Leptin increase in multiple sclerosis associates with reduced number of CD4+CD25+ regulatory T cells
Leptin increase in multiple sclerosis associates with reduced number of CD4+CD25+ regulatory T cells
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DOI：
10.1073/pnas.0408995102
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发表时间：
2005-04-05
影响因子：
11.1
通讯作者：
Zappacosta, S
中科院分区：
文献类型：
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作者：
Matarese, G;Carrieri, PB;Zappacosta, S
我们分析了初治复发缓解型多发性硬化（RRMS）患者血清和脑脊液（CSF）瘦素分泌以及血清瘦素与CD4（+）CD25（+）调节性T细胞（T-Regs）之间的相互作用。RRMS患者血清和CSF中瘦素的产生显著增加，并与CSF中IFN-γ的分泌相关。针对人髓鞘碱性蛋白（hMBP）的T细胞系产生免疫反应性瘦素，并在用hMBP激活后上调瘦素受体（ObR）的表达。用抗瘦素或抗瘦素受体中和抗体处理抑制了响应于hMBP的体外增殖。有趣的是，在RRMS患者中，还观察到血清瘦素与循环TReg百分比之间的负相关。为了更好地分析这一发现，我们对瘦素缺乏（ob/ob）和瘦素受体缺乏（db/db）小鼠的T-Reg进行了计数，并观察到T-Reg的显著增加。此外，用可溶性ObR融合蛋白（ObR：Fc）治疗WT小鼠增加了T-Reg的百分比，并改善了蛋白脂质蛋白肽（PLP139 - 151）诱导的复发性实验性自身免疫性脑脊髓炎（R-EAE）（RRMS的动物模型）的临床病程和疾病进展。这些研究结果表明，瘦素分泌和TReg在RRMS中的频率之间存在负相关关系，可能对多发性硬化的发病机制和治疗有意义。
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 TRegs 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 (PLP139-151)-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 TRegs in RRMS and may have implications for the pathogenesis of and therapy for multiple sclerosis.