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Analysis of lymphocytic DNA damage in early multiple sclerosis by automated γ-H2AX and 53BP1 foci detection: A case control study

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Item Type:Article
Title:Analysis of lymphocytic DNA damage in early multiple sclerosis by automated γ-H2AX and 53BP1 foci detection: A case control study
Creators Name:Rasche, L. and Heiserich, L. and Behrens, J.R. and Lenz, K. and Pfuhl, C. and Wakonig, K. and Gieß, R.M. and Freitag, E. and Eberle, C. and Wuerfel, J. and Doerr, J. and Bauer, P. and Bellmann-Strobl, J. and Paul, F. and Roggenbuck, D. and Ruprecht, K.
Abstract:Background: In response to DNA double-strand breaks, the histone protein H2AX becomes phosphorylated at its C-terminal serine 139 residue, referred to as {gamma}-H2AX. Formation of {gamma}-H2AX foci is associated with recruitment of p53-binding protein 1 (53BP1), a regulator of the cellular response to DNA double-strand breaks. {gamma}-H2AX expression in peripheral blood mononuclear cells (PBMCs) was recently proposed as a diagnostic and disease activity marker for multiple sclerosis (MS). Objective: To evaluate the significance of {gamma}-H2AX and 53BP1 foci in PBMCs as diagnostic and disease activity markers in patients with clinically isolated syndrome (CIS) and early relapsing-remitting MS (RRMS) using automated {gamma}-H2AX and 53BP1 foci detection. Methods: Immunocytochemistry was performed on freshly isolated PBMCs of patients with CIS/early RRMS (n = 25) and healthy controls (n = 27) with {gamma}-H2AX and 53BP1 specific antibodies. Nuclear {gamma}-H2AX and 53BP1 foci were determined using a fully automated reading system, assessing the numbers of {gamma}-H2AX and 53BP1 foci per total number of cells and the percentage of cells with foci. Patients underwent contrast enhanced 3 Tesla magnetic resonance imaging (MRI) and clinical examination including expanded disability status scale (EDSS) score. {gamma}-H2AX and 53BP1 were also compared in previously frozen PBMCs of each 10 CIS/early RRMS patients with and without contrast enhancing lesions (CEL) and 10 healthy controls. Results: The median (range) number of {gamma}-H2AX (0.04 [0-0.5]) and 53BP1 (0.005 [0–0.2]) foci per cell in freshly isolated PBMCs across all study participants was low and similar to previously reported values of healthy individuals. For both, {gamma}-H2AX and 53BP1, the cellular focus number as well as the percentage of positive cells did not differ between patients with CIS/RRMS and healthy controls. {gamma}-H2AX and 53BP1 levels neither correlated with number nor volume of T2-weighted lesions on MRI, nor with the EDSS. Although {gamma}-H2AX, but not 53BP1, levels were higher in previously frozen PBMCs of patients with than without CEL, {gamma}-H2AX values of both groups overlapped and {gamma}-H2AX did not correlate with the number or volume of CEL. Conclusion: {gamma}-H2AX and 53BP1 foci do not seem to be promising diagnostic or disease activity biomarkers in patients with early MS. Lymphocytic DNA double-strand breaks are unlikely to play a major role in the pathophysiology of MS.
Source:PLoS ONE
ISSN:1932-6203
Publisher:Public Library of Science (U.S.A.)
Volume:11
Number:1
Page Range:e0147968
Date:28 January 2016
Official Publication:https://doi.org/10.1371/journal.pone.0147968
PubMed:View item in PubMed

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