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Polymorphic estrogen receptor binding site causes Cd2-dependent sex bias in the susceptibility to autoimmune diseases.

ABSTRACT: Complex autoimmune diseases are sexually dimorphic. An interplay between predisposing genetics and sex-related factors probably controls the sex discrepancy in the immune response, but the underlying mechanisms are unclear. Here we positionally identify a polymorphic estrogen receptor binding site that regulates Cd2 expression, leading to female-specific differences in T cell-dependent mouse models of autoimmunity. Female mice with reduced Cd2 expression have impaired autoreactive T cell responses. T cells lacking Cd2 costimulation upregulate inhibitory Lag-3. These findings help explain sexual dimorphism in human autoimmunity, as we find that CD2 polymorphisms are associated with rheumatoid arthritis and 17-β-estradiol-regulation of CD2 is conserved in human T cells. Hormonal regulation of CD2 might have implications for CD2-targeted therapy, as anti-Cd2 treatment more potently affects T cells in female mice. These results demonstrate the relevance of sex-genotype interactions, providing strong evidence for CD2 as a sex-sensitive predisposing factor in autoimmunity.

SUBMITTER: Fernandez Lahore G

PROVIDER: S-EPMC8458462 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Polymorphism in estrogen receptor binding site causes CD2-dependent sex bias in T cell autoimmune diseases

Project description:Complex autoimmune diseases are sexually dimorphic. An interplay between predisposing genetics and sex-related factors likely determines the sex discrepancy in the immune response, but conclusive evidence regarding the underlying molecular mechanisms is lacking. Using forward genetics, we positionally identified a polymorphic estrogen receptor binding site that regulates CD2 expression, leading to female-specific differences in mouse models of T cell-dependent autoimmunity. Female mice with reduced CD2 levels displayed a diminished T cell activation and autoimmune T cell response. Mechanistically, CD2 affected LAG-3 expression. Our findings help to explain the sexual dimorphism in human autoimmunity, as CD2 associated with rheumatoid arthritis and its regulation through 17-β-estradiol was conserved in human T cells. Hormonal regulation of CD2 has implications for CD2-targeted therapy. Indeed, anti-CD2 treatment more potently affected female mice. In conclusion, our results demonstrate the relevance of sex-genotype interactions and deliver strong evidence for CD2 as a sex-sensitive predisposing factor in autoimmunity.

2021-07-15 | PXD024126 | Pride

Lack of the MHC class II chaperone H2-O causes susceptibility to autoimmune diseases.

Project description:DO (HLA-DO, in human; murine H2-O) is a highly conserved nonclassical major histocompatibility complex class II (MHC II) accessory molecule mainly expressed in the thymic medulla and B cells. Previous reports have suggested possible links between DO and autoimmunity, Hepatitis C (HCV) infection, and cancer, but the mechanism of how DO contributes to these diseases remains unclear. Here, using a combination of various in vivo approaches, including peptide elution, mixed lymphocyte reaction, T-cell receptor (TCR) deep sequencing, tetramer-guided naïve CD4 T-cell precursor enumeration, and whole-body imaging, we report that DO affects the repertoire of presented self-peptides by B cells and thymic epithelium. DO induces differential effects on epitope presentation and thymic selection, thereby altering CD4 T-cell precursor frequencies. Our findings were validated in two autoimmune disease models by demonstrating that lack of DO increases autoreactivity and susceptibility to autoimmune disease development.

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Sex Bias in CNS Autoimmune Disease Mediated by Androgen Control of Autoimmune Regulator

Project description:Male gender is protective against multiple sclerosis and other T cell-mediated autoimmune diseases. This protection may be due, in part, to higher androgen levels in males. Androgen binds to the androgen receptor (AR) to regulate gene expression, but how androgen protects against autoimmunity is not well-understood. Autoimmune Regulator (Aire) prevents autoimmunity by promoting self-antigen expression in medullary thymic epithelial cells, such that developing T cells that recognize these self-antigens within the thymus undergo clonal deletion. Here, we show that androgen upregulates Aire-mediated thymic tolerance to protect against autoimmunity. Androgen recruits AR to Aire promoter regions, with consequent enhancement of Aire transcription. In mice and humans, thymic Aire expression is higher in males compared to females. Androgen administration and male gender protect against autoimmunity in a multiple sclerosis mouse model in an Aire-dependent manner. Thus, androgen control of an intrathymic Aire-mediated tolerance mechanism contributes to gender differences in autoimmunity. RNA-seq comparison of male vs. female expression in mTEC cells. Pools of 10 mice each were used for each replicate (two for male and two for female)

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Sex Bias in CNS Autoimmune Disease Mediated by Androgen Control of Autoimmune Regulator

2016-03-09 | GSE79014 | GEO

FOXP3(+) Treg Cells and Gender Bias in Autoimmune Diseases.

Project description:CD4(+)CD25(+) regulatory T (Treg) cells play a pivotal role in the maintenance of immune homeostasis, where the X-linked master transcription factor forkhead box P3 (FOXP3) determines Treg cell development and function. Genetic deficiency of foxp3 induces dysfunction of Treg cells and immuno-dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome in humans. Functionally deficient Treg cells or the development of exTreg cells positively correlate with autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), and ankylosing spondylitis (AS). In general, females are more susceptible to SLE and MS but less susceptible to AS, where the expression of FOXP3 and its protein complex are perturbed by multiple factors, including hormonal fluctuations, inflammatory cytokines, and danger signals. Therefore, it is critical to explore the potential molecular mechanisms involved and these differences linked to gender. Here, we review recent findings on the regulation of FOXP3 activity in Treg cells and also discuss gender difference in the determination of Treg cell function in autoimmune diseases.

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Sex bias in CNS autoimmune disease mediated by androgen control of autoimmune regulator.

Project description:Male gender is protective against multiple sclerosis and other T-cell-mediated autoimmune diseases. This protection may be due, in part, to higher androgen levels in males. Androgen binds to the androgen receptor (AR) to regulate gene expression, but how androgen protects against autoimmunity is not well understood. Autoimmune regulator (Aire) prevents autoimmunity by promoting self-antigen expression in medullary thymic epithelial cells, such that developing T cells that recognize these self-antigens within the thymus undergo clonal deletion. Here we show that androgen upregulates Aire-mediated thymic tolerance to protect against autoimmunity. Androgen recruits AR to Aire promoter regions, with consequent enhancement of Aire transcription. In mice and humans, thymic Aire expression is higher in males compared with females. Androgen administration and male gender protect against autoimmunity in a multiple sclerosis mouse model in an Aire-dependent manner. Thus, androgen control of an intrathymic Aire-mediated tolerance mechanism contributes to gender differences in autoimmunity.

| S-EPMC5512610 | biostudies-literature

Polymorphic Inversions Underlie the Shared Genetic Susceptibility of Obesity-Related Diseases.

Project description:The burden of several common diseases including obesity, diabetes, hypertension, asthma, and depression is increasing in most world populations. However, the mechanisms underlying the numerous epidemiological and genetic correlations among these disorders remain largely unknown. We investigated whether common polymorphic inversions underlie the shared genetic influence of these disorders. We performed an inversion association analysis including 21 inversions and 25 obesity-related traits on a total of 408,898 Europeans and validated the results in 67,299 independent individuals. Seven inversions were associated with multiple diseases while inversions at 8p23.1, 16p11.2, and 11q13.2 were strongly associated with the co-occurrence of obesity with other common diseases. Transcriptome analysis across numerous tissues revealed strong candidate genes for obesity-related traits. Analyses in human pancreatic islets indicated the potential mechanism of inversions in the susceptibility of diabetes by disrupting the cis-regulatory effect of SNPs from their target genes. Our data underscore the role of inversions as major genetic contributors to the joint susceptibility to common complex diseases.

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X Chromosome Dose and Sex Bias in Autoimmune Diseases: Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjogren's Syndrome.

Project description:OBJECTIVE:More than 80% of autoimmune disease predominantly affects females, but the mechanism for this female bias is poorly understood. We suspected that an X chromosome dose effect accounts for this, and we undertook this study to test our hypothesis that trisomy X (47,XXX; occurring in ?1 in 1,000 live female births) would be increased in patients with female-predominant diseases (systemic lupus erythematosus [SLE], primary Sjögren's syndrome [SS], primary biliary cirrhosis, and rheumatoid arthritis [RA]) compared to patients with diseases without female predominance (sarcoidosis) and compared to controls. METHODS:All subjects in this study were female. We identified subjects with 47,XXX using aggregate data from single-nucleotide polymorphism arrays, and, when possible, we confirmed the presence of 47,XXX using fluorescence in situ hybridization or quantitative polymerase chain reaction. RESULTS:We found 47,XXX in 7 of 2,826 SLE patients and in 3 of 1,033 SS patients, but in only 2 of 7,074 controls (odds ratio in the SLE and primary SS groups 8.78 [95% confidence interval 1.67-86.79], P?=?0.003 and odds ratio 10.29 [95% confidence interval 1.18-123.47], P?=?0.02, respectively). One in 404 women with SLE and 1 in 344 women with SS had 47,XXX. There was an excess of 47,XXX among SLE and SS patients. CONCLUSION:The estimated prevalence of SLE and SS in women with 47,XXX was ?2.5 and ?2.9 times higher, respectively, than that in women with 46,XX and ?25 and ?41 times higher, respectively, than that in men with 46,XY. No statistically significant increase of 47,XXX was observed in other female-biased diseases (primary biliary cirrhosis or RA), supporting the idea of multiple pathways to sex bias in autoimmunity.

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Sex differences in DNA methylation of the cord blood are related to sex-bias psychiatric diseases

Project description:Gender differences in the prevalence of psychiatric disorders are well documented in epidemiological studies. Exposure to stress during gestation impacts differentially between females and males. Environmental or biological factors can alter DNA methylation and affect the development of neurodevelopmental diseases. In this study, we explored gender-specific DNA methylation in regarding their potential connection to psychiatric outcomes. We assessed the methylation of cord blood of 39 females and 32 males born at term and with appropriate weight at birth. Mothers between 18 and 48 years of age (median: 28 years) were interviewed to gather information about environmental factors (gestational exposure) that can potentially interfere with the methylation profiles in the newborns. Bisulphite converted DNA was hybridized to Illumina HumanMethylation450 BeadChips. After exclusion of XYS probes, there were 2,332 differentially methylated CpG sites (DMS) between sexes, with an overlap of 890 (38%) CpG sites with an a cohort submitted to gestational stress exposition. Using externals datasets, we found that the DMSs were enriched within brain modules of co-methylated CpGs during gestation and were also differentially methylated in the brain comparing boys and girls during brain development. Genes associated to the DMSs were enriched for neurodevelopmental disorders. Accordingly, we described an enrichment of the DMSs among the differentially methylated CpG sites in brain tissue between schizophrenics and controls. Here, we suggest that gender changes methylation in the autosomes working as a primary driver to stress exposition which potentially contributes for gender differences found in psychiatric outcomes.

2017-05-01 | GSE85042 | GEO

Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases.

Project description:Autoimmune diseases affect 5% to 8% of the population, and females are more susceptible to these diseases than males. Here, we analyzed human thymic transcriptome and revealed sex-associated differences in the expression of tissue-specific antigens that are controlled by the autoimmune regulator (AIRE), a key factor in central tolerance. We hypothesized that the level of AIRE is linked to sexual dimorphism susceptibility to autoimmune diseases. In human and mouse thymus, females expressed less AIRE (mRNA and protein) than males after puberty. These results were confirmed in purified murine thymic epithelial cells (TECs). We also demonstrated that AIRE expression is related to sexual hormones, as male castration decreased AIRE thymic expression and estrogen receptor ?-deficient mice did not show a sex disparity for AIRE expression. Moreover, estrogen treatment resulted in downregulation of AIRE expression in cultured human TECs, human thymic tissue grafted to immunodeficient mice, and murine fetal thymus organ cultures. AIRE levels in human thymus grafted in immunodeficient mice depended upon the sex of the recipient. Estrogen also upregulated the number of methylated CpG sites in the AIRE promoter. Together, our results indicate that in females, estrogen induces epigenetic changes in the AIRE gene, leading to reduced AIRE expression under a threshold that increases female susceptibility to autoimmune diseases.

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