Advisory Committee Chair
Advisory Committee Members
Alexander J Szalai
Date of Award
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Rheumatoid Arthritis (RA) is a systemic autoimmune disease with debilitating side effects, from joint swelling to bone erosion and bone deformation. Geographically, RA affect 0.5 – 1% of the worldwide populations, affecting women more than men. Studies have shown that CD4 T cells infiltrate RA synovium and are key to the pathogenesis of RA. Furthermore, drugs targeting co-stimulatory T cell molecules such as abatacept can be beneficial in controlling RA disease activity.Interferon gamma (IFN) is a pleotropic cytokine that contributes to inflammation by aiding in CD4 T cell differentiation into Th1 subtype, enhancing MHC class II presentation, supplementing lymphocyte trafficking, and increasing regulatory T cell function. Multiple reports demonstrate evidence of expression of Interferon gamma (IFN) in the synovium of patients with RA and IFN induced genes are reported to be significantly upregulated in synovial monocytes from RA patients compared to healthy control (HC). Our lab has previously shown that elevated gene expression of IFNGR in peripheral blood leukocytes was significantly associated with severe radiographic damage. Therefore, I investigated the proximal downstream consequences of IFN induced signaling in patients with RA and controls. In this work, we report three main findings. First, we report that IFN induced STAT1 activation is significantly reduced from patients with RA compared in CD4 effector memory, effector, and regulatory T cells. This was in-tandem with a significant reduction in total STAT1 protein levels in CD4 T cells. We then showed, that engaging the TCR complex in conjunction with IFN stimulation, “rescues” the dampened response to IFN stimulation. Second, we show that IFN induced STAT1 activation was significantly elevated in active RA compared to RA in remission. Third, we report a significant change in the topology of CD4 and CD8 T cells associated with RA disease activity, specifically in high disease activity. Collectively, our findings provide a new insight into the role of IFN’s contribution to the pathogenesis of RA. If validated by independent groups, our findings in this study have far reaching implications in precision medicine, such as identifying RA patients who may not respond clinically to JAK/STAT inhibitors.
Sharma, Vishal, "Assesing The Degree Of Intereron Gamma Induced Stat1 Activation On Peripheral Lymphocytes In Patietns With Rheumatoid Arthritis" (2021). All ETDs from UAB. 915.