Predictive drivers of new onset, relapse, and progression of human autoimmunity in skin

人类皮肤自身免疫新发、复发和进展的预测驱动因素

• 批准号: 10658149
• 负责人: Manuel Garber
• 金额: $ 126.5万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-20 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658149
• 关键词: Affect; Age of Onset; Autoantibodies; Autoimmune Diseases; Autoimmunity; Biological Markers; Blood; Blood capillaries; Cells; Clinical; Clinical Management; Collection; Cutaneous Lupus Erythematosus; Data; Dermatologist; Development; Devices; Diagnosis; Disease; Disease Marker; Disease Progression; Engineering; Enrollment; Epithelial Cells; Exhibits; Face; Family member; Future; Gene Expression; Genetic; Genotype; Hazard Models; High Prevalence; Home; Human; Immune; Individual; Interferon Type I; Liquid substance; Longitudinal cohort; Lupus; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; Needles; Onset of illness; Organ; Participant; Patients; Physicians; Population; Populations at Risk; Prevalence; Property; Proteins; Proteomics; Public Health; Punch Biopsy; Questionnaires; Recurrent disease; Relapse; Reporting; Research Personnel; Risk; Sampling; Scientist; Scourge; Serum; Severity of illness; Skin; Statistical Models; Systemic Lupus Erythematosus; Systemic disease; Testing; Time; Tissue Sample; Tissues; UV induced; Vitiligo; Woman; biomarker identification; clinical diagnosis; cohort; design; health disparity; innovation; insight; interstitial; minimally invasive; mortality; multidisciplinary; multiple omics; pre-clinical; predictive modeling; prevent; response; sample collection; single-cell RNA sequencing; skin color; skin disorder; tool; transcriptome sequencing

ABSTRACT Autoimmune diseases affect up to 8% of the US population and their prevalence is rising, setting the stage for an impending public health crisis that we do not yet understand and are not prepared to face. Many autoimmune diseases disproportionately affect women and those with skin of color, potentially worsening existing health disparities within our population. We must define the mechanisms that drive this growing risk for autoimmunity so that we can better manage, or even prevent, a scourge of severe morbidity and mortality. Skin diseases are among the most prevalent autoimmune diseases and are simple to study due to the ability to diagnose and track the progression of disease through direct observation and sampling using minimally invasive tools. Thus, skin diseases provide unique insight into mechanisms of autoimmunity that are difficult to determine when studying other organs and tissues. We will leverage a multidisciplinary team of investigators, cutting edge tools designed for at-home, longitudinal tissue sampling, and an innovative strategy to discover how autoimmunity begins, relapses, and spreads in a large population of at-risk individuals. We and others have determined that unaffected, non-lesional skin from patients with autoimmunity exists in a disease-specific “preclinical” state, but whether this predisposes the patient to develop disease is an open question. We hypothesize that a molecular immune signature drives a preclinical state within the skin that predisposes to disease initiation and advancement of autoimmunity to other organs. To test this, we will use two ideally suited models of autoimmunity. To predict development of autoimmunity de novo as well as disease relapse, we will take advantage of the unique properties of vitiligo: a strong genetic component, early age of onset (majority <30 years old), strong association with other autoimmune diseases, high prevalence (>1%), and rapid relapse after stopping therapy. We will longitudinally monitor 200 individuals with vitiligo for disease relapse and 800 of their relatives who are “at-risk” for developing new onset disease. To predict the “progression” of autoimmunity to other organs we will monitor a cohort of patients with cutaneous lupus erythematosus (CLE): up to 20% of patients who initially exhibit skin-limited lupus eventually develop systemic disease, with a median time to progression of two years. We will monitor 50 subjects with CLE to detect disease progression to internal organs. We will use these innovative tools on a large scale through “population multiomics” to define immune drivers of autoimmunity in patients and their family members over time. To test our hypothesis, we will use computational integration of clinical, genetic, and molecular data points to define a “preclinical signature” of autoimmunity and use it to predict disease initiation and systemic progression. This approach will provide insight into autoimmunity that will help physicians better manage, or even prevent, devastating consequences of these diseases in the future.

抽象的 自身免疫性疾病影响多达8％的美国人口，其患病率正在上升，为 我们尚未理解且不准备面对的公共卫生危机即将发生的公共卫生危机。许多 自身免疫性疾病不成比例地影响妇女和有色皮肤的女性，可能会担心 我们人口中的现有健康差异。我们必须定义推动这种增长的机制 自身免疫的风险，以便我们可以更好地管理甚至防止严重发病的祸害 和死亡率。皮肤疾病是最普遍的自身免疫性疾病之一，很容易研究 由于能够通过直接观察和采样来诊断和跟踪疾病的进展 使用微创工具。那就是皮肤疾病提供了对自身免疫机制的独特见解 研究其他器官和组织时很难确定。 我们将利用一个由调查人员组成的多学科团队，尖端工具，专为家用，纵向 组织采样以及一种创新的策略，以发现自身免疫性如何开始，中继和传播 大量的高危个人。我们和其他人已经确定，从 自身免疫的患者存在于特异性的“临床前”状态，但这是否使人易于 患者发展疾病是一个悬而未决的问题。我们假设分子免疫特征驱动器 皮肤内的临床前状态，易于疾病的启动和进步 对其他器官的自身免疫性。为了测试这一点，我们将使用两种非常适合的自身免疫模型。预测 自身免疫的发展以及疾病的缓解，我们将利用独特的优势 白癜风的特性：强大的遗传成分，发病的早期（多数<30岁），强大 与其他自身免疫性疾病，高患病率（> 1％）和停止治疗后快速缓解相关。 我们将纵向监视200个为疾病缓解的白癜风的人，其中800名亲戚是 “高危”用于发展新的发病疾病。为了预测自身免疫到其他器官的“进展”，我们将 监测一群皮肤红斑狼疮（CLE）的患者：多达20％的患者 表现出皮肤有限的狼疮有时会出现全身性疾病，中位时间为两年。 我们将监视50名患有CLE的受试者，以检测疾病进展到内部器官。 我们将通过“人口多组学”大规模地使用这些创新工具来定义免疫 随着时间的推移，患者及其家人自身免疫的驱动因素。为了检验我们的假设，我们将 使用临床，遗传和分子数据点的计算整合来定义“临床前 自身免疫的签名”，并使用它来预测疾病的启动和全身进展。 方法将提供对自身免疫性的见解，这将帮助医生更好地管理，甚至预防， 这些疾病的毁灭性后果将来。