Dissertation

The Role of B Lymphocytes in the Pathophysiology of Hypertension in Response to Placental Ischemia

Herrock, Owen T

2023

Overview

Preeclampsia (PE) is new onset hypertension beyond the 20th week of gestation in conjunction with some type of end organ dysfunction. PE is one of the leading causes of maternal and fetal demise worldwide and effects roughly 5-8% of pregnancies each year. PE stems from placental ischemia which leads to release of placental factors and a chronic inflammatory environment in the placenta and the maternal circulation. The inflammation in PE is characterized by activated T helper (Th) cells, Natural Killer (NK) cells, B cells producing agonistic antibodies to the angiotensin II type 1 receptor (AT1-AA) and dysregulation of the complement system. Although these inflammatory mediators have been linked to hypertension in PE, there have been very few studies that have investigated a role of B cells, independent of the AT1-AA, in the pathophysiology of PE.B cells are divided into B1 and B2 subsets. B1 cells are innate-like B cells that spontaneously produce low-affinity antibodies independent of Th cell help. B2 cells are classical B cells that produce antigen specific, high-affinity antibodies and transform into memory B cells with the help of Th cells. B1 cells have previously been implicated in the pathophysiology of PE by producing AT1-AA; however, AT1-AA has been found 7 years postpartum thus suggesting that long-term memory mechanisms, such as those mediated by B2 cells, are involved in AT1-AA production. Our lab has previously shown that communication between Th cells and B cells leads to AT1-AA and hypertension in pregnant rats, suggesting that B2 cells are involved in the pathophysiology of PE. One aim of this work is to test if B2 cells are responsible for AT1-AA in response to placental ischemia in pregnant rats.B cells primarily induce inflammatory actions by producing antibodies. The AT1-AA was originally discovered in the serum of PE women. AT1-AA binds the second extracellular loop of the AT1 receptor, activates the AT1 receptor, induces anti-angiogenic factors, and induces endothelin and oxidative stress. Studies with the AT1-AA in animal models have also shown it sensitizes women to vasoconstrictors and can directly induce hypertension during pregnancy. As AT1-AA is an antibody, it also is an important activator of killer functions of the immune system. After AT1-AA binds its antigen, the FC region of the antibody can be bound by CD16 on human NK cells. CD16 activation on NK cells serves as a strong activating signal and induces cellular cytotoxicity which can contribute to cell mediated destruction and tissue dysfunction in PE. Antibodies can also activate the classical pathway of the complement system. After antibody binding, the C1 complex is built on the FC region of the antibody which starts a cascade of proteolytic cleavages that ultimately result in destruction of the antibody bound cell. Both NK cell activation and complement activation have been implicated in the pathophysiology of PE; but, there have not been any studies that directly studied the relationship between placental ischemiastimulated B cells and NK cell or complement activation. Thus, a second aim of this work was to examine the relationship between B cells in PE and complement activation or NK cell activation during pregnancy.Overall the goal of this dissertation is to further elucidate the role of AT1-AA producing B cells in the pathophysiology of PE. There have been little advancements in treatment strategies for PE over the last 50 years, so there is a dire need for new therapeutic options for clinicians. These studies could elucidate the direct role for B cells to induce hypertension, NK cell activation, complement dysregulation, or fetal growth restriction in PE. Data from these studies may provide insight into specific molecular targets to selectively inhibit known mechanisms of hypertension in women with PE.

• Publisher: ProQuest Dissertations & Theses
• Subject: Immunology / Obstetrics / Pharmacology
• ISBN: 9798379411763