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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：
10505915
负责人：
Michelle Rengarajan
金额：
$ 17.28万
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/10505915
关键词：
Address Affect Antigen Presentation Antigen-Presenting Cells Antigens Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmunity Autologous Award B-Lymphocytes CD4 Positive T Lymphocytes CD8B1 gene Cell Communication Cell Nucleus Cells Cellular biology Communication Data Dendritic Cells Development Development Plans Disease Dissection Endocrine Endocrine Glands Endocrine System Diseases Endocrinology Environment Epithelial Epithelial Cells Exhibits Five-Year Plans Funding Future General Hospitals Genes Genetic Transcription Genomics Global Change Goals Graves&apos Disease Hashimoto Disease Health Hormones Human Hypothyroidism Immune Immune system Immunology In Situ 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 Receptor T-Lymphocyte Testing Therapeutic Thyroid Gland Thyroid Hormones Tissue Preservation Tissues Training Tumor-infiltrating immune cells Work antigen-specific T cells autoimmune pathogenesis autoimmune thyroid disease autoreactive T cell base career career development cytokine disorder control experimental study immune checkpoint immunoregulation in vivo inflammatory milieu instructor loss of function medical schools monocyte new therapeutic target preservation prevent programs protein complex response single-cell RNA sequencing transcriptome 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细胞不恰当地靶向激素产生细胞，导致