Evaluating the contribution of the gene TARDBP in Italian patients with amyotrophic lateral sclerosis

Background and objectives: Genetic variants in the gene TARDBP, encoding TDP-43 protein, are associated with amyotrophic lateral sclerosis (ALS) in familial (fALS) and sporadic (sALS) cases. Objectives of this study were to assess the contribution of TARDBP in a large cohort of Italian ALS patients, to determine the TARDBP-associated clinical features and to look for genotype-phenotype correlation and penetrance of the mutations.Methods: A total of 1992 Italian ALS patients (193 fALS and 1799 sALS) were enrolled in this study. Sanger sequencing of TARDBP gene was performed in patients and, when available, in patients' relatives.Results: In total, 13 different rare variants were identified in 43 index cases (10 fALS and 33 sALS) with a cumulative mutational frequency of 2.2% (5.2% of fALS, 1.8% of sALS). The most prevalent variant was the p.A382T followed by the p.G294V. Cognitive impairment was detected in almost 30% of patients. While some variants, including the p.G294V and the p.G376D, were associated with restricted phenotypes, the p.A382T showed a marked clinical heterogeneity regarding age of onset, survival and association with cognitive impairment. Investigations in parents, when possible, showed that the variants were inherited from healthy carriers and never occurred de novo.Conclusions: In our cohort, TARDBP variants have a relevant frequency in Italian ALS patients and they are significantly associated with cognitive impairment. Clinical presentation is heterogeneous. Consistent genotype-phenotype correlations are limited to some mutations. A marked phenotypic variability characterizes the p.A382T variant, suggesting a multifactorial/oligogenic pathogenic mechanism

CD8(+)Foxp3(+) T cells in peripheral blood of relapsing-remitting multiple sclerosis patients

A defect of CD4(+) regulatory T cells (Treg) seems to be involved in the pathogenesis of multiple sclerosis (MS). Besides Treg, CD8(+) T cells also can suppress the immune response. Forkhead box p3 (Foxp3) is known to program the acquisition of suppressive capacities in CD4(+) T cells and recent studies showed that in vitro antigen activation leads to Foxp3 expression in CD8(+) T cells, gaining of suppressive activity. By flow cytometry we found a lower percentage of circulating CD8(+)Foxp3(+) T cells in relapsing than in remitting patients with MS and in controls. No significant differences were observed in CD8(+)Foxp3(+) T cell percentage between healthy subjects and patients in remission. Our data suggest that peripheral CD8(+)Foxp3(+) T cells may play a role in the maintenance of tolerance in MS. (C) 2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved

Circulating CD8(+)CD56(-)perforin(+) T cells are increased in multiple sclerosis patients

Relapsing-remitting multiple sclerosis (RRMS), secondary progressive (SP)MS and primary progressive (PP)MS patients showed higher percentages of circulating CD8(+)CD56(-)perforin(+) T cells than controls whereas only relapsing RRMS and PPMS patients showed higher perforin expression in CD8(+)CD56(-) T cells than controls. MS patients with EDSS >= 3 showed higher percentage of CD8(+)CD56(-)perforin(+) T cells than patients with EDSS <3 and controls whereas patients with EDSS <3 showed higher percentage of this T cell subpopulation than controls. Our data show that MS is characterized by a dysregulation of CD8(+)CD56(-)perforin(+) T cells that may play a role in the development of disability. (C) 2011 Elsevier B.V. All rights reserved

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

Type 1 immune response in progressive multiple sclerosis

The aim of the study was to evaluate the type-1 immune response by analyzing T-bet expression in circulating T and B cells in Primary Progressive (PP) and Secondary Progressive (SP) Multiple Sclerosis (MS) patients. We found higher percentages of circulating CD4(+)T-bet(+) and CD8(+)T-bet(+) T cells in SPMS and PPMS than in remitting-relapsing MS patients and controls. Moreover, in SPMS, we observed a positive correlation between the percentages of circulating CD4(+)T-bet(+) or CD8(+)T-bet(+) T cells and disease severity. The increased percentages of Th1 and Tc1 cells suggest that MS progressive forms, unlike RRMS, are characterized by a permanent peripheral type-1 immune activation. (C) 2012 Elsevier B.V. All rights reserved

Brainstem and spinal cord involvement in a paraneoplastic syndrome associated with anti-Yo antibody and breast cancer

No abstract availabl

T-bet and pSTAT-1 expression in PBMC from coeliac disease patients: new markers of disease activity

P>Coeliac disease (CD) is considered a T cell-mediated autoimmune disease, and up-regulation of T-bet and phosphorylated signal transducers and activators of transcription (pSTAT)1, key transcription factors for the development of T helper type 1 (Th1) cells, has been described in the mucosa of patients with untreated CD. Using transcription factor analysis, we investigated whether T-bet and pSTAT1 expressions are up-regulated in the peripheral blood of CD patients and correlate with disease activity. Using flow cytometry, we analysed T-bet, pSTAT1 and pSTAT3 expression in CD4(+), CD8(+) T cells, CD19(+) B cells and monocytes from peripheral blood of 15 untreated and 15 treated CD patients and 30 controls, and longitudinally in five coeliac patients before and after dietary treatment. We evaluated using enzyme-linked immunosorbent assay (ELISA), interferon (FN)-gamma, interleukin (IL)-17 and IL-10 production by peripheral blood mononuclear cell (PBMC) cultures. T-bet expression in CD4(+), CD8(+) T cells, CD19(+) B cells and monocytes and IFN-gamma production by PBMC was higher in untreated than in treated CD patients and controls. pSTAT1 expression was higher in CD4(+)T cells, B cells and monocytes from untreated than from treated CD patients and controls. pSTAT3 was increased only in monocytes from untreated patients compared with CD-treated patients and controls. The data obtained from the longitudinal evaluation of transcription factors confirmed these results. Flow cytometric analysis of pSTAT1 and T-bet protein expression in peripheral blood mononuclear cells could be useful and sensible markers in the follow-up of CD patients to evaluate disease activity and response to dietary treatment