Deciphering the immunological interactions: targeting preeclampsia with Hydroxychloroquine’s biological mechanisms

Abstract

Preeclampsia (PE) is a complex pregnancy-related disorder characterized by hypertension, followed by organ dysfunction and uteroplacental abnormalities. It remains a major cause of maternal and neonatal morbidity and mortality worldwide. Although the pathophysiology of PE has not been fully elucidated, a two-stage model has been proposed. In this model, a poorly perfused placenta releases various factors into the maternal circulation during the first stage, including pro-inflammatory cytokines, anti-angiogenic factors, and damage-associated molecular patterns into the maternal circulation. In the second stage, these factors lead to a systemic vascular dysfunction with consecutive clinical maternal and/or fetal manifestations. Despite advances in feto-maternal management, effective prophylactic and therapeutic options for PE are still lacking. Since termination of pregnancy is the only curative therapy, regardless of gestational age, new treatment/prophylactic options are urgently needed. Hydroxychloroquine (HCQ) is mainly used to treat malaria as well as certain autoimmune conditions such as systemic lupus and rheumatoid arthritis. The exact mechanism of action of HCQ is not fully understood, but several mechanisms of action have been proposed based on its pharmacological properties. Interestingly, many of them might counteract the proposed processes involved in the development of PE. Therefore, based on a literature review, we aimed to investigate the interrelated biological processes of HCQ and PE and to identify potential molecular targets in these processes.

Understanding the Pathophysiology of Preeclampsia: Exploring the Role of Antiphospholipid Antibodies and Future Directions

“…Hydroxychloroquine, which demonstrates no adverse effects on the baby, has been employed with success. Furthermore, it has been observed that hydroxychloroquine carries a protective effect on endothelial function, although further assessment is warranted [4,[54][55][56][57].…”

Hydroxychloroquine treatment for recurrent pregnancy loss: a study protocol for a randomized, double-blind, placebo-controlled trial

“…The anti-inflammatory immune modulatory effects of HCQ 16,17 and casuistic reports of live births by women with previous RPL after HCQ-treatment 18,19 , have given rise to hypothesizes of several mechanisms for how HCQ can reduce the risk for PL in RPL 15 . HCQ is suspected to prevent systemic inflammation, oxidative stress, endothelial dysfunction, and hypercoagulability in pregnant women-states presumed associated with RPL 15 .…”

“…HCQ is suspected to prevent systemic inflammation, oxidative stress, endothelial dysfunction, and hypercoagulability in pregnant women-states presumed associated with RPL 15 . The potential immune mechanisms of HCQ in preventing RPL include I) inhibition of Toll like receptors (TRL) 15,17,20 , altering the T-cell activation and proliferation and consequently decreasing the levels of circulating TNF-α 15,21,22 , interferon-gamma 15,22 , and different interleukins 15,22 promoting the switch to a TH2 phenotype of a healthy pregnancy 15 , and II) by inhibiting platelet aggregation reducing the formation of blood clots 15 .…”