At the center of our research is the mucosal immune system, in particular immune responses in the gut. More than 70% of the immune cells are located in the gastrointestinal tract and their proper function is essential to avoid inflammatory diseases, food allergies and infections. Thus, research on the gut immune system is of high relevance to human health and the development of new innovative strategies to cure human diseases.
The two organs, gut and liver, are closely linked in respect to ontogenesis, anatomy and function. This is reflected by many disease manifestations that affect both, gut and liver. Professor Oliver Pabst is the spokesperson of CRC1382 ‘Gut-Liver Axis. Functional Circuits and Therapeutic targets’, that is funded by DFG since 2019 and dedicated to explore the multifaceted interactions of gut and liver. All teams in our institute are significantly involved in projects of this collaborative research centre.
Flow cytometry is one of the core technologies that we use in a variety of experimental strategies for cell purification and analysis. Accordingly, we have a great deal of expertise in this field and the most modern technical equipment, which we are continuously developing further.
In 2017 we founded the Flow Cytometry Facility, FSF in short, to support other research projects at our medical faculty in the planning, execution and analysis of experiments based on flow cytometry using state-of-the-art, excellently maintained equipment. The FCF is currently the youngest service unit under the umbrella of the Interdisciplinary Centre for Clinical Research (IZKF). If you are interested, please visit our homepage.
The gut mucosa is constitutively exposed to foreign antigen in the form of food and the gut microbiota. These antigens are actively recognized by the gut immune system. Whereas encounter of pathogens has to initiate protective immune responses, the encounter of innocuous antigen has to trigger well-balanced tolerogenic immune responses. Failure to properly discriminate potentially harmful and harmless antigen can result in overshooting immune responses and manifests as food allergy or inflammatory bowel disease – pathologies that are markedly increasing in industrialized countries. We have established a multi-step model to describe the process of tolerance induction in the gut. This model serves as a framework to experimentally manipulate the balance between tolerance and immunity and eventually to identify cellular and molecular pathways that can be targeted to re-establish tolerance in patients.
Oral tolerance to food protein
On the road to tolerance--generation and migration of gut regulatory T cells.
Regulation of mucosal antibody responses
Day after day, gut plasma cells secrete several grams of immunoglobulin A (IgA) into the gut lumen. Hence, IgA is the most abundantly produced antibody type. IgA binds dietary components, pathogens and their toxins as well as the microbiota. We use next-generation-sequencing to investigate the factors shaping the intestinal IgA repertoire under homeostatic conditions and its adaption upon infection, inflammation or changes in diet and microbiota composition. This approach will allow us to understand how different pathways of IgA induction synergize to produce antibodies –knowledge which is critical for the development of oral vaccines and therapeutic manipulation of the gut microbiota.
Immune cell migration
Lymphocytes need guidance cues, i.e. a molecular address code, to reach their target organs via blood stream. Whereas the migration of immune cells from the blood into tissues and lymphoid organs is comparably well understood, we have little information on immune cell egress, i.e. their migration out of tissues and lymphoid organs into the lymphatic system. Inflammation and infection block exit of lymphocytes from lymph nodes into efferent lymphatics, resulting in the well-known phenomenon of lymph node swelling. This observation shows that immune cell exit into lymphatics, like immune cell migration from blood to tissues, is a regulated process. Our team investigates the molecular events that regulate the migration of immune cells in the gastrointestinal tract in the steady state as well as in case of inflammation or infection.
Hypertrophy of infected Peyer's patches arises from global, interferon-receptor, and CD69-independent shutdown of lymphocyte egress.
Dynamics of gastrointestinal infections
Secretory antibodies of the IgA isotype play a major role in mucosal immune responses. They are mainly found in secreted body fluids, such as saliva, tears, breast milk and gastrointestinal secretions. IgA binds to food components, pathogens and their toxins as well as to intestinal microbiota. The gut comprises the body’s largest population of IgA producing plasma cells. However, IgA-secreting plasma cells are also present in the liver where IgA is secreted into bile.
We will study the interrelation between hepatic and intestinal plasma cells. In particular, we will investigate the clonal relatedness of plasma cells in both organs. We will track B cell migration in vivo from inductive compartments into gut and liver and explore their microbiota-specificity. Moreover, the role of antibodies in shielding gut, liver and systemic compartments from disseminating microbiota and the contribution of biliary compared to gut-derived IgA will be investigated. Our findings will cast a comprehensive picture of how secretory antibodies regulate gut-liver interactions.
Pabst and Slack, IgA and the intestinal microbiota: the importance of being specific.
This project is funded by Deutsche Forschungsgemeinschaft (DFG) in the context of Collaborative research Centre 1382 ‚Gut-Liver Axis – Functional Circuits and Therapeutic Targets‘ (https://www.crc1382.org/).