Abstract
Multiple sclerosis (MS) represents the leading cause of neurological deficit among young adults, affecting women more frequently than men. In MS, the extent of central nervous system lesions is determined by the net balance between self-reactive and regulatory T-cells at any given time, among other factors, as well as by the effect of inflammatory response. Here, we studied both CD4+ and CD8+ TReg in parallel in blood and CSF during MS relapse. A recruitment of both regulatory CD4+ and CD8+ T cells (TReg) within the cerebrospinal fluid (CSF) takes place during MS relapse. Not previously described, the presence of CD4+ TReg in CSF was higher in women than in men, which could account for the sexual dimorphism in the incidence of MS. A direct correlation between plasma oestradiol (E2) and IL-2 levels was observed, in line with a putative circuit of E2 and perforin expression by CD4+ TReg playing a role in MS. Also, serum IFN-alpha was higher in females, with direct correlation with serum E2 levels. This is the first study to analyze perforin expression by CD4+ TReg in MS, which was greatly enhanced in CSF, what points out a relevant role of this molecule in the suppressive effects of the CD4+ TReg in MS, and contributes to the understanding of MS pathophysiology.
Highlights
Multiple sclerosis (MS), a prototype autoimmune disease of the central nervous system (CNS), is the leading cause of neurological deficit among Caucasian young adults [1]
When we studied paired samples of peripheral blood and cerebrospinal fluid (CSF) in MS patients at first clinical relapse, the frequencies of CD4+ TReg (CD4+CD25+FoxP3+ and CD4+CD25bright) were significantly higher in CSF in comparison to their peripheral blood counterparts: CD4+CD25+FoxP3+ were
The mean fluorescence intensity (MFI) of the co-stimulatory molecule CD28 on CD4+ TReg was analyzed in a subgroup of patients (n = 10) and interestingly, we found that the expression of this co-stimulatory signal was significantly reduced in CD4+ TReg in the CSF compared to the periphery (MFI CD4+CD25med: 69.71 ± 40.76 vs. 289.75 ± 63.87, p < 0.0001; MFI CD4+CD25hi+: 79.08 ± 40.28 vs. 325.77 ± 68.01, p = 0.006)
Summary
Multiple sclerosis (MS), a prototype autoimmune disease of the central nervous system (CNS), is the leading cause of neurological deficit among Caucasian young adults [1]. The cerebrospinal fluid (CSF) seems to be an adequate compartment to analyze the immunological signature reflecting the actual inflammation within the CNS, due to the difficulty of studying the brain, the target organ in MS disease In this observational study, we studied the presence of CD4+ and CD8+ TReg lymphocytes in the CSF and peripheral blood. CD4+ TReg that causes autologous target cell death in cancer and autoimmunity involves the perforin-granzyme pathway [11,17,18], we sought to ascertain whether the expression of perforin by these regulatory lymphocytes was a relevant mechanism in MS pathophysiology. Our group has demonstrated that oestradiol (E2) enhances the suppressive function of CD4+ TReg in vitro, process mediated in part by perforin [17] For this reason, we sought to determine the contribution of.
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