Project description:Bulk RNAsequencing of CD8+ T-cells in SLE patients with (SLE-P) and without (SLE-NP) subclinical atherosclerotic plaques in carotid and femoral arteries, scanned by vascular ultrasound.
Project description:Bulk RNAsequencing of CD4+ T-cells in SLE patients with (SLE-P) and without (SLE-NP) subclinical atherosclerotic plaques in carotid and femoral arteries, scanned by vascular ultrasound.
Project description:T cell abnormalities are well-known features of patients with systemic lupus erythematosus (SLE). The role of CD4 and CD8 T lymphocytes, however, remains poorly understood with data suggesting both protective and deleterious roles. This project aimed to identify a cell-specific transcriptional signature in patients with SLE that could be used as a prognostic disease marker. The overall objective is to correlate the clinical presentation with specific RNA signatures to determine if there are signatures that correlate with disease outcome
Project description:To examine mononuclear cell gene expression profiles in patients with and without SLE and subsets with and without atherosclerosis Monocytes were obtained from 20 patients with SLE and 16 healthy controls and were in vitro differentiated into macrophages. Subjects also underwent laboratory and imaging studies of the coronary arteries, carotid arteries, and aorta to evaluate for subclinical atherosclerosis.
Project description:Systemic Lupus Erythematosus (SLE) is an autoimmune disease that affects 20-150 out of 100,000 people globally. Reactive oxygen species (ROS) generation from mitochondrial dysfunction contributes to risk for SLE and autoimmune states and are potential targets for the treatment of autoimmunity. HRES-1/Rab4 (Rab4A) is a GTPase linked to mitochondrial oxidative stress and activation of the mechanistic target of rapamycin (mTOR), and has been linked to SLE pathogenesis. Here, RNA-sequencing (RNA-seq) was used to examine the expression of different classes of splenocytes (CD4+, CD8+, CD19+) from the lupus-prone SLE1.2.3. triple-congenic (B6.TC) mouse, as well as Rab4AQ72L mutant mice (which exhibits constitutive overexpression of Rab4a), and mice with CD4 T cell-specific deletion of Rab4A (KO).
Project description:Atherosclerotic cardiovascular disease (ASCVD) remains an important cause of morbidity in the general population and risk for ASCVD is increased approximately 2-fold in persons living with HIV infection (PLWH). This risk is linked to elevated CD8 T cell counts that are abundant in atherosclerotic plaques and have been implicated in disease pathogenesis yet the mechanisms driving T cell recruitment to and activation within plaques are poorly defined. Here we investigated the role of CD8 T cells in atherosclerosis in a non-human primate model of HIV infection and in the HIV-uninfected elderly; we sought to identify factors that promote the activation, function, and recruitment to endothelium of CX3CR1+ CD8 T cells. We measured elevated expression of CX3CL1 and IL-15, and increased CD8 T cell numbers in the aortas of rhesus macaques infected with SIV or SHIV, and demonstrated similar findings in atherosclerotic vessels of HIV-uninfected humans. We found that recombinant TNF enhanced the production and release of CX3CL1 and bioactive IL-15 from aortic endothelial cells, but not from aortic smooth muscle cells. IL-15 in turn promoted CX3CR1 surface expression on and TNF synthesis by CD8 T cells, and IL-15-treated 60 CD8 T cells exhibited enhanced CX3CL1-dependent chemoattraction toward endothelial cells in vitro. Finally, we show that CD8 T cells in human atherosclerotic plaques have an activated, resident phenotype consistent with in vivo IL-15 and CX3CL1 exposure. In this report, we define a novel model of CD8 T cell involvement in atherosclerosis whereby CX3CL1 and IL-15 operate in tandem within the vascular endothelium to promote infiltration by activated CX3CR1+ memory CD8 T cells that drive further endothelial activation via TNF. We propose that these interactions are prevalent in aging and in PLWH, populations where circulating activated CX3CR1+ CD8 T cell numbers are often expanded.
Project description:Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease affecting multiple heterogeneous organs and systems. SLE is associated with increased risk of atherosclerosis and increased cardiovascular complications. In this study, we specifically aimed to identify patients with SLE who are genetically at risk for developing atherosclerosis. Sureprint G3 Human Gene Expression 8x60K Microarray kit (Agilent technologies, Santa Clara, CA, USA) was used in our study. Genes showing differences in expression between the groups were identified by using GeneSpring GX 10.0 program. A total of 155 genes showing expression level difference were detected between SLE patients and healthy controls. In molecular network analysis.
Project description:Autoimmune diseases are common and debilitating, but their severe manifestations could be reduced if biomarkers were available to allow individual tailoring of the potentially toxic immunosuppressive therapy required for their control. Clinically useful biomarkers have been identified using DNA microarrays in cancer but not autoimmunity. We show that transcriptional profiling of purified CD8 T cells, but not unseparated cells, identifies two distinct patient subgroups predicting long-term prognosis in two different autoimmune diseases, anti-neutrophil cytoplasmic antibody (ANCA) – associated vasculitis (AAV) and systemic lupus erythematosus (SLE). We show that genes defining the poor prognostic group are enriched for genes of the IL7R pathway, TCR signalling and those expressed by memory T cells. Furthermore, the poor prognostic group is associated with an expanded CD8 T cell memory population. These subgroups, which are also found in the normal population and can be identified by measuring expression of only three genes, raise the prospect of individualized therapy and suggest novel potential therapeutic targets in autoimmunity.