Systematic review of the complement components as potential biomarkers of pre-eclampsia: pitfalls and opportunities

Abstract

The complement system (C) is a crucial component of the innate immune system. An increasing body of research has progressively shed light on the pivotal role of C in immunological tolerance at the feto-maternal interface. Excessive C activation or impaired C regulation may determine the onset of pregnancy-related pathological conditions, including pre-eclampsia (PE). Thus, several studies have investigated the presence of C components or split products in blood matrixes (i.e., plasma, serum), urine, and amniotic fluid in PE. In the current study, we systematically reviewed the currently available scientific literature reporting measurements of C components as circulating biomarkers in PE, based on a literature search using Pubmed, Scopus, and Embase databases. A total of 41 out of 456 studies were selected after full-text analysis. Fourteen studies (34.1%) were identified as measuring the blood concentrations of the classical pathway, 5 (12.1%) for the lectin pathway, 28 (68.3%) for the alternative pathway, 17 (41.5%) for the terminal pathway components, and 16 (39%) for C regulators. Retrieved results consistently reported C4, C3, and factor H reduction, and increased circulating levels of C4d, Bb, factor D, C3a, C5a, and C5b-9 in PE compared to normal pregnancies, depicting an overall scenario of excessive C activation and aberrant C regulation. With evidence of C activation and dysregulation, C-targeted therapy is an intriguing perspective in PE management. Moreover, we also discussed emerging pitfalls in C analysis, mainly due to a lack of experimental uniformity and biased cohort selection among different studies and laboratories, aiming to raise a more comprehensive awareness for future standardization.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42024503070.

Keywords: biomarker; complement system; pre-eclampsia; pregnancy; systematic review.

Figure 1

Schematic overview of the complement system cascade. The complement system (C) operates via three pathways: classical (green), lectin (pink), and alternative (cyan). The classical pathway is mainly triggered by the binding of C1q to antigen-antibody complexes. The lectin pathway is activated by mannan-binding lectin (MBL), ficolins, or collectins (CLs), which recognize microbial carbohydrates and form a complex with MASP-1 and MASP-2. The alternative pathway is constitutively active at basal levels, with C3 undergoing spontaneous hydrolysis (tick-over). All three pathways converge on the common component C3 and proceed with the terminal pathway (grey). The C activation is tightly controlled by several fluid-phase (yellow) and membrane-bound (orange) regulators. FI activity is supported by several cofactors: ^1-2) C4BP, CD46, CR1; ³⁾ FH/FH-L1; ⁴⁾ FH, FH-L1, CD46, CR1; and ⁵⁾ CD46, CR1. C1-INH, C1-inhibitor; C4BP, C4b-binding protein; CFHR1, complement factor H-related protein 1; CLU, clusterin; CP-N, carboxypeptidase-N; CR1, complement receptor 1; CRIg, complement receptor immunoglobulin; DAF, decay-accelerating factor; FB, factor B; FD, factor D; FH, factor H; FI, factor I; MAC, membrane attack complex; MCP, membrane cofactor protein; VTN, vitronectin. Image created with BioRender.com.

Figure 2

Flow diagram for article selection according to PRISMA guidelines.