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Updated: May 13, 2026
Multiplexed Fluorescent Immunohistochemical Staining of Four Endometrial Immune Cell Types in Recurrent Miscarriage
Published on: August 4, 2021
Analysis of genes coding for CD46, CD55, and C4b-binding protein in patients with idiopathic, recurrent, spontaneous
Frida C Mohlin1, Eric Mercier, Veronique Fremeaux-Bacchi
1Department of Laboratory Medicine, Lund University, Malmö, Sweden.
Insights
Alterations in complement inhibitors like C4BP and CD46 are linked to recurrent miscarriages. These genetic changes may affect the immune system
Area of Science:
- Reproductive Immunology
- Complement System Biology
Background:
- A well-regulated complement system is crucial for successful pregnancy.
- Idiopathic recurrent miscarriage (IRM) affects numerous women, with unknown causes in many cases.
- Complement inhibitors play a key role in preventing excessive immune responses.
Purpose of the Study:
- To investigate the association between genetic alterations in complement inhibitors and idiopathic recurrent miscarriage.
- To identify specific mutations in C4b-binding protein (C4BP), CD46, and CD55 linked to recurrent pregnancy loss.
Main Methods:
- Sequencing of all coding exons for C4BP, CD46, and CD55.
- Study cohort comprised 384 women with at least two unexplained recurrent miscarriages.
- Functional analysis of identified mutations using recombinant proteins and cofactor activity assays.
Main Results:
- Several alterations were identified in C4BPA, with specific mutations (R120H, I126T, G423T) impacting C4BP expression and cofactor activity.
- A variant in C4BPB did not affect protein polymerization.
- Four CD46 alterations were found in patients but not controls; one variant (P324L) showed decreased expression, and another (N213I) impaired protein processing and cofactor activity.
Conclusions:
- This study identifies, for the first time, genetic alterations in C4BP associated with recurrent miscarriages.
- Identified CD46 variants may contribute to recurrent pregnancy loss through impaired function.
- Further studies in larger cohorts are needed to confirm the association and clinical significance of these findings.
Abstract:
Since a tightly regulated complement system is needed for a successful pregnancy, we hypothesized that alterations in complement inhibitors may be associated with idiopathic, recurrent miscarriage. We sequenced all exons coding for three complement inhibitors: C4b-binding protein (C4BP), CD46, and CD55 in 384 childless women with at least two miscarriages that could not be explained by known risk factors. Several alterations were found in C4BPA, of which the R120H, I126T, and the G423T mutations affected the expression level and/or the ability of recombinant C4BP to serve as cofactor for factor I. The only variant in C4BPB was located in the C-terminal part, and did not impair the polymerization of the molecule. Our results identify for the first time alterations in C4BP in women experiencing recurrent miscarriages. We also found four CD46 alterations in individual patients that were not found in healthy controls. One of the rare variants, P324L, showed decreased expression, whereas N213I resulted in deficient protein processing as well as an impaired cofactor activity in the degradation of both C4b and C3b. The identified alterations may result in in vivo consequences and contribute to the disorder but the degree of association must be evaluated in larger cohorts.
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