Alessandro Marti

CD8+ T Cells in Facioscapulohumeral Muscular Dystrophy Patients with Inflammatory Features at Muscle MRI

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited disease, and although strongly suggested, a contribution of inflammation to its pathogenesis has never been demonstrated. In FSHD patients, we found by immunohistochemistry inflammatory infiltrates mainly composed by CD8+ T cells in muscles showing hyperintensity features on T2-weighted short tau inversion recovery magnetic resonance imaging (T2-STIR-MRI) sequences. Therefore, we evaluated the presence of circulating activated immune cells and the production of cytokines in patients with or without muscles showing hyperintensity features on T2-STIR-MRI sequences and from controls. FSHD patients displaying hyperintensity features in one or more muscles showed higher CD8+pSTAT1+, CD8+T-bet+ T cells and CD14+pSTAT1+, CD14+T-bet+ cells percentages and IL12p40, IFNγ and TNFα levels than patients without muscles displaying hyperintense features and controls. Moreover, the percentages of CD8+pSTAT1+, CD8+T-bet+ and CD14+pSTAT1+ cells correlated with the proportion of muscles displaying hyperintensity features at T2-STIR sequences. These data indicate that circulating activated immune cells, mainly CD8+ T cells, may favour FSHD progression by promoting active phases of muscle inflammation.

Regulatory T cells fail to suppress CD4+T-bet+ T cells in relapsing multiple sclerosis patients

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and a defect in the regulatory T‐cell subset seems to be involved in the pathogenesis of the disease. Foxp3 is a transcription factor that is selectively expressed in CD4+ CD25+ regulatory T cells and is required for their development and function. T‐bet is a key transcription factor for the development of T helper 1 (Th1) cells. We found that both the percentage of circulating CD4+ CD25+ Foxp3+ cells and Foxp3 expression were lower in relapsing‐remitting (RR) MS patients during relapses than during remission. Otherwise, the percentage of CD4+ T‐bet+ T cells and T‐bet expression in CD4+ T cells were higher in relapsing than in remitting RRMS patients. CD4+ CD25+ T cells both from relapsing and from remitting RRMS patients showed significantly less capacity than corresponding cells from healthy subjects to suppress autologous CD4+ CD25− T‐cell proliferation, despite a similar Foxp3 expression level. CD4+ CD25+ T cells from healthy subjects and patients in remission clearly reduced T‐bet mean fluorescence intensity (MFI) in CD4+ CD25− T cells up to a ratio of 1:10, whereas CD4+ CD25+ T cells from patients in relapse were able to reduce T‐bet expression only at a high ratio. Our data indicate that the increased number of regulatory T (T‐reg) cells and the increased Foxp3 expression in circulating CD4+ CD25+ T cells may contribute to the maintenance of tolerance in the remission phase of MS. Moreover, the inhibitory capacity of CD4+ CD25+ T cells seems to be impaired in relapsing patients under inflammatory conditions, as shown by the high levels of T‐bet expression in CD4+ T cells.

IL17 and IFNgamma production by peripheral blood mononuclear cells from clinically isolated syndrome to secondary progressive multiple sclerosis.

We evaluated the spontaneous IL17, IFNgamma and IL10 production by peripheral blood mononuclear cells from patients affected by clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) both in acute phase and in remission, relapsing remitting MS (RRMS) both in relapse and in remission, not-relapsing secondary progressive MS (SPMS) and controls. We observed higher IL17 levels in CIS patients both in acute phase and in remission than in SPMS patients and controls. On the contrary no difference in IL17 production was observed among RRMS patients and CIS, SPMS patients and controls. IFNgamma levels were significantly higher in CIS patients in acute phase than in CIS and RRMS patients in remission, SPMS patients and controls. Moreover, we observed higher IFNgamma spontaneous production in relapsing RRMS patients than in remitting RRMS and SPMS patients and controls. IL10 levels were significantly higher in remitting CIS and in relapsing RRMS patients than in SPMS patients and controls. There was no difference in IFNgamma, IL10 and IL17 levels between SPMS patients and controls. Our data suggest that IL17 might play a crucial role mainly in the early phase of MS, while IFNgamma seems to be involved both in the early phase and in the following relapses of the disease.

Increased CD4(+)CD25(+)Foxp3(+) T Cells in Peripheral Blood of Celiac Disease Patients: Correlation with Dietary Treatment.

Regulatory CD4+ CD25+Foxp3+ T cells are involved in the regulation of immune response and inhibit protective antitumor immunity. Celiac disease (CD), a food gluten-sensitive enteropathy, is considered a T-cell-mediated autoimmune disease and is generally associated with an overall increased risk of cancer in CD patients. We observed a higher percentage of circulating CD4+CD25+Foxp3+ T cells and an increased Foxp3 expression in CD4+CD25+ T cells from untreated than from treated CD patients. In co-culture, CD4+CD25+ T cells from both treated and untreated CD patients significantly suppressed the proliferation of autologous CD4+CD25(-) T cells similarly to values in healthy subjects. Our study suggests that Treg proportion and Foxp3 expression in circulating CD4+CD25+ T cells could justify the increased global risk of malignancy in CD population and support the efficacy of lifelong gluten-free diet in the reduction of the cancer risk.

Distinctive clinical and neuroimaging characteristics of longitudinally extensive transverse myelitis associated with aquaporin-4 autoantibodies

Longitudinally extensive transverse myelitis (LETM) is a characteristic feature of Neuromyelitis Optica (NMO), but it can also occur in several other inflammatory diseases of the central nervous system (CNS). An IgG autoantibody that binds to aquaporin-4 (AQP4), the predominant water channel of the CNS, is a reliable biomarker of the NMO spectrum disorders, and if detected predicts the recurrence of the myelitis. In this study, we compared the clinical and neuroimaging characteristics of AQP4-IgG+ and AQP4-IgG− LETM patients. Thirty-seven first-ever LETM patients were retrospectively evaluated and divided into two groups according to the presence of AQP4 autoantibodies. AQP4-IgG was detected in the serum and in the cerebrospinal fluid of sixteen patients. The female to male ratio was higher in AQP4-IgG+ patients. Intractable nausea and vomiting and paroxysmal tonic spasms often accompanied the LETM in AQP4-IgG+ patients. T2-weighted spinal cord MRI revealed that inflammatory lesions extending into the brainstem and involving the central grey matter occurred more frequently in AQP4-IgG+ LETM patients. Hypointense lesions on T1-weighted spinal cord MRI were detected more frequently in the seropositive group, and their presence correlated with attack severity. In conclusion, this study provides clinical and spinal cord neuroimaging clues that can help distinguishing AQP4-IgG+ LETM patients.

CD4+T-bet+, CD4+pSTAT3+ and CD8+T-bet+ T cells accumulate in peripheral blood during NZB treatment.

Circulating T cells and monocytes expressing T-bet, pSTAT1 and pSTAT3 increase in relapsing–remitting multiple sclerosis (RRMS) during relapse. Natalizumab (NZB) is an effective drug in RRMS, but exacerbation of the disease after its discontinuation has been described in some patients. The aim of this research was to study the effect of NZB treatment on circulating lymphomonocyte subpopulations expressing T-bet, pSTAT1, pSTAT3 and CD4+CD25+Foxp3+ regulatory T cells. Flow cytometry was used to evaluate the percentages of circulating CD4+ and CD8+ T cells, CD14+ monocytes and B cells expressing T-bet, pSTAT1, and pSTAT3, and CD4+CD25+Foxp3+ regulatory T cells from RRMS patients before and after 6–12 NZB infusions. In NZB-treated RRMS patients, the percentages of CD4+pSTAT1+ and CD8+pSTAT1+ T cells, CD14+pSTAT1+ monocytes, CD4+T-bet+, CD8+T-bet+ and CD4+pSTAT3+ T cells and CD14+pSTAT3+ monocytes increased after 12 drug infusions and were similar to those observed in untreated relapsing RRMS patients. Otherwise in vitro NZB exposure of peripheral blood mononuclear cells from untreated RRMS patients and controls had no effect. It was concluded that NZB treatment determines an accumulation of CD4+pSTAT1+, CD8+pSTAT1+, CD4+T-bet+, CD8+T-bet+ and CD4+STAT3+ T cells in peripheral blood that may account for the exacerbation of the disease observed in some patients after the discontinuation of the drug.

Movement disorders in multiple sclerosis: Causal or coincidental association?

Despite the relatively frequent involvement of the basal ganglia and subthalamic nucleus by multiple sclerosis (MS) plaques, movement disorders (MD), other than tremor secondary to cerebellar or brainstem lesions, are uncommon clinical manifestations of MS. MD were present in 12 of 733 patients with MS (1.6%): three patients had parkinsonism, two blepharospasm, five hemifacial spasm, one hemidystonia, and one tourettism. MD in patients with MS are often secondary to demyelinating disease. Also in cases without response to steroid treatment and demyelinating lesions in critical regions, it is not possible to exclude that MD and MS are causally related.

Epstein-Barr virus antibodies in serum and cerebrospinal fluid from Multiple sclerosis, Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Amyotrophic Lateral Sclerosis

Elevated anti-Epstein-Barr virus (EBV) antibody levels are present in serum of Multiple sclerosis (MS) patients but literature lacks of studies comparing anti-EBV antibody levels between MS and other neurological diseases. We evaluate anti-VCA IgG and IgM, anti-EBNA1 IgG, anti-Cytomegalovirus IgG and IgM titres in serum and cerebrospinal fluid (CSF) of 267 MS, 50 Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) and 88 Amyotrophic Lateral Sclerosis (ALS) patients. We found increased titres of anti-EBV-IgG in serum and CSF of MS subjects as compared to CIDP and ALS patients thus providing additional evidence for a possible involvement of EBV in MS.

The detection of neural autoantibodies in patients with antiepileptic-drug-resistant epilepsy predicts response to immunotherapy

The detection of antibodies binding neural antigens in patients with epilepsy has led to the definition of ‘autoimmune epilepsy’. Patients with neural antibodies not responding to antiepileptic drugs (AEDs) may benefit from immunotherapy. Aim of this study was to evaluate the frequency of autoantibodies specific to neural antigens in patients with epilepsy and their response to immunotherapy.

The persistency of high levels of pSTAT3 expression in circulating CD4+ T cells from CIS patients favors the early conversion to clinically defined multiple sclerosis

Not all patients with clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS) develop clinically defined MS (CDMS). At first clinical event we observed increased production of IL17, IFNgamma and IL10 by peripheral blood mononuclear cells from patients with CIS that remained high in remission. In CD4+ T cells pSTAT3 expression was higher in patients who subsequently converted to CDMS than in patients who did not and controls. The persistency of high levels of pSTAT3 in circulating CD4+ T cells from CIS patients after the first clinical event may favor the early conversion to CDMS.