Autoimmunity and age-related changes in thymic induction of self-tolerance

自身免疫和胸腺诱导自我耐受的年龄相关变化

• 批准号: 8986069
• 负责人: Ann Venables Griffith
• 金额: $ 5.31万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-15 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8986069
• 关键词: Autoimmunity; age; related; changes; thymic

Summary Autoimmune disease is clearly linked to aging, but the mechanism by which self-tolerance breaks down with age is not clear. Inducing T cells to become self-tolerant is a function of the thymus, and is thought to involve presentation (directly or through cross-priming) of a broad spectrum of peripheral self-antigens (tissue-restricted antigens, TRA) expressed by medullary thymic epithelial cells (mTEC). We have recently shown that expression of TRA by mTEC decreases with age. Progressive, age-related loss of TRA expression would ultimately be expected to lead to progressive failure of central tolerance, and the release of potentially self-reactive cells into the periphery. The experiments described in this application are designed to test this hypothesis. Using a published computational approach, we will revise our list of TRA expressed by mTEC to include multiple sortable quantitative parameters, and direct (hypertext) links to relevant informatic (body atlas) and genetic (mouse mutant) resources, as well as to predicted MHC class II-binding peptides from these TRA. These will be used to generate 10-15 high-priority candidates for construction of peptide:MHC tetramers that can detect the presence of potentially self-reactive T cells. Such cells will be quantitated in young mice (where tolerance should be highly efficient) and mice of progressively advancing ages. We anticipate that aging will result in the appearance and gradual accumulation of T cells that can recognize, and potentially react against, peripheral self-antigens. These studies thus have the potential to provide a mechanistic explanation for the relationship of aging to autoimmunity. The thymus exhibits rapid atrophy with age, reaching peak size at around puberty, and declining progressively thereafter. Consequently, loss of peripheral self-antigens by the thymus could simply be a secondary response to atrophy. However, the thymus is one of the few adult organs with nascent regenerative potential, and can be completely regrown (albeit transiently) using stimuli such as surgical castration. In the same study mentioned above, we showed that most of the affects of aging on the thymus, including the loss peripheral self-antigen expression, persist in the regrown thymus (which, from the standpoint of its molecular signature, is almost indistinguishable from the aged thymus before regrowth). Thus, the aged, regrown thymus would not only be expected to fail to delete potentially self-reactive cells, but to produce them in even larger numbers, since T cell output from the thymus is proportional to its mass. Since pharmaceutical androgen blockade is being tested for its ability to restore thymic output and immune senescence in the elderly, including in otherwise healthy volunteers, we believe it is important to determine whether the regrown thymus does, in fact, produce an even larger pool of cells that recognize self-antigens, and thus may have the potential to be harmful. This will also be tested in the proposed project.

摘要 自身免疫性疾病显然与衰老有关，但自我耐受性崩溃的机制是 年龄尚不清楚。诱导T细胞变得自我耐受是胸腺的一种功能，被认为是 包括(直接或通过交叉启动)呈递广泛的外周自身抗原 (TRA)由胸腺髓质上皮细胞(MTEC)表达。我们最近做了 MTEC对TRA的表达随增龄而减少。进行性、与年龄相关的TRA丢失 表达最终预计会导致中枢耐受的进行性失败，并释放 潜在的自我反应细胞进入外围。此应用程序中描述的实验包括 旨在检验这一假说。使用已公布的计算方法，我们将修改我们的TRA列表 由mTEC表示，包括多个可排序的定量参数，并直接(超文本)链接到 相关信息(身体图谱)和遗传(小鼠突变)资源，以及预测的MHC类别 这些TRA中的II结合肽。这些将用于生成10-15个高优先级候选人 多肽的构建：MHC四聚体可以检测潜在的自我反应性T细胞的存在。是这样的 在幼鼠(耐受性应该是高效的)和渐进性小鼠中，细胞将被量化。 年事已高。我们预计，衰老会导致T细胞的出现和逐渐积累 能够识别并有可能对外周自身抗原做出反应的细胞。因此，这些研究具有 有可能为衰老与自身免疫之间的关系提供一种机械解释。 胸腺随着年龄的增长迅速萎缩，在青春期前后达到峰值，然后逐渐下降。 从那以后逐渐地。因此，胸腺失去外周自身抗原可能只是一种 对萎缩的二次反应。然而，胸腺是为数不多的具有新生的成年器官之一。 再生潜力，使用外科手术等刺激可以完全再生(尽管是暂时的) 阉割。在上面提到的同一项研究中，我们表明，衰老对胸腺的大部分影响， 包括外周自身抗原表达的丧失，持续存在于再生的胸腺(从 从其分子特征的观点来看，与再生前老化的胸腺几乎无法区分)。 因此，衰老、再生的胸腺不仅预计不会删除潜在的自我反应细胞， 但要产生更多的T细胞，因为胸腺输出的T细胞与其质量成正比。 由于药物雄激素阻滞剂正在测试其恢复胸腺输出和免疫的能力 老年人的衰老，包括其他健康的志愿者，我们认为确定 再生的胸腺是否真的会产生更大的识别自身抗原的细胞池， 因此有可能是有害的。这也将在拟议的项目中进行测试。