Sex-specific differences in peripheral blood leukocyte transcriptional response to LPS are enriched for HLA region and X chromosome genes

Stein, Michelle M.; Conery, Mitchell; Magnaye, Kevin M.; Clay, Selene M.; Billstrand, Christine; Nicolae, Raluca; Naughton, Katherine A.; Ober, Carole; Thompson, Emma E.

doi:10.1038/s41598-020-80145-z

Cited by 12 publications

(10 citation statements)

References 79 publications

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“…Several studies have shown biallelic expression of the X-encoded TLR7 in females, which results in higher levels of type I interferon induction by plasmacytoid dendritic cells and a greater propensity for immunoglobulin G (IgG) class switching in B cells 40,41 . By contrast, analyses of whole-blood transcriptional responses to LPS found that the vast majority of X-linked genes are commonly induced in both males and females, including the majority of genes known to escape X inactivation 39 . TLR7 may thus represent a unique case, rather than a general rule.…”

Section: Sex and Immune Variationmentioning

confidence: 85%

“…At the level of immune parameters, the most consistently observed associations with sex are altered baseline cellular traits and differential responses to vaccinations 38 . A recent study also found that 47% of HLA class I and II genes showed differences between sexes in expression following stimulation with lipolysaccharide (LPS), a far greater rate than the genome average 39 . While much of the effect of sex is unexplained, the best-studied drivers for this variation are sex chromosomes and sex hormones.…”

Section: Sex and Immune Variationmentioning

confidence: 98%

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Human immune diversity: from evolution to modernity

et al. 2021

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Section: Sex and Immune Variationmentioning

confidence: 85%

Section: Sex and Immune Variationmentioning

confidence: 98%

Human immune diversity: from evolution to modernity

et al. 2021

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“…Some of the sex‐dependent activities of LPS could be ascribed to the fact that LPS binds the Toll‐like receptors TLR4 (Lu et al, 2008 ), which are more expressed in male human monocytes and neutrophils (Aomatsu et al, 2013 ; Bannister et al, 2013 ). In this regard, it is relevant to recall that in human leukocytes, 1217 autosomal, 54 X‐linked genes have sex‐specific responses to LPS, as well as 71 autosomal and one X‐linked sex‐specific expression quantitative trait loci (Stein et al, 2021 ), suggesting that LPS activity may occur through multiple pathways.…”

Section: Discussionmentioning

confidence: 99%

Human monocytes respond to lipopolysaccharide (LPS) stimulation in a sex‐dependent manner

Campesi

Montella

Franconi

2021

Journal Cellular Physiology

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Monocytes play a critical role in inflammation and immune response, their activity being sex‐dependent. However, the basis of sex differences is not well understood. Therefore, we investigated the lipopolysaccharide (LPS) effects on tumor necrosis factor‐α (TNF‐α) release, autophagy, and chemotaxis in freshly isolated monocytes from healthy young men and women. In basal conditions, male and female monocytes had similar TNF‐α release, chemotaxis, and estrogen receptors (ER‐α) and ER‐β expression, while the LC3II/I ratio was significantly higher in males. LPS treatment induced qualitative and quantitative sex differences. It reduced autophagy and increased TNF‐α release only in male monocytes, while, chemotaxis was significantly influenced only in female cells. Moreover, it reduced the expression of ER‐α only in female cells, while ER‐β expression was reduced in both sexes, but more markedly in female cells. Finally, the interplay between LPS treatment and 17‐β‐estradiol (E2) was present only in female cells. Globally, these findings expand the concept that sex plays a role in regulating monocytes' functions, being sex differences cell‐ and parameter‐specific.

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“…5). Sex-specific differences have been further studied during immune activation, in which cells from men and women were exposed to lipopolysaccharide to identify sex-specific responses to microbial stimuli 156 . Interestingly, seven genes in pSS-associated loci showed significant sex by treatment interactions, including four HLA genes, IRF5, OAS1 and IKZF1 (ref.…”

Section: Female Sexmentioning

confidence: 99%

Genetics and epigenetics of primary Sjögren syndrome: implications for future therapies

2023

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In primary Sjögren syndrome (pSS), chronic inflammation of exocrine glands results in tissue destruction and sicca symptoms, primarily of the mouth and eyes. Fatigue, arthralgia and myalgia are also common symptoms, whereas extraglandular manifestations that involve the respiratory, nervous and vascular systems occur in a subset of patients. The disease predominantly affects women, with an estimated female to male ratio of 14 to 1. The aetiology of pSS, however, remains incompletely understood, and effective treatment is lacking. Largescale genetic and epigenetic investigations have revealed associations between pSS and genes in both innate and adaptive immune pathways. The genetic variants mediate context-dependent effects, and both sex and environmental factors can influence the outcome. As such, genetic and epigenetic studies can provide insight into the dysregulated molecular mechanisms, which in turn might reveal new therapeutic possibilities. This Review discusses the genetic and epigenetic features that have been robustly connected with pSS, putting them into the context of cellular function, carrier sex and environmental challenges. In all, the observations point to several novel opportunities for early detection, treatment development and the pathway towards personalized medicine. Key points• Advances in the past few years provide new insight into the genetic and epigenetic basis of primary Sjögren syndrome (pSS), and how environmental factors and carrier sex might interact with risk-associated loci.• Immunomodulatory treatments that affect disease progression and activity have not been identified for pSS and remain unmet clinical needs.• Data from genetic and epigenetic studies point to Toll-like receptor and interferon signalling, lymphocyte regulation, antigen presentation and target tissue maintenance as the most relevant processes for therapeutic targeting.• Of the implicated pathogenic processes, Toll-like receptor and interferon signalling, as well as lymphocyte regulation, contain targets of various treatments in development or in clinical trials.• Novel treatment approaches for pSS could include modification of epigenetic signatures, interference with antigen presentation pathways and antigen-specific immunotherapy.Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author selfarchiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

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Sex-specific differences in peripheral blood leukocyte transcriptional response to LPS are enriched for HLA region and X chromosome genes

Cited by 12 publications

References 79 publications

Human immune diversity: from evolution to modernity

Human immune diversity: from evolution to modernity

Human monocytes respond to lipopolysaccharide (LPS) stimulation in a sex‐dependent manner

Genetics and epigenetics of primary Sjögren syndrome: implications for future therapies

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