Leptin increase in multiple sclerosis associates with reduced number of CD4 + CD25 + regulatory T cells (original) (raw)
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Journal of Clinical Immunology, 2000
Leptin, a hormone synthesized mainly by adipocytes, can modulate the immune response and seems to be involved in the induction of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis (MS). However, the possible role of leptin in MS pathogenesis has not yet been elucidated. In this study we investigated the effect of leptin on cytokine production by peripheral blood mononuclear cells (PBMCs) of MS patients (either in the acute or in the stable phase of the disease) and healthy controls. We also analyzed leptin effects on cytokine production by monocytes in relapsing MS patients. Our data showed that leptin induced tumor necrosis factor-alpha, interleukin-6, and interleukin-10 production by PBMCs of patients in an acute phase of disease but not in patients in a stable phase or in healthy controls. Moreover, we found no effect of leptin in monocytes from relapsing MS patients. Therefore we conclude that leptin may modulate the MS inflammatory process during relapses.
Journal of Neuroimmunology, 2007
In this study we observed higher serum leptin levels in relapsing-remitting multiple sclerosis (RRMS) patients during remission than in controls. The expression of leptin receptor (ObR) was higher in CD8+ T cells and monocytes from RRMS patients in relapse than in patients in remission and in controls. Relapsing patients showed high levels of pSTAT3 and low expression of SOCS3 and leptin administration induced an up-regulation of pSTAT3 only in monocytes from patients in relapse. Our data suggest that ObR may be involved in the development of clinical relapses in RRMS patients and suggest a rationale for potential targeting of the leptin axis during MS.
Journal of Autoimmunity, 2004
Leptin is synthesized by adipocytes to regulate appetite. Leptin has also been implicated in the pathogenesis of multiple sclerosis (MS) leading to speculation about a beneficial effect of fasting to autoimmune patients. We measured plasma leptin and its soluble receptor (OB-Rs) in 52 MS patients and 50 controls. We also cultured MS and control peripheral blood mononuclear cells (PBMC), T-cells and monocytes G recombinant leptin (rleptin), to assess leptin's direct effect on pro-and anti-inflammatory cytokine secretion. We found similar leptin and OB-Rs plasma levels between patients and controls. Untreated patients in the acute phase or in remission, or patients treated with methylprednisolone, had lower leptin levels than patients in the acute phase or in remission receiving IFN-b. OB-Rs levels were low in patients refractory to IFN-b but higher in patients receiving methylprednisolone or patients in remission receiving IFN-b. PBMC from untreated patients in the acute phase, secreted spontaneously IFN-g, TNF-a and IL-10. IFN-g was contributed by T-cells, TNF-a and IL-10 primarily by monocytes and to a lesser extent by T-cells. The overall effect of rleptin on PBMC was a net increase in IL-10 production and a net reduction in IFN-g production. These results do not warrant a beneficial effect of fasting to MS patients.
Leptin as a metabolic link to multiple sclerosis
Nature Reviews Neurology, 2010
Clinical and experimental data, together with epidemiological studies, have suggested that the pathogenesis of multiple sclerosis (MS) might involve factors that link the immune system with metabolic status. Moreover, recent research has shown that leptin, the adipocyte-derived hormone that controls food intake and metabolism, can promote experimental autoimmune encephalomyelitis, an animal model of MS. In patients with MS, the association of leptin with disease activity has been dissected at the molecular level, providing new mechanistic explanations for the role of this hormone in MS. Here, we review the intricate relationship between leptin and other metabolic modulators within a framework that incorporates the latest advances linking the CNS, immune tolerance and metabolic status. We also consider the translational implications of these new findings for improved management of MS.
Leptin as a marker of multiple sclerosis activity in patients treated with interferon-beta
Journal of Neuroimmunology, 2003
The role of leptin was investigated in relapsing -remitting multiple sclerosis (MS). Control and MS patients showed comparable baseline serum leptin levels. During the first year of IFNbeta-1a treatment, leptin significantly decreased since 2 months after starting therapy in 11 patients who had no relapses. A significant decrease in IL12/IL10 ratio was observed in this group of patients only after 1 year of treatment. An increase of leptin was observed before the first clinical exacerbation in 13 relapsing patients. Leptin may play a pathogenic role in MS and can be a useful marker of disease activity and response to therapy. D
Neurologia i Neurochirurgia Polska, 2012
FoxP3 (p < 0,001) by³y znamiennie mniejsze u chorych na RRMS. Stwierdzono ujemn¹ korelacjê pomiêdzy stê¿eniem leptyny a MFC dla czynnika transkrypcyjnego FoxP3 w limfocytach nTreg u chorych na RRMS (r =-0,7; p < 0,05). Wnioski: Prozapalny profil adipocytokin i zmniejszenie odsetka limfocytów nTreg sugeruje ich udzia³ w przebiegu reakcji zapalnej u chorych na RRMS niezale¿nie od terapii kortykosteroidami. Korelacja pomiêdzy stê¿eniem leptyny i wskaŸnikiem MFC dla czynnika transkrypcyjnego FoxP3 w limfocytach nTreg u chorych na RRMS wskazuje na ha muj¹cy wp³yw leptyny na jego ekspresjê.
Journal of Clinical Investigation, 2006
Recent evidence has indicated that leptin, an adipocyte-secreted hormone belonging to the helical cytokine family, significantly influences immune and autoimmune responses. We investigate here the mechanisms by which in vivo abrogation of leptin effects protects SJL/J mice from proteolipid protein peptide PLP 139-151induced EAE, an animal model of MS. Blockade of leptin with anti-leptin Abs or with a soluble mouse leptin receptor chimera (ObR:Fc), either before or after onset of EAE, improved clinical score, slowed disease progression, reduced disease relapses, inhibited PLP 139-151 -specific T cell proliferation, and switched cytokine secretion toward a Th2/regulatory profile. This was also confirmed by induction of forkhead box p3 (Foxp3) expression in CD4 + T cells in leptin-neutralized mice. Importantly, anti-leptin treatment induced a failure to downmodulate the cyclin-dependent kinase inhibitor p27 (p27 Kip-1 ) in autoreactive CD4 + T cells. These effects were associated with increased tyrosine phosphorylation of both ERK1/2 and STAT6. Taken together, our data provide what we believe is a new molecular basis for leptin antagonism in EAE and envision novel strategies of leptin-based molecular targeting in the disease.
Autoimmune Diseases, 2014
Several studies have investigated leptin levels in patients with multiple sclerosis (MS) with somewhat conflicting results. They have all focused on patients with established relapsing-remitting (RR) MS but have not specifically looked at patients with clinically isolated syndrome (CIS) suggestive of MS, in the early stages of disease. In this study, serum leptin levels were measured in 89 treatment-naïve patients with CIS (53 patients) or RRMS (36 patients) and 73 controls searching for differences between the groups and for associations with several disease parameters. The expected significant sexual dimorphism in leptin levels (higher levels in females) was observed in both MS patients and controls. Increased leptin levels were found in female patients with RRMS compared to female controls (P=.003) and female CIS patients (P=.001). Female CIS patients had comparable levels to controls. Leptin levels correlated positively to disease duration, but not to EDSS, in female patients wi...
F1000 - Post-publication peer review of the biomedical literature, 2006
Recent evidence has indicated that leptin, an adipocyte-secreted hormone belonging to the helical cytokine family, significantly influences immune and autoimmune responses. We investigate here the mechanisms by which in vivo abrogation of leptin effects protects SJL/J mice from proteolipid protein peptide PLP 139-151induced EAE, an animal model of MS. Blockade of leptin with anti-leptin Abs or with a soluble mouse leptin receptor chimera (ObR:Fc), either before or after onset of EAE, improved clinical score, slowed disease progression, reduced disease relapses, inhibited PLP 139-151-specific T cell proliferation, and switched cytokine secretion toward a Th2/regulatory profile. This was also confirmed by induction of forkhead box p3 (Foxp3) expression in CD4 + T cells in leptin-neutralized mice. Importantly, anti-leptin treatment induced a failure to downmodulate the cyclin-dependent kinase inhibitor p27 (p27 Kip-1) in autoreactive CD4 + T cells. These effects were associated with increased tyrosine phosphorylation of both ERK1/2 and STAT6. Taken together, our data provide what we believe is a new molecular basis for leptin antagonism in EAE and envision novel strategies of leptin-based molecular targeting in the disease. Nonstandard abbreviations used: DTH, delayed-type hypersensitivity; Foxp3, forkhead box p3; ObR:Fc, leptin receptor chimera-Fc; PLP, proteolipid protein; p27 Kip-1 , cyclin-dependent kinase inhibitor p27; VLA-4, very late antigen-4. Conflict of interest: The authors have declared that no conflict of interest exists.
Peptides, 2005
Leptin is a peptide hormone which acts on cells of immune system by influencing the production of cytokines. Serum leptin levels and cytokine production by peripheral blood mononuclear cells (PBMC) were measured in 18 secondary progressive multiple sclerosis (SPMS) patients under IFN-beta-1b treatment. There were no overall effects on leptin, interleukin-6 (IL-6), IL-10 and IL-12 p40 after 2, 6 and 12 months of treatment. However, leptin and IL-6 decreased after 6 and 12 months of treatment in 12 patients who did not show progression of disability. Thus, our pilot data show that the beneficial effect of IFN-beta on some SPMS patients might be associated with the reduced levels of leptin and reduced IL-6 production by PBMC.