Modulation of immune cell phenotype by hormone-producing epithelia in autoimmune endocrinopathies

自身免疫性内分泌病中产生激素的上皮细胞对免疫细胞表型的调节

基本信息

批准号：
10696090
负责人：
Michelle Rengarajan
金额：
$ 17.24万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10696090
关键词：
Address Affect American Antigen Presentation Antigen-Presenting Cells Antigens Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Autologous Award B-Lymphocytes CD4 Positive T Lymphocytes CD8B1 gene Cell Communication Cells Cellular biology Clonal Expansion Communication Data Dendritic Cells Development Development Plans Disease Dissection Endocrine Endocrine Glands Endocrine System Diseases Endocrinology Environment Epithelial Cells Epithelium Exhibits Five-Year Plans Funding Future General Hospitals Genes Genetic Transcription Genomics Global Change Goals Graves&apos Disease Hashimoto Disease Health Hormones Human Immune Immune system Immunology In Situ Infiltration Insulin-Dependent Diabetes Mellitus Interferons Leadership MHC Class II Genes Major Histocompatibility Complex Massachusetts Medicine Mentors Mentorship Modeling Patients Phenotype Physicians Population Positioning Attribute Process Production Regulatory T-Lymphocyte Research Research Personnel Resources Role Scientist System T cell infiltration T-Cell Receptor T-Lymphocyte Testing Therapeutic Thyroid Gland Thyroid Hormones Thyroiditis Tissue Preservation Tissues Training Work antigen-specific T cells autoimmune pathogenesis autoimmune thyroid disease autoreactive T cell career career development cytokine experimental study immune cell infiltrate immune checkpoint immunomodulatory therapies immunoregulation in vivo inflammatory milieu inflammatory modulation instructor loss of function medical schools monocyte new therapeutic target patient retention preservation prevent programs protein complex response single nucleus RNA-sequencing single-cell RNA sequencing

项目摘要

In autoimmune endocrine disease, self-reactive T cells inappropriately target hormone-producing cells, leading to tissue damage and obliteration of hormone production. One of the most common autoimmune diseases, Hashimoto’s thyroiditis, offers an ideal model to decipher how hormone production is lost in autoimmune endocrine disease. Surprisingly, only 20-40% of patients with Hashimoto’s thyroiditis exhibit loss of hormone production (hypothyroid). The remainder of patients retain hormone production despite immune infiltration of the thyroid (euthyroid). Understanding how hormone production is preserved requires dissection of interactions between infiltrating T cells and hormone-producing epithelial cells, such as thyrocytes. To address this challenge, I have performed single-cell RNA sequencing in human thyroid from patients with Hashimoto’s thyroiditis, Graves’ disease (an autoantibody-driven form of thyroid autoimmunity) and those without autoimmune thyroid disease. We have identified a transcriptionally unique population of thyrocytes that is significantly expanded in Hashimoto’s thyroiditis and ectopically expresses class II MHC. In addition, our preliminary data indicate several thyroid-infiltrating CD4+ T cell populations that appear to distinguish Graves’ disease from Hashimoto’s thyroiditis. Epithelial cells are known to express MHCII in inflamed tissue, however it is not known whether these cells present antigen to CD4+ T cells in vivo. We hypothesize that MHCII+ thyrocytes present antigen to and modulate the phenotype of CD4+ T cells, leading to global changes in the inflammatory environment. We further hypothesize that the transcriptional phenotype of MHCII+ thyrocytes differs in euthyroid and hypothyroid Hashimoto’s thyroiditis. To test these hypotheses, I will compare the transcriptional and functional phenotype of MHCII+ thyrocytes in euthyroid and hypothyroid Hashimoto’s thyroiditis and Graves’ disease (Aim 1). I will then determine how thyroid-infiltrating self-reactive T cells differ among these conditions (Aim 2). This project may define how tissue function can be preserved in autoimmune disease more broadly. This proposal presents a five-year plan for Dr. Michelle Rengarajan to train in immunology to decipher how epithelial-immune interactions underly endocrine autoimmunity. Dr. Rengarajan will be an Instructor in Medicine at Harvard Medical School (HMS) and Massachusetts General Hospital (MGH). She will perform the proposed work under mentorship from Drs. Andrew Luster and Alexandra-Chloe Villani. Dr. Rengarajan has outlined a career development plan focused on single-cell genomics, epithelial-immune interactions, antigen-specific T cells, with additional training in scientific communication and leadership. Dr. Rengarajan’s long-term goal is to develop an independent research program studying the mechanistic basis of autoimmune endocrinopathies. The experiments and training plan outlined in this proposal, with the collaborative opportunities, intellectual environment, and resources available at HMS and MGH will successfully position Dr. Rengarajan for her first R01 and an independent career as a physician-scientist.

在自身免疫性内分泌疾病中，自反应性T细胞不适当地靶向产生激素的细胞，领先为了组织损伤和hors鼠的产生。最常见的自身免疫性疾病之一，桥本的甲状腺炎，提供了一个理想的模型，可以解释hosene生产如何在自身免疫中丢失内分泌疾病。令人惊讶的是，只有20-40％的桥本甲状腺炎患者暴露于马赛酮的损失生产（甲状腺功能减退）。其余的患者保留了Horsene生产目的地免疫渗透甲状腺（甲状腺）。了解如何保留骑马的生产需要解剖相互作用在浸润的T细胞和产生马的上皮细胞（例如甲状腺细胞）之间。为了应对这个挑战，我已经在桥本甲状腺炎患者的人甲状腺中进行了单细胞RNA测序， Graves病（甲状腺自身免疫的自身驱动形式）和没有自身免疫性甲状腺的疾病疾病。我们已经确定了具有独特独特的甲状腺细胞群体，该群显着扩展桥本的甲状腺炎和生态表达II类MHC。此外，我们的初步数据指示了几个甲状腺浸润的CD4+ T细胞群体似乎将Graves疾病与桥本的疾病区分开甲状腺炎。已知上皮细胞在发炎的组织中表达MHCII，但是尚不清楚这些是否是否细胞在体内呈现与CD4+ T细胞的抗原。我们假设MHCII+甲状腺细胞呈现抗原与调节CD4+ T细胞的表型，从而导致炎症环境的全球变化。我们进一步假设MHCII+甲状腺细胞的转录表型在甲状腺和甲状腺功能下有所不同桥本的甲状腺炎。为了检验这些假设，我将比较 MHCII+甲状腺和甲状腺甲状体甲状腺甲状腺炎和坟墓疾病中的甲状腺细胞（AIM 1）。然后我会确定这些条件之间的甲状腺浸润自我反应性T细胞的不同（AIM 2）。这个项目可能定义如何更广泛地在自身免疫性疾病中保存组织功能。该提案为米歇尔·伦加拉扬（Michelle Rengarajan）博士提供了五年计划，以训练免疫学，以解读如何解读内分泌自身免疫的基础上皮 - 免疫相互作用。 Rengarajan博士将担任医学教练在哈佛医学院（HMS）和马萨诸塞州综合医院（MGH）。她将执行提议的 Drs的指导下工作。安德鲁·劳斯特（Andrew Luster）和亚历山德拉·克洛伊·维拉尼（Alexandra-Chloe Villani）。 Rengarajan博士概述了职业发展计划的重点是单细胞基因组学，上皮免疫相互作用，抗原特异性T 细胞，并在科学沟通和领导方面进行额外的培训。 Rengarajan博士的长期目标是制定一个独立的研究计划，研究自身免疫性内分泌病的机理基础。这该提案中概述的实验和培训计划，以及协作机会，知识分子环境和HMS和MGH的资源将成功定位Rengarajan博士的第一个 R01和独立职业作为身体科学家。