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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，自身反应性 T 细胞不适当地针对产生激素的细胞，导致组织损伤和激素产生的消除。最常见的自身免疫性疾病之一，桥本甲状腺炎提供了一个理想的模型来破译自身免疫中激素产生的损失内分泌疾病。令人惊讶的是，只有 20-40% 的桥本甲状腺炎患者出现激素损失生产（甲状腺功能减退）。尽管免疫浸润，其余患者仍然保留激素产生甲状腺（甲状腺功能正常）。了解激素产生如何得以保存需要剖析相互作用浸润性 T 细胞和产生激素的上皮细胞（例如甲状腺细胞）之间。为了应对这一挑战，我对桥本甲状腺炎患者的人类甲状腺进行了单细胞 RNA 测序，格雷夫斯病（一种自身抗体驱动的甲状腺自身免疫性疾病）和无自身免疫性甲状腺疾病的患者疾病。我们已经鉴定出转录独特的甲状腺细胞群，其在桥本甲状腺炎并异位表达 II 类 MHC。此外，我们的初步数据表明甲状腺浸润性 CD4+ T 细胞群似乎可以区分格雷夫斯病和桥本氏病甲状腺炎。已知上皮细胞在发炎组织中表达 MHCII，但尚不清楚这些细胞是否表达 MHCII。细胞在体内向 CD4+ T 细胞呈递抗原。我们假设 MHCII+ 甲状腺细胞呈递抗原调节 CD4+ T 细胞的表型，导致炎症环境的整体变化。我们进一步假设 MHCII+ 甲状腺细胞的转录表型在甲状腺功能正常和甲状腺功能减退中存在差异桥本氏甲状腺炎。为了检验这些假设，我将比较转录和功能表型甲状腺功能正常和甲状腺功能减退、桥本甲状腺炎和格雷夫斯病中的 MHCII+ 甲状腺细胞（目标 1）。然后我会确定甲状腺浸润性自身反应性 T 细胞在这些情况下有何不同（目标 2）。该项目可能更广泛地定义如何在自身免疫性疾病中保留组织功能。该提案为 Michelle Rengarajan 博士提出了一项五年计划，旨在进行免疫学培训，以破译如何上皮-免疫相互作用是内分泌自身免疫的基础。 Rengarajan 博士将担任医学讲师哈佛医学院（HMS）和马萨诸塞州总医院（MGH）。她将执行提议的在博士的指导下工作。安德鲁·卢斯特和亚历山德拉-克洛伊·维拉尼。 Rengarajan 博士概述了职业发展计划重点关注单细胞基因组学、上皮免疫相互作用、抗原特异性T 细胞，并接受科学沟通和领导力方面的额外培训。 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制基础。这本提案中概述的实验和培训计划，以及合作机会、智力 HMS 和 MGH 的环境和资源将成功为 Rengarajan 博士提供她的第一个 R01 和作为医师科学家的独立职业。