Pregnancy loss due to early developmental defects in lupus mice expressing human TLR8

Abstract Anti-phospholipid (APL) autoantibodies confer a high risk for adverse pregnancy outcomes, especially in Systemic Lupus Erythematosus (SLE). While human TLR8 (huTLR8) has been implicated in APL antibody-mediated placental injury in vitro, its in vivo role in pregnancy is unexplored. We report a novel mouse model of pregnancy loss in SLE-prone mice expressing huTLR8. Placental analysis revealed early developmental defects starting post-implantation, including a thin junctional zone, impaired vascularization, infarcts, and inflammation. Profound immune dysregulation was evident at E8.5 including increased myeloid cells and CD8 T cells and decreased uterine natural killer (uNK) cells. RNA sequencing revealed downregulated pregnancy-specific glycoproteins, reduced uNK cell-associated genes, and an upregulated myeloid cell signature. Bone marrow chimera studies demonstrated preferential activation of huTLR8-expressing placental Ly6C+ monocytes. Spatial transcriptomics at E9.5 confirmed uNK cell loss, decreased IL15 expression by both stromal and myeloid cells, and discrete inflammatory aggregates in the maternal layers containing myeloid cells and IFNγ-expressing CD8 T cells. We propose that huTLR8, likely through myeloid cell activation and cytolytic T cell recruitment, drives placental injury in the context of SLE and APL autoantibodies. This model provides a valuable platform to dissect early pathogenic events in APL-associated pregnancy loss and identify new therapeutic targets. Competing Interest Statement The authors have declared no competing interest. Footnotes https://urldefense.proofpoint.com/v2/url?u=https-3A__www.ncbi.nlm.nih.gov_geo_query_acc.cgi-3Facc-3DGSE316139&d=DwIEAg&c=shNJtf5dKgNcPZ6Yh64b-ALLUrcfR-4CCQkZVKC8w3o&r=PPojkf3d9PyvRj2TR5wp37jaN2L_b6FdLjgtwkYRmuw&m=Jz6O7VkrWkQ02KdxEp9VLkDENfnYnym6EbihddMWU9vlkOcPSaHOR_ZRv-8SVcgw&s=7J1xw_N_JHv86a1Wp5x5k3nQ5rLURA5uT2dk6bgiAoE&e=