Mitigating placental injuries through up-regulating DAF in experimental APS mice: new mechanism of progesterone

Abstract

Summary Anti‐phospholipid syndrome (APS) is characterized by recurrent pathological pregnancy, arterial or venous thrombosis in the presence of anti‐phospholipid antibody (aPL). Complement activation is recognized as an intermediate link leading to placental thrombosis and placental inflammation in APS model mice. Decay accelerating factor (DAF, CD55), MAC‐inhibitory protein (MAC‐IP, CD59) and membrane co‐factor protein (MCP, CD46) are important complement inhibitory proteins (CIPs) highly expressed in normal placenta to curb excessive complement activation and its mediated injuries. Anti‐β2 glycoprotein I (anti‐β2GPI) antibody is an important aPL. We found that placental DAF and CD46 decreased in β2GPI passively immunized APS model mice, accompanied by C3 deposition, neutrophil infiltration and increased proinflammatory cytokine levels detected in its placenta. Progesterone supplement can up‐regulate DAF but not CD46 expression, curb C3 activation and decrease proinflammatory cytokines levels to reduce fetal loss frequency. Progesterone receptor antagonist (mifepristone) or knock‐down DAF with specific siRNA, above the protective effects of progesterone, were significantly weakened. Another sex hormone, oestrogen, has no significant effect on placental DAF and C3 contents and fetal loss frequency in the APS mice model. This may be an important mechanism by which progesterone induces maternal–fetal immune tolerance. At the same time, it may provide evidence for the use of progesterone in APS abortion patients.

The immunology of the fetal–placental unit comes of age

“…Proteins that physiologically curb the activation of complement, such as decay accelerating factor (DAF, CD55) and the membrane co-factor protein (MCP, CD46) are expressed in the placenta. Zhang and collaborators report in an experimental APS that antiphospholipid antibodies modulate in vivo the expression of these signals [16]. Complement deposition and neutrophil infiltration reflect the decreased expression of placental DAF and CD46.…”

“…Complement deposition and neutrophil infiltration reflect the decreased expression of placental DAF and CD46. Progesterone, but not estrogens, prompts selectively up-regulated expression of DAF, curbs complement activation and protects from fetal loss, highlighting the role played by hormones in the cross-talk between the maternal immune system and the feto-placental unit [16].…”

“…Complement activation plays an important role in the pathogenesis, and molecular interventions targeting the pathway hold promise for prevention of the uncommon but life-threatening complication, the catastrophic APS (e.g. Progesterone, but not estrogens, prompts selectively up-regulated expression of DAF, curbs complement activation and protects from fetal loss, highlighting the role played by hormones in the cross-talk between the maternal immune system and the feto-placental unit [16]. Proteins that physiologically curb the activation of complement, such as decay accelerating factor (DAF, CD55) and the membrane co-factor protein (MCP, CD46) are expressed in the placenta.…”

Sex-Specific Causal Relations between Steroid Hormones and Obesity—A Mendelian Randomization Study

“…To estimate the HLA subtypes, we selected all SNPs of the MHC region on chromosome 6 (25,392,(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)392,022 Mb according to hg19, a long-range LD region) that could be matched to the Axiom HLA reference set [61]. The best-guess genotype was defined with the threshold of genotype probability >0.9, and SNPs with more than 3% missing genotype calls were excluded.…”

“…Using ECLIA measurements for N = 5575 (2928 males, 2648 females) in LIFE-Adult.Eleven of these loci have not yet been described for the respective traits and, hence, are considered as novel findings. For P4, there were three novel loci: CD55 at 1q32.2 (female-specific)[26], VIPR2 at 7q36.3 (sex-related, stronger effect in females)[27], and RBFOX1 at 16p13.3 (female-specific)[28]. For 17-OHP, we also detected three novel hits: HSD3B1 at 1p12 (male-specific)[22], REL at 2p15 (sex-unspecific)[29], and CYB5A at 18q22.3 (male-specific)[30].…”