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. 2005 Apr 5;102(14):5150-5.
doi: 10.1073/pnas.0408995102. Epub 2005 Mar 23.

Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25+ regulatory T cells

Giuseppe Matarese  1 , Pietro Biagio Carrieri, Antonio La Cava, Francesco Perna, Veronica Sanna, Veronica De Rosa, Daniela Aufiero, Silvia Fontana, Serafino Zappacosta
Affiliations

Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25+ regulatory T cells

Giuseppe Matarese et al. Proc Natl Acad Sci U S A. .

Abstract

We analyzed the serum and cerebrospinal fluid (CSF) leptin secretion and the interaction between serum leptin and CD4(+)CD25+ regulatory T cells (T(Regs)) in naive-to-therapy relapsing-remitting multiple sclerosis (RRMS) patients. Leptin production was significantly increased in both serum and CSF of RRMS patients and correlated with IFN-gamma secretion in the CSF. T cell lines against human myelin basic protein (hMBP) produced immunoreactive leptin and up-regulated the expression of the leptin receptor (ObR) after activation with hMBP. Treatment with either anti-leptin or anti-leptin-receptor neutralizing antibodies inhibited in vitro proliferation in response to hMBP. Interestingly, in the RRMS patients, an inverse correlation between serum leptin and percentage of circulating T(Regs) was also observed. To better analyze the finding, we enumerated T(Regs) in leptin-deficient (ob/ob) and leptin-receptor-deficient (db/db) mice and observed the significant increase in T(Regs). Moreover, treatment of WT mice with soluble ObR fusion protein (ObR:Fc) increased the percentage of T(Regs) and ameliorated the clinical course and progression of disease in proteolipid protein peptide (PLP(139-151))-induced relapsing-experimental autoimmune encephalomyelitis (R-EAE), an animal model of RRMS. These findings show an inverse relationship between leptin secretion and the frequency of T(Regs) in RRMS and may have implications for the pathogenesis of and therapy for multiple sclerosis.

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Figures

Fig. 1.
Fig. 1.
Naïve-to-therapy RRMS patients show an increased secretion of leptin in serum and CSF that correlates with IFN-γ production in CSF. Statistical analyses of these data are summarized in Table 1. (a and b) Simple regression analysis between serum leptin and BMI in RRMS patients (n = 126) and NIND controls (n = 117). The correlation was lost in RRMS patients, whereas correlation was maintained in NIND controls. (c and d) The correlation between CSF leptin and BMI was lost in RRMS patients whereas correlation was very strong in NIND controls. (e and f) Significant correlation between serum and CSF leptin in both RRMS patients and NIND controls; the correlation was stronger in patients than in controls. (g and h) Simple regression analysis between the CSF leptin and the IFN-γ levels in CSF in both RRMS patients and NIND controls. Only in RRMS patients was there a statistically significant positive correlation between the CSF leptin and the IFN-γ levels in CSF. In NIND controls, the IFN-γ average levels were very low (see Table 1), and no correlation was observed with CSF leptin.
Fig. 2.
Fig. 2.
T cell lines against hMBP derived from naïve-to-treatment RRMS patients produce immunoreactive leptin, up-regulate the ObR, and are inhibited in their proliferation by anti-leptin or anti-leptin-receptor blocking antibodies. (a–c) Expression of leptin in T cells from a naïve-to-treatment RRMS patient in the presence of medium alone (a) or after activation with hMBP (b and c). Leptin was detectable only after activation in the cytoplasm of T cells. (d–f) Expression of ObR on T cells in the presence of medium only (d) or after activation with hMBP (e and f). The ObR was expressed at very low levels before activation and was significantly up-regulated on the cell membrane after activation with hMBP (e and f). All photos show immunoperoxidase staining with diaminobenzidine chromogen (brown) and hematoxylin counterstaining (violet). The open squares in b and e represent the zone of higher magnification shown in c and f, respectively. (Magnification: a, b, d, and e, ×100; c and f, ×400.) (g) Anti-hMBP short-term T cell lines secrete immunoreactive leptin. (h) The anti-hMBP proliferative response of T cells is inhibited by the addition to cell cultures of either of the anti-Ob or anti-ObR antibodies. The data shown are from one representative experiment of three.
Fig. 3.
Fig. 3.
Inverse correlation between serum leptin and circulating TRegs in RRMS patients. (a) The immune phenotype of circulating lymphocytes in RRMS patients selected on the basis of their increase in serum leptin (RRMS patients with a serum leptin increase to ≥2.5-fold higher than the mean of serum leptin observed in NIND and healthy controls) revealed a significant reduction in the percentage and the absolute number of circulating TRegs. (*, P = 0.0001 and *, P = 0.0001, respectively). (b and c) A statistically significant inverse correlation was observed between serum leptin and circulating TRegs in RRMS patients (b), whereas no correlation was observed in healthy controls (c). (d) Functional analysis of CD4+CD25+ TRegs of two RRMS patients selected on the basis of an increase in serum leptin. The proliferative response was inhibited upon addition of CD4+CD25+ cells to the CD4+CD25– responder population at a 1:1 ratio in normal controls (black bars). CD4+CD25+ cells from two naïve-to-therapy patients with RRMS exhibited significantly less suppressor activity (white and gray bars). *, P = 0.03. CD4+CD25+ cells alone were unresponsive upon stimulation as reported in ref. . The numbers above the bars represent the percent of inhibition of proliferation in the experiment. The data shown are from one representative experiment of five.
Fig. 4.
Fig. 4.
Neutralization of leptin with ObR:Fc increases the number of TRegs and ameliorates the clinical course of R-EAE. (a) Treatment of R-EAE-susceptible SJL/J female mice with ObR:Fc induced a significant increase in the circulating TRegs. *, P = 0.01. (b) Mean clinical score (bars) and body weight (curves) of SJL/J female mice pretreated with the ObR:Fc (white bars and squares) or the CTR-Ab (black bars and squares) on d –1, d 0, and d +1 and immunized with the PLP139–151 on d 0. Statistical analyses of these data are summarized in Table 2. The data shown are from one representative experiment of two (n = 6 mice per group). *, P = 0.01; **, P = 0.002.
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References

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