Our immune system plays a vital role to maintain our health and protects us from infections. It has the ability to recognize our own cells and discriminate our 'self' proteins or antigens from 'foreign' antigens that could harm us. When these layers of tolerance breakdown, it can result in autoimmune disease. Despite advances in targeted biologic and pharmacologic interventions, many patients with autoimmune disease continue to have inadequate response to therapies, or intolerable side effects, with resultant progression of their disease. The ASHOURI Lab is focused on understanding how abnormal immune cell signaling disrupts immune tolerance, resulting in autoimmunity. We are particularly interested in T cell mechanisms that contribute to the onset of rheumatoid arthritis (RA), a chronic, destructive autoimmune disease that targets joints and other organs. A specific aim of our lab is to identify antigen-activated T cells in RA in order to capture and profile arthritogenic clones and elucidate the earliest events in disease pathogenesis.
Our work takes advantage of a specific reporter of T cell antigen receptor (TCR) signaling. Tracking the expression of this reporter of TCR signaling in murine and human T cells facilitates our ability to identify and study arthritis-causing T cells before and during RA disease development and addresses the following questions:
- How are T cells that are relatively deficient in TCR signaling able to mediate arthritis development? Our lab uses molecular and biochemical techniques to examine how chronic TCR signaling can enhance T cell sensitivity to cytokine signaling and its dysregulation in disease.
- How are arthritis causing CD4 T cells initially triggered in disease and to what antigen do these T cells respond?
We utilize multi-dimensional and high-throughput technologies including paired single-cell RNA and TCR-sequencing from mouse and human samples with significant potential to identify the TCR specificity, gene expression profile, and signaling networks of cells involved in antigen recognition in RA. Our model system provides a platform to track antigen-specific T cell responses in human diseases in which the inciting antigen is not known and could be broadly applied to other autoimmune diseases, transplant rejection, cancer, and even checkpoint blockade.
