Heme oxygenase-1 deficiency results in splenic T-cell dysregulation in offspring of mothers exposed to late gestational inflammation

Maide Ozen; Hui Zhao; Flora Kalish; Yang Yang; Ann Folkins; Irina Burd; Ronald J Wong; David K Stevenson

doi:10.1111/aji.12829

Heme oxygenase-1 deficiency results in splenic T-cell dysregulation in offspring of mothers exposed to late gestational inflammation

Am J Reprod Immunol. 2018 May;79(5):e12829. doi: 10.1111/aji.12829. Epub 2018 Feb 27.

Authors

Maide Ozen^{1

2}, Hui Zhao¹, Flora Kalish¹, Yang Yang³, Ann Folkins⁴, Irina Burd⁵, Ronald J Wong¹, David K Stevenson¹

Affiliations

¹ Department of Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Stanford, CA, USA.
² Department of Pediatrics, Johns Hopkins University, Baltimore, MD, USA.
³ Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁵ Department of Gynecology and Obstetrics, Integrated Research Center for Fetal Medicine, Johns Hopkins University, Baltimore, MD, USA.

PMID: 29484761
DOI: 10.1111/aji.12829

Abstract

Problem: Infection during pregnancy can disrupt regulatory/effector immune system balance, resulting in adverse pregnancy and fetal-neonatal outcomes. Heme oxygenase-1 (HO-1) is a major regulatory enzyme in the immune system. We observed maternal immune response dysregulation during late gestational inflammation (LGI), which may be mediated by HO-1. Here, we extend these studies to examine the immune response of offspring.

Method of study: Pregnant wild-type (Wt) and HO-1 heterozygote (Het) dams were treated with lipopolysaccharide (LPS) or vehicle at E15.5. Pups' splenic immune cells were characterized using flow cytometry.

Results: CD3⁺ CD4⁺ CD25⁺ (Tregs) and CD3⁺ CD8⁺ (Teffs) T cells in Wt and Het were similar in control neonates and increased with age. We showed not only age- but also genotype-specific and long-lasting T-cell dysregulation in pups after maternal LGI. The persistent immune dysregulation, mediated by HO-1 deficiency, was reflected as a decrease in Treg FoxP3 and CD3⁺ CD8⁺ T cells, and an increase in CD4⁺ /CD8⁺ T-cell and Treg/Teff ratios in Hets compared with Wt juvenile mice after maternal exposure to LGI.

Conclusion: Maternal exposure to LGI can result in dysregulation of splenic T cells in offspring, especially in those with HO-1 deficiency. We speculate that these immune alterations are the basis of adverse outcomes in neonates from mothers exposed to low-grade (subclinical) infections.

Keywords: heme oxygenase-1; maternal inflammation; neonatal immune response.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / metabolism
CD8-Positive T-Lymphocytes / immunology*
CD8-Positive T-Lymphocytes / metabolism
Female
Fetal Diseases / immunology
Fetal Diseases / metabolism
Heme Oxygenase-1 / deficiency*
Humans
Infant, Newborn
Infant, Newborn, Diseases / immunology*
Infant, Newborn, Diseases / metabolism
Inflammation / immunology*
Inflammation / metabolism
Mother-Child Relations
Pregnancy
Pregnancy Complications / immunology*
Pregnancy Complications / metabolism
Spleen / immunology*
Spleen / metabolism
T-Lymphocytes, Regulatory / immunology
T-Lymphocytes, Regulatory / metabolism

Substances

HMOX1 protein, human
Heme Oxygenase-1