The Importance of B Cells in Causing Hypertension During Pregnancy; to B or Not to B

Abstract

Preeclampsia (PE), new onset hypertension associated with placental ischemia during pregnancy, is associated with a pro-inflammatory state characterized by increased T Helper cells and B lymphocytes secreting agonistic autoantibodies against the angiotensin II type 1 receptor (AT1-AA). We have shown that adoptive transfer of CD4+T cells from PE women causes a PE-like phenotype in immunodeficient pregnant rats. Moreover, our lab has shown that depletion of B Cells or inhibition of AT1-AA, a product of B cell activation, attenuates hypertension in various rat models of PE. Recent studies have touted that B cells don't play a role in the hypertension in response to placental ischemia. However, to date studies have only investigated B cells from animal models of PE, no studies have examined the effects of B cells from PE patients to cause hypertension during pregnancy. Therefore, we hypothesize that B cells and B cell communication with T cells, play an important role to cause hypertension and other features of PE during pregnancy. We tested our hypothesis in two separate studies involving adoptive transfer of PE cells into immunodeficient pregnant rats. First, placental CD4+T cells, isolated from either normal pregnant control (NP) or PE patients upon delivery, were transferred i.p. into Nude athymic rats at gestation day (GD) 12. Blood pressure (MAP) and circulating A Proliferation Inducing Ligand (APRIL), a cytokine necessary for B cell/plasma cell maturation and survival, were examined on GD19. In a separate group of Nude athymic rats, PE placental B cells were transferred on GD12 and MAP was determined at GD19. Recipients of placental PE CD4+ T cells had elevated MAP, 114±1 mmHg, compared to recipients of NP CD4+T cells, 97±3 mmHg (p<0.05). Recipients of PE CD4+T cells had smaller pups (1.23±0.075g) compared to recipients of NP CD4+T Cells (1.507±0.139g)(p=0.07)(ns). Importantly, recipient rats of PE CD4+T cells also had elevated APRIL (1.276±0.0.13 ng/mL) compared to recipients of NP CD4+ T cells (0.434±0.11 ng/mL)(p<0.01). MAP increased in Nude athymic pregnant rats that received placental PE B cells (114 ±5 mmHg)(n=3) compared to control Nude athymic pregnant rats (102±1 mmHg)(n=3). These studies show that 1)PE CD4+T cells stimulate factors necessary for B cell maturation which is associated with hypertension during pregnancy and that 2)PE B cells indeed cause hypertension in during pregnancy. Therefore, these studies demonstrate a role for B cells and T cell communication with B cells stimulated in response to PE to directly and indirectly play a role in hypertension during pregnancy.