Leptin increase in multiple sclerosis associates with reduced number of CD4(+)CD25+ regulatory T cells.
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.
Matarese
Giuseppe
G
Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Naples, Italy. gmatarese@napoli.com
Carrieri
Pietro Biagio
PB
La Cava
Antonio
A
Perna
Francesco
F
Sanna
Veronica
V
De Rosa
Veronica
V
Aufiero
Daniela
D
Fontana
Silvia
S
Zappacosta
Serafino
S
D000328:Adult; D000818:Animals; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D002460:Cell Line; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000134:cerebrospinal fluid; D020738:Leptin / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000172:deficiency / Q000235:genetics; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology*; D004676:Myelin Basic Protein / Q000276:immunology; D009500:Neutralization Tests; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D054411:Receptors, Leptin; D016176:T-Lymphocyte Subsets / Q000276:immunology*
C515448:LEPR protein, human; D020738:Leptin; D004676:Myelin Basic Protein; D011956:Receptors, Cell Surface; D015375:Receptors, Interleukin-2; D054411:Receptors, Leptin; C515447:leptin receptor, mouse; D007371:Interferon-gamma