3. Complement activation is well balanced by CIPs during pregnancy
Apoptotic cells lose the expression of “don’t eat-me” signals and instead exposing “eat-me” signals such as phosphatidylserine on its cell surface. They are exposed on the cell surface then attracts C1q, MBL, binding strongly to the late apoptotic cells and leading to activation of complement cascade on its cell surface. The “first-half” complement components MBL/C1q and C3b/iC3b recognize and bind to its specific receptors on phagocytes to mediate silent and timely clearance of the apoptotic cell. But if the complement cascade is uncontrolled, it would result in potent anaphylatoxin C5a and MAC formation, the “second-half” products of the complement cascade, with strong cytotoxicity and pro-inflammation potency. However, due to the presence of two potent complement inhibitors C4BP, complement factor H (FH), which are strongly binding to the apoptotic cells surface, the complement cascade is finely attenuated at C3 level, thus cell lysis and the further inflammation is curved.
C4bp and FH level increased in both peripheral blood and placenta in early pregnancy 119. C4bp is a protein binding to C4b and regulating C3 convertase in CP. C4bp was stained in apoptotic fragments in normal placenta 119, serve as a potent soluble inhibitor of the CP and LP. FH is a potent soluble inhibitor of the complement alternative pathway (AP). FH level in peripheral blood and placenta increased in early pregnancy 119. Intense FH deposition was detected in the stroma of the placenta119. FH acts the similar role as to C4BP, they accelerate the decay of C3 convertase and play as a co-factor with complement factor I (FI) to cleave and inactivate C3b.
Aside from controlling spontaneous activation of the complement AP, FH also plays an important role in silent removal of apoptotic cells120. FH can be actively internalized by apoptotic cells, promote intracellular catalyzation of C3 to C3b. Cell-derived C3b additionally translocate to the cell surface and promote its clearance.
The levels of C3a and C4d (involved in AP and LP) in the uterus and peripheral blood were significantly higher in pregnant women than the none-pregnant one 121. But it does not reach to the level of PE patients. CRP, C4d/C4, C3a/C3, SC5b9 levels in PE patients are significantly higher than healthy pregnant women. Buurma and its colleagues found that C3a increased in a larger extent than sC5b-9 in normal pregnancy but the production of sC5b-9 and C3a is completely synchronized in PE patients 80. sC5b-9 has strong cytotoxicity and pro-inflammation potency. sC5b-9 is sharply increased in PE women, while finely controlled in normal pregnant women. And sC5b-9 level in blood and urine are potent indicator for severity and prognosis of PE patient122.
Though complement is also obviously activated in normal pregnancy, it is different from the pathological status. Under physiological condition, complement activation is more moderate and finely regulated in the presence of CIPs, especially the terminal pathway which has strong pro-inflammation potency.