The role of complement in preterm birth and prematurity

Galindo-Sevilla, Norma; Reyes-Arroyo, Frida; Mancilla-Ramı́rez, Javier

doi:10.1515/jpm-2019-0175

Cited by 15 publications

(12 citation statements)

References 44 publications

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“…The complement system is an important component of innate host defense, enhancing killing of pathogens, and clearance of microbes. The complement system is impaired in preterm infants and has been associated with preterm birth and susceptibility to neonatal sepsis (16). The complement component 5 (C5) protein cleaves into two protein fragments upon activation: C5a and C5b.…”

Section: Introductionmentioning

confidence: 99%

Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice

et al. 2020

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Background: Staphylococcus epidermidis is the most common nosocomial infection and the predominant pathogen in late-onset sepsis in preterm infants. Infection and inflammation are linked to neurological and developmental sequelae and bacterial infections increase the vulnerability of the brain to hypoxia-ischemia (HI). We thus tested the hypothesis that S. epidermidis exacerbates HI neuropathology in neonatal mice.Methods: Male and female C57Bl/6 mice were injected intraperitoneally with sterile saline or 3.5 × 10 7 colony-forming units of S. epidermidis on postnatal day (PND) 4 and then subjected to HI on PND5 (24 h after injection) or PND9 (5 d after injection) by left carotid artery ligation and exposure to 10% O 2 . White and gray matter injury was assessed on PND14-16. In an additional group of animals, the plasma, brain, and liver were collected on PND5 or PND9 after infection to evaluate cytokine and chemokine profiles, C5a levels and C5 signaling.Results: HI induced 24 h after injection of S. epidermidis resulted in greater gray and white matter injury compared to saline injected controls in males, but not in females. Specifically, males demonstrated increased gray matter injury in the cortex and striatum, and white matter loss in the subcortical region, hippocampal fimbria and striatum. In contrast, there was no potentiation of brain injury when HI occurred 5 d after infection in either sex. In the plasma, S. epidermidis-injected mice demonstrated increased levels of pro-and anti-inflammatory cytokines and chemokines and a reduction of C5a at 24 h, but not 5 d after infection. Brain CCL2 levels were increased in both sexes 24 h after infection, but increased only in males at 5 d post infection.Conclusion: Ongoing S. epidermidis infection combined with neonatal HI increases the vulnerability of the developing brain in male but not in female mice. These sex-dependent effects were to a large extent independent of expression of systemic cytokines or brain CCL2 expression. Overall, we provide new insights into how systemic S. epidermidis infection affects the developing brain and show that the time interval between infection and HI is a critical sensitizing factor in males.

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Section: Introductionmentioning

confidence: 99%

Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice

et al. 2020

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“…On the other hand, the increase in anaphylotoxins in our preterm group could be attributed to the crosstalk between coagulation and complement cascades. Certain coagulation system components, such as thrombin and factor Xa, can activate C3 and C5 independently of the established complement activation pathways and these anaphylotoxins may in turn intensify coagulation 18 , 35 . Therefore, given that prematurity is associated with various vascular events like thrombosis and ischemia, we cannot exclude that the observed increase in anaphylotoxins levels is due to intensified coagulation and thus activation of complement cascade components.…”

Section: Discussionmentioning

confidence: 99%

“…Term infants could be considered 'lucky' to have received maternal antibodies that serve as supplemental protection, whereas preterm infants 'missed' the largest part of transfer of maternal antibodies, as it increases with foetal age 17 . As one of the most important constituents of innate immunity, the role of complement in PTB and prematurity has also been implicated 18 . The maturity of complement components and their concentrations seems inadequate even in healthy term newborns, and these deficiencies are even more profound in preterm neonates 18 .…”

Section: Introductionmentioning

confidence: 99%

“…As one of the most important constituents of innate immunity, the role of complement in PTB and prematurity has also been implicated 18 . The maturity of complement components and their concentrations seems inadequate even in healthy term newborns, and these deficiencies are even more profound in preterm neonates 18 . Complement activation is crucial in pathogen opsonization, anaphylatoxins synthesis, leukocyte recruitment and bacteria lysis 19 .…”

Section: Introductionmentioning

confidence: 99%

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Comparative Analysis of Global Gene Expression and Complement Components Levels in Umbilical Cord Blood from Preterm and Term Neonates: Implications for Significant Downregulation of Immune Response Pathways related to Prematurity

Gródecka-Szwajkiewicz

Ulańczyk

Zagrodnik

et al. 2020

Int. J. Med. Sci.

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Background: Preterm birth is the most frequent cause of neonatal death, but its aetiology remains unclear. It has been suggested that the imbalance of immunological mechanisms responsible for maintaining pregnancy is contributing to preterm birth pathogenesis. We aimed to investigate global gene expression and the levels of several complement system components in umbilical cord blood samples from preterm neonates and compare them to term newborns. We sought to examine how differentially expressed genes could affect various immune-related pathways that are believed to be crucial factors in preterm birth. Material and methods: We enrolled 27 preterm infants (<37 weeks GA) and 52 term infants (>37 weeks GA), from which umbilical cord blood samples were collected. From these samples, peripheral blood mononuclear cells were isolated and subsequent RNA isolation was performed. We used Affymetrix Human Gene 2.1 ST Array Strip for microarray experiment and DAVID resources for bioinformatics analysis of the obtained data. Concentrations of C2, C3a, C5/C5a, C9, FactorD, Properdin were measured in umbilical cord blood plasma samples using multiplex fluorescent bead-based immunoassays using Luminex technology. Results: The levels of C3a and C5/5a were significantly elevated in preterm neonates compared to term babies, whereas C9 concentration was evidently increased in term infants. The expression of 250 genes was upregulated at least 2-fold and 3781 genes were downregulated at least 2-fold in preterm neonates in comparison with term infants. Functional annotation analysis revealed that in preterm infants in comparison to term babies there was a significant downregulation of genes encoding several Toll-like receptors, interleukins and genes involved in major signalling pathways (e.g. NF-κB, MAPK, TNF, Notch, JAK) and vital cellular processes (e.g. intracellular signal transduction, protein ubiquitination, protein transport, RNA splicing, DNA-templated transcription). Conclusions: Preterm birth results in immediate and long-term complications. Our results indicate that infants born prematurely show significant differences in complement components concentration and a downregulation of over 3,000 genes, involved mainly in various immune-related pathways, including innate immune response, phagocytosis and TLR function, when compared to full-term babies. Further studies on larger cohorts are needed to elucidate the role of immunity in prematurity.

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“…A number of pregnancy complications including recurrent abortion 7 , premature delivery 8 , fetal intrauterine growth restriction (IUGR) 9 , hypertensive disorders, preeclampsia (PE) 10 , HELLP syndrome 11 are associated with aberrant complement activation. And women with inherited or acquired complement system dysfunction is a risk factor of suffering from these pregnancy disorders.…”

Section: Aberrant Complement Activation In Pathological Pregnancymentioning

confidence: 99%

Complement in structure and immune homeostasis in placenta

Jin¹,

Zhang³

2021

Preprint

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Aberrant complement activation can induce “thrombo-inflammation” attacks to host tissue. Beside kidney and blood vessel, the placenta is also susceptible to these attacks. Complement dysregulation is recently classified as one of the new mechanisms leading to pregnancy disorders. Studies have indicated that dampening complement activation can ameliorate pregnancy outcomes. During pregnancy, the mother’s immune system is finely domesticated to accept the semi-allogeneic fetal antigens. As an important part of the innate immune system, some interesting changes have also taken place in complement system during pregnancy. The complement proteins are highly expressed in placenta, and their split products are increased. They are tuned in maintain placental immunity and structural homeostasis. An abundance of evidence shew that complement protein deficiency lead to autoimmunity disease and pathological pregnancy marked by excessive inflammation. Although complement suppressing strategies have been proven effective in treating some pathological pregnancy in individual case studies. we should take the dual role of the complement into consideration that fully and completely inhibit of complement may not be a wise choice.

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The role of complement in preterm birth and prematurity

Cited by 15 publications

References 44 publications

Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice

Staphylococcus epidermidis Sensitizes Perinatal Hypoxic-Ischemic Brain Injury in Male but Not Female Mice

Comparative Analysis of Global Gene Expression and Complement Components Levels in Umbilical Cord Blood from Preterm and Term Neonates: Implications for Significant Downregulation of Immune Response Pathways related to Prematurity

Complement in structure and immune homeostasis in placenta

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