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Distribution of exogenous complement factor H in mice invivo

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Title: Distribution of exogenous complement factor H in mice invivo
Authors: Koskinen, AR
Cheng, Z-Z
Pickering, MC
Kairemo, K
Meri, T
Cook, HT
Meri, S
Jokiranta, TS
Item Type: Journal Article
Abstract: Factor H is an important regulator of complement activation in plasma and on cell surfaces in both humans and mice. If FH function is compromised, inappropriate complement activation on self‐surfaces can have disastrous effects as seen in the kidney diseases atypical haemolytic uremic syndrome (aHUS) and C3 glomerulopathy. As FH constructs have been proposed to be used in treatment for these diseases, we studied the distribution of exogenous FH fragments in mice. Full‐length mFH, mFH1‐5 and mFH18‐20 fragments were radiolabelled, and their distribution was examined in WT, FH−/− and FH−/−C3−/− mice in vivo. Whole body scintigraphy revealed accumulation of radioactivity in the abdominal part of the mice, but also to the thyroid gland and urinary bladder. At organ level in WT mice, some full‐length FH accumulated in internal organs, but most of it remained in the circulation. Both of the mFH fragments accumulated in the kidneys and were excreted in urine. For mFH1‐5, urinary secretion is the likely cause for the accumulation. Concentration of mFH18‐20 to kidneys was slower, and at tissue level, mFH18‐20 was localized at the proximal tubuli in WT and FH−/−C3−/− mice. No C3‐independent binding to glomeruli was detected. In conclusion, these results show that glomerular glycosaminoglycans and sialic acids alone do not collect FH in kidneys. Deposition of C3 fragments is also needed, which implies that in aHUS, the problem is in simultaneous recognition of C3 fragments and glycosaminoglycans or sialic acids by FH, not just the inability of FH to recognize glomerular endothelium as such.
Issue Date: 1-Jul-2018
Date of Acceptance: 24-Apr-2018
URI: http://hdl.handle.net/10044/1/61702
DOI: https://dx.doi.org/10.1111/sji.12671
ISSN: 0300-9475
Publisher: Wiley
Journal / Book Title: Scandinavian Journal of Immunology
Volume: 88
Issue: 1
Copyright Statement: © 2018 The Foundation for the Scandinavian Journal of Immunology. This is the accepted version of the following article: Koskinen AR, Cheng Z‐Z, Pickering MC, et al. Distribution of exogenous complement factor H in mice in vivo. Scand J Immunol. 2018;88:e12671, which has been published in final form at https://dx.doi.org/10.1111/sji.12671
Sponsor/Funder: Wellcome Trust
Wellcome Trust
Funder's Grant Number: 082291/Z/07/Z
098476/Z/12/Z
Keywords: Science & Technology
Life Sciences & Biomedicine
Immunology
atypical haemolytic uremic syndrome
C3 glomerulopathy
complement
factor H
kidney
HEMOLYTIC-UREMIC SYNDROME
EXPERIMENTAL C3 GLOMERULOPATHY
ENDOTHELIAL-CELLS
MACULAR DEGENERATION
SURFACE RECOGNITION
DEFICIENT MICE
BOUND C3B
MUTATIONS
BINDING
ACTIVATION
Animals
Complement Factor H
Mice
Mice, Inbred C57BL
Mice, Knockout
Peptide Fragments
Tissue Distribution
1107 Immunology
Publication Status: Published
Article Number: e12671
Online Publication Date: 2018-05-23
Appears in Collections:Department of Medicine (up to 2019)