Perinatal granulopoiesis and risk of pediatric asthma
Abstract
There are perinatal characteristics, such as gestational age, reproducibly associated with risk for pediatric asthma. Identification of biologic processes influenced by these characteristics could facilitate risk stratification or new therapeutic targets. We hypothesized that transcriptional changes associated with multiple epidemiologic risk factors would be mediators of pediatric asthma risk. Using publicly available transcriptomic data from cord blood mononuclear cells, transcription of genes involved in myeloid differentiation were observed to be inversely associated with a pediatric asthma risk stratification based on multiple perinatal risk factors. This gene signature was validated in an independent prospective cohort and was specifically associated with genes localizing to neutrophil specific granules. Further validation demonstrated that umbilical cord blood serum concentration of PGLYRP-1, a specific granule protein, was inversely associated with mid-childhood current asthma and early-teen FEV1/FVCx100. Thus, neutrophil specific granule abundance at birth predicts risk for pediatric asthma and pulmonary function in adolescence.
Data availability
Data from RNAseq is available on NCBI Bioproject database PRJNA577955.
-
Whole blood mRNA expression profiling of host molecular networks in neonatal sepsisNCBI Gene Expression Omnibus, GSE25504.
-
Comprehensive Study of Tobacco Smoke-Related Transcriptome Alterations in Maternal and Fetal CellsNCBI Gene Expression Omnibus, GSE27272.
-
Deregulation of Gene Expression induced by Environmental Tobacco Smoke Exposure in PregnancyNCBI Gene Expression Omnibus, GSE30032.
-
Genome-wide analysis of gene expression levels in placenta and cord blood samples from newborns babiesNCBI Gene Expression Omnibus, GSE36828.
-
Prenatal arsenic exposure and the epigenome: altered gene expression profiles in newborn cord bloodNCBI Gene Expression Omnibus, GSE48354.
-
Standard of hygiene and immune adaptation in newborn infantsNCBI Gene Expression Omnibus, GSE53473.
-
The obese fetal transcriptomeNCBI Gene Expression Omnibus, GSE60403.
Article and author information
Author details
Funding
National Heart, Lung, and Blood Institute (F30HL136001)
- Benjamin A Turturice
National Institute of Allergy and Infectious Diseases (R01AI053878)
- Patricia W Finn
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD034568)
- Emily Oken
National Institutes of Health (UH3OD023286)
- Emily Oken
Robert Wood Johnson Foundation (Nurse Faculty Scholars Program #72117)
- Mary Dawn Koenig
University of Illinois at Chicago (College of Nursing Dean's Award)
- Mary Dawn Koenig
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The current study was approved by the University of Illinois at Chicago IRB, 20160326 and 20150353, and the IRB of Harvard Pilgrim Health Care.
Copyright
© 2021, Turturice et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,487
- views
-
- 130
- downloads
-
- 2
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Immunology and Inflammation
Natural killer (NK) cells can control metastasis through cytotoxicity and IFN-γ production independently of T cells in experimental metastasis mouse models. The inverse correlation between NK activity and metastasis incidence supports a critical role for NK cells in human metastatic surveillance. However, autologous NK cell therapy has shown limited benefit in treating patients with metastatic solid tumors. Using a spontaneous metastasis mouse model of MHC-I+ breast cancer, we found that transfer of IL-15/IL-12-conditioned syngeneic NK cells after primary tumor resection promoted long-term survival of mice with low metastatic burden and induced a tumor-specific protective T cell response that is essential for the therapeutic effect. Furthermore, NK cell transfer augments activation of conventional dendritic cells (cDCs), Foxp3-CD4+ T cells and stem cell-like CD8+ T cells in metastatic lungs, to which IFN-γ of the transferred NK cells contributes significantly. These results imply direct interactions between transferred NK cells and endogenous cDCs to enhance T cell activation. We conducted an investigator-initiated clinical trial of autologous NK cell therapy in six patients with advanced cancer and observed that the NK cell therapy was safe and showed signs of effectiveness. These findings indicate that autologous NK cell therapy is effective in treating established low burden metastases of MHC-I+ tumor cells by activating the cDC-T cell axis at metastatic sites.
-
- Cancer Biology
- Immunology and Inflammation
The current understanding of humoral immune response in cancer patients suggests that tumors may be infiltrated with diffuse B cells of extra-tumoral origin or may develop organized lymphoid structures, where somatic hypermutation and antigen-driven selection occur locally. These processes are believed to be significantly influenced by the tumor microenvironment through secretory factors and biased cell-cell interactions. To explore the manifestation of this influence, we used deep unbiased immunoglobulin profiling and systematically characterized the relationships between B cells in circulation, draining lymph nodes (draining LNs), and tumors in 14 patients with three human cancers. We demonstrated that draining LNs are differentially involved in the interaction with the tumor site, and that significant heterogeneity exists even between different parts of a single lymph node (LN). Next, we confirmed and elaborated upon previous observations regarding intratumoral immunoglobulin heterogeneity. We identified B cell receptor (BCR) clonotypes that were expanded in tumors relative to draining LNs and blood and observed that these tumor-expanded clonotypes were less hypermutated than non-expanded (ubiquitous) clonotypes. Furthermore, we observed a shift in the properties of complementarity-determining region 3 of the BCR heavy chain (CDR-H3) towards less mature and less specific BCR repertoire in tumor-infiltrating B-cells compared to circulating B-cells, which may indicate less stringent control for antibody-producing B cell development in tumor microenvironment (TME). In addition, we found repertoire-level evidence that B-cells may be selected according to their CDR-H3 physicochemical properties before they activate somatic hypermutation (SHM). Altogether, our work outlines a broad picture of the differences in the tumor BCR repertoire relative to non-tumor tissues and points to the unexpected features of the SHM process.