T cell gene expression profiling identifies distinct subgroups of Japanese multiple sclerosis patients

109

Clinically isolated syndrome (CIS) refers to the earliest clinical manifestation of multiple sclerosis (MS). Currently there are no prognostic biological markers that accurately predict conversion of CIS to clinically definite MS (CDMS). Furthermore, the earliest molecular events in MS are still unknown. We used microarrays to study gene expression in naïve CD4 ؉ T cells from 37 CIS patients at time of diagnosis and after 1 year. Supervised machine-learning methods were used to build predictive models of disease conversion. We identified 975 genes whose expression segregated CIS patients into four distinct subgroups. A subset of 108 genes further discriminated patients in one of these (group 1) from other CIS patients. Remarkably, 92% of patients in group 1 converted to CDMS within 9 months. Consistent down-regulation of TOB1, a critical regulator of cell proliferation, was characteristic of group 1 patients. Decreased TOB1 expression at the RNA and protein levels also was confirmed in experimental autoimmune encephalomyelitis. Finally, a genetic association was observed between TOB1 variation and MS progression in an independent cohort. These results indicate that CIS patients at high risk of conversion have impaired regulation of T cell quiescence, possibly resulting in earlier activation of pathogenic CD4 ؉ cells.clinically isolated syndrome ͉ gene expression M ultiple sclerosis (MS) is a common disabling neurologic disease of young adults (1). Most patients with MS initially present with a clinically isolated syndrome (CIS) caused by an inflammatory demyelinating insult in the central nervous system (CNS). Approximately one-third of CIS patients progress to clinically definite MS (CDMS) within 1 year after diagnosis, and approximately half do so after 2 years (2, 3). It is estimated that Ϸ10% of CIS patients remain free of further demyelinating attacks and neurological complications even in the presence of radiological evidence of white matter lesions (4). Although structural neuroimaging studies are invaluable in the diagnosis and clinical surveillance of MS (3, 5), there currently is no biological marker that accurately predicts MS conversion in CIS patients. Individualized early prognosis and prediction of CDMS would be of substantial value because patients at high risk for rapid progression could be offered disease-modifying therapy, an approach shown to be beneficial in early MS (2). In addition, CIS patients represent a unique population for the study of early molecular events that lead to demyelination and axonal degeneration.In this article we describe the analysis of gene expression in naïve (unstimulated) CD4 ϩ T cells isolated from well characterized CIS patients at the time of diagnosis and after 1 year and show a distinct molecular signature that differentiates CIS patients from healthy controls. The expression of a subset of those genes successfully identifies a group of patients at high risk of MS conversion. Molecular changes observed in individuals who rapidly converted to MS are consistent ...

Section: Gene Expression Microarray Analysis Was Performed In Negativsupporting

confidence: 93%

Abrogation of T cell quiescence characterizes patients at high risk for multiple sclerosis after the initial neurological event

Corvol

Pelletier

Henry

et al. 2008

109

“…However, it was recently demonstrated that peripheral T cells from MS and healthy subjects significantly differ in surface phenotype or gene expression profiling (17,23,28). Using cDNA microarray, we have identified NR4A2 as a gene most significantly up-regulated in the peripheral T cells of MS (17).…”

Section: Discussionmentioning

confidence: 88%

“…We analyzed gene expression profiles of peripheral blood T cells from MS and control subjects (17,23). Comparison of the patients and healthy donors has revealed that 286 of 1,263 genes are differentially expressed between MS and controls.…”

Section: Up-regulation Of Nr4a2 In Peripheral Blood T Cells Of Msmentioning

confidence: 99%

Orphan nuclear receptor NR4A2 expressed in T cells from multiple sclerosis mediates production of inflammatory cytokines

Doi¹,

Oki²,

Ozawa³

et al. 2008

Self Cite

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) mediated by Th17 and Th1 cells. DNA microarray analysis previously showed that NR4A2, an orphan nuclear receptor, is strongly up-regulated in the peripheral blood T cells of MS. Here, we report that NR4A2 plays a pivotal role for mediating cytokine production from pathogenic T cells. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, NR4A2, was selectively up-regulated in the T cells isolated from the CNS. Strikingly, a forced expression of NR4A2 augmented promoter activities of IL-17 and IFN-␥ genes, leading to an excessive production of these cytokines. Conversely, treatment with siRNA for NR4A2, resulted in a significant reduction in the production of IL-17 and IFN-␥. Furthermore, treatment with NR4A2 siRNA reduced the ability of encephalitogenic T cells to transfer EAE in recipient mice. Thus, NR4A2 is an essential transcription factor for triggering the inflammatory cascade of MS/EAE and may serve as a therapeutic target.

“…Fifty-eight genes were found to be downregulated significantly by cefuroxime, but most of these genes (56 of 58) were up-regulated by ampicillin. Interestingly, eight of these genes were reported to be down-regulated in the peripheral blood lymphocytes of multiple sclerosis patients in Israel (9), and 15 genes were down-regulated in the T cells of multiple sclerosis patients in Japan (10). The products of these genes included cytokines; chemokines and their receptors; signaling molecules; and transcription factors (Table S2).…”

Section: Resultsmentioning

confidence: 99%

Beta-lactam antibiotics modulate T-cell functions and gene expression via covalent binding to cellular albumin

Mor

Cohen

2013

Recent work has suggested that beta-lactam antibiotics might directly affect eukaryotic cellular functions. Here, we studied the effects of commonly used beta-lactam antibiotics on rodent and human T cells in vitro and in vivo on T-cell–mediated experimental autoimmune diseases. We now report that experimental autoimmune encephalomyelitis and adjuvant arthritis were significantly more severe in rats treated with cefuroxime and other beta-lactams. T cells appeared to mediate the effect: an anti-myelin basic protein T-cell line treated with cefuroxime or penicillin was more encephalitogenic in adoptive transfer experiments. The beta-lactam ampicillin, in contrast to cefuroxime and penicillin, did not enhance encephalomyelitis, but did inhibit the autoimmune diabetes developing spontaneously in nonobese diabetic mice. Gene expression analysis of human peripheral blood T cells showed that numerous genes associated with T helper 2 (Th2) and T regulatory (Treg) differentiation were down-regulated in T cells stimulated in the presence of cefuroxime; these genes were up-regulated in the presence of ampicillin. The T-cell protein that covalently bound beta-lactam antibiotics was found to be albumin. Human and rodent T cells expressed albumin mRNA and protein, and penicillin-modified albumin was taken up by rat T cells, leading to enhanced encephalitogenicity. Thus, beta-lactam antibiotics in wide clinical use have marked effects on T-cell behavior; beta-lactam antibiotics can function as immunomodulators, apparently through covalent binding to albumin.