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Tissue microarray methodology identifies complement pathway activation and dysregulation in progressive multiple sclerosis

Lookup NU author(s): Professor Claire Harris

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Blackwell Publishing Ltd, 2017.

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Abstract

© 2017 International Society of Neuropathology. The complement pathway has potential contributions to both white (WM) and grey matter (GM) pathology in Multiple Sclerosis (MS). A quantitative assessment of complement involvement is lacking. Here we describe the use of Tissue MicroArray (TMA) methodology in conjunction with immunohistochemistry to investigate the localization of complement pathway proteins in progressive MS cortical GM and subcortical WM. Antibodies targeting complement proteins C1q, C3b, regulatory proteins C1 inhibitor (C1INH, complement receptor 1 (CR1), clusterin, factor H (FH) and the C5a anaphylatoxin receptor (C5aR) were utilised alongside standard markers of tissue pathology. All stained slides were digitised for quantitative analysis. We found that numbers of cells immunolabelled for HLA-DR, GFAP, C5aR, C1q and C3b were increased in WM lesions (WML) and GM lesions (GML) compared to normal appearing WM (NAWM) and GM (NAGM), respectively. The complement regulators C1INH, CR1, FH and clusterin were more abundant in WM lesions, while the number of C1q+ neurons were increased and the number of C1INH+, clusterin+, FH+ and CR1+ neurons decreased in GM lesions. The number of complement component positive cells (C1q, C3b) correlated with complement regulator expression in WM, but there was no statistical association between complement activation and regulator expression in the GM. We conclude that TMA methodology and quantitative analysis provides evidence of complement dysregulation in MS GML, including an association of the numerical density of C1q+ cells with tissue lesions. Our work confirms that complement activation and dysregulation occur in all cases of progressive MS and suggest that complement may provide potential biomarkers of the disease.


Publication metadata

Author(s): Loveless S, Neal JW, Howell OW, Harding KE, Sarkies P, Evans R, Bevan RJ, Hakobyan S, Harris CL, Robertson NP, Morgan BP

Publication type: Article

Publication status: Published

Journal: Brain Pathology

Year: 2017

Volume: 28

Issue: 4

Pages: 449-592

Print publication date: 01/07/2018

Online publication date: 14/07/2017

Acceptance date: 04/07/2017

Date deposited: 20/02/2019

ISSN (print): 1015-6305

ISSN (electronic): 1750-3639

Publisher: Blackwell Publishing Ltd

URL: https://doi.org/10.1111/bpa.12546

DOI: 10.1111/bpa.12546


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