Inflammatory lung diseases in childhood
Cystic fibrosis (CF) is the most common monogenetically inherited inflammatory lung disease. About every 2000th newborn child in Germany suffers from this disease. This makes CF a "common" rare disease. Although the treatment of CF is a unique success story of modern medicine, it is still associated with reduced life expectancy and a very high therapy effort.
In the CF airways, the secretion is more viscous than in healthy individuals. Therefore, the respiratory secretion cannot sufficiently fulfill its role to protect against infections. Recurrent infections and chronic colonization with bacteria occur, accompanied by neutrophilic inflammation with progressive lung damage. A typical feature of the CF inflammatory response is the greatly increased production of certain messenger substances, cytokines, such as IL-1, IL-6, TNF-α and IL-17A, which have a pro-inflammatory effect. These cytokines or the signaling pathways triggered by them could represent promising targets for new therapeutic approaches in CF patients, for example.
Innate lymphoid cells (ILCs) localized in the airway mucosa play a critical role in the first line of defense against lung pathogens by producing pro-inflammatory cytokines in response to airway epithelial signals. We have recently shown that ILCs in human CF lungs produce the pro-inflammatory cytokine IL17A. In a murine model of CF-like lung disease, we found that neutrophilic inflammation is reduced in the absence of ILCs and IL17 (see publications). We therefore hypothesize that ILCs and cytokines produced by ILC, such as IL-17A, may represent critical determinants of lung inflammation in CF.
In our project in the DFG priority program SPP 1937, we aim to understand the contribution of ILCs and ILC-produced cytokines to the pathogenesis of CF. To this end, we are investigating the composition, phenotype and function of ILCs in lung tissue from human CF patients and in a mouse model of CF-like disease (bENaC mice) using advanced deep phenotyping methods such as chip cytometry and RNA sequencing. In addition, we are exploring targets for potential therapeutic interventions based on our findings on the role of ILCs in chronic inflammation.
We conduct a variety of local, national and international studies at our CF center. National studies are mainly embedded in the network of the German Center for Lung Research (DZL), international studies in the European CF study network ECFS-CTN or the pediatric study network conect4children (c4c). In many of these studies, specific questions from us at the Hannover site are integrated.
Within the DZL, we have gained a high expertise in complex endpoints for lung disease in cystic fibrosis, such as washout lung functions (MBW) and MRI examinations of the lung, which we perform in our clinical study center and in collaboration with our colleagues from radiology. We also work closely with Prof. Tümmler's group by contributing clinical expertise to understand airway microbiology, electrophysiology and genetics in patients with CF (see publications).
Through our many years of clinical work with CF patients, we have long-term histories and biomaterial collections that have been collected over many years. These data collections allow us to investigate a wide range of clinical questions on various aspects of CF disease progression.
Asthma and allergies are the most common chronic diseases in childhood, often accompanying children throughout their lives. In the vast majority of cases, childhood asthma is allergic asthma, i.e. allergies to inhalable environmental components, so-called allergens, such as pollen, animal hair or dust mites trigger the asthma symptoms.
In the vast majority of cases, asthma can be treated so well with anti-inflammatory drugs that the affected children can lead a largely unaffected life. However, there are still severe courses of the disease that cannot be "adjusted" well with medication. Preventive approaches against the development of allergic asthma do not yet exist.
Cells of the immune system, especially so-called T cells, play a prominent role in the development and maintenance of allergic asthma, as they produce cytokines that trigger the airway inflammation in asthma. More recently, ILCs have also been shown to play a role in the early phase of the disease, but their precise contribution has been less studied.
In addition, IgE-type antibodies directed against allergens play a special role in allergic asthma. They signal cells of the immune system to release messenger substances that trigger inflammation in the airways. The earlier in life such antibodies are formed, the higher the risk of a child developing permanent bronchial asthma. Moreover, the more such antibodies are formed against different allergens, the higher the risk of a severe course. In this context, each antibody response (=sensitization) increases the risk of developing further sensitizations, which can lead to a so-called polysensitization, a phenomenon that is not yet well understood.
In the past, we have developed various mouse models to study the phenomenon of polysensitization and were able to use these models to highlight the critical involvement of different cytokines and cells (see publications) . In the DFG priority program SPP 1937 we are currently investigating the role of ILCs in the development of an allergic complication of CF lung disease, allergic bronchopulmonary aspergillosis, to understand the role of secretion in the development of allergic immune responses.
Within the DZL we have established an asthma cohort over the past 10 years, which now includes more than 1000 subjects between 6 months and >60 years of age, who are followed up annually. Our focus is on the investigation of different inflammatory (bio-)markers (see publications). especially in young children, to understand how disease symptoms become chronic and what role (airway) inflammation plays in this process. Another focus is the investigation of antibody responses against classical allergens and pathogens, i.e. viruses and bacteria. We try to identify similarities and differences of these antibody responses in different lung diseases in order to understand whether modulation of these antibody responses can influence the development of allergies and asthma.