The role of cell type-specific type I interferon production in the pathogenesis of systemic autoimmunity

• Applicant: Professor Dr. Rayk Behrendt
• Subject Area: Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 493165053

Systemic lupus erythematosus (SLE) is a detrimental systemic autoimmune disease, which is associated with aberrant production of the antiviral cytokine type I interferon (IFN) and an unexplained lymphopenia, affecting the majority of patients. IFN-signaling protects cells from viral infections but it also potently activates antigen presenting cells like dendric cells (DCs). Recently, IFN has been shown to regulate various forms of programmed cell death (PCD). The individual contribution of these different effects of IFN signaling to the development of systemic autoimmunity remains to be fully established. We generated a mouse model that allows for conditional expression of murine Ifna4 from the Rosa26 safe harbor locus. Ubiquitous and epidermis-specific activation resulted in embryonic death at different developmental stages. Conditional activation of Ifna4 expression in dendritic cells caused lethal systemic autoimmunity. Surprisingly, conditional activation of IFN expression in B cells did not cause disease up to 80 weeks of age. These data suggest that the level of pathogenicity of caused by IFN depends on the IFN producing cell type. Despite the chronic immune activation, we observed lymphopenia in our mice, with the IFN-producing cell type being severely reduced. The latter finding might indicate an increased frequency of IFN-induced programmed cell death. We want to investigate why DC-derived IFN but not B cell-derived IFN causes disease. Furthermore, we will investigate the mode and role of cell death induced by IFN-signaling in embryonic lethality and in the pathogenesis of systemic autoimmunity. Our project will address a so far unrecognized role of the cellular source of IFN as well it´s consequences and mechanisms that contribute to the development of systemic autoimmunity. We believe that our project could reveal an important mechanistical link between IFN production, cell death and lymphopenia in the context of systemic autoimmunity.

• DFG Programme: Research Grants
• International Connection: United Kingdom
• Cooperation Partner: Professor Dr. David Hunt