Development of antiphosholipid antibodies in the context of autoimmune diseases and viral infections

• Applicant: Privatdozentin Dr. Nadine Müller-Calleja
• Subject Area: Immunology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 547555931

Antiphospholipid antibodies (aPL) are considered to trigger antiphospholipid syndrome (APS), an autoimmune disease characterized by thrombosis and abortion. aPL may be directed against phospholipids or phospholipid-binding proteins, particularly ß2-glycoprotein I. In contrast to their pathogenetic role, little is known about the mechanisms leading to the development and persistence of aPL. Interestingly, aPL occur not only in the context of autoimmune diseases but also in the context of infections. In contrast to APS, aPL that occur in the context of infections are usually only transiently detectable and disappear when the infection resolves. To date, infection-associated aPL are thought to be directed against phospholipids and not against phospholipid-binding proteins. Until now, there is no explanation for this apparent difference in the development of autoimmune and infection-associated aPL. By elucidating the signal transduction of lipid-binding aPL and demonstrating their role in autoimmunity, we have created the basis for the project on the development of aPL proposed here. In our project we want to address three specific questions: (1) We are particularly interested in the time course of aP: development and the question of whether there are differences between autoimmune and infection-associated aPL formation. (2) The detection of aPL and the characterization of aPL-secreting B cells will be followed by a detailed analysis of the binding properties of aPL including the sequencing of the variable regions of the respective antibodies. It will also be clarified whether the aPL against phospholipid-binding proteins, which typically develop later in the course of the disease, arise through somatic mutation from lipid-binding aPL or independently and whether these aPL are also secreted by B1 cells or B2 cells. (3) Finally, an analysis of viral structures involved in the formation of aPL will be carried out based on viral peptides described in the literature and our own investigations with these peptides. In preliminary work on the above questions, we have developed or adapted three mouse models that can be used to study the formation of aPL paradigmatically for autoimmune diseases (Mrl/lpr mouse) and viral infections (murine CMV virus). In addition, we have a model in which immunization with a human aPL induces the production of murine aPL. The findings thus obtained are central to understanding the development of aPL and thus APS and possible links with infections. They will show whether aPL, as natural antibodies, may be part of the innate immune system that normally disappear with the resolution of infection, and the development of persistence is the pathogenetically relevant step in terms of APS.

• DFG Programme: Research Grants