Rho-GTPases in Rheumatoid Arthritis

Abstract

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.