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

自身免疫和年龄相关的胸腺诱导自我耐受的变化。

• 批准号: 8649022
• 负责人: Ann Venables Griffith
• 金额: $ 17.01万
• 依托单位: SCRIPPS FLORIDA
• 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 2014-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649022
• 关键词: Adult; Affect; Age; Aging; Algorithms; Androgens; Antigens; Appearance; Atlases; Atrophic; Autoantigens; Autoimmune Diseases; Autoimmunity; Binding; Castration; Cells; Clinical Trials; Cross-Priming; Databases; Elderly; Ensure; Epithelial Cells; Etiology; Exhibits; Failure; Frequencies; Genetic; Histocompatibility; Human; Hypertext; Immune; Incidence; Influenza; Informatics; Insecta; Laboratories; Lead; Link; Lymphoid; Lymphopoiesis; MHC Class II Genes; Methodology; Minnesota; Molecular Profiling; Mus; Mutant Strains Mice; Natural regeneration; Organ; Output; Peptide/MHC Complex; Peptides; Peripheral; Pharmacologic Substance; Puberty; Publishing; Resources; Self Tolerance; Stimulus; System; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Thymic epithelial cell; Thymus Gland; Tissues; Universities; Vaccines; Work; age related; aged; base; central tolerance; clinically relevant; design; healthy volunteer; human disease; insight; novel; public health relevance; receptor binding; regenerative; research study; response; senescence; theories; thymocyte; tissue resource

DESCRIPTION (provided by applicant): 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 thi 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.

描述（由申请人提供）：自身免疫性疾病显然与衰老有关，但是随着年龄的增长，自耐分解的机制尚不清楚。诱导T细胞变得自耐是胸腺的函数，被认为涉及（直接或直接通过交叉染色），以髓性胸膜上皮细胞（MTEC）表达的各种外围自我抗原（组织限制性抗原，TRA）的广泛谱。我们最近表明，MTEC的TRA表达随着年龄的增长而降低。最终将期望进行性，与年龄相关的TRA表达的丧失导致中央耐受性的进行性衰竭，并释放潜在的自反应性细胞到周围。应用程序中描述的实验旨在检验该假设。使用已发表的计算方法，我们将修改MTEC表达的TRA列表，其中包括多种可排序的定量参数，并直接（超文本）链接到相关信息（身体ATLAS）和遗传（小鼠突变体）资源，以及从这些TRA中预测的MHC II类结合肽。这些将用于生成10-15个高优先级候选肽：MHC四聚体，可检测潜在的自反应性T细胞的存在。这些细胞将在年轻小鼠（耐受性高度高效）和逐渐发展的小鼠中进行定量。我们预计，衰老将导致T细胞的外观和逐渐积累，这些T细胞可以识别并可能反应外周的自我抗原。因此，这些研究有可能为衰老与自身免疫的关系提供机械解释。胸腺随着年龄的增长而表现出快速的萎缩，在青春期附近达到峰值大小，此后逐渐下降。因此，胸腺对周围自我抗原的丧失可能只是对萎缩的次要反应。然而，胸腺是少数具有新生再生潜力的成年器官之一，可以使用诸如手术cast割的刺激（尽管是短暂的）重新生产的。在上面提到的同一项研究中，我们表明，大多数对胸腺衰老的影响，包括损失的外周自我抗原表达，持续存在于重生的胸腺（从其分子特征的角度来看，这几乎与重生前的老年胸腺几乎没有区别）。因此，老化的胸腺不仅预计无法删除潜在的自反应性细胞，而且要以更大的数量产生它们，因为胸腺的T细胞输出与其质量成正比。由于药物雄激素阻滞的能力正在测试其恢复老年人的胸腺输出和免疫衰老的能力，包括在其他健康的志愿者中，因此我们认为，确定胸腺重生确实会产生更大的细胞池是否会识别自我抗原，因此可能会有可能有害的潜力，这一点很重要。这也将在拟议的项目中进行测试。