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Review
. 2020 Jul 31:11:1681.
doi: 10.3389/fimmu.2020.01681. eCollection 2020.

Essential Role of Complement in Pregnancy: From Implantation to Parturition and Beyond

Guillermina Girardi  1 , Joshua J Lingo  2 , Sherry D Fleming  2 , Jean F Regal  3
Affiliations
Review

Essential Role of Complement in Pregnancy: From Implantation to Parturition and Beyond

Guillermina Girardi et al. Front Immunol. .

Abstract

The complement cascade was identified over 100 years ago, yet investigation of its role in pregnancy remains an area of intense research. Complement inhibitors at the maternal-fetal interface prevent inappropriate complement activation to protect the fetus. However, this versatile proteolytic cascade also favorably influences numerous stages of pregnancy, including implantation, fetal development, and labor. Inappropriate complement activation in pregnancy can have adverse lifelong sequelae for both mother and child. This review summarizes the current understanding of complement activation during all stages of pregnancy. In addition, consequences of complement dysregulation during adverse pregnancy outcomes from miscarriage, preeclampsia, and pre-term birth are examined. Finally, future research directions into complement activation during pregnancy are considered.

Keywords: complement; fetal development; innate immunity; preeclampsia; pregnancy; pregnancy loss; preterm birth.

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Figures

Figure 1
Figure 1
Three extracellular complement initiation pathways culminate in a common terminal pathway. Grey boxes identify initiation and terminal pathways with complement components identified along the arrows. The Classical pathway is activated by antigen/antibody complexes, recognized by C1q in complex with C1r and C1s. Proteases C1r and C1s cleave C4 and C2 to generate the Classical pathway C3 convertase C4b2a. The Lectin pathway is triggered by binding of mannose-binding lectin (MBL) or ficolins to carbohydrates on the target membrane. The MBL-associated serine proteases (MASPs) then cleave C4 and C2 generating the C3-convertase C4b2a. The Alternative pathway, an amplification loop, is triggered when the C3b protein directly binds a microbe, foreign material, or damaged tissue. C3b also binds factor B (fB) to form C3bB. FB is cleaved by factor D (fD) to form Alternative pathway C3-convertase, C3bBb. This convertase is stabilized by properdin (P). C3b opsonizes targets for phagocytosis and B-cell activation. All 3 initiation pathways converge on C3 with distinct C3 convertases which cleave C3 to generate the anaphylatoxin C3a, and more C3b to form the C5-convertases (C4b2a3b and C3bBb3b). C5-convertase then cleaves C5 into C5a and C5b. C3a and C5a can attract and activate inflammatory cells and contract smooth muscle through receptors (C3aR, C5aR1, and C5aR2). C5b binds C6, C7, C8, and multiple copies of C9 forming the membrane attack complex (MAC) complex. MAC pores can cause cell death by osmotic flux.
Figure 2
Figure 2
Intracellular complosome activation in the T cell. During homeostasis, lysosomal Cathepsin L cleaves C3 to C3b and C3a. C3a binds to C3aR on the vesicular membrane to activate mTOR resulting in T cell survival (upper panel). Cognate antigen engagement by T cells results in lysosome fusion with the membrane, release of a Cathepsin L and C3 containing vesicle resulting in extracellular Cathepsin L-mediated cleavage of C3. C3b binds complement receptor 1 or CD46 (MCP) and C3a binds C3a receptor (C3aR) (Upper right) inducing T cell proliferation and differentiation. In addition, upon TCR activation, intracellular C5 is cleaved by an unknown protease allowing C5a to bind either intracellular C5aR1 or C5aR2 (lower half of diagram). C5aR1 induces reactive oxygen production (ROS) and NLRP3. NLRP3 cleaves pro-interleukin 1 (IL-1) producing IL-1β. The autocrine signaling induces IFNγ release and Th1 T cell differentiation.
Figure 3
Figure 3
Regulators of the complement pathway. Both surface and soluble complement regulatory molecules identified in the red boxes inhibit critical junctures of the cascade and degrade C3 convertases (C4b2a or C3bBb) or C5 convertases (C4b2a3b or C3bBbC3b) and the anaphylatoxins C3a and C5a. C1 inhibitor prevents excessive activation of both Classical and Lectin pathways. The Classical and Lectin pathway C3 convertase, C4b2a, is regulated by complement receptor 1 (CR1), C4 binding protein (C4BP), decay accelerating factor (DAF), membrane cofactor protein (MCP), and factor I. The Alternative pathway C3-convertase, C3bBb, is regulated by CR1, factor I, factor H, DAF, and MCP. The anaphylatoxins, C3a and C5a, are degraded by carboxypeptidase N. Finally, Vitronectin and Clusterin inhibit the C5b-8 complex while CD59 (protectin) inhibits C9 insertion into membrane attack complex (MAC).
Figure 4
Figure 4
Consequences of dysregulated complement throughout pregnancy. Dysregulated complement activation from pre-implantation through parturition may lead to pregnancy complications. Excessive complement activation and neutrophil infiltration or lack of complement during pre-implantation or implantation may result in implantation failure or miscarriage. Insufficient complement regulation may lead to placental malperfusion, placental damage, and/or preeclampsia. While the C5a-C5aR axis stimulates macrophage production of metalloproteinases (MMPs) leading to normal parturition and labor, inappropriate timing may result in preterm birth.
Figure 5
Figure 5
In utero events can have lifelong consequences. Insufficient or dysregulated complement may result in lifelong sequelae in both mother and child. Either a lack of complement activation or excessive activation of complement or cytokine production in utero may lead to problems throughout the life of the mother or child. The mother may experience cardiac, vascular, or renal dysfunction, hypertension, metabolic disease, or cognitive changes. The child may also experience hypertension, metabolic disease, diabetes, or cardiovascular disease. In addition, fetal brain injury may result in cognitive and/or psychiatric disorders in the offspring.
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