The role of JAK-STAT signaling pathway in early arthritis

• Autor(a) principal: Mariano, Ana Rita Faísca
• Data de Publicação: 2023
• Tipo de documento: Dissertação
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10362/162939
• topic: Rheumatoid arthritis; JAK-STAT signaling pathway; leukocytes; methotrexate; upadacitinib; Domínio/Área Científica::Engenharia e Tecnologia::Outras Engenharias e Tecnologias

Rheumatoid arthritis (RA) is a systemic, inflammatory, immune-mediated disorder, impacting approximately 1% of the world population. It is characterized by chronic joint inflammation due to accumulation of activated leukocytes in the synovial membrane, causing pain, swelling and progres- sive joint destruction. The JAK-STAT signaling pathway is a conserved phosphorylation cascade with an important role in many inflammatory cellular processes. Disturbances in this pathway have been documented in autoimmune diseases such as RA. In this work we aimed to characterize peripheral blood leukocyte populations of untreated early arthritis patients (with <1 year of disease duration) and evaluate the effect of conventional treatment with methotrexate (MTX) on JAK-STAT signaling pathway. Moreover, a group of refractory RA patients was also recruited and the effect of upadacitinib, a JAK inhibitor recently approved for RA treatment, was assessed. We aimed to uncover new knowledge about the effect of upadacitinib on the immune system, particularly in the early phases of arthritis. We have found significant alterations in both the frequency and phenotype of immune cells' populations between controls and early arthritis patients, particularly in seropositive RA. Treatment with MTX restored some of these alterations, which supports its efficacy in disease amelioration. The measurement of STAT phosphorylation levels showed decreased STAT activation in early RA, which was maintained or exacerbated after conventional treatment with MTX, suggesting a role of JAK- STAT signaling pathway since early disease onset. In addition, we have found that upadacitinib main- ly affected the frequency of dendritic cell subpopulations and T cell phenotype, but did not signifi- cantly impact STAT phosphorylation levels in peripheral blood leukocytes from established refractory RA patients. Overall, our results support the immunomodulatory effects of MTX and upadacitinib in peripheral blood leukocytes from early and established arthritis patients and reinforce the role of JAK- STAT signaling pathway since early disease onset.