Project 1: Identification of Peripheral Blood Subsets Dysregulated in Lupus and Scleroderma
Often considered as related diseases, systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are severe autoimmune disorders characterized by immune cell dysregulation, production of high titers of autoantibodies, clinical heterogeneity and gender and ethnic disparities. Despite progress in elucidating their genetic etiology, the immune cell subsets, their functions and regulation are poorly defined in disease pathogenesis. The goal of this project is to understand the cellular causes of SLE and SSc. Since the cellular responses in SLE and SSc are not well defined, the specific goal of this study is to define the leukocyte subsets that differ from healthy individuals in SLE and SSc. In order to identify specific cell subsets that differentiate cases from controls, we propose the pecific aim of identifying peripheral blood leukocyte subsets associated with SLE and SSc. We will identify the phenotypic differences among leukocyte subsets between patients with SLE or SSc and controls. In order to define the phenotypic subsets that differentiate between cases and controls, we will use high-dimensional CyTOF mass cytometry immunophenotyping to characterize cell surface molecules and identify the cellular subsets on peripheral blood mononuclear cells (PBMCs) from 15 patients with SLE, 15 with SSc, and 15 controls.
Project 2: Identification of Accessible Chromatin Marks in Activated Dendritic Cells from Female and male SLE Patients
Epigenetic regulation in DCs (myeloid or monocyte-derived) is critical for cell differentiation and activation in response to environmental triggers such as TLR agonists, which are prototypical inflammatory stimuli. Open chromatin marks impact gene expression, and can govern cell function. Our goal is to identify the molecular mechanisms underpinning dysfunctional DC responses to TLR stimulation in SLE, with a focus on differences between females and males. To elucidate differential molecular regulation of genes critical to TLR responses in DCs, we will identify accessible chromatin marks in TLR-treated DCs from female and male SLE patients.