Inhibiting B cell activating factor attenuates preeclamptic symptoms in placental ischemic rats

Abstract

Problem Preeclampsia (PE), new‐onset hypertension during pregnancy, is associated with a pro‐inflammatory state with activated T cells, cytolytic natural killer (NK) cells, dysregulated complement proteins, and B cells secreting agonistic autoantibodies to the angiotensin II type‐1 receptor (AT1‐AA). The reduced uterine perfusion pressure (RUPP) model of placental ischemia recapitulates these features of PE. Blocking CD40L‐CD40 communication between T and B cells or B cell depletion with Rituximab prevents hypertension and AT1‐AA production in RUPP rats. This suggests that T cell‐dependent B cell activation contributes to the hypertension and AT1‐AA associated with PE. B2 cells maturing into antibody producing plasma cells are the product of T cell‐dependent B cell‐interactions and B cell Activating Factor (BAFF) is an integral cytokine in the development of B2 cells specifically. Thus, we hypothesize that BAFF blockade will selectively deplete B2 cells, therefore reducing blood pressure, AT1‐AA, activated NK Cells, and complement in the RUPP rat model of PE. Method of study Gestational Day (GD) 14 pregnant rats underwent the RUPP procedure, and a subset were treated with 1 mg/kg Anti‐BAFF antibodies via jugular catheters. On GD19, blood pressure was measured, B cells and NK cells were measured by flow cytometry, AT1‐AA was measured by cardiomyocyte bioassay, and complement activation was measured by ELISA. Results Anti‐BAFF therapy attenuated hypertension, AT1‐AA, NK cell activation, and APRIL levels in RUPP rats without negatively impacting fetal outcomes. Conclusions This study demonstrates that B2 cells contribute to hypertension, AT1‐AA, and NK cell activation in response to placental ischemia during pregnancy.

Spatial profiling of the placental chorioamniotic membranes reveals upregulation of immune checkpoint proteins during Group B Streptococcus infection in a nonhuman primate model

“…Dysregulation of immune checkpoints have been associated with adverse pregnancy outcomes. Expression of immune checkpoints are also increased in the pro-inflammatory state of preeclampsia (PD-1/PD-L1 system, TIM-3, CD40/CD40L) ( Matsubara et al., 2016 ; Herrock et al., 2023 ). During early stages of pregnancy, LAG-3 CTLA4 T+ regulatory cells have been found in the periphery and decidua and have been postulated to inhibit proliferation of tolerance against the fetus ( Marozio et al., 2023 ).…”

“…All 56 immunoproteins have been included, to evaluate the correlation in either the amnion, chorion or decidua using Spearman rank-order correlation (*, p <0.05; **, p<0.01; ***, p<0.001). (Matsubara et al, 2016;Herrock et al, 2023). During early stages of pregnancy, LAG-3 CTLA4 T+ regulatory cells have been found in the periphery and decidua and have been postulated to inhibit proliferation of tolerance against the fetus (Marozio et al, 2023).…”

Angiotensin II type-1 receptor autoantibodies and effects in neonates of preeclamptic women.

“…IgG is mainly transferred in the third trimester and the newborn IgG antibodies' levels is correlated with maternal ones [26]. Another hypothesis can be discussed to explain the presence of AT1-AA in the newborn : direct fetal production via B lymphocytes [27][28][29].…”

Progesterone‐induced blocking factor blockade causes hypertension in pregnant rats

“…34,35 Its immunological effects include inhibition of natural killer (NK) cell activity and can regulate the proinflammatory balance. 36,37 PIBF has been suggested to mediate the immunomodulatory effects through the modulation of Th2 cytokines, which are reduced during PE and increased during healthy pregnancy. Indeed, PIBF receptor binds to and signals through the IL-4 receptor.…”

“…Progesterone is crucial for establishing and maintaining pregnancy and it exerts immune modulatory effects by the lymphocyte‐derived protein progesterone‐induced blocking factor (PIBF) 34,35 . Its immunological effects include inhibition of natural killer (NK) cell activity and can regulate the proinflammatory balance 36,37 …”