title: Expression ratios of the Bcl-2 family proteins and disease activity in multiple sclerosis.
abstract: There is emerging evidence that failure of apoptosis (programmed cell death) of potentially pathogenic T lymphocytes may be involved in the pathogenesis of multiple sclerosis (MS). The commitment of T lymphocytes to die is partly regulated by the Bcl-2 family proteins, which act as a checkpoint upstream of mitochondrial dysfunction. These proteins include the death antagonists Bcl-2 and Bcl-X(L), and death agonists Bax and Bad. Recent studies suggest that altered expression of Bcl-2 family proteins in T lymphocytes is involved in promoting cellular resistance to apoptosis in patients with MS. However, the relationship between these alterations in Bcl-2 proteins expression and clinical disease activity has not yet been evaluated. In this study, we analyzed the expression ratios of pro- to anti-apoptosis Bcl-2 family proteins in patients with clinically active MS and compared results to corresponding ratios in patients with stable MS and relevant control groups. We observed a significant reduction in the expression ratios of pro- to anti-apoptosis Bcl-2 members in peripheral lymphocytes from patients with active MS when compared to corresponding ratios in patients with stable MS or other controls. This imbalance in the expression ratios of pro- and anti-apoptosis proteins was functionally active in reducing cellular susceptibility to apoptosis in active MS. It also correlated with clinical features of disease activity, such as the number of gadolinium-enhancing MRI lesions and clinical relapses. Our findings indicate that dysregulated expression of Bcl-2 family proteins in peripheral lymphocytes is a feature of clinically active multiple sclerosis.
authors.affiliation: Department of Neuroimmunology, Guy's, King's and St. Thomas' School of Medicine, Guy's Hospital, London SE1 1UL, UK. m.k.sharief@kcl.ac.uk
authors.forename: M K
authors.initials: MK
authors.lastname: Sharief
authors.forename: H
authors.initials: H
authors.lastname: Matthews
authors.forename: M A
authors.initials: MA
authors.lastname: Noori
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D002352:Carrier Proteins / Q000097:blood / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D003574:Cytochrome c Group / Q000097:blood; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D011518:Proto-Oncogene Proteins / Q000097:blood / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000097:blood / Q000276:immunology*; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D019014:fas Receptor / Q000097:blood / Q000276:immunology
chemical_list: C494819:BAD protein, human; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D002352:Carrier Proteins; D003574:Cytochrome c Group; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D019014:fas Receptor