Critical Role and Therapeutic Control of the Lectin Pathway of Complement Activation in an Abortion-Prone Mouse Mating

Abstract

The abortion-prone mating combination CBA/J × DBA/2 has been recognized as a model of preeclampsia, and complement activation has been implicated in the high rate of pregnancy loss observed in CBA/J mice. We have analyzed the implantation sites collected from DBA/2-mated CBA/J mice for the deposition of the complement recognition molecules using CBA/J mated with BALB/c mice as a control group. MBL-A was observed in the implantation sites of CBA/J × DBA/2 combination in the absence of MBL-C and was undetectable in BALB/c-mated CBA/J mice. Conversely, C1q was present in both mating combinations. Searching for other complement components localized at the implantation sites of CBA/J × DBA/2, we found C4 and C3, but we failed to reveal C1r. These data suggest that complement is activated through the lectin pathway and proceeds to completion of the activation sequence as revealed by C9 deposition. MBL-A was detected as early as 3.5 d of pregnancy, and MBL-A deficiency prevented pregnancy loss in the abortion-prone mating combination. The contribution of the terminal complex to miscarriage was supported by the finding that pregnancy failure was largely inhibited by the administration of neutralizing Ab to C5. Treatment of DBA/2-mated CBA/J mice with Polyman2 that binds to MBL-A with high affinity proved to be highly effective in controlling the activation of the lectin pathway and in preventing fetal loss.

RNA sequencing of chorionic villi from recurrent pregnancy loss patients reveals impaired function of basic nuclear and cellular machinery

“…Among the down-regulated genes we selected for validation experiments HIST1H1B (encoding histone H1) and HIST1H4A (histone H4), and among the upregulated gene-list C3 (complement component 3), CAPNS1 (calpain, small subunit 1) and PLTP (phospholipid transfer protein). Among these, C3 and PLTP have also literature evidence for the involvement of RPL and/or function at the feto-maternal interface185859. For CAPNS1 a role in acute allograft rejection has been reported60.…”

The Complement System and Preeclampsia

“…Thus, its usefulness as a model of preeclampsia is limited. More recent studies in this model demonstrated that MBL and C1q deposition were evident at GD3.5 and C3 at GD6.5 indicating that complement activation occurred early in the implantation phase [62], similar to the BPH/5 mouse. If lectin pathway activation was controlled using either a molecule that binds MBL with high affinity (Polyman 2), MBL-A deficient mice, or anti-C5 antibody, fetal loss was prevented, consistent with an important role for lectin pathway activation in fetal loss.…”

Lectin pathway proteins of the complement system in normotensive pregnancy and pre‐eclampsia

“…Complement activation generates inflammatory mediators which facilitate a crucial danger signal to surrounding cells and migrating leucocytes . The lectin pathway, which is the most recently described complement activation pathway, has gained much interest in the development of pre‐eclampsia and IUGR . The lectin pathway consists of the pattern recognition molecules mannose‐binding lectin (MBL), ficolins (H‐, L‐ and M‐) and collectins liver‐1 (CL‐L1) and kidney‐1 (CL‐K1), together with the MBL‐associated serine protease (MASP)‐1, MASP‐2 and MASP‐3 and the regulatory MBL‐associated proteins of 19 kDa (MAp19) and 44 kDa (MAp44) .…”

“…The lectin pathway consists of the pattern recognition molecules mannose‐binding lectin (MBL), ficolins (H‐, L‐ and M‐) and collectins liver‐1 (CL‐L1) and kidney‐1 (CL‐K1), together with the MBL‐associated serine protease (MASP)‐1, MASP‐2 and MASP‐3 and the regulatory MBL‐associated proteins of 19 kDa (MAp19) and 44 kDa (MAp44) . MBL may be directly involved in the impairment of spiral artery remodelling and trophoblast invasion in early pregnancy . Furthermore, the pattern recognition molecules recognize not only pathogens but also necrotic or apoptotic cells .…”