Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants.

Human regulatory T cells (T(reg) cells) that develop from conventional T cells (T(conv) cells) following suboptimal stimulation via the T cell antigen receptor (TCR) (induced T(reg) cells (iT(reg) cells)) express the transcription factor Foxp3, are suppressive, and display an active proliferative and metabolic state. Here we found that the induction and suppressive function of iT(reg) cells tightly depended on glycolysis, which controlled Foxp3 splicing variants containing exon 2 (Foxp3-E2) through the glycolytic enzyme enolase-1. The Foxp3-E2-related suppressive activity of iT(reg) cells was altered in human autoimmune diseases, including multiple sclerosis and type 1 diabetes, and was associated with impaired glycolysis and signaling via interleukin 2. This link between glycolysis and Foxp3-E2 variants via enolase-1 shows a previously unknown mechanism for controlling the induction and function of T(reg) cells in health and in autoimmunity.

Migraine attack restores the response of vascular smooth muscle cells to nitric oxide but not to norepinephrine.

AIM: To clarify whether the vasoconstrictory response is impaired and to study vascular function in patients with migraine during the headache attack. METHODS: We studied vascular reactivity in the resistance arteries by using the forearm perfusion technique associated with plethysmography. We measured forearm blood flow by strain-gauge plethysmography during intra-brachial infusion of acetylcholine, sodium nitroprusside or norepinephrine in 11 controls and 13 patients with migraine, 11 of them (M) in the interval between the migraine attacks and 4 during a headache attack (MH). Written informed consent was obtained from patients and healthy controls, and the study was approved by the Ethics Committee of the University Federico II. RESULTS: Compared to healthy control subjects, in patients with migraine studied during the interictal period, the vasodilating effect of acetylcholine, that acts through the stimulation of endothelial cells and the release of nitric oxide, was markedly reduced, but became normal during the headache attack (P < 0.05 by analysis of variance). The response to nitroprusside, which directly relaxes vascular smooth muscle cells (VSMCs), was depressed in patients with migraine studied during the interictal period, but normal during the headache attack (P < 0.005). During norepinephrine infusion, forearm blood flow decreased in control subjects (-40% ± 5%, P < 0.001). In contrast, in patients with migraine, either when studied during or free of the headache attack forearm blood flow did not change compared to the baseline value (-3% ± 13% and -10.4% ± 15%, P > 0.05). CONCLUSION: In migrainers, the impaired relaxation of VSMCs is restored during the headache attack. The vasoconstrictory response is impaired and remains unchanged during the migraine attack.

Tolosa-Hunt syndrome in a patient with autoimmune hemolytic anemia.

Tolosa-Hunt syndrome is a steroid responsive painful opthalmoplegia due to a nonspecific inflammation of the cavernous sinus. Autoimmune hemolytic anemia is caused by antibodies directed against unmodified autologous red cells. They are both rare conditions. Here we describe the simultaneous occurrence of Tolosa-Hunt syndrome and severe hemolytic crisis in the same patient.

Leptin as a metabolic link to multiple sclerosis.

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.

Glossopharyngeal neuralgia as onset of multiple sclerosis.

OBJECTIVES AND METHODS: Glossopharyngeal neuralgia is a painful condition, affecting the ninth cranial nerve, rarely described in the course of multiple sclerosis. Here we describe a case of multiple sclerosis presenting with glossopharyngeal neuralgia. RESULTS AND DISCUSSION: We suggest the presence of demyelinating areas at the nerve root entry zone as principal trigger mechanism.

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.