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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., Heiserich, L., Behrens, J.R., Lenz, K., Pfuhl, C., Wakonig, K., Gieß, R.M., Freitag, E., Eberle, C., Wuerfel, J., Doerr, J., Bauer, P., Bellmann-Strobl, J., Paul, F., 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 |
| 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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