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Complement proteins are central to the innate immune system and serve a
critical role in host defense against foreign pathogens. However,
complement proteins are also critical for normal clearance of damaged
and apoptotic host cells, through the process of opsonization. This
process is particularly critical in pregnancy, due to the large burden
of semi-allogenic placental apoptotic debris released into the maternal
circulation throughout gestation (Huppertz et al. Placenta 2003;
24:181-190). In placentally mediated disorders such as preeclampsia,
there is an increase in apoptotic and necrotic placental debris, leading
to an excess inflammatory response (Redman et al. Placenta 2000;
21:597-602). To achieve normal pregnancy, placental apoptotic debris
must be cleared in an orderly fashion.
Complement component C3b, the central opsonin in the complement cascade,
marks apoptotic cells for phagocytosis. Accumulation of C3b leads to
activation of the terminal complement pathway, which propagates
inflammation and cellular injury, while cleavage of C3b (by complement
factor I) leads to generation of iC3b and reduced complement activation.
Generation of iC3b is important because complement receptors on
phagocytes recognize iC3b, facilitating clearance of apoptotic cells.
Complement receptors, and the interaction between complement receptors
and their ligands, are therefore critical to complement homeostasis in
normal pregnancy.
In this journal of BJOG, Lokki et al. sought to determine if genetic
variants in complement receptors predispose women to develop
preeclampsia. Investigators performed targeted exome sequencing of 11
genes coding for complement receptors, in 609 preeclampsia cases and
2,092 controls from two cohorts (The Finnish Genetics of Preeclampsia
Consortium; National FINRISK study cohort). They discovered that
missense variants in genes coding for complement receptor 3 (CR3) and
complement receptor 4 (CR4), which are β2-integrins that bind iC3b and
are widely expressed on phagocytic cells, were significantly associated
with preeclampsia. Through functional studies, Lokki et al. showed that
two missense variants caused increased binding of CR3 and CR4 to iC3b,
respectively, while another variant led to decreased binding of CR4 to
iC3b. Other variants in complement receptors, including C3aR, C5aR,
C1qR, CR1 and CR2, were not significant or of borderline significance.
Notably, missense variants in CR3 and CR4 were common, with minor allele
frequency 11-15% among controls compared with 15-20% among
preeclampsia cases. Thus, while these variants are not causative of
preeclampsia in isolation, they may predispose to preeclampsia in
combination with other risk factors. While it is presumed that these
variants in CR3 and CR4 lead to pro-inflammatory effects as seen in
preeclampsia, this was not investigated in the current study. Thus,
further studies are needed to determine if altered binding of CR3 and
CR4 to iC3b, as well as other ligands, impacts cytokine release and
inflammatory effects in preeclampsia. Regardless, the current study is
an important addition to the rapidly expanding literature showing that
complement dysregulation predisposes to preeclampsia. With the report
that complement blockade may be an effective strategy to treat
preeclampsia (Burwick et al. Placenta 2013; 34:201-3), there is an
urgent need to identify women who may be predisposed to altered
complement regulation in pregnancy.
Disclosure: RMB has received speaker fees and research grants
from Alexion Pharmaceuticals