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Nucleic acid-driven immunopathology

Cellular and molecular mechanisms of nucleic acid recognition in ANCA-associated pulmonary vasculitis (B16)



Project leaders: Prof. Natalio Garbi and Dr. Lino Teichmann 


Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of life-threatening autoimmune diseases that can affect multiple organs. Using a novel model of pulmonary AAV established in our laboratory, we have identified the STING signaling pathway to be critical in disease development, indicating a principal role for nucleic acid detection. The goal of our study is to delineate how nucleic acid recognition via the STING axis and other nucleic acid sensing pathways promotes disease, define the immune cell subsets that contribute to AAV and elucidate the mechanism by which microbial products and ANCAs synergize in the activation nucleic acid sensors. 

Mechanisms of pathogenic activation of cytosolic nucleic acid sensors and type I IFN responses by endogenous nucleic acids (B17)



Project leader: Prof. Axel Roers


One cause of aberrant type I interferon (IFN) production in Aicardi-Goutières syndrome and Lupus is loss of cytosolic 3’ repair exonuclease 1 (TREX1), which leads to chronic activation of the cytosolic DNA sensor cGAS. To identify the source and nature of the unknown ligand triggering cGAS in TREX1-deficient cells, we will define conditions under which TREX1-/- cells produce IFN and assess whether their IFN response depends on cell cycle, mitosis or senescence. We will determine whether active DNA repair or genome instability are prerequisites for IFN release by TREX1-/- cells and we will screen for genes that are essential for the IFN response in the absence of TREX1.

Perturbed type I interferon responses in pediatric autoinflammatory disease with vascular inflammation (B18)



Project leader: Prof. Angela Rösen Wolff


Type I interferonopathies are often associated with vasculitis. Activating mutations in STING, a key adapter in cGAS-dependent cytosolic DNA sensing, were shown to cause a lethal condition characterized by severe systemic vasculitis (STING-associated vasculopathy with onset in infancy; SAVI). We introduced a SAVI-associated mutation into the locus encoding STING in mice, tmem173, and found that these tmem173N153S knock-in animals strikingly recapitulate key features of the human disease. The aim of the present project is to answer the questions, which cytokines mediate vascular pathology, which proinflammatory factors contribute in addition to type I IFN, and which cell types play a role in vasculitis induced by uncontrolled activity of STING. In addition, we want to study if pathology resulting from constitutive STING activation can be treated by inhibition of individual cytokines or their signaling or by bone marrow transplantation.

The role of SAMHD1 in controlling the innate immune response to endogenous nucleic acids (B19)



Project leader: Dr. Rayk Behrendt 


SAMHD1 is a deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase (dNTPase), which degrades cellular dNTPs into nucleosides and inorganic triphosphate in a cell cycle-dependent manner. Deficiency for SAMHD1 is associated with systemic autoimmunity and cancer. On a molecular level, loss of SAMHD1 causes a spontaneous activation of the type I IFN System and DNA damage by so far unknown mechanisms. We aim to investigate how alterations in the dNTP levels caused by loss of SAMHD1 affect the intracellular nucleic acid sensing pathways, how this causes genome instability, whether this leads to an increased mutation rate and which mechanisms control the mutational burden in SAMHD1-deficient cells. Finally, we ask whether the loss of SAMHD1 is sufficient to cause neoplastic transformation.

Intracellular nucleic acid sensing as a trigger of type I interferon-driven autoimmunity affecting muscle and skin (B20)



Project leader: Prof. Claudia Günther 


Type I interferon (IFN)-driven autoimmunity can be induced by inappropriate activation of intracellular innate immune nucleic acid sensor pathways. This novel pathogenic principle is relevant in an expanding spectrum of diseases. Our project focuses on two conditions in which muscle and skin are affected. We will analyze the molecular pathway leading from repeat expansion mutations to autoimmunity in patients with myotonic dystrophy and will investigate the role of cell-intrinsic innate nucleic acid sensing in the pathogenesis of the autoimmune disease dermatomyositis.

Phenotypic and genetic dissection of type I interferonopathies (B21)



Project leader: Prof. Min Ae Lee-Kirsch


The prototypic type I interferonopathy is Aicardi-Goutières syndrome, an infancy-onset inflammatory encephalopathy causing severe neurological impairment. Understanding the mechanisms leading to neurodegeneration will be important for the development of specific therapeutic approaches. We want to establish neuronal cells from patient-derived reprogrammed induced pluripotent stem cells to investigate the consequences of constitutive type I IFN activation in a cell type-specific manner. In addition, we want to characterize novel genetic causes underlying type I IFN-driven autoinflammation and autoimmunity. 

Characterization of autoimmune disorders in a RIG-I mutant mouse model (B22)



Project leader: Prof. Hiroki Kato 


Singleton Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, glaucoma, osteoporosis and psoriasis, and no fundamental treatment is currently available. Recently gain-of-function mutations in DDX58 encoding human RIG-I, a cytoplasmic viral RNA sensor have been discovered in SMS patients; however, the mechanism by which the constitutively active RIG-I mutants cause the pathogenesis of SMS remains to be clarified. Generating mice expressing SMS-related RIG-I mutant protein, we herein aim to elucidate the mechanisms of SMS onset and development, to establish effective treatments targeting the RIG-I-mediated signaling pathway, and finally to determine environmental and behavioral risk factors driving the onset SMS pathologies.



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