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SFB 1160:  Immune-mediated pathology as a consequence of impaired immune reactions (IMPATH)

Subject Area Medicine
Biology
Term since 2015
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Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 256073931
 
Immunopathology is the basis of a variety of diseases and can affect any organ. Traditionally, it has been assumed that immunologically mediated diseases are caused by overactivity of the immune system and that immunosuppression is therefore the correct therapeutic principle. Paradoxically, however, immunopathology can also arise from impaired immune responses. This principle is very clearly illustrated by patients with congenital immunodeficiencies (PID) in whom specific genetic alterations cause impaired immune responses that lead to immunopathology. This “IMPATH paradox” has important implications. From a biological perspective, it may change our understanding of how the immune system works. From a clinical point of view, it becomes clear that immune stimulation or immune reconstitution can be important therapeutic approaches. The SFB wants to contribute to a better understanding of immunopathology that arises from impaired immune responses. In the first two funding periods it was shown that the "IMPATH paradox" represents a biologically important and clinically relevant principle. We were able to identify impaired immune responses as the cause of inflammatory responses in various disease models. This includes a disturbed T-cell effector function in viral hepatitis or PID, disturbed B-cell activation in autoimmune diseases or disturbed immune regulation in inflammatory bowel disease, severe pneumonia or GVHD. The close cooperation in the IMPATH consortium has also prepared us conceptually for the challenges of the SARS-CoV2 pandemic, which has led to a number of important research contributions. In the third funding period, we will continue to explore the mechanisms of impaired immune reactions and immune-mediated pathologies and use this knowledge for therapeutic approaches. In area A we want to understand genetic and antigen-induced mechanisms of impaired T cell cytotoxicity and T cell exhaustion and explore reversion or induction of T cell exhaustion as therapeutic principles. In area B we will analyze how B cell receptor activation is modulated by intrinsic and extrinsic factors and how this is causally related to autoantibody-mediated immunopathology. We will explore the mechanisms how the microbiome or a dysregulated metabolic milieu interacts with an immune system without CTLA4, CD8aa IELs or during GvHD and how the resulting immunopathology can be treated by protein substitution or metabolic interventions. In area C, we will unravel the genetic and molecular mechanisms of impaired viral control, inflammasome homeostasis and macrophage metabolic homeostasis leading to uncontrolled immune stimulation and evaluate therapeutic cytokines.
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Applicant Institution Albert-Ludwigs-Universität Freiburg
 
 

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