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Sensitive and specific assays for C3 nephritic factors clarify mechanisms underlying complement dysregulation

Paixao-Cavalcante, Danielle; Lopez-Trascasa, Margarita; Melander Skattum, Lillemor LU ; Giclas, Patricia C.; Goodship, Timothy H.; Rodriguez de Cordoba, Santiago; Truedsson, Lennart LU ; Morgan, B. Paul and Harris, Claire L. (2012) In Kidney International 82(10). p.1084-1092
Abstract
C3 nephritic factors are autoantibodies that prolong the half-life or prevent regulation of the alternative pathway C3 convertase, resulting in uncontrolled complement activation. They are strongly associated with renal disease but their role in pathogenesis remains controversial. Here we optimized and compared a panel of assays to identify and interrogate nephritic factor activities. Of 101 patients with histologic or clinically evident disease, 48 were positive in some or all assays. In the presence of properdin, binding of autoantibody was detected in 39 samples and convertase stabilization was detected in 36. Forty-two of 48 nephritic factors tested prevented convertase decay by factor H, and most of these by decay accelerating factor... (More)
C3 nephritic factors are autoantibodies that prolong the half-life or prevent regulation of the alternative pathway C3 convertase, resulting in uncontrolled complement activation. They are strongly associated with renal disease but their role in pathogenesis remains controversial. Here we optimized and compared a panel of assays to identify and interrogate nephritic factor activities. Of 101 patients with histologic or clinically evident disease, 48 were positive in some or all assays. In the presence of properdin, binding of autoantibody was detected in 39 samples and convertase stabilization was detected in 36. Forty-two of 48 nephritic factors tested prevented convertase decay by factor H, and most of these by decay accelerating factor (28) and complement receptor 1 (34). Representative properdin-independent nephritic factors had no effect on C5 cleavage and terminal pathway activity, while properdin-dependent nephritic factors enhanced activity. Biacore analysis of four purified IgG samples confirmed resistance to decay and showed that properdin-independent nephritic factors increased convertase half-life over 50-fold, whereas properdin-dependent nephritic factors increased the half-life 10- to 20-fold and also increased activity of the C3 convertase up to 10-fold. Thus, our study provides a rational approach to detect and characterize nephritic factors in patients. Kidney International (2012) 82, 1084-1092; doi:10.1038/ki.2012.250; published online 1 August 2012 (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
alternative pathway, complement, convertase, nephritic factor
in
Kidney International
volume
82
issue
10
pages
1084 - 1092
publisher
Nature Publishing Group
external identifiers
  • wos:000310710300008
  • scopus:84868585648
ISSN
1523-1755
DOI
10.1038/ki.2012.250
language
English
LU publication?
yes
id
3e3b655b-295a-4b60-8206-10dddc93bd3b (old id 3259401)
date added to LUP
2013-01-07 09:39:07
date last changed
2017-11-05 04:01:46
@article{3e3b655b-295a-4b60-8206-10dddc93bd3b,
  abstract     = {C3 nephritic factors are autoantibodies that prolong the half-life or prevent regulation of the alternative pathway C3 convertase, resulting in uncontrolled complement activation. They are strongly associated with renal disease but their role in pathogenesis remains controversial. Here we optimized and compared a panel of assays to identify and interrogate nephritic factor activities. Of 101 patients with histologic or clinically evident disease, 48 were positive in some or all assays. In the presence of properdin, binding of autoantibody was detected in 39 samples and convertase stabilization was detected in 36. Forty-two of 48 nephritic factors tested prevented convertase decay by factor H, and most of these by decay accelerating factor (28) and complement receptor 1 (34). Representative properdin-independent nephritic factors had no effect on C5 cleavage and terminal pathway activity, while properdin-dependent nephritic factors enhanced activity. Biacore analysis of four purified IgG samples confirmed resistance to decay and showed that properdin-independent nephritic factors increased convertase half-life over 50-fold, whereas properdin-dependent nephritic factors increased the half-life 10- to 20-fold and also increased activity of the C3 convertase up to 10-fold. Thus, our study provides a rational approach to detect and characterize nephritic factors in patients. Kidney International (2012) 82, 1084-1092; doi:10.1038/ki.2012.250; published online 1 August 2012},
  author       = {Paixao-Cavalcante, Danielle and Lopez-Trascasa, Margarita and Melander Skattum, Lillemor and Giclas, Patricia C. and Goodship, Timothy H. and Rodriguez de Cordoba, Santiago and Truedsson, Lennart and Morgan, B. Paul and Harris, Claire L.},
  issn         = {1523-1755},
  keyword      = {alternative pathway,complement,convertase,nephritic factor},
  language     = {eng},
  number       = {10},
  pages        = {1084--1092},
  publisher    = {Nature Publishing Group},
  series       = {Kidney International},
  title        = {Sensitive and specific assays for C3 nephritic factors clarify mechanisms underlying complement dysregulation},
  url          = {http://dx.doi.org/10.1038/ki.2012.250},
  volume       = {82},
  year         = {2012},
}