The mannose binding lectin pathway and early complement activation in (murine) abortion

Introduction: Girardi and Salmon highlighted the role of complement in early gestation failures in mice. We wanted to identify the pathway of its early activation in the murine natural immune resorbtion model she used. Methods: We monitored the protein and mRNAs expression of MBL-A and C, C3, at different days of gestation, in the uteri of either an “abortive murine combination” DBA/2-mated CBA/J females or a non abortive control mating and established MBL KO congenics on CBA/J background. Results: BALB/c-mated CBA/J females. We also comparatively quantified their expression by RT-PCR. The immunohistochemistry experiments revealed the presence of these (3) proteins and a differential expression of MBL-A between CBA/J × BALB/c and CBA/J × DBA/2 pregnancies while MBL-C was undetectable. However our results of RT-PCR revealed a very low or null local expression of MBL-A and C RNAs and no change in C3 RNA expression in the two combinations. We suggest that MBL-A, and C3 are produced elsewhere but activated locally. To verify the role of MBL, we established at INRA animal facility from breeders from Charles River Iffac Credo France on CBA/J background MBL-A, MBL-C, and MBL-A + C double congenics KO strain starting from MBL KO mice provided by Drs. Jensenius and Thiel Denmark. Albeit the results are still preliminary, at the 5th generation (96.88% of the genome of the KO is already CBA/J), our first results reveal a significant decrease of resorption (using chi-squared test with correction for small samples) in MBL-A KO CBA/J × DBA/2 compared with CBA/J × DBA/2 mating (4.3%, e.g. the incompressible rate of pregnancy loss due to chromosomal anomalies induced foetal demises in mice) versus 12.2% (the usual abortion rate seen in conventional but very clean breeding conditions as is the case at INRA). Depending on breeding and backcrosses, data at the 6th or 7th generation, and with more mice, will eventually be presented. Published data about MBL in human will also be discussed. Conclusions: These results reconcile the “danger” signals and the classical abortive cytokinic pathways, and have profound implications both in murine models and human clinics, which will also be discussed.