Abstract
In the current study, we have developed a magnetic resonance imaging-based method for non-invasive detection of complement activation in placenta and foetal brain in vivo in utero. Using this method, we found that anti-complement C3-targeted ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles bind within the inflamed placenta and foetal brain cortical tissue, causing a shortening of the T2* relaxation time. We used two mouse models of pregnancy complications: a mouse model of obstetrics antiphospholipid syndrome (APS) and a mouse model of preterm birth (PTB). We found that detection of C3 deposition in the placenta in the APS model was associated with placental insufficiency characterised by increased oxidative stress, decreased vascular endothelial growth factor and placental growth factor levels and intrauterine growth restriction. We also found that foetal brain C3 deposition was associated with cortical axonal cytoarchitecture disruption and increased neurodegeneration in the mouse model of APS and in the PTB model. In the APS model, foetuses that showed increased C3 in their brains additionally expressed anxiety-related behaviour after birth. Importantly, USPIO did not affect pregnancy outcomes and liver function in the mother and the offspring, suggesting that this method may be useful for detecting complement activation in vivo in utero and predicting placental insufficiency and abnormal foetal neurodevelopment that leads to neuropsychiatric disorders.
Highlights
Identification of new biomarkers to predict bad pregnancy/foetal outcomes would be of enormous clinical benefit
A spectrum of brain abnormalities and cognitive impairment has been described in infants born to mothers affected by antiphospholipid syndrome (APS).[9,10,11]
Positive staining was found in the kidneys from MRL/lpr mice. Detection of C3 deposition in the kidneys from MRL/lpr mice using unlabelled anti-C3 antibodies. USPIOconjugated anti-C3 antibodies did not bind to the kidneys from C3-deficient mice Immunohistochemical studies using unlabelled anti-C3 antibodies demonstrate the absence of C3 deposition in renal glomeruli from C3-deficient mice (C3 − / − ), indicating that the binding of ultrasmall superparamagnetic iron oxide (USPIO)-conjugated anti-C3 antibodies to C3 is specific. (c) Immunohistochemical studies, using fluorescein isothiocyanate (FITC)-conjugated anti-rat immunoglobulin G1 (IgG1) performed after the magnetic resonance imaging studies show the presence of USPIO-conjugated antiC3 antibodies in the placental labyrinth of antiphospholipid syndrome (APS) mice (c), foetal brain from APS mice (d) and in foetal brain from preterm birth mice injected with USPIO-anti-C3 (e)
Summary
Identification of new biomarkers to predict bad pregnancy/foetal outcomes would be of enormous clinical benefit. There are very few methods to predict adverse pregnancy/foetal outcomes. Bad pregnancy outcomes have been associated with the activation of inflammatory pathways,[1] in particular the complement system.[2,3] Pregnancy complications such as antiphospholipid (aPL) antibody-induced placental pathology and foetal growth restriction and preterm birth (PTB) has been associated with complement activation.[4,5,6,7] Complement activation has been related to abnormal development of the foetal brain cortex in premature birth in mice.[8] In addition, a spectrum of brain abnormalities and cognitive impairment has been described in infants born to mothers affected by antiphospholipid syndrome (APS).[9,10,11]
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