diagnose bzw. von Sepsis als Grund für eine stationäre Behandlung wurde von 0,2 % (HIV/Aids) bis 8,6 % (HZ) der Befragten im Interview angegeben. Im Touchscreenmodul wurde das mindestens einmalige Auftreten einer Infektion der oberen Atemwege (IOA), der unteren Atemwege, des Magen-Darm-Traktes, der Harnblase oder von Fieber in den letzten 12 Monaten von 12 % (Zystitis) bis 81 % (IOA) berichtet. AUSBLICK: Weitere Ergebnisse anhand von Daten aus den hier vorgestellten Fragebögen sind im Querschnittsdesign – beispielsweise zu Determinanten der Anfälligkeit für selbst berichtete Infektionen – ab 2021 zu erwarten. Die Bearbeitung darüber hinausgehender Forschungsfragen der Infektionsepidemiologie wird insbesondere nach Analysen von NAKO-Bioproben möglich sein.

BACKGROUND: Asthma is one of the most common chronic diseases in both children and adults. Asthma first occurring in adulthood (adult-onset asthma, AOA) is associated with poorer prognosis compared to childhood-onset asthma (COA), which urgently calls for more research in this area. The aim of this work was to analyze the data on asthma collected in the German National Cohort and compare it with the German Health Interview and Examination Survey for Adults (DEGS), in particular regarding AOA. MATERIAL AND METHODS: Our analysis was based on the dataset of the main questionnaire at mid-term of the German National Cohort baseline examination, comprising 101,723 participants. Variables considered in the analyses were self-reported diagnosis of asthma, age at first diagnosis, asthma treatment in the past 12 months, age, and sex. RESULTS: In the midterm dataset, 8.7% of women and 7.0% of men in the German National Cohort reported that they had ever been diagnosed with asthma. Approximately one third of participants with asthma received their initial diagnosis before their 18th birthday. COA affected 2.2% of women and 2.8% of men, whereas AOA affected 6.5% of women and 4.2% of men. During the previous 12 months, 33% of COA cases and 60% of AOA cases were medically treated. CONCLUSION: The proportion of persons affected by asthma in the German National Cohort, as well as observed patterns regarding age and gender, corresponds to other data sources such as DEGS. However, in our analysis, the proportion of individuals with AOA was higher than described in the literature. The increase in cumulative asthma diagnoses with age is markedly steeper in younger participants, indicating a rising trend over time. HINTERGRUND: Asthma bronchiale stellt über alle Bildungsschichten hinweg eine der häufigsten chronischen Erkrankungen im Kindes- und Erwachsenenalter dar. Im Erwachsenenalter erstmals auftretendes Asthma (Adult-onset Asthma, AOA) ist im Vergleich zu Childhood-onset Asthma (COA) mit einer schlechteren Prognose assoziiert, was verstärkte Untersuchungen in diesem Bereich erfordert. Ziel der Arbeit war es, Häufigkeiten und das Alter bei Erstdiagnose aus Selbstangaben zu Asthma bei Erwachsenen in der NAKO Gesundheitsstudie darzustellen und mit Daten der Studie zur Gesundheit Erwachsener in Deutschland (DEGS) zu vergleichen. MATERIAL UND METHODEN: Unsere Analyse beruht auf einem Datensatz zur Halbzeit der NAKO-Basiserhebung mit 101.284 Personen. Verwendete Variablen waren die Selbstangabe zum jemals ärztlich diagnostizierten Asthma, Alter bei Erstdiagnose, Behandlung in den letzten 12 Monaten, Alter und Geschlecht. ERGEBNISSE: Laut Datenbasis zur Halbzeit berichteten in der NAKO 8,7 % der Frauen und 7,0 % der Männer, dass bei ihnen jemals Asthma diagnostiziert wurde. Etwa bei einem Drittel der Teilnehmenden mit Asthma wurde die Diagnose bereits im Kindes‑/Jugendalter (

Die körperliche Fitness ist das Maß für die individuelle Fähigkeit, körperlich aktiv zu sein. Ihre wesentlichen Komponenten sind die kardiorespiratorische Fitness (Cardiorespiratory Fitness, CRF), die Muskelkraft und die Beweglichkeit. Neben der körperlichen Aktivität ist die körperliche Fitness ein wesentlicher Prädiktor für Morbidität und Mortalität. Ziel der Arbeit sind die Beschreibung der Erhebungsmethoden körperlicher Fitness in der NAKO Gesundheitsstudie und die Darstellung erster deskriptiver Ergebnisse. In der NAKO-Basiserhebung wurden die maximale Handgreifkraft (Grip Strength, GS) und die CRF als Komponenten der körperlichen Fitness über ein Handdynamometer bzw. über einen Fahrradergometertest mit submaximaler Belastung erhoben. Daraus wurde die maximale Sauerstoffaufnahme (VO2max) zur Beurteilung der CRF abgeleitet. Die Ergebnisse von insgesamt 99.068 GS-Messungen und 3094 Messungen der CRF beruhen auf einem Datensatz zur Halbzeit der Basiserhebung der NAKO (Alter 20–73 Jahre, 47 % Männer). Männer zeigten im Vergleich zu Frauen höhere Werte der körperlichen Fitness (Männer: GS = 47,8 kg, VO2max = 36,4 ml·min−1 · kg−1; Frauen: GS = 29,9 kg, VO2max = 32,3 ml·min−1 · kg−1). Ungefähr ab dem 50. Lebensjahr konnte ein Rückgang der GS verzeichnet werden, wohingegen die CRF ab der Altersgruppe 20–29 Jahre bis zu den ≥60-Jährigen kontinuierlich abfiel. Die GS und die VO2max zeigten nach Korrektur für das Körpergewicht einen linear positiven Zusammenhang (Männer β = 0,21; Frauen β = 0,35). Die Analysen zeigten eine gute Übereinstimmung der Verteilung der körperlichen Fitness in der NAKO im Vergleich zu anderen bevölkerungsbasierten Studien. Zukünftige Auswertungen werden insbesondere die unabhängige Bedeutung der GS und CRF bei der Prädiktion von Morbidität und Mortalität beleuchten. Physical fitness is defined as an individual’s ability to be physically active. The main components are cardiorespiratory fitness (CRF), muscle strength, and flexibility. Regardless of physical activity level, physical fitness is an important determinant of morbidity and mortality. The aim of the current study was to describe the physical fitness assessment methodology in the German National Cohort (NAKO) and to present initial descriptive results in a subsample of the cohort. In the NAKO, hand grip strength (GS) and CRF as physical fitness components were assessed at baseline using a hand dynamometer and a submaximal bicycle ergometer test, respectively. Maximum oxygen uptake (VO2max) was estimated as a result of the bicycle ergometer test. The results of a total of 99,068 GS measurements and 3094 CRF measurements are based on a data set at halftime of the NAKO baseline survey (age 20–73 years, 47% men). Males showed higher values of physical fitness compared to women (males: GS = 47.8 kg, VO2max = 36.4 ml·min−1 · kg−1; females: GS = 29.9 kg, VO2max = 32.3 ml · min−1 · kg−1). GS declined from the age of 50 onwards, whereas VO2max levels decreased continuously between the age groups of 20–29 and ≥60 years. GS and VO2max showed a linear positive association after adjustment for body weight (males β = 0.21; females β = 0.35). These results indicate that the physical fitness measured in the NAKO are comparable to other population-based studies. Future analyses in this study will focus on examining the independent relations of GS and CRF with risk of morbidity and mortality.

Hintergrund Lärmbelästigung geht mit gesundheitlicher Beeinträchtigung und reduziertem Wohlbefinden einher. Die subjektive Lärmbelästigung steht im Zusammenhang mit der objektiven Lärmbelastung sowie individuellen und regionalen Faktoren. Fragestellung Wie viele Teilnehmende der NAKO Gesundheitsstudie fühlen sich durch nächtlichen Verkehrslärm belästigt und welche Faktoren stehen damit im Zusammenhang? Material und Methoden Diese Querschnittsanalyse basiert auf Daten von 86.080 NAKO-Teilnehmenden aus 18 Studienzentren, die von 2014 bis 2017 untersucht wurden. Um die Beziehungen zwischen individuellen und regionalen Faktoren und Verkehrslärmbelästigung in den Kategorien nicht belästigt, leicht/mittel und stark/sehr stark belästigt zu untersuchen, wurden multinomiale logistische Regressionsmodelle mit wechselseitiger Adjustierung der Faktoren verwendet. Ergebnisse Zwei Drittel der Teilnehmenden fühlten sich nicht durch Verkehrslärm belästigt; jeder Zehnte berichtete von starker/sehr starker Belästigung, mit den höchsten Anteilen in Berlin-Mitte und Leipzig. Die stärksten Assoziationen mit Lärmbelästigung wurden für Faktoren der individuellen Wohnsituation beobachtet, wie z. B. die Position des Schlafraums zur Hauptstraße (OR für leicht/mittel belästigt: 4,26 [95 % KI: 4,01; 4,52]; OR für stark/sehr stark belästigt: 13,36 [95 % KI: 12,47; 14,32] im Vergleich zu Garten/Innenhof). Teilnehmende im Alter von 40–60 Jahren oder der mittleren und niedrigen Einkommensklasse fühlten sich eher durch Verkehrslärm belästigt als jüngere bzw. ältere Teilnehmende oder solche mit hoher Einkommensklasse. Diskussion Teilnehmende der NAKO Gesundheitsstudie wiesen Unterschiede in der Belästigung durch nächtlichen Verkehrslärm in Bezug auf individuelle und regionale Faktoren auf., Background Noise annoyance is associated with adverse health-related conditions and reduced wellbeing. Thereby, subjective noise annoyance depends on the objective noise exposure and is modified by personal and regional factors. Objective How many participants of the German National Cohort Study (GNC; NAKO Gesundheitsstudie) were annoyed by transportation noise during nighttime and what factors were associated with noise annoyance? Materials and methods This cross-sectional analysis included 86,080 participants from 18 study centers, examined from 2014 to 2017. We used multinomial logistic regression to investigate associations of personal and regional factors to noise annoyance (slightly/moderately or strongly/extremely annoyed vs. not annoyed) mutually adjusting for all factors in the model. Results Two thirds of participants were not annoyed by transportation noise during nighttime and one in ten reported strong/extreme annoyance with highest percentages for the study centers Berlin-Mitte and Leipzig. The strongest associations were seen for factors related to the individual housing situation like the bedroom being positioned towards a major road (OR of being slightly/moderately annoyed: 4.26 [95% CI: 4.01;4.52]; OR of being strongly/extremely annoyed: 13.36 [95% CI: 12.47;14.32]) compared to a garden/inner courtyard. Participants aged 40–60 years and those in low- and medium-income groups reported greater noise annoyance compared to younger or older ones and those in the high-income group. Conclusion In this study from Germany, transportation noise annoyance during nighttime varied by personal and regional factors.

BACKGROUND: Data on self-reported cardiovascular and metabolic diseases are available for the first 100,000 participants of the population-based German National Cohort (GNC, NAKO Gesundheitsstudie). OBJECTIVES: To describe assessment methods and the frequency of self-reported cardiovascular and metabolic diseases in the German National Cohort. MATERIALS AND METHODS: Using a computer-based, standardized personal interview, 101,806 participants (20–75 years, 46% men) from 18 nationwide study centres were asked to use a predefined list to report medical conditions ever diagnosed by a physician, including cardiovascular or metabolic diseases. For the latter, we calculated sex-stratified relative frequencies and compared these with reference data. RESULTS: With regard to cardiovascular diseases, 3.5% of men and 0.8% of women reported to have ever been diagnosed with a myocardial infarction, 4.8% and 1.5% with angina pectoris, 3.5% and 2.5% with heart failure, 10.1% and 10.4% with cardiac arrhythmia, 2.7% and 1.8% with claudicatio intermittens, and 34.6% and 27.0% with arterial hypertension. The frequencies of self-reported diagnosed metabolic diseases were 8.1% and 5.8% for diabetes mellitus, 28.6% and 24.5% for hyperlipidaemia, 7.9% and 2.4% for gout, and 10.1% and 34.3% for thyroid diseases. Observed disease frequencies were lower than reference data for Germany. CONCLUSIONS: In the German National Cohort, self-reported cardiovascular and metabolic diseases diagnosed by a physician are assessed from all participants, therefore representing a data source for future cardio-metabolic research in this cohort. HINTERGRUND: Aus der NAKO Gesundheitsstudie, der größten deutschen bevölkerungsbasierten Studie zur Gesundheit, liegen die Daten zu selbst berichteten kardiovaskulären und metabolischen Erkrankungen der ersten ca. 100.000 Teilnehmenden vor. ZIEL: Beschreibung der Methoden zur Erhebung sowie Berechnung der Häufigkeit kardiovaskulärer und metabolischer Erkrankungen in der NAKO. MATERIAL UND METHODEN: 101.806 Teilnehmende (20–75 Jahre, 46 % Männer) aus 18 bundesweiten Studienzentren wurden in einem computergestützten, standardisierten persönlichen Interview gebeten, anhand einer vorgegebenen Liste anzugeben, welche Erkrankungen bei ihnen jemals ärztlich diagnostiziert wurden, darunter auch kardiovaskuläre und metabolische Erkrankungen. Für Letztere wurden deren geschlechtsspezifische relative Häufigkeiten berechnet und diese mit Referenzzahlen verglichen. ERGEBNISSE: Bezogen auf die kardiovaskulären Erkrankungen berichteten 3,5 % der Männer und 0,8 % der Frauen, jemals einen Herzinfarkt diagnostiziert bekommen zu haben, 4,8 % bzw. 1,5 % eine Angina pectoris, 3,5 % bzw. 2,5 % eine Herzinsuffizienz, 10,1 % bzw. 10,4 % Herzrhythmusstörungen, 2,7 % bzw. 1,8 % eine Claudicatio intermittens und 34,6 % bzw. 27,0 % eine arterielle Hypertonie. Die Häufigkeit berichteter diagnostizierter metabolischer Erkrankungen lag bei 8,1 % bzw. 5,8 % für Diabetes mellitus, bei 28,6 % bzw. 24,5 % für Hyperlipidämie, bei 7,9 % bzw. 2,4 % für Gicht und bei 10,1 % bzw. 34,3 % für Schilddrüsenerkrankungen. Die beobachteten Häufigkeiten lagen insgesamt etwas niedriger als Vergleichsdaten für Deutschland. DISKUSSION: Die NAKO erhebt von allen Teilnehmenden selbst berichtete, ärztlich diagnostizierte kardiovaskuläre und metabolische Erkrankungen und stellt damit eine Datenressource für weitergehende kardiometabolische Forschungsfragestellungen dar.

kein Abstract!

HINTERGRUND: Arterielle Hypertonie ist einwichtiger Risikofaktor für Herz-Kreislauf-Er-krankungen. Epidemiologische Studien führen meist drei konsekutive Blutdruckmessungen durch. Der 1. Messwert wird für Auswertungen verworfen, da dieser am stärksten durch vorhergehende Aktivitäten beeinflusst sein kann. Aus zeitlichen Gründen wurden in der NAKO Gesundheitsstudie nur zwei Messungen durchgeführt. FRAGESTELLUNG: Die vorliegende Analyse untersucht Auswirkungen methodischer Unterschiede bei der Blutdruckmessungauf die Hypertoniehäufigkeit und mittlere Blutdruckwerte anhand eines Vergleichsder ersten Hälfte der NAKO-Teilnehmenden(nur 2 Messungen) mit 5 deutschen populationsbasierten Studien (3 Messungen). MATERIAL UND METHODEN: Es wurden Daten der Teilnehmenden aus der NAKO (erste 101.816 Personen), der bundesweiten Studie zur Gesundheit Erwachsener des Robert Koch-Instituts (DEGS1) und aus 4 regionalen populationsbasierten Kohortenstudien (CARLA, HNR, KORA, SHIP) analysiert. Alters- und geschlechtsspezifische mittlere Blutdruckwerte und Hypertoniehäufigkeiten wurden auf Basis des 2. Messwertes, des Mittelwerts aus 1. und 2. sowie aus 2. und 3. Messung berechnet. ERGEBNISSE: Die mittleren Blutdruckwerte der beiden aktuellsten Studien (NAKO und DEGS1) sind sehr ähnlich und niedriger als in den anderen Studien. Die Differenz zwischen dem 2. Messwert und dem Mittelwert aus 2. und 3. Messung ist gering (maximale mittlere Abweichung: 1,5mmHg systolisch), jedoch ist die mittels des 2. Messwertes berechnete Hypertoniehäufigkeit der Bevölkerung höher als bei Verwendung des Mittelwertsaus 2. und 3. Messung. DISKUSSION: Die Ergebnisse der vorliegenden Analyse zeigen, dass für die wissenschaftliche Auswertung der NAKO-Daten die Verwendung des 2. Blutdruckmesswerts zu empfehlen ist. BACKGROUND: Arterial hypertension is an important risk factor for cardiovascular diseases. Epidemiological studies typically perform three consecutive blood pressure measurements. The first measurement is discarded in subsequent analyses, as this value may be strongly affected by previous activities. Due to time constraints the German National Cohort (GNC NAKO) performed only two blood pressure measurements. OBJECTIVES. The present analysis examined the possible effects of methodological differences in blood pressure measurement by comparing the first 101,816 GNC participants (two blood pressure measurements) with those of five German population-based studies (three measurements). MATERIALS AND METHODS: Blood pressure data from participants aged 20 to 79 years from the GNC, the German Health Interview and Examination Survey for Adults by the Robert Koch Institute (DEGS1), and four regional population-based cohort studies (CARLA, HNR, KORA, SHIP) were used to calculate age-and sex-specific mean blood pressure values and hypertension frequencies based on the second blood pressure measurement, the arithmetic mean of the first and second value and of the second and third (the latter not available in the GNC). RESULTS: The mean blood pressure values of the two most recent studies (GNC, DEGS1) were very similar and lower than in the other studies. The difference of the second measurement and the mean of second and third measurement was small (maximum mean difference: 1.5mmHg systolic blood pressure), but leads to higher estimated hypertension frequencies. CONCLUSIONS: The current results show that using the second blood pressure measurement should be recommended for scientific analyses of GNC data.

The function and stability of collagens depend on the accurate triple helix formation of three distinct polypeptide chains. Disruption of this triple-helical structure can result in connective-tissue disorders. Triple helix formation is thought to depend on three-stranded coiled-coil oligomerization sites within non-collagenous domains. However, only little is known about the physiological relevance of these coiled-coil structures. Transmembrane collagen XVII, also known as 180 kDa bullous pemphigoid antigen provides mechanical stability through the anchorage of epithelial cells to the basement membrane. Mutations in the collagen XVII gene, COL17A1, cause junctional epidermolysis bullosa (JEB), characterized by chronic trauma-induced skin blistering. Here we exploited a novel naturally occurring COL17A1 mutation, leading to an in-frame lysine duplication within the coiled-coil structure of the juxtamembranous NC16A domain of collagen XVII, which resulted in a mild phenotype of JEB due to reduced membrane-anchored collagen XVII molecules. This mutation causes structural changes in the mutant molecule and interferes with its maturation. The destabilized coiled-coil structure of the mutant collagen XVII unmasks a furin cleavage site that results in excessive and non-physiological ectodomain shedding during its maturation. Furthermore, it decreases its triple-helical stability due to defective coiled-coil oligomerization, which makes it highly susceptible to proteolytic degradation. As a consequence of altered maturation and decreased stability of collagen XVII trimers, reduced collagen XVII is incorporated into the cell membrane, resulting in compromised dermal-epidermal adhesion. Taken together, using this genetic model, we provide the first proof that alteration of the coiled-coil structure destabilizes oligomerization and impairs physiological shedding of collagen XVII in vivo.

Summary The skin comprises tissue macrophages as the most abundant resident immune cell type. Their diverse tasks including resistance against invading pathogens, attraction of bypassing immune cells from vessels, and tissue repair require dynamic specification. Here, we delineated the postnatal development of dermal macrophages and their differentiation into subsets by adapting single-cell transcriptomics, fate mapping, and imaging. Thereby we identified a phenotypically and transcriptionally distinct subset of prenatally seeded dermal macrophages that self-maintained with very low postnatal exchange by hematopoietic stem cells. These macrophages specifically interacted with sensory nerves and surveilled and trimmed the myelin sheath. Overall, resident dermal macrophages contributed to axon sprouting after mechanical injury. In summary, our data show long-lasting functional specification of macrophages in the dermis that is driven by stepwise adaptation to guiding structures and ensures codevelopment of ontogenetically distinct cells within the same compartment.

Integrin α3β1, a major epidermal adhesion receptor is critical for organization of the basement membrane during development and wound healing. Integrin α3 deficiency leads to interstitial lung disease, nephrotic syndrome and epidermolysis bullosa (ILNEB), an autosomal recessive multiorgan disease characterized by basement membrane abnormalities in skin, lung and kidney. The pathogenetic chains from ITGA3 mutation to tissue abnormalities are still unclear. Although integrin α3 was reported to regulate multiple extracellular proteins, the composition of the extracellular compartment of integrin α3-negative keratinocytes has not been resolved so far. In a comprehensive approach, quantitative proteomics of deposited extracellular matrix, conditioned cultured media as well as of the intracellular compartment of keratinocytes isolated from an ILNEB patient and from normal skin were performed. By mass spectrometry-based proteomics, 167 proteins corresponding to the GO terms “extracellular” and “cell adhesion”, or included in the “human matrisome” were identified in the deposited extracellular matrix, and 217 in the conditioned media of normal human keratinocytes. In the absence of integrin α3, 33% and 26% respectively were dysregulated. Dysregulated proteins were functionally related to integrin α3 or were known interaction partners. The results show that in the absence of integrin α3 ILNEB keratinocytes produce a fibronectin-rich microenvironment and make use of fibronectin-binding integrin subunits αv and α5. The most important results were validated in monolayer and organotypic coculture models. Finally, the in vivo relevance of the most dysregulated components was demonstrated by immunostainings of skin, kidney and lung samples of three ILNEB patients.

Collagen XVII is a hemidesmosomal anchorage molecule of basal keratinocytes that promotes stable epidermal-dermal adhesion. One unique feature of collagen XVII is that its collagenous ectodomain is constitutively released from the cell surface by a disintegrin and metalloproteinases (ADAMs) through cleavage within its juxtamembranous linker domain. The responsivity of shedding to environmental stimuli and the high stability of the released ectodomain in several tissues suggests functions in cell detachment during epidermal morphogenesis, differentiation, and regeneration, but its physiologic relevance remained elusive. To investigate this, we generated knock-in mice, which express a functional non-sheddable collagen XVII mutant, with a 41 amino acid deletion in the linker domain spanning all ADAM cleavage sites. These mice showed no macroscopic phenotypic changes, were fertile, and had a normal lifespan. Prevention of collagen XVII shedding interfered neither with skin development nor with epidermal adhesion and differentiation. However, it led to faster wound closure due to accelerated re-epithelialization at the wound edges where shedding of wild-type collagen XVII was strongly induced. Taken together, we have successfully generated a functional non-shedding collagen XVII mouse model, which represents a powerful tool to investigate the pathophysiologic relevance of ectodomain shedding during wound regeneration and cancer invasion.

Squamous cell carcinoma (SCC) is one of the most common skin cancers and causes significant morbidity. Although the expression of the epithelial adhesion molecule collagen XVII (ColXVII) has been linked to SCC invasion, only little is known about its mechanistic contribution. Here, we demonstrate that ColXVII expression is essential for SCC cell proliferation and motility. Moreover, it revealed that particularly the post-translational modification of ColXVII by ectodomain shedding is the major driver of SCC progression, because ectodomain-selective immunostaining was mainly localized at the invasive front of human cutaneous SCCs, and exclusive expression of a non-sheddable ColXVII mutant in SCC-25 cells inhibits their matrix-independent growth and invasiveness. This cell surface proteolysis, which is strongly elevated during SCC invasion and metastasis, releases soluble ectodomains and membrane-anchored endodomains. Both released ColXVII domains play distinct roles in tumor progression: the endodomain induces proliferation and survival, whereas the ectodomain accelerates invasiveness. Furthermore, specific blockage of shedding by monoclonal ColXVII antibodies repressed matrix-independent growth and invasion of SCC cells in organotypic co-cultures. Thus, selective inhibition of ColXVII shedding may offer a promising therapeutic strategy to prevent SCC progression.

Collagen XVII and integrin alpha 6 beta 4 have well-established roles as epithelial adhesion molecules. Their binding partner laminin 332 as well as integrin alpha 6 beta 4 are largely recognized to promote invasion and metastasis in various cancers, and collagen XVII is essential for the survival of colon and lung cancer stem cells. We have studied the expression of laminin.2, collagen XVII and integrin beta 4 in tissue microarray samples of squamous cell carcinoma (SCC) and its precursors, actinic keratosis and Bowen's disease. The expression of laminin.2 was highest in SCC samples, whereas the expression of collagen XVII and integrin beta 4 varied greatly in SCC and its precursors. Collagen XVII and integrin beta 4 were also expressed in SCC cell lines. Virus-mediated RNAi knockdown of collagen XVII and integrin beta 4 reduced the migration of less aggressive SCC-25 cells in horizontal scratch wound healing assay. Additionally, in a 3D organotypic myoma invasion assay the loss of collagen XVII or integrin beta 4 suppressed equally the migration and invasion of SCC-25 cells whereas there was no effect on the most aggressive HSC-3 cells. Variable expression patterns and results in migration and invasion assays suggest that collagen XVII and integrin beta 4 contribute to SCC tumorigenesis.

The vitally important skin barrier is formed by extensive cross-linking activity of transglutaminases (TGs) during terminal epidermal differentiation. We have previously shown that epidermal deficiency of a disintegrin and metalloproteinase 17 (ADAM17), the principal EGFR ligand sheddase, results in postnatal skin barrier defects in mice due to impeded TG activity. However, the mechanism by which ADAM17/EGFR signalling maintains TG activity during epidermal differentiation remains elusive. Here we demonstrate that ADAM17-dependent EGFR signalling promotes TG activity in keratinocytes committed to terminal differentiation by direct induction of TG1 expression. Restored TG1 expression of EGF-stimulated differentiated Adam17

The vitally important skin barrier is formed by extensive cross-linking activity of transglutaminases (TGs) during terminal epidermal differentiation. We have previously shown that epidermal deficiency of a disintegrin and metalloproteinase 17 (ADAM17), the principal EGFR ligand sheddase, results in postnatal skin barrier defects in mice due to impeded TG activity. However, the mechanism by which ADAM17/EGFR signalling maintains TG activity during epidermal differentiation remains elusive. Here we demonstrate that ADAM17-dependent EGFR signalling promotes TG activity in keratinocytes committed to terminal differentiation by direct induction of TG1 expression. Restored TG1 expression of EGF-stimulated differentiated Adam17−/− keratinocytes was strongly repressed by inhibitors for PLCγ1 or protein kinase C (PKC) pathways, while treatment with the PKC stimulator 12-O-tetradecanoylphorbol-13-acetate restored TG activity in the epidermis of keratinocyte-specific Adam17−/− (AD17ΔKC) mice. Further investigations emphasized the expression of PKCη, a mediator of TGM1 transcription, to be sensitive to EGFR activation. In agreement, topical skin application of cholesterol sulfate, an activator of PKCη, significantly improved TG activity in epidermis of AD17ΔKC mice. Our results suggest ADAM17/EGFR-driven PLCγ1 and PKC pathways as important promoters of TG1 expression during terminal keratinocyte differentiation. These findings may help to identify new therapeutic targets for inflammatory skin diseases related to epidermal barrier defects.

Keratinocyte-specific deletion of ADAM17 in mice impairs terminal differentiation of keratinocytes leading to severe epidermal barrier defects. Mice deficient for ADAM17 in keratinocytes phenocopy mice with a keratinocyte-specific deletion of epidermal growth factor receptor (EGFR), which highlights the role of ADAM17 as a "ligand sheddase" of EGFR ligands. In this study, we aim for the first proteomic/degradomic approach to characterize the disruption of the ADAM17-EGFR signaling axis and its consequences for epidermal barrier formation. Proteomic profiling of the epidermal proteome of mice deficient for either ADAM17 or EGFR in keratinocytes at postnatal days 3 and 10 revealed highly similar protein alterations for ADAM17 and EGFR deficiency. These include massive proteome alterations of structural and regulatory components important for barrier formation such as transglutaminases, involucrin, filaggrin, and filaggrin-2. Cleavage site analysis using terminal amine isotopic labeling of substrates revealed increased proteolytic processing of S100 fused-type proteins including filaggrin-2. Alterations in proteolytic processing are supported by altered abundance of numerous proteases upon keratinocyte-specific Adam17 or Egfr deletion, among them kallikreins, cathepsins, and their inhibitors. This study highlights the essential role of proteolytic processing for maintenance of a functional epidermal barrier. Furthermore, it suggests that most defects in formation of the postnatal epidermal barrier upon keratinocyte-specific ADAM17 deletion are mediated via EGFR.

α-Helical coiled coils, frequent protein oligomerization motifs, are commonly observed in vital proteins. Here, using collagen XVII as an example, we provide evidence for a novel function of coiled coils in the regulation of ectodomain shedding. Transmembrane collagen XVII, an epithelial cell surface receptor, mediates dermal-epidermal adhesion in the skin, and its dysfunction is linked to human skin blistering diseases. The ectodomain of this collagen is constitutively shed from the cell surface by proteinases of a disintegrin and metalloprotease family; however, the mechanisms regulating shedding remain elusive. Here, we used site-specific mutagenesis to target the coiled-coil heptad repeats within the juxtamembranous, extracellular noncollagenous 16th A (NC16A) domain of collagen XVII. This resulted in a substantial increase of ectodomain shedding, which was not mediated by disintegrin and metalloproteases. Instead, conformational changes induced by the mutation(s) unmasked a furin recognition sequence that was used for cleavage. This study shows that apart from their functions in protein oligomerization, coiled coils can also act as regulators of ectodomain shedding depending on the biological context.

Inflammation is frequently linked to preterm delivery (PTD). Here, we tested the hypothesis that complement activation plays a role in cervical remodeling and PTD. We studied two mouse models of inflammation-induced PTD. The first model was induced by vaginal administration of lipopolysaccharide (LPS) and the second one by administration of progesterone antagonist RU486. Increased cervical C3 deposition and macrophages infiltration and increased serum C3adesArg and C5adesArg levels were observed in both models when compared to gestational age matched controls. A significant increase in collagen degradation, matrix metalloproteinase 9 (MMP-9) activity and tissue distensibility was observed in the cervix in both models. Mice deficient in complement receptor C5a did not show increased MMP-9 activity and cervical remodeling and did not deliver preterm in response to LPS or RU486, suggesting a role for C5aR in the cervical changes that precede PTD. In vitro studies show that macrophages release MMP-9 in response to C5a. Progesterone diminished the amount of C5aR on the macrophages surface, inhibited the release of MMP-9 and prevented PTD. In addition, macrophages depletion also prevented cervical remodeling and PTD in LPS-treated mice. Our studies show that C5a-C5aR interaction is required for MMP-9 release from macrophages, and the cervical remodeling that leads to PTD. Complement inhibition and supplementation with progesterone may be good therapeutic options to prevent this serious pregnancy complication.

As a type II transmembrane protein in basal keratinocytes, collagen XVII provides stable adhesion between epidermis and dermis in the skin. Its ectodomain can be shed from the cell surface, and autoantibodies in certain blistering diseases preferentially recognize the shed form. Major epitopes of collagen XVII are clustered within the juxtamembranous noncollagenous 16th A domain, and ectodomain shedding occurs within this region, suggesting that cleavage generates neoepitopes. However, the candidate cleavage sites have been controversial, and the mechanism of neoepitope generation is unclear. In this study, we investigated cleavage sites in the noncollagenous 16th A domain to understand the generation of neoepitopes and their pathological role. Polyclonal Abs recognizing the stretch Leu524-Gly532 preferentially reacted with the shed ectodomain, but not with the full-length form, indicating that a neoepitope was localized at this site. The neoepitope-specific Ab fixed complement and induced granulocyte-dependent dermal-epidermal separation in cryosections of normal human skin. The physiological cleavage sites were identified using mass spectrometry. N termini were found at Asp514, Leu524, Glu525, and Gly526, among which Asp514 and Glu525 were blocked by acetylation and pyroglutaminate. In silico prediction of B cell epitopes indicated that the antigenicity of the Leu524-Gly532 region increased substantially after shedding, regardless of the cleavage sites. Correspondingly, neoepitopes were found in the skin and blister fluids of patients with bullous pemphigoid, and bullous pemphigoid sera reacted with the peptide Leu524-Gly532. Taken together, these data demonstrate that physiological shedding of collagen XVII generates neoepitopes, which may serve as a target of blister-inducing autoantibodies.

Glomerulonephritis is a major cause of morbidity in patients with systemic lupus erythematosus. Although substantial progress has been made in the identification of pathogenic triggers that result in autoantibody production, little is known about the pathogenesis of aggressive proliferative processes that lead directly to irreversible glomerular damage and compromise of renal function. In this study, we describe a model of polyinosinic: polycytidylic acid-accelerated lupus nephritis in NZB/W mice that is characterized by severe glomerular proliferative lesions with de novo crescent formation, findings that are linked with decreased survival and adverse outcomes in lupus. Proliferative glomerulonephritis was associated with infiltrating kidney macrophages and renal expression of IFN-inducible genes, matrix metalloproteinases (MMPs), and growth factors. Crescent formation and renal MMP and growth factor expression were dependent on renal macrophages that expressed Il10 , MMPs, osteopontin , and growth factors, including Pdgfc and Hbegf . Infiltrating macrophages and renal MMP expression were induced by type I IFN. These findings reveal a role for type I IFNs and alternatively activated macrophages in aggressive proliferative lesions of lupus nephritis.

Using different mouse monoclonal and human antiphospholipid (aPL) antibodies, we developed a new animal model of renal injury that shares many features with thrombotic microangiopathy (TMA). We found that more than 1 mechanism/signaling pathway is involved in glomerular injury induced by aPL antibodies in this model. Both complement-dependent and complement-independent pathways were identified that lead to glomerular endothelial cell damage and renal function impairment. We also found that C5a-C5aR interaction is a crucial step for the activation of the coagulation cascade and glomerular injury induced by complement-activating antibodies. In addition, our studies demonstrated complement-independent mechanisms in which reactivity with β2 glycoprotein I (β2GPI) plays an important role in aPL-induced glomerular damage and renal failure. Independently of the mechanism responsible for aPL-induced TMA, mice that express low levels of tissue factor (TF) were protected from glomerular injury. That genetic reduction of TF prevents renal injury induced by different aPL antibodies indicates that TF is a common mediator of glomerular damage and a possible target for selective pharmacologic intervention. Treatment with pravastatin, which down-regulates glomerular TF synthesis, prevents aPL-induced TMA in this mouse model, thus emphasizing that targeting TF might be a good therapeutic intervention in patients with TMA.

Collagen XVII is a transmembrane collagen and the major autoantigen of the autoimmune skin blistering disease bullous pemphigoid. Collagen XVII is proteolytically released from the membrane, and the pathogenic epitope harbors the cleavage site for its ectodomain shedding, suggesting that proteolysis has an important role in regulating the function of collagen XVII in skin homeostasis. Previous studies identified ADAMs 9, 10, and 17 as candidate collagen XVII sheddases and suggested that ADAM17 is a major sheddase. Here we show that ADAM17 only indirectly affects collagen XVII shedding and that ADAMs 9 and 10 are the most prominent collagen XVII sheddases in primary keratinocytes because (a) collagen XVII shedding was not stimulated by phorbol esters, known activators of ADAM17, (b) constitutive and calcium influx-stimulated shedding was sensitive to the ADAM10-selective inhibitor GI254023X and was strongly reduced in Adam10(-/-) cells, (c) there was a 55% decrease in constitutive collagen XVII ectodomain shedding from Adam9(-/-) keratinocytes, and (d) H(2)O(2) enhanced ADAM9 expression and stimulated collagen XVII shedding in skin and keratinocytes of wild type mice but not of Adam9(-/-) mice. We conclude that ADAM9 and ADAM10 can both contribute to collagen XVII shedding in skin with an enhanced relative contribution of ADAM9 in the presence of reactive oxygen species. These results provide critical new insights into the identity and regulation of the major sheddases for collagen XVII in keratinocytes and skin and have implications for the treatment of blistering diseases of the skin.

Collagen XVII (BP180) and its shed ectodomain represent major autoantigens in dermatoses of the pemphigoid group. The 120 kDa ectodomain is constitutively shed from the cell surface by disintegrin-metalloproteinases (ADAMs). Part of it is further processed to a 97 kDa fragment (LABD97), an autoantigen in linear IgA dermatosis (LAD), but the responsible proteinases remain elusive. In this study, we identified the 120 and the 97 kDa ectodomain in blister fluids of bullous pemphigoid patients using new mAbs. As blister fluids contain significant plasmin-like serine protease activity, HaCaT keratinocytes or purified 120 kDa ectodomain were incubated with several human serine proteases. In vitro, only plasmin generated a stable 97 kDa fragment that was also targeted by LAD sera. Characterization of the plasmin-derived 97 kDa fragment with domain-specific collagen XVII antibodies, heparin binding and N-glycosylation studies indicates that the N-terminus is located approximately at AA 515 and the C-terminus N-terminally from AA 1,421. Interestingly, plasmin-derived LABD97 was also generated in the presence of ADAM inhibitors and remained stable over more than 12 hours incubation at 37 degrees C, indicating that this disease relevant collagen XVII fragment can also arise in an ADAM-independent manner through direct action by plasmin.

In pemphigoid gestationis (PG), autoantibodies target collagen XVII, a hemidesmosomal transmembrane protein, which is an important element in cutaneous epithelial adhesion and signalling. We report that collagen XVII is expressed in the first trimester and term syncytial and cytotrophoblastic cells of normal placenta and in epithelial cells of amniotic membrane. Immunoelectron microscopy confirmed the localization of collagen XVII to the hemidesmosomes of amniotic epithelium. Examination of three PG placentas showed mild villitis, but there were no differences between collagen XVII expression levels or immunostaining signals as compared to normal placenta. Collagen XVII expression was also detected in cultured extravillous trophoblast HTR-8/SVneo cells, where collagen XVII expression was upregulated by PMA and TGF-beta1. Interestingly, the presence of Col15, the cell migration domain of collagen XVII, induced the migration of HTR-8/SVneo cells in transmigration assay. Analysis of amniotic fluid samples at different gestational weeks revealed that a large quantity of collagen XVII ectodomain was shed into amniotic fluid throughout pregnancy. Biochemical and immunoblotting analysis indicated that the ectodomain in amniotic fluid is structurally very similar to the ectodomain produced by cultured keratinocytes. Cultured cells from amniotic fluid samples also expressed collagen XVII. Our results suggest that collagen XVII may contribute to the invasion of extravillous trophoblasts during placental development and is also required for the integrity of amniotic basement membrane. Although the exact pathomechanism of PG is still largely unknown, the clinical symptoms of PG are initiated after the expression of collagen XVII in placenta during the first trimester of pregnancy.

Transmembrane collagen XVII is traditionally viewed as an important hemidesmosomal attachment component that promotes stable dermal-epidermal adhesion in the skin. However, its expression is highly elevated at the leading edges of cutaneous wounds or invasive carcinomas, suggesting alternative functions in cell migration. The collagenous ectodomain of collagen XVII is constitutively shed from the cell surface by a disintegrin and metalloproteinases, and this shedding is strongly induced during wound healing. Recently, we investigated the physiological relevance of collagen XVII shedding by generating knock-in mice, which exclusively express a functional non-sheddable collagen XVII mutant. Prevention of ectodomain shedding in these mice caused no spontaneous phenotype in resting skin, but accelerated re-epithelialization on skin wounding. Here, we investigated the mechanistic function of shedding during wound healing. Using the non-shedding collagen XVII mice as a model, we uncovered ectodomain shedding as a highly dynamic modulator of in vivo proliferation and motility of activated keratinocytes through tight coordination of α6β4 integrin-laminin-332 interactions and dampening of mechanistic target of rapamycin signaling at the wound edges. Thus, our studies identify ectodomain shedding of collagen XVII as an interactive platform that translates shedding into a signal for directed cell growth and motility during skin regeneration.

Collagen XXIII belongs to the class of type II orientated transmembrane collagens. A common feature of these proteins is the presence of two forms of the molecule: a membrane-bound form and a shed form. Here we demonstrate that, in mouse lung, collagen XXIII is found predominantly as the full-length form, whereas in brain, it is present mostly as the shed form, suggesting that shedding is tissue-specific and tissue-regulated. To analyze the shedding process of collagen XXIII, a cell culture model was established. Mutations introduced into two putative proprotein convertase cleavage sites showed that altering the second cleavage site inactivated much of the shedding. This supports the idea that furin, a major physiological protease, is predominantly responsible for shedding. Furthermore, our studies indicate that collagen XXIII is localized in lipid rafts in the plasma membrane and that ectodomain shedding is altered by a cholesterol-dependent mechanism. Moreover, newly synthesized collagen XXIII either is cleaved inside the Golgi/trans-Golgi network or reaches the cell surface, where it becomes protected from processing by being localized in lipid rafts. These mechanisms allow the cell to regulate the amounts of cell surface-bound and secreted collagen XXIII.

Collagen XVII, a hemidesmosomal component, mediates the adhesion of epidermal keratinocytes to the underlying basement membrane. It exists as a full-length transmembrane protein and a soluble ectodomain that is proteolytically released from the cell surface by sheddases of a disintegrin and metalloproteinase (ADAM) family; TACE, the tumor necrosis factor-alpha-converting enzyme, is the major physiological proteinase. Because both collagen XVII and the ADAMs are transmembrane proteins, their plasma membrane microenvironment can influence shedding. Lipid rafts, assemblies of sphingolipids and cholesterol within the plasma membrane, are responsible for the separation of membrane proteins and are thought to regulate shedding of cell surface proteins. In this study we analyzed the influence of the cholesterol-depleting agent methyl-beta-cyclodextrin (MbetaCD), which disintegrates lipid rafts, on the shedding of collagen XVII in HaCaT keratinocytes and in transfected COS-7 cells. Increasing concentrations of MbetaCD led to a dose-dependent decrease of membrane cholesterol levels and to stimulation of collagen XVII shedding. The stimulation was completely inhibited by sheddase inhibitors, and experiments with COS-7 cells co-transfected with TACE and collagen XVII demonstrated that TACE mediated the low cholesterol-dependent shedding. Co-patching analysis by double immunofluorescence staining revealed co-localization of collagen XVII with the raft resident phosphatidylinositol-linked placental alkaline phosphatase and segregation from the non-raft protein human transferrin receptor, indicating that a majority of collagen XVII molecules was incorporated into lipid rafts. These data deliver the first evidence for the role of plasma membrane lipid organization in the regulation of collagen XVII shedding and, therefore, in the regulation of keratinocyte migration and differentiation.

Collagen XVII/BP180, an epithelial adhesion molecule, belongs to the group of collagenous transmembrane proteins, which are characterized by ectodomain shedding. We recently showed that ADAMs can cleave collagen XVII, but also that furin participates in this process (Franzke, C. W., Tasanen, K., Schacke, H., Zhou, Z., Tryggvason, K., Mauch, C., Zigrino, P., Sunnarborg, S., Lee, D. C., Fahrenholz, F., and Bruckner-Tuderman, L. (2002) EMBO J. 21, 5026–5035). To define the cleavage region in the juxtamembranous NC16A linker domain and assess its structure and requirements for shedding, we constructed deletion mutants of the NC16A domain, expressed them in COS-7 cells, and analyzed their structural integrity and shedding behavior. A mutant lacking the furin consensus sequence was shed in a normal manner, demonstrating that furin does not cleave collagen XVII but rather activates ADAMs (a disintegrin and metalloproteinase). Large deletions of the NC16A domain prevented shedding, and analysis of defined smaller deletions pointed to the stretch of amino acid residues 528–547 as important for sheddase recognition and cleavage. Secondary protein structure predictions showed that deletion of this stretch resulted in an NC16A domain with a positive net charge and an amphipathic α-helix, which can cause conformational changes in the collagen XVII homotrimer. Assessment of triple-helix folding of the mutants revealed a lower thermal stability of all non-shed variants than of wild-type collagen XVII or the shed mutants. In contrast, deletion of the putative nucleation site for triple-helix folding of collagenous transmembrane proteins did not affect folding of collagen XVII. The data indicate that the conformation of the NC16A domain and steric availability of the cleavage site influence shedding and is important for folding of collagen XVII.

In skin, hemidesmosomal protein complexes attach the epidermis to the dermis and are critical for stable connection of the basal epithelial cell cytoskeleton with the basement membrane (BM). In muscle, a similar supramolecular aggregate, the dystrophin glycoprotein complex links the inside of muscle cells with the BM. A component of the muscle complex, dystroglycan (DG), also occurs in epithelia. In this study, we characterized the expression and biochemical properties of authentic and recombinant DG in human skin and cutaneous cells in vitro. We show that DG is present at the epidermal BM zone, and it is produced by both keratinocytes and fibroblasts in vitro. The biosynthetic precursor is efficiently processed to the alpha- and beta-DG subunits; and, in addition, a distinct extracellular segment of the transmembranous beta-subunit is shed from the cell surface by metalloproteinases. Shedding of the beta-subunit releases the alpha-subunit from the DG complex on the cell surface into the extracellular space. The shedding is enhanced by IL-1beta and phorbol esters, and inhibited by metalloproteinase inhibitors. Deficiency of perlecan, a major ligand of alpha-DG, enhanced shedding suggesting that lack of a binding partner destabilizes the epithelial DG complex and makes it accessible to proteolytic processing.