Innate Lymphoid Cells as Regulators of Epithelial Integrity: Therapeutic Implications for Inflammatory Bowel Diseases

The occurrence of epithelial defects in the gut relevantly contributes to the pathogenesis of inflammatory bowel diseases (IBD), whereby the impairment of intestinal epithelial barrier integrity seems to represent a primary trigger as well as a disease amplifying consequence of the chronic inflammatory process. Besides epithelial cell intrinsic factors, accumulated and overwhelmingly activated immune cells and their secretome have been identified as critical modulators of the pathologically altered intestinal epithelial cell (IEC) function in IBD. In this context, over the last 10 years increasing levels of attention have been paid to the group of innate lymphoid cells (ILCs). This is in particular due to a preferential location of these rather newly described innate immune cells in close proximity to mucosal barriers, their profound capacity to secrete effector cytokines and their numerical and functional alteration under chronic inflammatory conditions. Aiming on a comprehensive and updated summary of our current understanding of the bidirectional mucosal crosstalk between ILCs and IECs, this review article will in particular focus on the potential capacity of gut infiltrating type-1, type-2, and type-3 helper ILCs (ILC1s, ILC2s, and ILC3s, respectively) to impact on the survival, differentiation, and barrier function of IECs. Based on data acquired in IBD patients or in experimental models of colitis, we will discuss whether the different ILC subgroups could serve as potential therapeutic targets for maintenance of epithelial integrity and/or mucosal healing in IBD

Regulation of Human Innate Lymphoid Cells in the Context of Mucosal Inflammation

Since their identification as a unique cell population, innate lymphoid cells (ILCs) have revolutionized our understanding of immune responses, leaving their impact on multiple inflammatory and fibrotic pathologies without doubt. Thus, a tightly controlled regulation of local ILC numbers and their activity is of crucial importance. Even though this has been extensively studied in murine ILCs in the last few years, our knowledge of human ILCs is still lagging behind. Our review article will therefore summarize recent insights into the function of human ILCs and will particularly focus on their regulation under inflammatory conditions. The quality and intensity of ILC involvement into local immune responses at mucosal sites of the human body can potentially be modulated via three different axes: (1) activation of tissue-resident mature ILCs, (2) plasticity and local transdifferentiation of specific ILC subsets, and (3) tissue migration and accumulation of peripheral ILCs. Despite a still ongoing scientific effort in this field, already existing data on the fate of human ILCs under different pathologic conditions clearly indicate that all three of these mechanisms are of relevance for the clinical course of chronic inflammatory and autoimmune diseases and might likewise provide new target structures for future therapeutic strategies

Functional Contribution and Targeted Migration of Group-2 Innate Lymphoid Cells in Inflammatory Lung Diseases: Being at the Right Place at the Right Time

During the last decade, group-2 innate lymphoid cells (ILC2s) have been discovered and successfully established as crucial mediators of lung allergy, airway inflammation and fibrosis, thus affecting the pathogenesis and clinical course of many respiratory diseases, like for instance asthma, cystic fibrosis and chronic rhinosinusitis. As an important regulatory component in this context, the local pulmonary milieu at inflammatory tissue sites does not only determine the activation status of lung-infiltrating ILC2s, but also influences their motility and migratory behavior. In general, many data collected in recent murine and human studies argued against the former concept of a very strict tissue residency of innate lymphoid cells (ILCs) and instead pointed to a context-dependent homing capacity of peripheral blood ILC precursors and the inflammation-dependent capacity of specific ILC subsets for interorgan trafficking. In this review article, we provide a comprehensive overview of the so far described molecular mechanisms underlying the pulmonary migration of ILC2s and thereby the numeric regulation of local ILC2 pools at inflamed or fibrotic pulmonary tissue sites and discuss their potential to serve as innovative therapeutic targets in the treatment of inflammatory lung diseases

Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD)

Peer reviewedPublisher PD

Charakterisierung zirkulierender Typ 2 angeborener lymphoider Zellen bei der Lungenerkrankung von Patienten mit zystischer Fibrose

Standing out from classical type-2 T helper cells by their rapid, antigen-independent activation, type-2 innate lymphoid cells (ILC2s) have emerged as key immunological orchestrators of pulmonary inflammation and fibrosis in the last decade. However, their functional involvement in cystic fibrosis (CF)-associated lung disease is still largely unknown, although this progressive, terminal fibro-inflammatory disorder is characterized by an often underappreciated type-2 inflammatory milieu as well. Thus, we investigated the functional relevance of human ILC2s in CF lung disease. In addition, the general role of circulating blood ILC2s has been scrutinized only insufficiently so far. Since, however, frequency and phenotype of blood ILC2s are known to be significantly altered in patients with local fibro-inflammatory diseases, we hypothesized the targeted homing of blood ILC2s to the inflamed lung tissue in CF patients to influence disease progression locally. By the flow cytometric analysis of human blood samples, our data revealed a significantly decreased number of CCR6+ blood ILC2s in CF patients compared to control subjects, which significantly correlated with an advanced pulmonary disease severity. Together with the published finding of drastically increased levels of the CCR6 ligand CCL20 in CF airways, this implied a CCR6-driven lung homing pathway of blood ILC2s in CF, which was further supported by functional chemotaxis assays and a newly established humanized mouse model. In the latter, the pulmonary accumulation of patient-derived and ex vivo expanded blood ILC2s was visualized in the context of the inflamed lung tissue via light-sheet fluorescence microscopy. By the intranasal administration of recombinant human CCL20 in this model, CCL20 was identified as chemotactic stimulus for lung-directed ILC2 migration in vivo. Together with in vitro data, showing the suppression of the ILC2 transmigration towards a CCL20 gradient by a CCR6-blocking antibody, this could further affirm ILC2 lung homing in a CCR6-CCL20-dependent manner. Locally, blood-derived ILC2s triggered the pulmonary accumulation of neutrophils and eosinophils and directly promoted remodeling of the inflamed lung tissue by inducing collagen VI expression in vitro and in vivo. Using primary human lung fibroblasts, the additive effect of ILC2-derived IL-4 and IL-13 was determined as important mediator of this phenomenon. Likewise, increased collagen VI levels were detected in pulmonary fibroblasts derived from a CF patient compared to a control subject when reevaluating a published RNA sequencing dataset. Although ILC2s could be demonstrated to express the CFTR gene, which carries the disease-causing mutations in CF, ILC2s derived from CF patients proved to be functionally competent with regard to their general lung homing capacity and the release of effector cytokines. Our data thus suggest lung homing, blood-derived ILC2s as relevant disease drivers in CF lung disease. Collectively, we identified circulating human blood ILC2s as cellular reservoir, enabling the adaption of local ILC2 pools on demand by the targeted homing of peripheral blood ILC2s. In CF, we propose the CCL20-driven recruitment of CCR6+ blood ILC2s to the inflamed lung tissue to trigger pulmonary inflammation and fibrosis, suggesting lung homing blood ILC2s and their local effector functions as innovative therapeutic targets for the treatment of the chronically inflamed lung in CF patients.Typ 2 angeborene lymphoide Zellen (ILC2s, engl. type-2 innate lymphoid cells) zeichnen sich durch ihre schnelle, Antigen-unabhängige Aktivierung aus und heben sich dadurch von klassischen Typ 2 T-Helferzellen ab. Im letzten Jahrzehnt konnte ihre zentrale Schlüsselrolle in der Regulierung entzündlicher und fibrotischer Erkrankungen, insbesondere der Lunge, eindrucksvoll beschrieben werden. Ihr funktioneller Einfluss auf den Krankheitsverlauf der zystischen Fibrose (CF, engl. cystic fibrosis) ist jedoch noch weitgehend ungeklärt, obwohl Patienten mit CF unter anderem auch an einer fortschreitenden und meist tödlich verlaufenden Lungenerkrankung leiden, die von entzündlichen und fibrotischen Umbauprozessen sowie einer oftmals wenig beachteten Typ 2 Immunantwort geprägt ist. Darauf basierend wurde in dieser Studie untersucht, ob ILC2s auch bei der chronischen Lungenerkrankung von CF Patienten eine Rolle spielen. Zudem ist die grundsätzliche Funktion von ILC2s im peripheren Blut bisher nur unzureichend analysiert worden. Da jedoch bekannt ist, dass sowohl der Anteil der im Blut zirkulierenden ILC2s als auch ihr Phänotyp in Patienten mit entzündlichen und fibrotischen Erkrankungen maßgeblich verändert sind, befasste sich diese Arbeit mit der Frage, ob ILC2s aus dem peripheren Blutstrom gezielt in das entzündete Lungengewebe von CF Patienten einwandern und so direkt Einfluss auf den lokalen Krankheitsverlauf nehmen können. Mit Hilfe durchflusszytometrischer Analysen von humanen Blutzellen konnte gezeigt werden, dass die Anzahl der CCR6+ ILC2s im peripheren Blut von CF Patienten verglichen mit gesunden Kontrollprobanden signifikant reduziert war und dass dies mit der Progression der Lungenerkrankung korrelierte. Zusammen mit den massiv erhöhten Spiegeln des CCR6 Liganden CCL20, die bereits in den Atemwegen von CF Patienten beschrieben wurden, könnte diese Beobachtung auf die CCR6-vermittelte Auswanderung der ILC2s aus dem Blutstrom in das entzündete Lungengewebe von CF Patienten hindeuten. Die funktionelle Bestätigung dessen erfolgte mittels Chemotaxis-Analysen sowie eines eigens etablierten humanisierten Mausmodells. Letzteres ermöglichte die Analyse der Akkumulation patienteneigener ILC2s direkt im entzündeten Lungengewebe. Dazu wurden humane ILC2s aus dem Blut isoliert, ex vivo expandiert und ihre Akkumulation in der entzündeten Lunge mit Hilfe der Lichtblatt-Fluoreszenzmikroskopie visualisiert. Mittels intranasaler Verabreichung von rekombinant hergestelltem humanem CCL20 in diesem Modellsystem konnte CCL20 in vivo als chemotaktischer Stimulus für die gezielte Einwanderung humaner ILC2s in die Lunge identifiziert werden. Zusammen mit in vitro Daten, welche die Hemmung der ILC2 Migration in Richtung eines CCL20 Gradienten durch einen CCR6 Block zeigten, erhärtete dies die Hypothese einer CCR6-CCL20-vermittelten Auswanderung von ILC2s aus dem Blut in die Lunge. In der entzündeten Lunge induzierten diese ursprünglich aus dem Blut stammenden ILC2s die Anreicherung neutrophiler und eosinophiler Granulozyten und trieben zudem direkt den Gewebsumbau voran. Dies äußerte sich in einer vermehrten Kollagen VI Expression sowohl in vivo als auch in vitro. Mit Hilfe primärer menschlicher Lungenfibroblasten konnte die additive Wirkung von IL-4 und IL-13, die beide von ILC2s sezerniert wurden, als Vermittler dieser Kollagen VI-induzierenden Wirkung bestimmt werden. In Übereinstimmung damit wurden bei der Neuauswertung eines bereits veröffentlichten RNA-Sequenzierungsdatensatzes auch in Lungenfibroblasten, die aus einem CF Patienten stammten, erhöhte Kollagen VI Spiegel im Vergleich zu Fibroblasten eines gesunden Kontrollprobanden gemessen. Obwohl wir zeigen konnten, dass auch ILC2s das CFTR Gen exprimieren, das die für CF ursächlichen Mutationen trägt, erwiesen sich ILC2s von CF Patienten im Hinblick auf ihre grundsätzliche Fähigkeit gezielt in die entzündete Lunge einzuwandern sowie Effektorzytokine auszuschütten als uneingeschränkt funktionsfähig. Unsere Daten deuten daher darauf hin, dass ILC2s, die aus dem peripheren Blutstrom gezielt in das entzündete Lungengewebe einwandern, maßgeblich die Lungenerkrankung in CF Patienten vorantreiben. Zusammenfassend konnte diese Arbeit zeigen, dass humane ILC2s im Blut als zelluläres Revervoir dienen, das es erlaubt, gewebsständige ILC2 Populationen durch die gezielte Rekrutierung von zirkulierenden ILC2s an den akuten Bedarf anzupassen. Im Fall von CF konnte CCL20 als chemotaktischer Faktor identifiziert werden, der die pulmonale Anreicherung von CCR6+ ILC2s aus dem Blutstrom fördert, um so entzündliche wie auch fibrotische Prozesse in der Lunge anzustoßen. Die Einwanderung von ILC2s aus dem peripheren Blut sowie deren Effektorfunktionen könnten demnach als neue therapeutische Zielstrukturen dienen und so eine innovative Behandlungsmöglichkeit für die chronisch überschießenden Immunreaktionen in der Lunge von CF Patienten ermöglichen

Twelve-Month and Lifetime Prevalence of Mental Disorders in Cancer Patients

Background: Psychological problems are common in cancer patients. For the purpose of planning psycho-oncological interventions and services tailored to the specific needs of different cancer patient populations, it is necessary to know to what extent psychological problems meet the criteria of mental disorders. The purpose of this study was to estimate the 12-month and lifetime prevalence rates of mental disorders in cancer patients. Methods: A representative sample of patients with different tumour entities and tumour stages (n = 2,141) in outpatient, inpatient and rehabilitation settings underwent the standardized computer-assisted Composite International Diagnostic Interview for mental disorders adapted for cancer patients (CIDI-O). Results: The overall 12-month prevalence for any mental disorder was 39.4% (95% CI: 37.3–41.5), that for anxiety disorders was 15.8% (95% CI: 14.4–17.4), 12.5% (95% CI: 11.3–14.0) for mood disorders, 9.5% (95% CI: 8.3–10.9) for somatoform disorders, 7.3% (95% CI: 6.2–8.5) for nicotine dependence, 3.7% (95% CI: 3.0–4.6) for disorders due to general medical condition, and 1.1% (95% CI: 0.7–1.6) for alcohol abuse or dependence. Lifetime prevalence for any mental disorder was 56.3% (95% CI 54.1–58.6), that for anxiety disorders was 24.1% (95% CI: 22.3–25.9), 20.5% (95% CI: 18.9–22.3) for mood disorders, 19.9% (95% CI: 18.3–21.7) for somatoform disorders, 18.2% (95% CI: 16.6–20.0) for nicotine dependence, 6.4% (95% CI: 5.4–7.6) for alcohol abuse or dependence, 4.6% (95% CI: 3.8–5.6) for disorders due to general medical condition, and 0.2% (95% CI: 0.1–0.6) for eating disorders. Conclusions: Mental disorders are highly prevalent in cancer patients, indicating the need for provision of continuous psycho-oncological support from inpatient to outpatient care, leading to an appropriate allocation of direct personnel and other resources