Pathogenesis – Immunology Poster Presentation

P0985 - Obesity and Multiple Sclerosis risk. The role of Leptin (ID 1008)

Speakers
  • M. Marrodan
Authors
  • M. Marrodan
  • M. Farez
  • M. Balbuena
  • J. Correale
Presentation Number
P0985
Presentation Topic
Pathogenesis – Immunology

Abstract

Background

Obesity in childhood and in adolescence increases the risk of MS by inducing a chronic low-grade inflammatory state, characterized by altered secretion of adipokines, of which leptin is the best characterized.

Objectives

The main goal of this study was to investigate the effects of leptin on different T cell populations, in order to gain more insight into the link between leptin and obesity.

Methods

Three hundred and nine RRMS patients and 322 matched controls were invited to participate in a cross-sectional survey, to confirm whether excess weight/obesity in adolescence or early adulthood were associated with increased risk of MS.

Serum leptin levels were determined by ELISA. MBP83-102, and MOG63-87 peptide-specific T cells lines were expanded from peripheral blood mononuclear cells. Leptin receptor, p-STAT3, pERK1/2, and p27kip1 expression were assayed using RT-PCR. Apoptosis induction was determined by Annexin V detection. Cytokines were assessed by ELISPOT and ELISA, and regulatory T cells (Treg cells) detected by flow cytometry.

Results

Logistic regression analysis, with smoking as covariate, showed excess weight at age 15 and obesity at age 20 increased the risk of developing MS (OR=2.16, p=0.01 and OR=3.89, p=0.009). Leptin levels correlated with BMI(r=0.88, p<0.0001) in both groups. Addition of Leptin to cultures increased proliferation of autoreactive T cells, reduced apoptosis induction, and promoted pro-inflammatory cytokines secretion (p values < 0.001). Obese patients produced higher numbers of pro- inflammatory cytokines-secreting cells compared to overweight/normal/underweight subjects (p<0.001).

Inverse correlation was found between leptin levels and circulating CD4+CD25+ Treg cells (r=-0.97, p<0.0001). Leptin also inhibited Treg cell proliferation, inducing hypo-responsiveness. Effects of leptin on autoreactive T cells were mediated by increased STAT3 and ERK1/2 phosphorylation and down modulation of the cell cycle inhibitor P27kip1. By contrast, leptin effects on Treg cells were mediated by decreased phosphorylation of ERK1/2 and upregulation of p27kip1.

Conclusions

Leptin has a dual effect on T cell modulation. On one hand it promotes proliferation of autoreactive T cells, secretion of pro-inflammatory cytokines, and exerts an anti-apoptotic action. On the other, leptin inhibits Treg cell proliferation, inducing hypo-responsiveness, mediated by the opposite effects of STAT3, ERK1/2 phosphorylation, and p27kip1 expression.

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