Expression of Sex Hormone Receptor and Immune Response Genes in Peripheral Blood Mononuclear Cells During the Menstrual Cycle

Brundin, Peik M. A.; Landgren, Britt-Marie; Fjällström, Peter; Shamekh, Mohamed M.; Gustafsson, Jan‐Åke; Johansson, Anders; Nalvarte, Ivan

doi:10.3389/fendo.2021.721813

Cited by 16 publications

(10 citation statements)

References 36 publications

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“…49 The expressions of several immune response genes in human PBMCs including GATA3, IFNG, IL1B, LTA, NFKB1, PDCD1, STAT3, STAT5A, TBX21, TGFB1, TNFA changes during menstrual cycle. 50 In this present study, we showed that many immune response genes were highly expressed in women, along with many immune response signaling pathways. Furthermore, we showed from ML analysis that many immune response genes like IFITM2 and IFITM3, or IL32 are important to separate CAD vs non-CAD in female.…”

Section: Discussionsupporting

confidence: 48%

Sex differences in coronary artery disease and diabetes revealed by scRNA-Seq and CITE-Seq of human CD4+ T cells

Saigusa

Vallejo

Gulati

et al. 2022

Preprint

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BackgroundDespite the decades-old knowledge that diabetes mellitus (DM) is a major risk factor for cardiovascular disease (CVD), the reasons for this association are only partially understood. Among the immune cells involved in CVD development, accumulating evidence supports the critical role of T cells as drivers and modifiers of this condition. CD4+ T cells are commonly found in atherosclerotic plaques. The activity and distribution of CD4+ T cell subsets differs between the sexes.MethodsPeripheral blood mononuclear cells (PBMCs) of 61 men and women who underwent cardiac catheterization were interrogated by single cell RNA sequencing (scRNA-Seq, ∼200,000 cells) combined with 49 protein markers (CITE-Seq). Coronary artery disease (CAD) was quantified using Gensini scores, with scores above 30 considered CAD+ and below 6 considered CAD-. Four pairs of groups were matched for clinical and demographic parameters. To test how DM changed cell proportions and gene expression, we compared matched groups of diabetic and non-diabetic subjects. We analyzed 41,782 single CD4+ T cell transcriptomes for sex differences in 61 mostly statin-treated coronary artery disease patients with and without DM.ResultsWe identified 16 clusters in CD4 T cells. The proportion of cells in CD4 cluster 8 (CD4T8, CCR2+ Em) was significantly decreased in CAD+, especially among DM+ participants. The proportions of cells in CD4T2, CD4T11, CD4T16 were increased and CD4T13 was decreased in CAD+ among DM+Statin+ participants. CD4T12 was increased in DM+ participants. In female participants, CD4T8, 12, and 13 were decreased compared to in male participants. In CD4 T cells, 31 genes showed significant and coordinated upregulation in both CAD and DM. The DM gene signature was partially additive to the CAD gene signature.ConclusionsWe conclude that CAD and DM are clearly reflected in PBMC transcriptomes and that significant differences exist between women and men and between subjects treated with statins or not.

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Section: Discussionsupporting

confidence: 48%

Sex differences in coronary artery disease and diabetes revealed by scRNA-Seq and CITE-Seq of human CD4+ T cells

Saigusa

Vallejo

Gulati

et al. 2022

Preprint

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“…Analysis of PBMCs has revealed significant changes in gene expressions, including that of TNF superfamily member 14 and signal regulatory protein-γ, during the menstrual cycle of patients with SLE compared to that of HCs ( 72 ). A study analyzing the expression of sex hormone receptor genes in PBMCs, and cell subsets reported that several immune response genes were more highly expressed during the ovulatory and mid-luteal phase ( 73 ). In addition, the level of sex hormone-binding globulin, a steroid hormone transport protein, was correlated with ERβ1 gene expression.…”

Section: Resultsmentioning

confidence: 99%

Sex hormones affect the pathogenesis and clinical characteristics of systemic lupus erythematosus

Kim

Suh

et al. 2022

Front. Med.

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Systemic lupus erythematosus (SLE) affects women more frequently than men, similar to the female predilection for other autoimmune diseases. Moreover, male patients with SLE exhibit different clinical features than female patients. Sex-associated differences in SLE required special considerations for disease management such as during pregnancy or hormone replacement therapy (HRT). Sex hormones, namely, estrogen and testosterone, are known to affect immune responses and autoimmunity. While estrogen and progesterone promote type I immune response, and testosterone enhances T-helper 1 response. Sex hormones also influence Toll-like receptor pathways, and estrogen receptor signaling is involved in the activation and tolerance of immune cells. Further, the clinical features of SLE vary according to hormonal changes in female patients. Alterations in sex hormones during pregnancy can alter the disease activity of SLE, which is associated with pregnancy outcomes. Additionally, HRT may change SLE status. Sex hormones affect the pathogenesis, clinical features, and management of SLE; thus, understanding the occurrence and exacerbation of disease caused by sex hormones is necessary to improve its management.

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“…In contrast to this, Brundin et al have shown an upregulation of genes associated with NF‐κB signaling in peripheral blood monocytes in the luteal phase. Noteworthy, however, is the finding that genes associated with both Th1 and Th2 cytokine responses were upregulated in the luteal phase compared to the follicular phase, therefore suggesting a differential regulation between cycle phases but not one separated into either pro−/anti‐inflammatory or Th1/Th2 response 206 . This suggests that it may be too simplistic to break down the actions of estrogen and progesterone or the different menstrual cycle phases into either pro‐ or anti‐inflammatory categories, as immune responses are regulated by a complex network of stimulatory and inhibitory pathways in multiple cell populations.…”

Section: Discussionmentioning

confidence: 99%

“…Noteworthy, however, is the finding that genes associated with both Th1 and Th2 cytokine responses were upregulated in the luteal phase compared to the follicular phase, therefore suggesting a differential regulation between cycle phases but not one separated into either pro−/anti-inflammatory or Th1/ Th2 response. 206 This suggests that it may be too simplistic to break down the actions of estrogen and progesterone or the different menstrual cycle phases into either pro-or anti-inflammatory categories, as immune responses are regulated by a complex network of stimulatory and inhibitory pathways in multiple cell populations. Therefore, we would encourage future research investigating inflammatory processes to focus more on individual regulatory networks rather than aiming to categorize effects.…”

Section: Cytokines and Their Release From Immune Cellsmentioning

confidence: 99%

The effects of menstrual cycle phases on immune function and inflammation at rest and after acute exercise: A systematic review and meta‐analysis

et al. 2023

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The immune system plays an important role in mediating exercise responses and adaptations. However, whether fluctuating hormone concentrations across the menstrual cycle may impact these processes remains unknown. The aim of this systematic review with meta‐analysis was to compare baseline concentrations as well as exercise‐induced changes in immune and inflammatory parameters between menstrual cycle phases. A systematic literature search was conducted according to the PRISMA guidelines using Pubmed/MEDLINE, ISI Web of Science, and SPORTDiscus. Of the 159 studies included in the qualitative synthesis, 110 studies were used for meta‐analysis. Due to the designs of the included studies, only the follicular and luteal phase could be compared. The estimated standardized mean differences based on the random‐effects model revealed higher numbers of leukocytes (−0.48 [−0.73; −0.23], p < 0.001), monocytes (−0.73 [−1.37; −0.10], p = 0.023), granulocytes (−0.85 [−0.1.48; −0.21], p = 0.009), neutrophils (−0.32 [−0.52; −0.12], p = 0.001), and leptin concentrations (−0.37 [−0.5; −0.23], p = 0.003) in the luteal compared to the follicular phase at rest. Other parameters (adaptive immune cells, cytokines, chemokines, and cell adhesion molecules) showed no systematic baseline differences. Seventeen studies investigated the exercise‐induced response of these parameters, providing some indications for a higher pro‐inflammatory response in the luteal phase. In conclusion, parameters of innate immunity showed cycle‐dependent regulation at rest, while little is known on the exercise responses. Due to a large heterogeneity and a lack of cycle phase standardization among the included studies, future research should focus on comparing at least three distinct hormonal profiles to derive more specific recommendations for exercise prescription.

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Expression of Sex Hormone Receptor and Immune Response Genes in Peripheral Blood Mononuclear Cells During the Menstrual Cycle

Cited by 16 publications

References 36 publications

Sex differences in coronary artery disease and diabetes revealed by scRNA-Seq and CITE-Seq of human CD4+ T cells

Sex differences in coronary artery disease and diabetes revealed by scRNA-Seq and CITE-Seq of human CD4+ T cells

Sex hormones affect the pathogenesis and clinical characteristics of systemic lupus erythematosus

The effects of menstrual cycle phases on immune function and inflammation at rest and after acute exercise: A systematic review and meta‐analysis

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