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.

摘要 性和性别有助于免疫系统以及我们作为人类如何应对外来感染。男性 传统上，从出生到老年，由于感染而住院的风险增加。然而，女性， 具有更强的保护性免疫系统，但患自身免疫的风险较高。因此， 对抗感染和限制免疫反应是分层的。动物模型让我们能够在很大程度上 性染色体和激素（如雌激素/睾丸激素）的作用，但他们几乎没有深入了解 人类性别对免疫反应的影响跨性别和顺性别妇女之间的差异是 在多种炎症和免疫表型中观察到，从HIV风险到风湿性疾病。作为 性别是一个非二元谱，许多精确的医学工具可以用来梳理出个人的 免疫系统调节剂侧重于对性染色体、性激素和 环境因素为此，我们组建了一个多PI团队， 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）。在这项工作中，我们强调了组蛋白甲基化调节剂 染色体对KDM 5C（chrX）和KDM 5D（chrY）通过全基因组免疫调节 表观遗传改变 我们已经开发了三个互补的目标，以建立KDM 5C/KDM 5D影响的综合模型， 个体的免疫反应。目的1）KDM 5C造血条件性敲除改变的遗传学 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 类型和全球表观遗传学改变调节的途径。目标2）KDM 5C/KDM 5D的精准洞察 在各种免疫挑战和激素和性别分离后， 染色体使用四核心基因型啮齿动物模型血液单细胞数据生成。目标3）整合 我们向个人提供有关人类变异、基因调控、环境调节和表型的知识 KDM 5C/KDM 5D的关联。这三个目标的结合代表了精确医学 方法，使我们能够深入了解细胞和途径的影响，性染色体基因在 感染（Aim 1），激素和性染色体如何协同促进免疫的解卷积 细胞（Aim 2），定义了广泛的感染和调节基因（Aim 2）的特征，并将其整合到 以非二元方法将知识应用于任何个人（目标3）。因为性别永远不会被归类 我们分成几个小组，每个小组内都有一个不确定的个体，我们提出了一种新颖的、创新的思维方式。 关于性和性别如何都有助于免疫系统，而不需要定义性别， 允许个性化评估。