Domenico Plantone

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.

Acute Necrotizing Encephalopathy during Novel Influenza A (H1N1) Virus Infection

A novel swine‐origin influenza A (H1N1) virus was recently identified in Mexico. Some cases of infection with neurological complications have been reported to date. We report a case of acute necrotizing encephalopathy associated with the novel H1N1 virus in a 2‐year‐old European girl who suddenly developed fever, seizures, and altered mental status. Brain and spinal cord magnetic resonance imaging showed bilateral symmetrical lesions of the insulae, thalami, geniculate bodies, and pons tegmentum suggestive of an acute necrotizing encephalopathy. An involvement of meninges and spinal cord was observed configuring an acute necrotizing meningoencephalomyelitis. ANN NEUROL 2010;68:111–114

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.

Cerebellar degeneration associated with mGluR1 autoantibodies as a paraneoplastic manifestation of prostate adenocarcinoma

Subacute cerebellar degeneration associated with metabotropic glutamate receptor type 1 (mGluR1) autoantibodies is an uncommon syndrome known to be part of the spectrum of paraneoplastic cerebellar degenerations associated with neuronal autoantibodies. We describe a patient with prostate adenocarcinoma who developed a subacute cerebellar ataxia. Autoantibodies specific to mGluR1 were detected in patients serum and cerebrospinal fluid (CSF). Immunohistochemistry analyses of patients prostate adenocarcinoma revealed abundant mGluR1 expression in luminal acinar epithelial cells and binding of patients IgGs to tumoral mGluR1. These findings suggest that cerebellar degeneration associated with mGluR1 antibodies can be a paraneoplastic accompaniment of prostate adenocarcinoma.

Tissue-Infiltrating Lymphocytes Analysis Reveals Large Modifications of the Duodenal “Immunological Niche” in Coeliac Disease After Gluten-Free Diet

OBJECTIVES:The role of T lymphocytes in the pathogenesis of Celiac disease (CD) is well established. However, the mechanisms of T-cell involvement remain elusive. Little is known on the distribution of T subpopulations: T-regulatory (Treg), Th17, CD103, and CD62L cells at disease onset and after gluten-free diet (GFD). We investigated the involvement of several T subpopulations in the pathogenesis of CD.METHODS:We studied T cells both in the peripheral blood (PB) and the tissue-infiltrating lymphocytes (TILs) from the mucosa of 14 CD patients at presentation and after a GFD, vs. 12 controls.RESULTS:Our results extend the involvement of Treg, Th1, and Th17 cells in active CD inflammation both in the PB and at the TILs. At baseline, Tregs, Th1, and Th17 cells are significantly higher in active CD patients in TILs and PB. They decreased after diet. Moreover, CD62L+ TILs were increased at diagnosis as compared with GFD patients.CONCLUSIONS:Our data show significant modifications of the above-mentioned subpopulations both in the PB and TILs. The increase of suppressive Tregs in active CD both in the PB and TILs is intriguing. T lymphocytes are known to have a crucial role in the pathogenesis of CD. We have shown that gluten trigger results in systemic recruitment of T lymphocytes, the unbalance between pro-inflammatory and anti-inflammatory populations and the increase of CD62L+ T cells in TILs. Our results delineate a more complete picture of T-cell subsets in active vs. GFD disease. Our data of T-cell subpopulations, combined with known data on cytokine production, support the concept that duodenal micro-environment acts as an immunological niche and this recognition may have an important role in the diagnosis, prognosis and therapeutical approach of CD.

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.

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

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)‐γ, 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‐γ 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.

Teaching NeuroImages: Basal ganglia involvement in facio-brachial dystonic seizures associated with LGI1 antibodies

A 30-year-old man developed right faciobrachial dystonic seizures (FBDS).1 Ictal and interictal EEGs were normal. CSF analysis was unremarkable. Brain MRI revealed a gadolinium-enhancing lesion involving the left caudate and globus pallidus (figure 1). Leucine-rich glioma inactivated protein 1 (LGI1) antibodies were detected in the serum. Total-body CT scan revealed no malignancies. The patient underwent 5 cycles of plasmapheresis followed by long-term steroid therapy with complete benefit. A brain MRI performed after 5 months showed reduction of contrast enhancement (figure 2). LGI1, a secreted protein complexed with voltage-gated potassium channels, is highly expressed in the neocortex and hippocampus.2 LGI1 mutations have been described in patients with autosomal dominant partial epilepsy with auditory features (ADPEAF). Our patient had no clinical features of ADPEAF. Whether FBDS can be classified as epilepsy or dystonia is a matter of debate.3 The involvement of basal ganglia described in our patient can be relevant to the ongoing debate.