Sex differences in genomics in lupus: girls with systemic lupus have high interferon gene expression while boys have high levels of tumour necrosis factor-related gene expression

Hui-Yuen, Joyce; Christiano, Angela M.; Askanase, Anca

doi:10.3109/03009742.2015.1132760

Cited by 5 publications

(2 citation statements)

References 16 publications

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“…We have previously shown that the response to CpG and R848 stimulation in terms of upregulation of ISGs, CXCL10, and CD86 is type I IFN/STAT-2-dependent, while IL-12, IL-6, and TNF- α were regulated in a type I IFN/STAT-2-independent manner [ 47 ]. A previous study of pediatric SLE patients reported an IFN signature in both female and males [ 6 ] while a recent study of treatment-naïve girls and boys with childhood onset SLE further described a “TNF signature” present in boys but absent in girls [ 78 ], suggesting that sex may affect disease differently by promoting type I IFN-dependent and type I IFNs-independent pathways. Recent studies have also shown that prior to diagnosis of SLE, there is elevated type II IFN in the serum of patients [ 79 ].…”

Section: Discussionmentioning

confidence: 99%

Conventional DCs from Male and Female Lupus-Prone B6.NZM Sle1/Sle2/Sle3 Mice Express an IFN Signature and Have a Higher Immunometabolism That Are Enhanced by Estrogen

Lee

Chakhtoura

Sriram

et al. 2018

Journal of Immunology Research

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Type I interferons (IFN) are pathogenic in systemic lupus erythematosus (SLE) and were proposed to control the immunometabolism of dendritic cells (DCs). We previously reported that DCs from female lupus-prone mice constitutively overexpress IFN-responsive genes resembling the IFN signature found in SLE patients. As SLE has higher incidence in women than men, more so in women of reproductive age, estrogens are suggested to affect lupus pathogenesis. We investigated the effects of sex and estrogens on the IFN signature in conventional GM-CSF-bone marrow-derived DCs (cDCs), from male and female Triple Congenic B6.NZM.Sle1/Sle2/Sle3 (TCSle) lupus-prone mice or from wild-type C57BL/6 mice, generated with titrations of 17-beta-estradiol (E2). We found that cDCs from prediseased TCSle male mice express the IFN signature as female TCSle cDCs do. Estrogens are necessary but not sufficient to express this IFN signature, but high doses of E2 can compensate for other steroidal components. E2 stimulation, regardless of sex, modulates type I IFN-dependent and type I IFN-independent activation of cDCs in response to TLR stimulation. Finally, we found that TCSle cDCs from both sexes have elevated markers of immunometabolism and estrogens enhance the metabolic pathways in cDCs, suggesting a mechanistic link between estrogens, immunometabolism, and the IFN signature in lupus.

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Section: Discussionmentioning

confidence: 99%

Conventional DCs from Male and Female Lupus-Prone B6.NZM Sle1/Sle2/Sle3 Mice Express an IFN Signature and Have a Higher Immunometabolism That Are Enhanced by Estrogen

Lee

Chakhtoura

Sriram

et al. 2018

Journal of Immunology Research

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“…In both mice and humans, estrogen and ER signaling is found to modulate the expression of immunostimulatory cytokines and exacerbates disease activity in lupus mouse model and in human patients [ 43 ] . Previous studies indicated the influence of male and female sex hormones on immune cell functions in SLE [ 44 ] . Particularly estrogen plays a pivotal role in functional modulation of T and B cells and their immune functions.…”

Section: Influence Of Sex Hormones and Receptors In Slementioning

confidence: 99%

Sex bias in systemic lupus erythematosus: a molecular insight

Bose

Jefferies

2022

Immunometabolism

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Acknowledging sex differences in immune response is particularly important when we consider the differences between men and women in the incidence of disease. For example, over 80% of autoimmune disease occurs in women, whereas men have a higher incidence of solid tumors compared to women. In general women have stronger innate and adaptive immune responses than men, explaining their ability to clear viral and bacterial infections faster, but also contributing to their increased susceptibility to autoimmune disease. The autoimmune disease systemic lupus erythematosus (SLE) is the archetypical sexually dimorphic disease, with 90% of patients being women. Various mechanisms have been suggested to account for the female prevalence of SLE, including sex hormones, X-linked genes, and epigenetic regulation of gene expression. Here, we will discuss how these mechanisms contribute to pathobiology of SLE and how type I interferons work with them to augment sex specific disease pathogenesis in SLE.

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Sex Differences in Pediatric Rheumatology

Cattalini

Soliani

Caparello

et al. 2017

Clinic Rev Allerg Immunol

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Autoimmune diseases affect up to 10% of the world's population and, as a whole, they are far more common in females, although differences exist according to the single disease and also in different age groups. In childhood-onset autoimmune diseases, the sex bias is generally less evident than in adults, probably for the different hormonal milieau, being estrogens strongly implicated in the development of autoimmunity. Still, some rheumatic conditions, such as juvenile idiopathic arthritis (JIA), show a strong predilection for girls (F:M = 3-6.6:1), and differences may coexist between males and females regarding disease outcome. For example, chronic anterior uveitis associated with JIA affects more commonly girls but boys tend to have a more severe course. Systemic lupus erythematosus predominantly affects girls and women (F:M = 3-5:1 in children, F:M = 10-15:1 in adults). Behςet's disease has been reported to be more prevalent in adult males (F:M = 1:1-4); in children, there are no differences. The sex ratio is equal in children and adults for Henoch-Schönlein purpura (F:M = 1:1). A higher male-to-female ratio exists for Kawasaki disease (F:M = 1:1.1-1.6 in children, F:M = 1:1,5 in adults). Juvenile dermatomyositis (F:M = 2-5:1), systemic sclerosis (F:M = 4:1 in children, F:M = 6:1 in adults), and Takayasu arteritis (F:M = 2:1 in children, F:M = 7-9:1 in adults) are more common in girls and women then in boys and men. There is no gender bias for acute rheumatic fever in children, while in adults, the F:M ratio is 2:1. Given that estrogen levels are not different between genders during childhood, pediatric rheumatic diseases could represent good models to study other mechanisms related to the development of autoimmunity. Recently, the levels of miRNA expression, and their variation according to sex chromosomes, have been linked to the development of autoimmune diseases, with different impact among sexes. This review will focus not only on the sex bias reported in the more common rheumatic conditions of childhood, focusing on differences in incidence, but also on outcome and trying to depict the mechanisms underlying those differences.

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Sex differences in genomics in lupus: girls with systemic lupus have high interferon gene expression while boys have high levels of tumour necrosis factor-related gene expression

Abstract: Our results suggest a potential application of genomics to differentially predict response to therapy between females and males with SLE.

Cited by 5 publications

References 16 publications

Conventional DCs from Male and Female Lupus-Prone B6.NZM Sle1/Sle2/Sle3 Mice Express an IFN Signature and Have a Higher Immunometabolism That Are Enhanced by Estrogen

Conventional DCs from Male and Female Lupus-Prone B6.NZM Sle1/Sle2/Sle3 Mice Express an IFN Signature and Have a Higher Immunometabolism That Are Enhanced by Estrogen

Sex bias in systemic lupus erythematosus: a molecular insight

Sex Differences in Pediatric Rheumatology

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