Obstet Gynecol Sci.  2023 Jul;66(4):253-269. 10.5468/ogs.22175.

The complement system in preeclampsia: a review of its activation and endothelial injury in the triad of COVID-19 infection and HIV-associated preeclampsia

• David M
• Naicker T

• KMID: 2544382
• DOI: http://doi.org/10.5468/ogs.22175

Abstract

This review assesses the complement system and its activation, with the pathological features of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), human immunodeficiency virus (HIV) infection and preeclampsia (PE). The complement system is the first defensive response by the host innate immune system to viral pathogens, including SARS-CoV-2. SARS-CoV-2 entry results in the release of pro-inflammatory cytokines and chemical mediators to create a “cytokine storm”. Endothelial cell (EC) dysfunction and cell-mediated injury are also present. These factors cause an exacerbated inflammatory state. During HIV infection and PE, various complement components are elevated, causing a hyper-inflammatory state. Furthermore, EC dysfunction and cell-mediated injury are also present. The similarities in pathological aspects of these three disorders may emanate from excessive complement activation. This review serves as a platform for further research on the complement system, coronavirus disease 2019, HIV infection and PE.

Keyword

Severe acute respiratory syndrome; Human immunodeficiency virus; Preeclampsia; Complement activation

Figure

• 

  Fig. 1 Schematic overview of the complement system, illustrating the three pathways. Activation of the complement cascade occurs via three pathways viz., the classical, lectin, and the alternative pathway. All three pathways result in C3 convertase being produced, which cleaves C3 into C3a and C3b. The complement system opsonises target surfaces, induction of pro-inflammatory responses, and causes lysis of cells and pathogens. Adapted from Beltrame et al. [21].

• 

  Fig. 2 Schematic overview of SARS-CoV-2 and the complement system. SARS-CoV-2 enters via the ACE2 receptor, where it is met by an aggressive inflammatory response caused by the complement system activation. Additionally, cellular and humoral immunity in tandem with antigen presentation becomes activated. This results in large amounts of pro-inflammatory cytokines and mediators being released, consequently exacerbating a hyperinflammatory state and endothelial tissue injury. Adapted from Chatterjee et al. [55]. SARS-CoV-2, syndrome coronavirus-2; ACE, angiotensin-converting enzyme; IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; GM-CSF, granulocyte-macrophage colony-stimulating factor; APC, antigen presenting cell; TCR, T cell receptor; CD, cluster of differentiation; BCR, B cell receptor; TH2, T-helper 2; Ig, immunoglobulin.

• 

  Fig. 3 Schematic diagram on the role of the complement system during HIV infection. It is activated by the HIV-1 virus binding to gp41 and gp120. HIV-specific antibodies also contribute to complement activation. HIV-1 uses the regulatory proteins to evade complement-mediated lysis. HIV, human immunodeficiency virus; MBL, mannose binding lectin; CD, cluster of differentiation.

• 

  Fig. 4 Schematic diagram on the role of the complement system in preeclampsia. The pathogenesis of preeclampsia is not fully elucidated; however, there is a potential link between complement dysregulation and angiogenic imbalance. Complement dysregulation leads to an elevated release of complement components such as C3a, C5a, C5b-9, which cause excessive inflammation, and this can lead to angiogenic imbalances and trophoblast injury. Adapted from Gao et al. [107]. APL Ab, antiphospholipid antibody; SLE, systemic lupus erymatosis; MCP, monocyte chemoattractant protein; FH, factor H; FI, factor 1.

• 

  Fig. 5 Schematic diagram of the complement system in HIV infection, Preeclampsia and COVID-19. Excessive or dysregulated complement activation results in the increase of pro-inflammatory cytokines and complement components, causing a hyperinflammatory state. HIV, human immunodeficiency virus; COVID-19, coronavirus disease 2019; IL, interleukin; TNF, tumor necrosis factor; MASP-2, mannan-binding lectin-associated serine protease 2.

Reference

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