Multicenter Systems Analysis of Human Blood Reveals Immature Neutrophils in Males and During Pregnancy

Abstract

Despite clear differences in immune system responses and in the prevalence of autoimmune diseases between males and females, there is little understanding of the processes involved. Here, we identified a gene signature of immature-like neutrophils (Immature-Like Neutrophil Signature, ILNS), characterized by the overexpression of genes encoding for several granule-containing proteins, which was found in higher levels (up to 3-fold) in young (20 – 30 years old) but not older (60 – >89 years old) males compared with females. Functional and phenotypic characterization of peripheral blood neutrophils revealed more mature and responsive neutrophils in young females, which also exhibited an elevated capacity in neutrophil extracellular trap (NET) formation at baseline and upon microbial or sterile autoimmune stimuli. Expression levels of the ILNS increased linearly with pregnancy, an immune state of increased susceptibility to and severity of certain infections. Using mass cytometry, we also find increased frequencies of immature forms of neutrophils in the blood of women in late pregnancy. Thus, our findings show novel sex-differences in innate immunity and identify a common neutrophil signature in males and in pregnant women.

An Inflammatory Clock Predicts Multi-morbidity, Immunosenescence and Cardiovascular Aging in Humans

“…S1 and Fig. S2) who had been recruited at Stanford University (the Stanford 1000 Immunomes Project, or Stanford 1KIP) for a longitudinal study of aging and vaccination (Blazkova et al, 2017;Brodin et al, 2015;Furman et al, 2017b;Furman et al, 2014;Furman et al, 2013;Furman et al, 2015;Price et al, 2013;Roskin et al, 2015;Shen-Orr et al, 2016;Wang et al, 2014), and for an independent study of chronic fatigue syndrome (Montoya et al, 2017), from which only healthy controls were included. Inclusion and exclusion criteria can be found under the Methods section.…”

“…The Stanford 1KIP consists in 1001 ambulatory individuals (339 males and 662 females) recruited at Stanford University during the years 2007 to 2016 for various studies of aging and vaccination (N = 605) (Blazkova et al, 2017;Brodin et al, 2015;Furman et al, 2017b;Furman et al, 2014;Furman et al, 2013;Furman et al, 2015;Price et al, 2013;Roskin et al, 2015;Shen-Orr et al, 2016;Wang et al, 2014), and for an independent study of chronic fatigue syndrome (Montoya et al, 2017), from which we utilized data from the control set of participants only (N = 396). diabetes mellitus treated with insulin, moderate to severe renal disease, blood pressure >150/95 at screening, chronic hepatitis B or C, recent or current use of immunosuppressive medication.…”

“…1000 Immunomes Study design: systematic analysis of immune systems via 'OMICS' approaches. The Stanford 1000 Immunomes Project consist of 1001 ambulatory subjects age 8 to >89 (34% males, 66% females) recruited during the years 2007 to 2016 for a longitudinal study of aging and vaccination (Blazkova et al, 2017;Brodin et al, 2015;Furman et al, 2017;Furman et al, 2014;Furman et al, 2013;Furman et al, 2015;Roskin et al, 2015;Shen-Orr et al, 2016;Wang et al, 2014), and for an independent study of chronic fatigue syndrome (Montoya et al, 2017) from which only healthy controls were included. For all samples of the Stanford 1KIP, deep immune phenotyping was conducted at the Stanford Human Immune Monitoring Center, where peripheral blood specimens were isolated and analyzed using standard procedures.…”

A Transcriptome Fingerprinting Assay for Clinical Immune Monitoring

“…It increases dramatically during pregnancy to more than 4-fold on average. This is likely in part due to the known increase in neutrophil numbers in the peripheral blood during the 2nd and 3rd trimesters, but likely also reflects changes in neutrophil function as previously observed [28]…”

Systems immunology: just getting started

“…Particularly relevant in the field of autoimmune diseases, since most of these are sex biased, are the differences in the activity of immune cells in males versus that in females. Applications of systems immunology to this area have just begun, and initial data show gross sex differences for healthy young adults, but for not older adults, in particular subsets of cells, including blood neutrophils, in their maturation status and responses to sera from patients with systemic lupus erythematosus 64 that were previously unappreciated. In the domain of systemic lupus erythematosus, work has shown that the application of systems approaches to these patients enables accurate identification of molecular networks that stratify disease activity 65 .…”