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B CELLS CONTRIBUTE TO HYPERTENSION AND CYTOLYTIC NK CELL ACTIVATION IN RESPONSE TO PLACENTAL ISCHEMIA OF PREGNANCY

Preeclampsia (PE), new onset hypertension during pregnancy, is associated with a pro‐inflammatory state and B lymphocytes secreting agonistic autoantibodies against the angiotensin II type 1 receptor (AT1‐AA). Two recognized subsets of B Cells are B1 and B2 B Cells. B2 B Cells are the classical B cell involved in adaptive immune responses and production of antibodies through affinity maturation. B1 B Cells produce natural antibodies and have recently been shown to communicate through TH17 cells, and are implicated in the pathophysiology of PE through AT1‐AA. The Reduced Uterine Perfusion Pressure (RUPP) rat model of placental ischemia recapitulates many characteristics of PE. We have previously shown that either B cell depletion or AT1‐AA epitope binding protein (7AA) in RUPP rats improved hypertension and AT1‐AA activity. The AT1‐AA is a specific IgG3 antibody to the AT1 receptor and thus could be produced by B1 or B2 B Cells in PE. This information would add to the design of new therapies targeting one B cell type for depletion. Therefore, we hypothesize that B cells and specifically B2 cells cause hypertension and NK cell activation during pregnancy through production of the AT1‐AA. To test this hypothesis, total splenic B Cells and B2 cells were isolated from RUPP rats on Gestation Day (GD)19 RUPP and adoptively transferred into NP rats on GD12, blood pressure (MAP), placental and circulating cNKs were measured by flow cytometry on GD19. To test the role of AT1‐AA in the hypertension, 7AA was administered to a group of recipient rats on GD14. MAP increased in NP+RUPP B cells to 117 ± 1 mmHg, n=10, and to 111 mmHg ± 3, n=8, in NP+RUPP B2 cells, compared to NP rats(p<0.001). Administration of 7AA attenuated hypertension in response to total RUPP B cells (99 mmHg ± 6, n=5)(p<0.01) and in response to RUPP B2s (95.5mmHg ± 4.5, n=2). Circulating cNKs were elevated in NP+RUPPBcells (6 ± 2.5, n=5)(p<0.01) and in NP+RUPP B2 cells (8 ± 3.33, n=4)(p<0.01) compared to NP (0.67 ± 0.33, n=10). Placental cNKs were elevated in NP+RUPPBcells (2.32 ± 0.73, n=6)(p<0.01) and in NP+RUPP B2 cells (1.33 ± 0.24, n=3)(p<0.01) compared to NP (0.2250 ± 0.133, n=10). Based on these data, we conclude that total B Cells and the B2 cell subset activated in response to placental ischemia cause hypertension via secretion of the AT1‐AA and NK cell activation during pregnancy and thus indeed play an important role in PE. Future studies will examine the role of B1 cells and their interaction with TH17s as possible contributors to AT1‐AA and hypertension during PE and in response to RUPP total B cells and RUPP B2 B cells.