Abstract
BackgroundMultiple sclerosis (MS) is an autoimmune, neuroinflammatory disease, with an unclear etiology. However, T cells play a central role in the pathogenesis by crossing the blood–brain-barrier, leading to inflammation of the central nervous system and demyelination of the protective sheath surrounding the nerve fibers. MS has a complex inheritance pattern, and several studies indicate that gene interactions with environmental factors contribute to disease onset.MethodsIn the current study, we evaluated T cell dysregulation at the protein level using electrospray liquid chromatography–tandem mass spectrometry to get novel insights into immune-cell processes in MS. We have analyzed the proteomic profiles of CD4+ and CD8+ T cells purified from whole blood from 13 newly diagnosed, treatment-naive female patients with relapsing–remitting MS and 14 age- and sex-matched healthy controls.ResultsAn overall higher protein abundance was observed in both CD4+ and CD8+ T cells from MS patients when compared to healthy controls. The differentially expressed proteins were enriched for T-cell specific activation pathways, especially CTLA4 and CD28 signaling in CD4+ T cells. When selectively analyzing proteins expressed from the genes most proximal to > 200 non-HLA MS susceptibility polymorphisms, we observed differential expression of eight proteins in T cells between MS patients and healthy controls, and there was a correlation between the genotype at three MS genetic risk loci and protein expressed from proximal genes.ConclusionOur study provides evidence for proteomic differences in T cells from relapsing–remitting MS patients compared to healthy controls and also identifies dysregulation of proteins encoded from MS susceptibility genes.
Highlights
Multiple sclerosis (MS) is an autoimmune, neuroinflammatory disease, with an unclear etiology
Differential protein expression is observed in T cells between MS patients and healthy control In this study, we monitored the difference in the proteomic profiles in T cells, i.e. CD4+ and CD8+ T cells, between relapsing remitting MS (RRMS) patients (n = 13) and healthy controls (n = 14) in a label-free manner
We show that there is a dysregulation at the protein level in T cells from RRMS patients at an early stage of disease
Summary
Multiple sclerosis (MS) is an autoimmune, neuroinflammatory disease, with an unclear etiology. Multiple sclerosis (MS) typically affects young adults and is the most common non-traumatic cause of neurological impairment. Parent-oforigin effects affect inheritance of MS in rodents, and several studies indicate that gene-environment interactions contribute to MS development. This suggests that epigenetic mechanisms play a role in MS etiology [7]. Both genome-wide studies on epigenetic modifications, such as DNA methylation, as well as transcriptomic analyses in immune cells have been conducted in order to investigate the potential dysregulation of immune cells in MS. Performing quantitative high-resolution mass spectrometry-based proteomics gives a unique opportunity for system-wide studies at the protein level
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