# Mechanisms for Human TLR8 induced pregnancy loss in a mouse model of SLE

> **NIH NIH R21** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2022 · $254,354

## Abstract

Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease that causes
a significant decrease in quality of life and early mortality. Genetic studies have identified
activation of the innate immune system, with excess production of Type I interferons as a major
causative pathway. RNA-sensing Toll-like receptors are crucial protective receptors of the innate
immune system but are also implicated in autoimmunity because they can recognize nucleic acids
released from damaged cells and within nucleic acid containing immune complexes. Functional
polymorphisms of the endosomal RNA-recognizing innate receptors TLR7 and TLR8 predispose
to SLE and excess mouse TLR7 and human TLR8 accelerate lupus in mouse models. Human
TLR8 differs in its function from TLR7 because it recognizes different ligands and is expressed
on different immune cell subsets.
 TLR8 is not an RNA sensor in mice because of a 5 amino acid deletion that attenuates its
RNA-binding site. We therefore bred a human TLR8 BAC transgene (huTLR8) into mice in which
a mild lupus phenotype is conferred by the susceptibility locus Sle1. Expression of the transgene
is physiologically regulated such that huTLR8 is expressed at high levels in myeloid DCs and
monocytes but at 50-100-fold lower levels in lymphocytes. We found that huTLR8 induces an anti-
phospholipid like syndrome in Sle1 mice that leads to spontaneous placental inflammation, fetal
resorptions and late-term pregnancy loss in up to 60% of female dams. In this proposal we will
test the mechanism for huTLR8 mediated pregnancy loss by addressing the role of huTLR8 as a
sensor of RNA in placental trophoblasts and immune cells.
 In Aim 1 we will examine the role of autoantibodies in placental injury in mice with or
without huTLR8 expression and determine whether huTLR8 expression in B cells results in the
production of autoantibodies with enhanced pathogenicity. In Aim 2 we will determine the timing
and characteristics of placental injury, the contribution of huTLR8 in maternal vs. fetal cells to
injury and whether placental trophoblasts activated by anti-phospholipid antibodies release
huTLR8 ligands that enhance local inflammation. In Aim 3 we will determine whether myeloid
cells from huTLR8tg mice are intrinsically more pro-inflammatory than those of their wild-type
counterparts and therefore amplify the effector response to antibody mediated placental injury.
 These experiments should allow us to distinguish the role of huTLR8 in maternal cells,
trophoblasts and immune cell subsets in the induction of placental damage that leads to
pregnancy loss. Our studies will inform us whether specific huTLR8 antagonists or antagonists of
huTLR8 ligands should be tested for their ability to prevent or treat placental injury.

## Key facts

- **NIH application ID:** 10434117
- **Project number:** 5R21AI156019-02
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** Anne Davidson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $254,354
- **Award type:** 5
- **Project period:** 2021-06-18 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10434117

## Citation

> US National Institutes of Health, RePORTER application 10434117, Mechanisms for Human TLR8 induced pregnancy loss in a mouse model of SLE (5R21AI156019-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10434117. Licensed CC0.

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