Angiotensin receptor blockers and CD4 T cell transcriptional and epigenetic states in systemic lupus erythematosus

Despite the characterization of systemic lupus erythematosus using autoantibodies and specifically anti-nuclear autoantibodies, B cell-directed therapies are not universally successful in patients. T cells play a vital role in lupus in several ways including supporting antibody responses and promoting inflammatory damage such as that seen in lupus nephritis. This study profiled circulating populations of CD4 T cells (Naive, circulating Tfh, activated circulating Tfh, and Th1-like cells) at the levels of chromatin accessibility and transcription from both lupus patients and healthy controls. For select patients and controls, multi-omic ATAC + GEX 10X sequencing was performed. This study revealed a lupus-driven chromatin accessibility signature present in quiescent disease that is found in all measured CD4 T cell subsets including the naive population. Cytokine signals were implicated as drivers of this distinct epigenetic phenotype in lupus. Importantly, these data identify the TNFa signaling pathway as a putative mechanisms involved in the establishment or maintenance of dysregulated chromatin in lupus T cells. The TNF family cytokine signaling pathway is separately regulated with therapeutics. Lupus patients prescribed angiotensin receptor blockers (ARBs) were shown to have altered plasma cytokines, including those in the TNF family. ARB-associated changes to plasma cytokines were further shown to correlate with changes in TNFa signaling transcription and T cell epigenetic states. These data are relevant for understanding the mechanisms which drive lupus T cell contributions to autoimmunity. These data are also relevant to future clinical studies and suggest that therapeutics may have unknown, potentially beneficial, influences over immune cell states in disease.