Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients

Abstract

We have investigated transcriptional and epigenetic differences in peripheral blood mononuclear cells (PBMCs) of monozygotic female twins discordant in the diagnosis of amyotrophic lateral sclerosis (ALS). Exploring DNA methylation differences by reduced representation bisulfite sequencing (RRBS), we determined that, over time, theALStwin developedhigher abundances of theCD14macrophages andlower abundances ofTcells compared to the non-ALS twin. Higher macrophage signature in the ALS twin was also shown by RNA sequencing (RNA-seq). Moreover, the twins differed in themethylome at loci near several genes, including EGFR and TNFRSF11A, and in the pathways related to the tretinoin and H3K27me3 markers. We also tested cytokine production by PBMCs. The ALS twin'sPBMCsspontaneouslyproduced IL-6 andTNF-α,whereasPBMCsof the healthy twinproduced these cytokines only when stimulated by superoxide dismutase (SOD)-1. These results and flow cytometric detection of CD45 and CD127 suggest the presence ofmemory T cells in both twins, but effector T cells only in theALS twin. The ALS twin's PBMCsupernatants,but not the healthy twin's,weretoxic torat cortical neurons,andthis toxicitywas strongly inhibited by an IL-6 receptor antibody (tocilizumab) and lesswell by TNF-α and IL-1b antibodies. The putative neurotoxicity of IL-6 andTNF-α is in agreementwith a high expression of these cytokines on infiltrating macrophages in theALSspinal cord.We hypothesize that higher macrophage abundance and increased neurotoxic cytokines have a fundamental role in thephenotype and treatment of certain individuals with ALS.-Lam, L.,Chin, L.,Halder,R.C.,Sagong, B., Famenini, S., Sayre, J., Montoya,D., Rubbi L., Pellegrini,M., Fiala, M. Epigenetic changes in T-cell and monocyte signatures and production of neurotoxic cytokines in ALS patients.