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

在自身免疫性内分泌疾病中，自我反应性T细胞不适当地靶向产生激素的细胞，导致 导致组织损伤和荷尔蒙分泌减少。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解释自身免疫中荷尔蒙的产生是如何丢失的 内分泌疾病。令人惊讶的是，只有20%-40%的桥本甲状腺炎患者表现出激素丢失 生产(甲状腺功能减退)。其余的患者保留了荷尔蒙的产生，尽管免疫渗透了 甲状腺(正常甲状腺)。要了解荷尔蒙的产生是如何保存的，需要剖析相互作用 在浸润性T细胞和产生激素的上皮细胞之间，如甲状腺细胞。为了应对这一挑战， 我在桥本甲状腺炎患者的甲状腺中进行了单细胞RNA测序， Graves病(一种自身抗体驱动的甲状腺自身免疫性疾病)和那些没有自身免疫性甲状腺的人 疾病。我们已经确定了一组转录上独特的甲状腺细胞，这种细胞在 桥本甲状腺炎和异位表达II类MHC。此外，我们的初步数据显示有几个 甲状腺浸润性CD4+T细胞群对Graves病和桥本病的鉴别作用 甲状腺炎。已知上皮细胞在炎症组织中表达MHCII，但尚不清楚这些细胞是否 在体内，细胞向CD4+T细胞递呈抗原。我们假设MHCII+甲状腺细胞呈递抗原给和 调节CD4+T细胞的表型，导致炎症环境的全球变化。我们进一步 假设MHCII+甲状腺细胞在甲状腺功能正常和甲状腺功能减退时转录表型不同 桥本甲状腺炎。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的桥本甲状腺炎和Graves病的MHCII+甲状腺细胞(目标1)。那我会的 确定甲状腺浸润性自身反应性T细胞在这些情况下的差异(目标2)。这个项目可能 更广泛地定义如何在自身免疫性疾病中保存组织功能。 这项提议为米歇尔·伦加拉扬博士提出了一个五年计划，以培训免疫学，以破译 上皮-免疫相互作用低于内分泌自身免疫。Rengarajan博士将担任医学讲师 在哈佛医学院(HMS)和马萨诸塞州综合医院(MGH)。她将执行拟议的 在安德鲁·卢斯特博士和亚历山德拉-克洛伊·维拉尼博士的指导下工作。Rengarajan博士概述了 职业发展计划侧重于单细胞基因组学、上皮-免疫相互作用、抗原特异性T细胞 细胞，并在科学交流和领导能力方面进行额外培训。伦加拉扬博士的长期目标是 制定一个独立的研究计划，研究自身免疫性内分泌疾病的机制基础。这个 本提案中概述的实验和培训计划，具有协作机会，智力 环境，以及HMS和MGH可用的资源将成功地定位Rengarajan博士 R01和作为一名内科科学家的独立职业。

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.