Extracellular Vimentin Modulation of Human Dendritic Cell Activation

Abstract

Vimentin is traditionally considered to be an intracellular protein with a primarily structural role. Evidence suggests that extracellular vimentin can be found in cancer, tissue injury, and autoimmunity. Extracellular vimentin has already been shown to alter innate immunity by increasing monocyte and macrophage ability to kill bacteria, but also decreasing neutrophil infiltration into inflamed tissue. How extracellular vimentin affects initiation of adaptive immunity has not been previously studied. To initiate adaptive immunity, antigen presenting cells prime naïve T cells. Since the most effective antigen-presenting cells are dendritic cells (DCs), the DCs are important in immune responses against cancer, self, and pathogens. In this dissertation, I used primary human cell culture to demonstrate the effects of extracellular vimentin on DCs and T cells. In activated DCs, extracellular vimentin decreases secretion of pro-inflammatory cytokines IL-6 and IL-12 and increases secretion of the anti-inflammatory cytokine IL-10. As a result, there is less Th1 activation, resulting in an anti-inflammatory effect. This data supports the hypothesis that vimentin is a modulator of DC induced activation, resulting in a mild anti-inflammatory effect. By inducing suppression of the adaptive immune response, vimentin could be involved in cancer or trauma-complications. I also had a clinically-focused side project focused on rheumatoid arthritis (RA), an autoimmune disease. The first line therapy for RA is methotrexate (MTX), but MTX is sometimes ineffective or has side effects. I attempted to correlate in vitro MTX induced changes with MTX efficacy and MTX side effects in a small group of RA patients. The in vitro assay focused on MTX induced decreases in IL-17, a cytokine from pro-inflammatoryTh17 cells thought to be involved in RA pathogenesis. I found that there is greater variation in the effect of MTX on in vitro IL-17 secretion in those with side effects vs those without. This suggests that patients that had an unusually large or small reduction in IL-17 levels in response to MTX in vitro ultimately had side effects to the drug