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，但自我耐受性随年龄下降的机制尚不清楚。诱导 T 细胞变得自我耐受是胸腺的一种功能，并且被认为涉及由髓质胸腺表达的广谱外周自身抗原（组织限制性抗原，TRA）的呈递（直接或通过交叉引发）上皮细胞（mTEC）。我们最近发现 mTEC 的 TRA 表达随着年龄的增长而降低。与年龄相关的 TRA 表达逐渐丧失，最终预计会导致中枢耐受性逐渐丧失，并将潜在的自身反应细胞释放到外周。本申请中描述的实验旨在检验该假设。使用已发布的计算方法，我们将修改 mTEC 表达的 TRA 列表，以包括多个可排序的定量参数，以及到相关信息（身体图谱）和遗传（小鼠突变体）资源以及预测 MHC 的直接（超文本）链接来自这些 TRA 的 II 类结合肽。这些将用于生成 10-15 个高优先级候选者，用于构建肽：MHC 四聚体，可以检测潜在自身反应性 T 细胞的存在。这些细胞将在年轻小鼠（耐受性应该非常有效）和年龄逐渐增长的小鼠中进行定量。我们预计，衰老将导致 T 细胞的出现和逐渐积累，这些 T 细胞可以识别外周自身抗原，并可能对其产生反应。因此，这些研究有可能为衰老与自身免疫的关系提供机制解释。随着年龄的增长，胸腺迅速萎缩，在青春期左右达到峰值，此后逐渐萎缩。因此，胸腺丧失外周自身抗原可能只是萎缩的继发反应。然而，胸腺是少数具有新生再生潜力的成人器官之一，并且可以通过手术去势等刺激完全再生（尽管是短暂的）。在上述同一项研究中，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，在再生的胸腺中持续存在（从其分子特征的角度来看，它与再生的胸腺几乎没有区别）。再生前老化的胸腺）。因此，老化、再生的胸腺不仅无法消除潜在的自身反应细胞，而且会产生更多数量的细胞，因为胸腺的 T 细胞输出与其质量成正比。由于药物雄激素阻断正在测试其恢复老年人胸腺输出和免疫衰老的能力，包括在其他方面健康的志愿者中，我们认为确定再生的胸腺是否确实产生更大的细胞库非常重要识别自身抗原，因此可能有害。这也将在拟议的项目中进行测试。