Body Mass Index and Multiple Sclerosis Risk. The Role of Leptin (S24.004)

Abstract

OBJECTIVE: To examine whether body mass index (BMI) is associated with higher risk of developing MS, and to study how overweight could alter immune tolerance. BACKGROUND: Obesity is associated with a chronic inflammatory state and cytokine release, ultimately affecting immune responses. Leptin, aside from its effect on metabolism is also a member of the long-chain helical cytokine family, suggesting a possible link between nutritional status and immune function. DESIGN/METHODS: BMI was calculated in 210 MS patients and in 210 age and gender matched control subjects at age 15 and 20 years, and at the present time. Leptin, 25-(OH) Vitamin D, Bcl-2, p21, P27 ^kip, STAT3, and SOCS3 were measured by ELISA. IL-1α, IL-2, IL-4, IL-5, IL-6, IL-10, IL-15, IL-21,TNF-α, and IFN-γ production were evaluated using ELISPOT. CD4+CD25+FoxP3+ Treg cells were assessed using flow cytometry. RESULTS: Obesity at 20 years of age (BMI > 30kg/m²) was associated with higher risk of developing MS (OR 2.1, 95% CI 1.2-3.7, p=0.02). BMI correlated directly with serum leptin levels, and inversely with 25(OH) Vitamin D levels. Obese MS patients showed higher number of IL-1α, IL-2, IL-6, IL-15, IL-17, IFN-γ, and TNF-α producing cells, compared to non-obese MS subjects. Moreover, leptin increased MBP-peptide specific CD4+ T cell proliferation, and inhibited apoptosis induction through increased expression of Bcl-2. Obese patients showed reduced numbers of CD4+CD25+FoxP3+ Treg cells. Furthermore, leptin induced hypo responsiveness of CD4+CD25+FoxP3+ Treg cells, a phenomenon associated with increased expression of p-STAT3, p21, and p27^kip, and lower expression of SOCS3. All these effects were reversed by leptin neutralization or leptin receptor inhibition. CONCLUSIONS: 1). Obesity in adolescence/early adulthood is associated with increased risk of MS. 2). Leptin exerts opposite effects on regulatory and CD4+ effector T cells, promoting inflammatory responses, potentially representing a putative link between obesity and autoimmunity in MS. Study Supported by: Institute fro Neurological Research Dr Raúl Carrea

Disclosure: Dr. Correale has received personal compensation for activities with Merck & Co., Inc., Biogen Idec, and Genzyme Corp. Dr. Correale has received research support from Novartis. Dr. Balbuena Aguirre has nothing to disclose. Dr. Farez has received personal compensation for activities with Merck Serono. Dr. Farez has received research support from Novartis.