SFB 1160:
Immune-mediated pathology as a consequence of impaired immune reactions (IMPATH)
Subject Area
Medicine
Biology
Term
since 2015
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.
DFG Programme
Collaborative Research Centres
Current projects
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A01 - Genetic defects impairing lymphocyte cytotoxicity: causes and consequences
(Project Heads
Aichele, Peter
;
Ehl, Stephan
)
-
A02 - Diverging mechanisms of antigen-specific CD8+ T cell dysfunction result in protective versus pathogenic responses in chronic hepatitis B virus infection
(Project Heads
Hofmann, Maike
;
Thimme, Robert
)
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A03 - Pathogenic instruction of CD8 T cell differentiation in Crohn’s disease
(Project Head
Bengsch, Ph.D., Bertram
)
-
A06 - Mechanisms of hepatitis E virus persistence and immunopathology in immunocompromised patients
(Project Head
Neumann-Haefelin, Christoph
)
-
A08 - Lymphoproliferative disease resulting from impaired deletion of FAS controlled T cells.
(Project Heads
Maccari, Maria Elena
;
Rensing-Ehl, Anne Katharina
)
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B01 - Caveolin-1 and Filamin A: a novel mechanistic axis regulating B cell responses and immunopathology
(Project Head
Minguet, Ph.D., Susana
)
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B02 - Autoimmunity because of defective B cell fate decisions in autoimmune lymphoproliferative syndrome
(Project Head
Rizzi, Marta
)
-
B03 - Immune-mediated pathology as a consequence of impaired lymphocyte-extracellular matrix interactions
(Project Heads
Kiritsi, Dimitra
;
Nyström, Alexander
)
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B05 - Studying the intestinal microbiome as a driver for immune pathology in CTLA4-insufficient individuals and mice
(Project Head
Grimbacher, Bodo
)
-
B08 - Bi-directional communication between intraepithelial lymphocytes and epithelial cells to maintain intestinal barrier integrity
(Project Heads
Sagar, Sagar
;
Tanriver, Yakup
)
-
B09 - Overcoming intestinal immune dysregulation by metabolic modification during acute graft-versus-host disease
(Project Heads
Köhler, Natalie
;
Zeiser, Robert
)
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B10 - Impact of wild-type intestinal microbiome on impaired immune regulation during acute graft-versus-host disease
(Project Heads
Rosshart, Stephan Patrick
;
Zeiser, Robert
)
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C01 - Immunopathology resulting from lack of early control of influenza virus infection by interferon-induced Mx proteins: causes and consequences
(Project Heads
Graf, Laura
;
Schwemmle, Martin
)
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C02 - GM-CSF-induced impairment of macrophage homeostasis resulting in lung immunopathology
(Project Head
Groß, Olaf
)
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C03 - Mapping cellular interactions of human tissue macrophages during health and immune-mediated pathology by spatial proteogenomics
(Project Head
Prinz, Marco
)
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C05 - Ctsd-deficiency in macrophages links lysosomal dysfunction to immune-mediated pathology across different organs
(Project Head
Kierdorf, Katrin
)
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C06 - Macrophage dysregulation as cause of chronic inflammation in NADPH oxidase deficiency
(Project Head
Henneke, Philipp
)
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INF - Research data management
(Project Head
Binder, Harald
)
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Z01 - Immunopathology Unit
(Project Heads
Bengsch, Ph.D., Bertram
;
Schell, Ph.D., Christoph B.
)
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Z02 - Bioinformatics Core
(Project Heads
Börries, Melanie
;
Sagar, Sagar
)
-
Z03 - Central Tasks
(Project Head
Ehl, Stephan
)
Completed projects
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A04 - Tipping the balance: Immune-mediated pathologies in CVID enteropathy
(Project Heads
Grimbacher, Bodo
;
Warnatz, Klaus
)
-
A07 - A preclinical therapeutic gene editing protocol to restore cytotoxic T cell function in acute haemophagocytic lymphohistiocytosis
(Project Heads
Aichele, Peter
;
Cathomen, Toni
;
Ehl, Stephan
)
-
B04 - The role of the CD4 T cell compartment in modulating HLH progression
(Project Head
Aichele, Peter
)
-
B07 - Molecular basis for the generation of a self-tolerant TCR repertoire
(Project Head
Boehm, Thomas
)
-
C04 - Metabolic regulation of macrophage activation in haemophagocytic lymphohistiocytosis (HLH)
(Project Head
Pearce, Ph.D., Edward
)
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P03 - Role of B cells in virus-induced T cell-mediated immunopathology
(Project Head
Pircher, Hanspeter
)
-
P12 - Impaired phagocyte function in the immunopathogenesis of systemic lupus erythematosus (SLE): Etiology and therapeutic intervention
(Project Heads
Triantafyllopoulou, Antigoni
;
Voll, Reinhard
)
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P15 - Impaired T cell cross-talk in infection-associated immunopathology
(Project Head
Rohr, Jan
)
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P16 - Somatic diversification of a transgenic TCR to enhance antiviral immunity and prevent immunopathology
(Project Head
Boehm, Thomas
)
-
Z02 - Central Tasks
(Project Head
Ehl, Stephan
)