Silvana Montella

Regulatory T cell proliferative potential is impaired in human autoimmune disease

Human CD4+CD25highCD127−FoxP3+ regulatory T (Treg) cells suppress immune responses in vitro and in vivo. Reduced suppressive function and/or number of peripheral Treg cells has been previously reported in autoimmune disorders. Treg cells represent the most actively replicating compartment within the CD4+ cells in vivo, but they are hyporesponsive to classical T cell receptor (TCR) stimulation in vitro, a condition that is secondary to their overactive metabolic state. Here we report that proliferation of Treg cells after TCR stimulation is impaired in subjects with relapsing-remitting multiple sclerosis (RRMS) because of altered interleukin-2 (IL-2) secretion and IL-2 receptor (IL-2R)–signal transducer and activator of transcription 5 (STAT5) signaling. This is associated with decreased expression of the forkhead box P3 (FoxP3) 44- and 47-kDa splicing forms, overactivation of S6 ribosomal protein (a downstream target of the mammalian target of rapamycin, mTOR) and altered activity of the cyclin-dependent kinase inhibitor p27 (p27kip1) and extracellular signal–related kinases 1 and 2 (ERK1/2). The impaired capacity of Treg cells to proliferate in RRMS correlates with the clinical state of the subject, where increasing disease severity is associated with a decline in Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmune disease.

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.

Interleukin-10 and Interleukin-12 Modulation in Patients with Relapsing-Remitting Multiple Sclerosis on Therapy with Interferon-beta 1a: Differences in Responders and Non Responders

We examined the effects of interferon (IFN)beta-1a on interleukin (IL)-12p70 and IL-10 secretion in 27 Relapsing Remitting Multiple Sclerosis (RRMS) patients, divided in responders and non-responders. In responders, IFNbeta-1a does not change the IL-12p70 concentrations, but it leads to a remarkable increase in the IL-10 production. Besides, a high IL-10/IL-12 ratio is demonstrated during the first six months of therapy. In non-responders, there were not significant alterations in the cytokine profile. We suggest that IFNbeta-1a effect in RRMS patients could be explained by its modifying effect on cytokine pattern. Moreover, we propose a possible role of IL-10/ IL-12 ratio as a serum marker predictive of favorable clinical course.

Longitudinal assessment of immuno-metabolic parameters in multiple sclerosis patients during treatment with glatiramer acetate

OBJECTIVE We investigated the effect of glatiramer acetate (GA) on the modulation of immune cell subpopulations and serum levels of multiple immune/metabolic markers in patients with relapsing-remitting multiple sclerosis (RRMS) to understand whether the treatment with GA could induce a specific change in the immunometabolic asset of patients with RRMS. MATERIAL AND METHODS We performed an extensive peripheral blood immunophenotyping and measured serum levels of several parameters involved in the pathogenesis of RRMS and also relevant in the pathogenesis of metabolic syndrome and obesity such as leptin, soluble leptin-receptor (sLep-R), myeloperoxidase (MPO), soluble CD40 ligand (sCD40-L), soluble tumor necrosis factor-receptor (sTNF-R), monocyte chemoattractant protein 1 (MCP-1), soluble Inter-Cellular Adhesion Molecule-1 (sICAM-1) and osteoprotegerin (OPG), in 20 naïve-to-treatment RRMS patients and 20 healthy controls. We repeated these analyses over time at 6 and 12 months after starting GA treatment. RESULTS Our analysis showed that naïve-to-treatment RRMS patients had a lower number of CD16(+)CD56(+) NK cells, CD19(+) B cells, CD4(+) T cells co-expressing the MHC class II activation marker HLA-DR (CD4(+)DR(+)) and naïve CD4(+)CD45RA(+) T cells in basal conditions. GA treatment induced a specific and significant decrease of circulating CD19(+) B cells. Naïve-to-treatment RRMS patients also showed a significantly higher number of CD4(+) T cells with a memory phenotype (CD4(+)CD45RO(+)) whose peripheral frequency was not affected by GA treatment. These changes over time associated with a higher serum concentration of leptin and lower levels of MPO. GA treatment also reduced significantly the circulating levels of sCD40-L and sTNF-R overtime. CONCLUSIONS Our data suggest that the clinical outcome of GA treatment is associated with changes in immune cell subpopulations and modulation of specific immunometabolic markers. These data add substantial evidence of the immune modulating effect of GA during RRMS and could be of relevance in understanding the pathogenesis of disease and its follow-up.

Sinus Venous Stenosis–Associated Idiopathic Intracranial Hypertension Without Papilledema as a Powerful Risk Factor for Progression and Refractoriness of Headache

Data from two recent studies strongly support the hypothesis that idiopathic intracranial hypertension without papilledema (IIHWOP) could represent a powerful risk factor for the progression of pain in primary headache individuals. The first study highlights that an asymptomatic IIHWOP is much more prevalent than believed in the general population and occurs only in central venous stenosis carriers. In the second study, about one half of a large consecutive series of unresponsive primary chronic headache patients shows significant sinus venous stenosis. A continuous or intermittent IIHWOP was detectable in 91% of this subgroup and in no patient with normal venography. Moreover, after the lumbar puncture, a 2- to 4-week improvement in headache frequency was observed in most of the intracranial hypertensive patients. These findings strongly suggest that patients prone to primary headache who carry central venous outflow abnormalities are at high risk of developing a comorbid IIHWOP, which in turn is responsible for the progression and the unresponsiveness of the pain. Based on the available literature data, we propose that central sinus stenosis–related IIHWOP, although highly prevalent among otherwise healthy people, represents an important modifiable risk factor for the progression and refractoriness of pain in patients predisposed to primary headache. The mechanism could refer to up to one half of the primary chronic headache patients with minimal response to treatments referring to specialized headache clinics. Due to the clinical and taxonomic relevance of this hypothesis further studies are urgently needed.

Sinus venous stenosis-associated IIHWOP is a powerful risk factor for progression and refractoriness of pain in primary headache patients: a review of supporting evidences.

Reported prevalence of idiopathic intracranial hypertension without papilledema (IIHWOP) in series of patients with chronic or transformed migraine is significantly higher than expected; yet, IIHWOP is not included among the risk factors for migraine progression. However, several studies provided evidences suggesting that IIHWOP could represent a possible, largely underestimated, risk factor for progression of pain in migraine and, possibly, in other primary headaches. Data from two recent studies, albeit aimed to different end-points, strongly support this hypothesis. In the first study, conducted on a large series of neurological patients without any sign or symptom of raised intracranial pressure (ICP), including chronic headache, the prevalence of bilateral central venous stenosis at magnetic resonance venography (MRV) was 23% and an IIHWOP at opening pressure was found in 48% of this subgroup (11% of the whole sample) while it was not detected in any of the subjects with normal MRV. This indicates that IIHWOP may be much more prevalent than believed in general population and that it can run without any symptom or sign of raised ICP in most of affected subjects. In the second paper, sinus venous stenosis-associated IIHWOP has been found in about one half of a large chronic primary headache patients series with poor response to treatments and in none of those with normal MRV. Moreover, after the diagnostic lumbar puncture, a transient improvement of headache frequency has been observed in the majority of intracranial hypertensive chronic headache subjects. Taken together, the data of these two recent papers rise the following hypothesis: (1) asymptomatic IIHWOP is much more prevalent than expected in general population; (2) IIHWOP is a powerful and largely unrecognized risk factor for progression of pain in primary headache patients; (3) sinus venous stenosis at MRV is a reliable predictor of raised intracranial hypertension also in asymptomatic patients; (4) sinus venous stenosis has a causative role in IIH pathophysiology. These assumptions share a potential high clinical impact and need to be urgently tested in adequately designed controlled studies.

Efficacy of levetiracetam in hemifacial spasm: a case report.

Objective: Safety and efficacy of levetiracetam in a man with hemifacial spasm (HFS). Methods and Results: The present work reports the case of a 54-year-old man with a 5-year history of left-sided HFS who, after treatment with levetiracetam (dosage, 500 mg bid), showed a marked improvement in condition. After 7 months of therapy with levetiracetam, the patient remains symptom free with no adverse drug reactions. Conclusions: Levetiracetam proved its effectiveness and safety in the treatment of a case of HFS. Nevertheless, there is a need for further controlled studies with larger samples.

Cortical spreading depression and central pain networks in trigeminal nuclei modulation: time for an integrated migraine pathogenesis perspective

The role of the cortical spreading depression (CSD)-dependent trigeminovascular activation in migraine etiopathogenesis, long considered paradigmatic, has remained substantially unproven in humans. The parallel advancement of functional neuroimaging techniques promoted the extensive exploration of the brain networks involved in pain processing in search of a possible central migraine generator. However, despite initial enthusiasms, it has not been possible to clarify whether the functional central “markers” of pain observed in primary headaches could be considered as causative or just the neural correlates of the ongoing pain. Nonetheless, our knowledge on the complex interactions between CSD, neurogenic inflammation, peripheral trigeminovascular input, central cortico-trigeminal nuclei direct modulation and pain processing and limbic system networks has enormously grown, allowing the reconceptualisation of migraine from a neurovascular to a pure neurolimbic pain disorder, therefore relocating it in the much broader frame of the brain and whole organism homeostatic control. In this work, the available evidences currently supporting the relevance of CSD, of peripheral trigeminovascular input and of direct cortico-trigeminal nuclei modulation in migraine pathogenesis are reviewed in the light of a possible integrated migraine etiopathogenetic perspective.

Glossopharyngeal neuralgia as onset of multiple sclerosis.

Objectives and MethodsGlossopharyngeal 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 DiscusionWe suggest the presence of demyelinating areas at the nerve root entry zone as principal trigger mechanism.

Anatomical and functional retinal changes in multiple sclerosis.

AimsThe aims of this study was to report anatomical changes of the ganglion cell complex (GCC), retinal nerve fiber layer (RNFL) thickness, and macular volume in patients with multiple sclerosis (MS). We also investigated the correlation between anatomical and functional changes in terms of visual acuity and macular sensitivity investigated and visual fields.MethodsProspective comparative study included 105 eyes of 53 consecutive patients. The patients were divided into two groups: group A included 56 eyes of 28 patients with diagnosis of MS; group B involved 49 eyes of 25 healthy patients. The examination included Goldmann tonometry, biomicroscopic and fundus oculi examination, retinography, GCC examination, circumpapillary RNFL (cpRNFL), and macular volume. The functional test included measurement of best-corrected visual acuity (BCVA), visual field, and MP.ResultsMS group showed a significant reduced GCC, cpRNFL, macular volume, BCVA, visual field, and macular sensitivity compared with the control group (P<0.001). This reduction was more representative (P<0.001) in patients with MS complicated by optic neuritis (ON). We found in the MS group a strong correlation between GCC thickness and macular volume (r2=0.59, P<0.001) and also between GCC and RNFL thickness (r2=0.48, P<0.001). There was also a correlation between macular sensitivity and macular volume reduction (r2=0.25, P<0.001) and also between RNFL and macular volume (r2=0.43, P<0.001).ConclusionsThe significant statistical evidence and the strong correlation between anatomical and functional parameters support the use of OCT and MP in the evaluation, treatment, and follow-up of patients diagnosed with MS.