Decoding CD4+ T cell transcriptome in giant cell arteritis: novel pathways and altered cross-talk with monocytes [RNA-seq]
Objectives: Giant cell arteritis (GCA) is an autoimmune large-vessels vasculitis with complex etiology. Although the pathogenic mechanisms remain poorly understood, a central role for CD4+ T cells has been demonstrated. In this context, delineating the transcriptome signatures of GCA CD4+ T cells will yield new insights into its pathogenesis.   Methods: Transcriptome analysis was conducted on CD4+ T cells from 70 patients with GCA with different disease activity (active patients before treatment and patients in remission with and without glucocorticoid treatment), along with 28 healthy controls. The study also evaluated potential impacts of DNA methylation on gene expression alterations and assessed cross-talk communication with CD14+ monocytes.   Results: This study has uncovered a substantial number of genes and pathways potentially contributing to the pathogenicity of CD4+ T cells in GCA. Specifically, CD4+ T cells from GCA patients with active disease exhibited altered expression levels of genes involved in multiple immune-related processes, including various interleukins (IL) signaling pathways. Notably, IL-2, a decisive interleukin for regulatory T cells homeostasis, was among the most significant. Additionally, impaired apoptotic pathways appear to be crucial in GCA development. Our findings also suggest that histone-related epigenetic pathways may be implicated in promoting an inflammatory phenotype in GCA active patients. Finally, our study observed altered signaling communication, such as the Jagged-Notch signaling, between CD4+ T cells and monocytes that could have pathogenic relevance in GCA. Conclusions: Our study suggests the participation of novel cytokines and pathways and the occurrence of a disruption of monocyte-T cell crosstalk driving GCA pathogenesis. Overall design: DNA methylation and gene expression profiling analysis of Illumina Infinium EPIC array and RNA-seq data sets for CD4+ T cells  in healthy individuals and giant cell arteritis patients within three different clinical status : a) active (n=17): newly diagnosed patients before starting GC treatment; b) in remission with treatment (n=26): patients in disease remission while receiving low doses of prednisone (= 10mg/day) for a minimum of 1 month; c) in remission without treatment (n=27): patients in remission without any treatment for at least 1 month. Remission was considered when individuals presented absence of GCA-related symptoms along with normal acute phase reactants.