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Testing the Activity of Complement Convertases in Serum/Plasma for Diagnosis of C4NeF-Mediated C3 Glomerulonephritis

Blom, Anna M. LU ; Corvillo, Fernando; Magda, Michal; Stasiłojć, Grzegorz; Nozal, Pilar; Pérez-Valdivia, Miguel Ángel; Cabello-Chaves, Virginia; Rodríguez de Córdoba, Santiago; López-Trascasa, Margarita and Okrój, Marcin LU (2016) In Journal of Clinical Immunology p.1-11
Abstract

Autoantibodies termed C3-nephritic factor (C3NeF), which stabilize convertases of the alternative complement pathway, often stimulate autoinflammatory diseases. However, knowledge about analogous autoantibodies acting on the classical pathway (C4NeF) is limited to a few reports, which indicate association with kidney dysfunction, systemic lupus erythematous, and infections. C4NeF may appear independently from C3NeF, but the lack of a routine diagnostic method predisposes C4NeF for being an underestimated player in autoinflammatory episodes. We tested the activity of classical convertases directly in serum/plasma to screen samples from 13 patients with C3 glomerulopathies and identified one patient showing significantly prolonged... (More)

Autoantibodies termed C3-nephritic factor (C3NeF), which stabilize convertases of the alternative complement pathway, often stimulate autoinflammatory diseases. However, knowledge about analogous autoantibodies acting on the classical pathway (C4NeF) is limited to a few reports, which indicate association with kidney dysfunction, systemic lupus erythematous, and infections. C4NeF may appear independently from C3NeF, but the lack of a routine diagnostic method predisposes C4NeF for being an underestimated player in autoinflammatory episodes. We tested the activity of classical convertases directly in serum/plasma to screen samples from 13 patients with C3 glomerulopathies and identified one patient showing significantly prolonged half-life of these enzymes. Observed effect was reproduced by immunoglobulins purified from patient’s plasma and additionally confirmed on classical convertase built from purified components. Isolated immunoglobulins protected classical convertases from both spontaneous and inhibitor-driven decay but not from C4b proteolysis. The patient had a decreased serum level of C3, elevated sC5b-9, and normal concentrations of factor B and C4. Neither C3NeF nor other autoantibodies directed against alternative pathway proteins (factor H, factor B, factor I, C3, and properdin) were found. Genetic analysis showed no mutations in C3, CFB, CFH, CFI, MCP, THBD, and DGKE genes. Renal biopsy revealed a membranoproliferative pattern with intense C3 deposits. Our results underline the importance of C4NeF as an independent pathogenic factor and a need for the implementation of routine examination of classical convertase activity. Proposed method may enable robust inspection of such atypical cases.

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author
organization
publishing date
type
Contribution to journal
publication status
in press
subject
keywords
C3 glomerulonephritis, C4NeF, complement convertase, Complement system
in
Journal of Clinical Immunology
pages
11 pages
publisher
Springer
external identifiers
  • Scopus:84966277509
ISSN
0271-9142
DOI
10.1007/s10875-016-0290-5
language
English
LU publication?
yes
id
8475ca57-e20e-4092-b31b-b297ec7b468d
date added to LUP
2016-05-31 15:18:54
date last changed
2016-09-20 03:21:39
@misc{8475ca57-e20e-4092-b31b-b297ec7b468d,
  abstract     = {<p>Autoantibodies termed C3-nephritic factor (C3NeF), which stabilize convertases of the alternative complement pathway, often stimulate autoinflammatory diseases. However, knowledge about analogous autoantibodies acting on the classical pathway (C4NeF) is limited to a few reports, which indicate association with kidney dysfunction, systemic lupus erythematous, and infections. C4NeF may appear independently from C3NeF, but the lack of a routine diagnostic method predisposes C4NeF for being an underestimated player in autoinflammatory episodes. We tested the activity of classical convertases directly in serum/plasma to screen samples from 13 patients with C3 glomerulopathies and identified one patient showing significantly prolonged half-life of these enzymes. Observed effect was reproduced by immunoglobulins purified from patient’s plasma and additionally confirmed on classical convertase built from purified components. Isolated immunoglobulins protected classical convertases from both spontaneous and inhibitor-driven decay but not from C4b proteolysis. The patient had a decreased serum level of C3, elevated sC5b-9, and normal concentrations of factor B and C4. Neither C3NeF nor other autoantibodies directed against alternative pathway proteins (factor H, factor B, factor I, C3, and properdin) were found. Genetic analysis showed no mutations in C3, CFB, CFH, CFI, MCP, THBD, and DGKE genes. Renal biopsy revealed a membranoproliferative pattern with intense C3 deposits. Our results underline the importance of C4NeF as an independent pathogenic factor and a need for the implementation of routine examination of classical convertase activity. Proposed method may enable robust inspection of such atypical cases.</p>},
  author       = {Blom, Anna M. and Corvillo, Fernando and Magda, Michal and Stasiłojć, Grzegorz and Nozal, Pilar and Pérez-Valdivia, Miguel Ángel and Cabello-Chaves, Virginia and Rodríguez de Córdoba, Santiago and López-Trascasa, Margarita and Okrój, Marcin},
  issn         = {0271-9142},
  keyword      = {C3 glomerulonephritis,C4NeF,complement convertase,Complement system},
  language     = {eng},
  month        = {05},
  pages        = {1--11},
  publisher    = {ARRAY(0x96711e8)},
  series       = {Journal of Clinical Immunology},
  title        = {Testing the Activity of Complement Convertases in Serum/Plasma for Diagnosis of C4NeF-Mediated C3 Glomerulonephritis},
  url          = {http://dx.doi.org/10.1007/s10875-016-0290-5},
  year         = {2016},
}