Pathophysiological relevance of Type III in Systemic Lupus Erythematosus - significance and differences to Type I interferons

• Applicant: Professorin Dr. Julia Weinmann-Menke
• Subject Area: Nephrology ; Rheumatology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 466417194

In the systemic autoimmune disease SLE is the renal manifestation especially serious, since it highly impacts the mortality of affected patients. No specific therapeutics are approved for LN; instead it is treated with immunosuppressors, that cause a variety of unwanted side effects. Hence, the development of new therapeutic approaches are urgent needed.The type III Interferon system – next to the type I Interferon system – could be such an approach: Both are expressed as early mediators after pattern recognition receptors are activated by nucleic acids. This occurs not only in viral infection but possibly during autoimmune diseases – this is indicated by the strongly enhanced expression of ANAs (Antinuclear Autoantibodies) and the described interferon signature in PBLs of SLE patients. While the type I IFN-receptor is expressed universally, the type III IFN-receptor expression seems to be restricted to epithelial cells. Hence, their influence could be more restricted. Which could be an advantage for a LN therapeutic approach, since unwanted side effects like susceptibility to infectious diseases could be minimized.In preliminary studies, we observed the functional expression of the type III IFN-receptor on renal tubular epithelial cells. Type III IFNs could induce the expression of proinflammatory mediators in TEC and thus promote the chronic inflammation during LN. Furthermore, we could observe an accelerated Type III IFN expression with increasing LN disease activity in kidneys and secondary lymphoid organs in lupus prone MRL Faslpr mice – correlating with the expression of type I IFNs.In this project we aim to determine the functional role of type III IFN signaling in LN with MRL Faslpr Type III IFN-receptor KO mice, and compare those to type I IFN-receptor KO MRL Faslpr mice. The distinct influence of each IFNR Knockout on the cytokine and chemokine milieu will be determined. The next step is to transfer the knowledge obtained in the murine model to human SLE: we aim to determine the type III IFN expression in kidney biopsies of LN patients on RNA and Protein level. Additionally, we want to determine the role of type III IFNs in the communication of renal TEC with kidney infiltrating immune cells in vitro. Diverse manifestations of SLE (LN, discoid Lupus, cardiovascular manifestation) could be affected by either type I and/or type III IFNs in a unique manner – to determine which interferon promotes which manifestation is an additional goal. Thus, type III IFNs shall be evaluated as potential disease activity markers for SLE and as a new therapeutic approach.

• DFG Programme: Research Grants