Complement in Pregnancy: A Delicate Balance Kerina J. Denny 1,2 , Trent M. Woodruff 1 , Stephen M. Taylor 1,2 , Leonie K. Callaway 2,3 1 School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia; 2 School of Medicine, The University of Queensland, Brisbane, QLD, Australia; 3 Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia Keywords C5a, preeclampsia, preterm birth, recurrent miscarriage Correspondence Kerina Denny, School of Biomedical Science, University of Queensland, Brisbane, QLD, Australia. E-mail: k.denny@uq.edu.au Submission May 15, 2012; accepted July 9, 2012. Citation Denny KJ, Woodruff TM, Taylor SM, Callaway LK. Complement in pregnancy: a delicate balance, Am J Reprod Immunol 2013; 69: 3–11 doi:10.1111/aji.12000 The complement system is a key component of innate host defence that, under normal conditions, is responsible for the opsonization and destruction of potential 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. The following review describes the results of in vitro, animal, and human clinical studies investigating the role of the complement system in healthy pregnancy, recurrent miscarriage, preterm birth, and preeclampsia. The complement system The complement system is an evolutionarily ancient component of innate immunity which, when activated, results in the recruitment and activation of immune cells leading to the rapid opsonization and destruction of pathogens. 1–4 Complement activa- tion occurs via three pathways: the classical pathway, triggered by antigen–antibody complexes; the alternative pathway which is spontaneously and continuously activated; and the lectin pathway, triggered by the binding of mannan-binding lectin to mannose residues on the surface of microorganisms. Independent of the mechanism of activation, all pathways converge to generate C3 convertases that cleave C3 into its active components, C3a and C3b. C3b is a principal effector of complement, responsi- ble for tagging nonself cells for destruction by phagocytes. C3b additionally binds to C3 convertases to form a C5 convertase that subsequently cleaves C5 into C5b and the potent pro-inflammatory mediator, C5a. C5b then associates with C6, C7, C8 and several units of C9 to form a lytic pore that inserts into cell membranes, the membrane attack complex (MAC; C5b-9; also known as the terminal complement complex). C3a and C5a, collectively known as the anaphyla- toxins because of their originally described role in anaphylactic shock, facilitate pathogen clearance by increasing vascular permeability, inducing inflamma- tory cell chemotaxis, and releasing cytokines. 5 C3a and C5a exert these pro-inflammatory effects by binding to their respective receptors, namely the C3a receptor (C3aR) and in the case of C5a to two recep- tors, C5a receptor (C5aR; CD88) and C5a receptor- like 2 receptor (C5L2). C5L2 shares homology with C5aR, although its exact biologic function remains unclear. 6 Finally, various serine proteases belonging to the coagulation system are also able to activate the complement cascade, independently of the afore- mentioned pathways. 7 Specifically, proteases such as American Journal of Reproductive Immunology 69 (2013) 3–11 ª 2012 John Wiley & Sons A/S 3 REVIEW ARTICLE