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Anne Davidson, MBBS

Professor

The Feinstein Institutes for Medical Research

Institute of Molecular Medicine

https://feinstein.northwell.edu/institutes-researchers/our-researchers/anne-davidson-mbbs

Mechanisms for human TLR8 induced placental injury

Anne Davidson, MBBS, The Feinstein Institutes for Medical Research 

Antibodies, produced by B cells, target foreign invaders like viruses and bacteria to protect us from infections. In systemic lupus erythematosus (SLE), antibodies can mistakenly target a person’s own cell contents, leading to inflammation and organ damage. Pregnant women with SLE are at a higher risk of pregnancy complications, and a certain kind of antibody, called anti-phospholipid (APL) antibodies, are partly responsible. APL antibodies are responsible for about 4% of stillbirths among the general population, yet the treatment options for high-risk people are limited. Dr. Davidson will explore how increased levels of a molecule called TLR8 drive these harmful effects and if targeting TLR8 is a promising therapeutic option to improve pregnancy outcomes for women with SLE. 

Toll-like receptors (TLRs) are immune sensors that monitor and patrol our bodies for microbes, damage, stress, or danger. In SLE, they can mistakenly detect a person’s own DNA or RNA as foreign, leading to the production of autoantibodies, inflammation, and tissue damage. There are many TLRs, but understanding the role of TLR8 has been particularly difficult due to differences in the molecule between mice and humans. Dr. Davidson found that a mouse model of lupus that makes human TLR8 had increased fetal loss, injury to the placenta, and decreased levels of molecules called pregnancy-specific glycoproteins (PSGs), which are important for the healthy development of the placenta’s blood vessels. She will now determine how human TLR8 causes negative pregnancy outcomes and if reduced levels of PSGs can be used as a biomarker to predict poor outcomes, like fetal loss, in pregnant women with APL antibodies. Lastly, she will explore the therapeutic potential of blocking TLR8 to improve pregnancy outcomes. 

What this study means for people with lupus 

Pregnancy complications are a devastating feature of SLE, and until now, there has not been a robust model for studying damage to the placenta seen in those with APL antibodies. Dr. Davidson’s generation of a lupus mouse model that makes human TLR8 could advance how this disease is being studied, highlight a new therapeutic avenue that could be tested in a clinical trial targeting TLR8 for at-risk pregnancies, and uncover a new biomarker for predicting adverse pregnancy outcomes. 

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by inflammatory organ manifestations, reduced quality of life, and increased mortality. The overproduction of Type I interferons via Toll-like receptors (TLRs) 7, 8, and 9 contributes to SLE development. Polymorphisms of both TLR7 and TLR8 are associated with SLE risk. While both TLRs 7 and 8 recognize endosomal RNA, they differ in their cellular expression and cytokine profiles. Mouse models have limitations in studying TLR8 due to a 5 amino acid deletion that confers the inability of mouse TLR8 to recognize RNA. However, the overexpression of human TLR8 (huTLR8) in mice induces inflammation and SLE-related autoantibodies. To investigate the role of huTLR8 in SLE, mice expressing huTLR8 as a BAC transgene were generated. These mice exhibited IL12 and TNF production upon TLR8 activation, and some founders displayed systemic autoimmune features. Only one founder transmitted the transgene to its offspring but displayed no evidence of spontaneous autoimmunity unless challenged with innate stimuli. Surprisingly, crossbreeding these huTLR8 mice with the Sle1 model (Sle1.huTLR8tg mice) resulted in a high frequency of fetal loss and placental injury resembling human anti-phospholipid syndrome. TLRs are expressed in the maternal-fetal interface, and exposure to APL antibodies triggers miRNA release and inflammatory cytokine production in trophoblasts. We have found that fetal loss in Sle1.huTLR8tg mice is associated with mid-trimester placental developmental defects including surprising abnormalities in placental NK cells and loss of the placental junctional zone resulting in a decreased trophoblast production of pregnancy-specific glycoproteins (PSGs) that promote placental vascular remodeling. The first aim of the proposed study aims to determine the mechanism behind huTLR8tg-induced adverse pregnancy outcomes, investigating whether the observed defect in placental NK cells in huTLR8tg.Sle1 mice is due to recruitment or maturation failure, if the inflammatory environment in the developing placenta of Sle1.huTLR8tg mice arises from altered recruitment or maturation of placental myeloid cells, and whether placental developmental abnormalities require maternal or fetal expression of huTLR8. In Aim 2, the study will examine whether decreased PSGs can predict adverse pregnancy outcomes in APL patients. Aim 3 will explore the possibility of rescuing pregnancies in huTLR8tg mice by inhibiting TLR7/8 or TLR8. The lack of a reliable model for APL-induced placental injury has hindered the development of new therapeutic strategies for adverse outcomes in SLE pregnancies. Our new spontaneous model fills this research gap, and will provide insights into whether targeting huTLR8 could be an effective approach.

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