Rho-GTPases in Rheumatoid Arthritis

Sammanfattning: The success of alleviating rheumatoid arthritis (RA) symptoms is complicated by both heterogeneity of the disease and lack of predictive markers to guide treatment options. Deregulated Rho-GTPases, a family of hydrolase enzymes catalyzing guanosine triphospate (GTP) to guanosine diphospate (GDP), have a detrimental role in many diseases including RA. The aims of this thesis were to identify intercellular interactions and molecular pathways in RA linked to signal transducers of the Rho-GTPase family and assess the effect of anti-rheumatic treatments on these molecular pathways. Paper I: Mice with a conditional knockout of Geranylgeranyl transferase type I (GGTase-I) in macrophages (GLC mice) develop RA due to hyper-activation of Rho-GTPases. Reciprocal expression of the Rho-GTPases Cell division control protein 42 homolog (Cdc42) and Ras-related C3 botulinum toxin substrate 1 (Rac1) in T cells, as well as suppression of caudal Homeobox A (HoxA) caused migration of thymic T regulatory cells (Tregs) into the joint-draining lymph node. Paper II: We examined Rho-GTPase dependent biological processes by utilizing the transcriptome of blood CD14+ monocytes and of synovial tissue macrophages at single cell resolution. These studies resulted in a metabolic gene signature which identified circulating progenitors of RA synovial antigen presenting cells. Inhibition of Janus Kinases (JAK) suppressed this progenitor population, partially explaining the anti-rheumatic effect. Paper III: Examining the transcriptome of blood CD4+ T helper cells, we demonstrated that Pre-B cell leukemia transcription factor 1 (PBX1) marks recent thymic emigrants. RA patients with high PBX1 expression in CD4+ T cells had favourable outcomes to anti-rheumatic treatment, predicting good response to inhibition of Tumor necrosis factor (TNF)-α and stable remission. Taken together, these studies demonstrates that Rho-GTPases mediate interplay between T-helper cells and macrophages supporting antigen presentation and IFN-γ signalling, which drives RA pathology. Moreover, we propose two approaches for endotyping RA, a metabolic signature in CD14+ monocytes and expression of PBX1 in CD4+ T cells which mark recent thymic emigrants. The former approach identifies patients which may benefit from inhibition of JAK whereas the latter from TNF-α inhibition.