Background: The complement system is a key component of innate host defence that, under normal conditions, is responsible for the opsonisation and destruction of pathogens. However, inappropriate or excessive activation of complement can have a detrimental effect on the host and has been implicated in the pathophysiology of numerous disease states. Recently, there has been increasing evidence for a role of the complement system and, in particular, the potent pro-inflammatory anaphylatoxin complement component 5a (C5a) in both normal and complicated pregnancy.
Aims: This thesis project aimed to further explore the role of C5a in pregnancy and development in order to evaluate the therapeutic utility and feasibility of inhibiting the principal C5a receptor, C5aR, in pregnancy. Specifically, this thesis project aimed to: (1) determine whether poor pregnancy outcomes are associated with altered levels of circulating C5a in a human clinical population; (2) evaluate the potential therapeutic value of C5aR blockade in pregnancy; and (3) determine whether inhibition of C5aR signalling is likely to have any adverse effects on fetal development.
Methods: A combination of both animal models and human clinical collection studies were employed to address the aims of the thesis.
Results: In a human clinical population, elevated levels of maternal and umbilical plasma C5a were associated with a poor pregnancy outcome, namely preeclampsia. Further, in a LPS-dependent pregnant mouse model of miscarriage and preterm birth, absence of the C5aR was found to be protective against both intrauterine growth restriction and fetal loss. In contrast, the C5aR was not found to be a key pathogenic mediator in LPS-induced preterm birth. Finally, a role for C5a in development was suggested by the finding that the C5aR and C5, the post-translational precursor of C5a, are expressed in the neuroepithelium of the developing mouse embryo throughout the period of neurulation. C5aRs were also found to be expressed in the neuroepithelium of early human embryos. Under folate-deficient, but not folate-replete, conditions genetic or pharmacological blockade of C5aR signalling in a mouse model of pregnancy was shown to result in a high prevalence of severe anterior neural tube defect (NTD)-associated congenital malformations.
Discussion: These studies support the thesis that blockade of the C5a-C5aR axis is likely to exert a predominately beneficial effect on fetal development by means of preventing poor placentation and consequent growth restriction and fetal loss. However, until the precise mechanisms by which complement and folate interact to contribute to NTDs and associated congenital malformations, it is recommended that therapeutics that target or are likely to affect the C5a-C5aR axis should be used in conjunction with supplemental folate.