Placental CD4 + T cells from preeclamptic patients cause autoantibodies to the angiotensin II type I receptor and hypertension in a pregnant rat model of preeclampsia.

Preeclampsia (PE) is a hypertensive disorder of pregnancy associated with activated CD4 + T cells and autoantibodies to angiotensin II type 1 receptor (AT1-AA). We have previously shown that CD4 + T cells isolated from women with PE cause hypertension, increased tumor necrosis factor alpha (TNF-α), endothelin-1, and soluble fms-like tyrosine kinase-1 (sFlt-1) when injected into pregnant nude-athymic rats compared to CD4 + T cells from normal pregnant (NP) women. However, the role of PE CD4 + T cells to cause AT1-AA as a mechanism of hypertension is not known. Aim: Our goal was to determine if PE CD4 + T cells stimulate AT1-AA in pregnant nude-athymic rats. CD4 + T cells were isolated from human NP and PE placentasand injected into nude-athymic rats on gestational day (GD) 12. In order to examine the role of the PE CD4 + T cells to stimulate B cell secretion of AT1-AA, a subset of the rats receiving PE CD4 + T cells were treated with rituximab on GD 14 or anti-CD40 ligand (anti-CD40L) on GD 12. On GD 19, mean arterial pressure (MAP) and tissues were obtained MAP [114 ± 1 mmHg ( n = 9)] and AT1-AA [19.8 ± 0.9 beats per minute (bpm, n = 4)] were increased in NP nude + PE CD4 + T cells compared to NP nude + NP CD4 + T cells [98 ± 2 mmHg ( n = 7, P < 0.05) and 1.3 ± 0.9 bpm ( n = 5, P < 0.05)]. Rituximab (103 ± 2 mmHg, n = 3, P < 0.05) and anti-CD40L (102 ± 1 mmHg, n = 3, P < 0.05) lowered MAP compared to NP nude + PE CD4 + T cells. Circulating a proliferation-inducing ligand (APRIL) and placental angiotensin-converting enzyme 2 (ACE-2) activity was increased in response to PE CD4 + T cells. These results show that placental CD4 + T cells play an important role in the pathophysiology of PE, by activating B cells secreting AT1-AA to cause hypertension during pregnancy.