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DFG

1. Graduiertenkolleg 2633 „Definition und gezielte Intervention bei Prädisposition zur Entwicklung von Autoimmunerkrankungen“

Förderzeitraum: 10.2021 - 09.2024

Projekt A5: Chronic danger signaling as driver of autoimmunity in granulomatosis with polyangiitis (GPA)

Principle Investigator: Peter Lamprecht
Young associated scientist: Anja Kerstein-Stähle
Doctoral candidate: n.n.

Break of tolerance is the fundamental step in development of autoimmune diseases. Dysregulation of cell death accompanied by excessive release of danger associated molecular patterns (DAMP) contributes to the break of tolerance. DAMP act as endogenous adjuvants perpetuating self-reactivity, chronic, non-resolving inflammation and subsequent tissue damage. In GPA, which is characterized by chronic granulomatous inflammation and systemic autoimmune vasculitis, we showed inflammation- and pathogen-driven alterations of the adaptive immune response. Moreover, we demonstrated (i) anomalous expression of the autoantigen proteinase 3 (PR3) and dysregulation of neutrophil cell death that contributes to non-resolving inflammation, and (ii) cell death-related release of two prototypic DAMP (HMGB1, IL-33) that contributed to receptor-mediated pro-inflammatory responses within the inflamed tissue in GPA. A causal link between persistent danger signaling and loss of tolerance against PR3 in GPA has to be proven yet.

Research aims of the project:
(i) Characterization of molecular patterns involved in danger signaling in GPA.
(ii) Analysis of the adjuvant function of DAMP (e.g. HMGB1) and their interaction with PR3 in the induction of inflammation and autoimmunity by in vitro and in vivo experiments.

Projekt A6: T cell memory differentiation in early autoimmune disease

Principle Investigator: Gabriela Riemekasten
Young associated scientist: Jens Humrich
Doctoral candidate: n.n.

Chronic T cell activation and memory differentiation contribute essentially to the perpetuation of ongoing autoimmune processes by diverse mechanisms . Apart from this, chronically activated memory T cells can shut down synthesis of IL-2 which promotes Treg defects and which in turn facilitates tolerance breakdown. However, little is known about the factors which drive memory formation and chronicity in an early stage of autoimmune disease when clinical symptoms are still unapparent. In the (NZBxNZW) F1 mouse model of lupus, signs of increased T cell activation and memory differentiation are detectable in lymphoid tissues long before the development of organ manifestations and even before the generation of autoantibodies, proposing that aberrant T cell activation is an early event in autoimmunity. In addition, Treg from these mice are in a highly activated state suggesting that active counter-regulation is already taking place at this early stage of disease

Research aims of the project:
(i) To understand the mechanisms of T cell memory differentiation and their escape from immune-regulation in early murine lupus.
(ii) To explore when and how chronically activated T cells shut down IL-2 synthesis as a major event in the breakdown of tolerance.

Webseite des GRK

 

2. Haupthistokompatibilitätskomplex-Peptidom bei Granulomatose mit Polyangiitis

Förderzeitraum: 2021-2023, DFG Sachbeihilfe

Antragsteller: Peter Lamprecht

 

3. Generierung und Charakterisierung eines Antikörper-basierten Mausmodells für die systemische Sklerose

Förderzeitraum: ab 2015, DFG Sachbeihilfe

Antragstellerin: Gabriela Riemekasten