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.

Kristin E Reeve,Tarek Ibrahim,Babbette Lamarca,Denise C Cornelius,Nathan Campbell,Evangeline Deer,Lorena M Amaral,Ralf Dechend,Owen Herrock,Sarah Fitzgerald,Ashlyn C Harmon,Gerd Wallukat

doi:10.37349/emed.2022.00077

Abstract

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.

Highlights

Preeclampsia (PE) is a multi-system disorder that complicates approximately 2–8% of all pregnancies and 12% of pregnancies in Mississippi [1]
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 when injected into pregnant nude-athymic rats compared to CD4+ T cells from normal pregnant (NP) women
Circulating a proliferation-inducing ligand (APRIL) and placental angiotensin-converting enzyme 2 (ACE-2) activity was increased in response to PE CD4+ T cells

Summary

Introduction

Preeclampsia (PE) is a multi-system disorder that complicates approximately 2–8% of all pregnancies and 12% of pregnancies in Mississippi [1]. We have shown that adoptive transfer of CD4+ T cells isolated from placentas of patients with PE leads to a PE-like response in pregnant nude-athymic rats [13] In these initial studies, adoptive transfer of human placental CD4+ T cells into pregnant nude-athymic rats increased MAP, circulating pro-inflammatory cytokines (TNF-α and IL-17), soluble fms-like tyrosine kinase-1 (sFlt-1), and renal endothelin-1 expression when compared to nude-athymic rats that received CD4+ T cells from NP women [13]. The role of CD4+ T cells to communicate with B cells in this model of PE pathophysiology was unknown

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