The roles of genetics, hormones, and gender in sexually dimorphic immune response

遗传学、激素和性别在性二态性免疫反应中的作用

• 批准号: 10532061
• 负责人: Connie Krawczyk
• 金额: $ 63.56万
• 依托单位: VAN ANDEL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532061
• 关键词: Animal Model; Antibodies; Antibody Formation; Antigen Presentation; Atlases; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Bacterial Infections; Biological; Biological Assay; Birth; Blood; Blood specimen; COVID-19; Cell physiology; Cells; Chromosome Mapping; Chromosome Pairing; Chronic; Cytomegalovirus; Data; Data Analyses; Data Set; Environment; Environmental Risk Factor; Epidemiology; Epigenetic Process; Equilibrium; Erythrocytes; Estrogens; Exposure to; Female; Four Core Genotypes; Gender; Gender Identity; Gender Role; Gene Expression Regulation; Generations; Genes; Genetic; Genetic Determinism; Genetic Models; Genetic Variation; Genomics; Gonadal Steroid Hormones; HIV risk; Hematopoiesis; Hematopoietic; Histones; Hormonal; Hormones; Hospitalization; Human; Human Genetics; Hypocellular Bone Marrow; Immune; Immune response; Immune system; Immunity; In Vitro; Individual; Infection; Inflammatory; Interferons; Knock-out; Knowledge; Lead; Link; Lupus; Mediator of activation protein; Messenger RNA; Modeling; Molecular; Molecular Genetics; Mus; Natural Immunity; Natural Killer Cells; Pathway interactions; Phenotype; Population; Production; Quantitative Trait Loci; Regulation; Regulator Genes; Resolution; Resources; Respiratory Syncytial Virus Infections; Risk; Rodent; Rodent Model; Role; Sex Chromosomes; Sex Differences; Shapes; Sjogren' s Syndrome; Societies; T-Lymphocyte; Testing; Testosterone; Thinking; Time; Tissues; Trans-Omics for Precision Medicine; Transcript; Tuberculosis; Vaccination; Validation; Variant; Viral; Virus Diseases; Work; adaptive immunity; autoimmune thyroid disease; biobank; biological sex; cell type; chronic infection; cis-female; conditional knockout; cost; data integration; differential expression; fighting; fitness; gender difference; genetic variant; genome-wide; genomic data; genotypic sex; histone methylation; hospitalization rates; human data; human model; human old age (65+); immune function; immunoregulation; infancy; infant infection; infectious disease model; innovation; insight; large scale data; male; mouse model; novel; novel strategies; outcome prediction; paralogous gene; precision medicine; proband; protective effect; response; sex; sexual dimorphism; synergism; tool; transcriptomics

ABSTRACT Sex and gender contribute to the immune system and how we as humans respond to foreign infections. Males traditionally have an elevated risk of hospitalizations due to infections from birth to old age. Females, however, have a more protective immune system, yet have an elevated risk of autoimmunity. Thus, the balance between fighting infections and limiting immune response is stratified. Animal models have allowed us to largely tease out the role of sex chromosomes and hormones (such as estrogen/testosterone), but they lend little insight into the role of human gender on the immune response. Disparities between trans- and cis-gender women are observed in multiple inflammatory and immune phenotypes, from HIV risk to rheumatological conditions. As gender is a non-binary spectrum, many precision medicine tools can be applied to tease out individuals’ immune system modulators focused on individual assessments of sex chromosomes, sex hormones, and environmental factors. To do this, we have compiled a multiple PI team that brings strengths from epigenetics/epidemiology (Dr. Triche), infectious disease modeling (Dr. Krawczyk), and sex chromosome/hormone genetics (Dr. Prokop). We highlight in this work how the histone methylation regulator chromosome pair, KDM5C (chrX) and KDM5D (chrY), results in an immune modulation through genome-wide epigenetic alteration. We have developed three complementary aims to build an integrated model of KDM5C/KDM5D influence on individuals’ immune responses. Aim1) Genetics of KDM5C hematopoiesis conditional knockout alteration at the cellular resolution of the immune system following a chronic viral infection, allowing us to determine cell types and global epigenetic alterations regulated by the pathway. Aim2) Precision insights for KDM5C/KDM5D of ~20,000 human blood samples following various immune challenges and the separation of hormone and sex chromosome using the four-core genotypes rodent model blood single-cell data generation. Aim3) Integrating our knowledge to individuals for human variants, gene regulation, environmental modulation, and phenotypic associations for KDM5C/KDM5D. The combination of the three aims represents a precision medicine approach, allowing us insights into the cells and pathways impacted by the sex chromosome genes during infection (Aim1), deconvolution of how hormones and sex chromosomes synergistically contribute to immune cells (Aim2), defining the broad infections and signatures that modulate the genes (Aim2), and integrating this knowledge to be applied to any individual in a non-binary approach (Aim3). As gender can never be binned into groups, with an undefined spectrum of individuals within, we lay forth a novel, innovative way for thinking about how sex and gender both contribute to immune systems without the need for defining gender but allowing for individualized assessments.

抽象的 性别和性别有助于免疫系统以及我们作为人类对外国感染的反应。男性 传统上，由于从出生到老年的感染而导致住院风险升高。但是，女性 具有更受保护的免疫系统，但自身免疫风险升高。那，之间的平衡 对抗感染和限制免疫反应是分层的。动物模型使我们在很大程度上教书 阐明性染色体和骑马的作用（例如雌激素/睾丸激素），但它们对 人性在免疫反应中的作用。跨性别妇女之间的差异是 从艾滋病毒风险到流变学条件，在多种炎症和免疫表型中观察到。作为 性别是一种非二元频谱 免疫系统调节剂专注于对性染色体，性激素和 环境因素。为此，我们编制了一个多个PI团队，从而带来了优势 表观遗传学/流行病学（Triche博士），传染病建模（Krawczyk博士）和性别 染色体/激素遗传学（Prokop博士）。我们在这项工作中强调了组蛋白甲基化调节剂 染色体对，KDM5C（CHRX）和KDM5D（CHRY），通过全基因组进行免疫调节 表观遗传改变。 我们已经开发了三个完整的目标，以建立KDM5C/KDM5D的综合模型对 个人的免疫反应。 AIM1）KDM5C造血的遗传学条件敲除改变 慢性病毒感染后免疫系统的细胞分辨率，使我们能够确定细胞 按途径调节的类型和全球表观遗传改变。 AIM2）KDM5C/KDM5D的精确见解 在各种免疫挑战和骑马和性别的分离之后，约有20,000个人类血液样本 使用四核基因型啮齿动物模型血液单细胞数据生成的染色体。 AIM3）整合 我们对人类变体，基因调节，环境调节和表型的知识 KDM5C/KDM5D的关联。这三个目标的结合代表了精确的药物 方法，使我们能够深入了解受到性染色体基因影响的细胞和途径 感染（AIM1），恐怖和性染色体如何协同促进免疫 细胞（AIM2），定义调节基因的广泛感染和特征（AIM2），并整合了它 以非二进制方法应用于任何个人的知识（AIM3）。因为性别永远不会被纳 分组，内部有一个不确定的个体，我们提出了一种新颖的创新思维方式 关于性别和性别如何对免疫系统做出贡献，而无需定义性别，但 允许进行个性化评估。