Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/275503

A mouse model of maternal obesity leads to uterine natural killer (uNK) cell activation and uterine artery remodeling defects

Baltayeva, J.·Castellana, B.·Mara, D.·Christians, J. K.·Beristain, A. G.
View original source ↗Export metadata ↓

Abstract

Maternal obesity associates with multiple adverse reproductive outcomes, negatively affecting the health and survival of both the mother and the fetus. The contributory effects of obesity on adipose-derived immune changes have been well established, however the mechanisms that link obesity to pregnancy complications remain unclear. Proper development of the placenta and establishment of utero-placental vasculature is essential in early pregnancy to allow for optimal fetal growth and survival. Uterine immune cells, particularly uterine natural killer (uNK) cells, play fundamental roles in promoting these events. Using an obesogenic high-fat/high-sucrose (HFD) mouse model of maternal obesity, uNK cells and placenta/uterine vascular remodeling were examined at gestational days (Gd) 10.5 and 14.5 of pregnancy. While mice fed a HFD 13 weeks prior to pregnancy significantly gained more weight than control mice fed a low-fat/no-sucrose diet (LFD), fetal survival was not different in either diet. At Gd 10.5, HFD had no effect on total uNK proportions, nor did it affect proportions of distinct CD122+/CD49a tissue resident or CD122+/DX5+ conventional uNKs. However, HFD resulted in increased proportions of NCR1+ uNK and overall heightened uNK activity. Moreover, HFD resulted in impairments in uterine vascular remodeling at Gd10.5. By Gd14.5, uterine artery defects were no longer observed and placental structure was comparable between HFD and LFD mice. Gene analysis of IFN{gamma}, TNF and VEGFA in Gd10.5 uNK indicated that, while not significant, a HFD leads to subtle alterations in uNK cytokine gene expression. These findings show that HFD in mice results in changes in uNK biology and temporary uterine artery remodeling impairments. Further, this work establishes insight into the cellular changes occurring in early pregnancy as a result of HFD exposure.

Source connections

Explore related subjects

immunologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Baltayeva, J., Castellana, B., Mara, D., Christians, J. K., Beristain, A. G.. 2018-03-03. A mouse model of maternal obesity leads to uterine natural killer (uNK) cell activation and uterine artery remodeling defects. https://doi.org/10.1101/275503

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

CD19-CAR T-cell therapy resets the EBV+ autoreactive B cell repertoire in autoimmune disease

Epstein-Barr virus (EBV) reprograms autoreactive B cells into activated antigen-presenting cells that drive pathogenic T- and B-cell responses in autoimmune disease. Using EBV B-cell sequencing (EBV-seq), we profiled EBV+ B cells in patients treated with CD19 chimeric antigen receptor (CAR) T cells (systemic lupus, n=6; idiopathic inflammatory myopathies, n=3; systemic sclerosis, n=3) or rituximab (n=15). CAR T cells, but not rituximab, depleted EBV+ B cells, resetting the repertoire toward a naive state: predominantly IgM+ with minimal somatic hypermutation. Post-rituximab B-cells remained class-switched, hypermutated, and activated. Monoclonal antibodies cloned from EBV+ B cells lost autoreactivity after CAR T cells but not rituximab. Sustained drug-free remission occurred in 8/12 CAR-treated but 0/15 rituximab-treated patients. EBV+ B cells were predominantly Latency III and resisted anti-CD20 and anti-CD19 antibodies, yet were killed by CAR T cells and T-cell engagers. CD19-CAR T-cell therapy resets the autoreactive EBV+ B-cell repertoire, which may underlie sustained drug-free remission.

immunology↗
bioRxiv2026

A minimal two-residue C-terminal truncation of AID in adult-onset hyper-IgM syndrome type 2 (HIGM2)

Activation-induced cytidine deaminase (AID), encoded by AICDA, facilitates class-switch recombination (CSR) and somatic hypermutation (SHM) in activated B cells. Loss of AID function causes hyper-IgM syndrome type 2 (HIGM2). While typically autosomal recessive, three C-terminal truncation variants have been reported to act in autosomal dominant manner. We describe a novel heterozygous AICDA nonsense variant, c.589G>T (p.G197*), that truncates the final two C-terminal residues of AID and results in adult-onset HIGM2. Single-cell sequencing of primary patient B cells revealed a complete block in CSR and a [~]10-fold reduction in SHM. AICDA mRNA expression was balanced between wild-type and variant alleles, yet AID protein abundance was reduced to [~]56% with normal subcellular localization. Remarkably, inducible germinal center (iGB) cultures restored CSR in purified naive patient B cells. CRISPR-Cas9 editing of healthy donor B cells confirmed that the iGB platform can rescue B cells harboring heterozygous, but not homozygous, AICDA variants. These results demonstrate that even a two-amino-acid truncation at the AID C-terminus is sufficient to disrupt its function and cause HIGM2.

immunology↗
bioRxiv2026

Defining the Functional Consequence of the Human Ocular Microbiome

The ocular surface is one of the body's most environmentally exposed mucosal barriers, yet it is considered low biomass and harbors orders of magnitude fewer bacteria than microbe-rich sites like the gut. This has cast doubt on whether a functional core ocular microbiome exists at all. Having previously defined a protective gd T cell and IL-17 axis engaged by the murine commensal Corynebacterium mastitidis, we asked whether human-derived bacteria could do the same. Pairing sequencing and culturomics of healthy human conjunctiva from two geographically distinct cohorts, we define a stable core microbiome and identify Corynebacterium bovis as a consistent eye-resident commensal rather than a transient contaminant. In humans, C. bovis elicits a non-pathogenic response marked by IL-17 secretion by {gamma}{delta} T cells and circulating C. bovis-specific IgG, which suggests commensalism rather than pathology. Colonizing mice with human C. bovis strains from Pittsburgh or Miami reproduced this program and conferred protection against ocular infection with Staphylococcus aureus. Together, these findings identify C. bovis as a human-derived ocular commensal that can drive protective {gamma}{delta} T cell immunity, translating a mechanism previously defined only in mice into human relevance and a rational target against sight-threatening infection.

immunology↗