The role of PTEN in autoimmune arthritis

Rheumatoid arthritis (RA) is a chronic disease characterized by excessive activation of the innate as well as the adaptive immune system. It leads to inflammatory destruction of joints and bones and is one of the most prevalent causes for disability worldwide. The pathogenesis of this disease, although intensely studied, remains poorly understood. For the development of new therapeutics, a deeper understanding of the events leading to inflammatory arthritis is needed. The PI3-kinase/PTEN axis is an important pathway in the regulation of cellcycle/proliferation, migration and angiogenesis. In addition to these well recognized functions, previous work published by us and others as well as new preliminary data suggest that the PI3K/PTEN pathway might be an important regulator of the innate as well as the adaptive immune system. In this proposal we therefore want to explore the role of the PI3-kinase/PTEN axis in the development of autoimmune arthritis using collagen-induced arthritis (CIA). The influence of PTEN deficiency on the development of CIA will be studied using an inducible conditional knock-out system. Arthritis will be evaluated clinically as well as histologically, with special emphasis on local bone destruction. Our preliminary data suggest a role of the PI3K/PTEN pathway in myeloid cells such as dendritic cells and macrophages in the regulation of cytokines essential for the development of inflammatory arthritis. Therefore, we will test the effect of PTEN deficiency selectively in myeloid cells alone on the development of arthritis. In vitro experiments such as analysis of signal transduction events as well as cellular activation of dendritic cells and macrophages will be performed to characterize the impact of PTEN deficiency on the behaviour of these cells in inflammatory settings. Taken together, this project will clarify the potential role of the PI3K/PTEN pathway in arthritis and therefore might lead to novel insights into the pathogenesis of rheumatoid arthritis. Furthermore, a better understanding of the molecular mechanisms leading to the development of destructive arthritis might pave the way for novel and innovative therapeutic approaches in RA.

Autoimmune diseases such as rheumatoid arthritis are characterized by an overshooting activation of the immune system, which then erroneously attacks organs in the body such as the joints or, in diseases such as multiple sclerosis, the brain. In RA, the chronicity of the inflammation in the joint then causes irreversible destruction of the articular structures, leading eventually to disability of many of the patients suffering from the disease. It is still unclear, which mechanisms govern initiation and perpetuation of the inflammatory response in autoimmune diseases such as RA.In our studies, we investigated the role of the PI3-kinase/PTEN axis, an important signal transduction pathway, in arthritis.We could demonstrate, that this signal transduction pathway controls joint destruction in chronic inflammatory arthritis. This could maybe used therapeutically, since blocking this pathway could ameliorate joint damage. In further experiments we also tested the importance of the PI3-kinase/PTEN axis in the development of autoimmunity. In many autoimmune diseases, certain cell types are formed that contribute substantially to the pathogenesis. We found, that the PI3-kinase/PTEN axis controls the development of a pathogenic cell type, which prevented the development of autoimmune arthritis. In further experiments, we could show, that similar mechanisms seem to be in place in other autoimmune diseases such as multiple sclerosis.In summary, we could show that the PI3-kinase/PTEN axis plays an important role in the initiation of autoimmunity. In addition it controls important steps leading to joint destruction in chronic arthritis.