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

描述（由申请人提供）：自身免疫性疾病显然与衰老有关，但自身耐受性随年龄增长而下降的机制尚不清楚。诱导T细胞变得自我耐受是胸腺的功能，并且被认为涉及由胸腺髓质上皮细胞（mTEC）表达的广谱外周自身抗原（组织限制性抗原，TRA）的呈递（直接或通过交叉致敏）。我们最近发现，TRA的表达mTEC随着年龄的增长而减少。TRA表达的进行性、年龄相关性丧失最终预期会导致中枢耐受性的进行性失败，并将潜在的自身反应性细胞释放到外周。本申请中描述的实验被设计为测试该假设。使用已发表的计算方法，我们将修改我们的列表中的TRA表达的mTEC，包括多个可排序的定量参数，并直接（超文本）链接到相关的信息（身体图谱）和遗传（小鼠突变）资源，以及预测MHC II类结合肽从这些TRA。这些将用于产生10-15个高优先级候选物，用于构建肽：MHC四聚体，其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（其中耐受性应该是高效的）和年龄逐渐增加的小鼠中定量。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，并可能与之发生反应。因此，这些研究有可能为衰老与自身免疫的关系提供一个机制性解释。胸腺随年龄增长而迅速萎缩，在青春期左右达到峰值，此后逐渐下降。因此，胸腺外周自身抗原的丢失可能只是萎缩的继发性反应。然而，胸腺是少数几个具有新生再生潜力的成年器官之一，并且可以通过手术阉割等刺激完全再生（尽管是短暂的）。在上述相同的研究中，我们发现老化对胸腺的大部分影响，包括外周自身抗原表达的丧失，在再生胸腺中持续存在（从其分子特征的角度来看，几乎无法与再生前的老化胸腺区分开来）。因此，老化的、再生的胸腺不仅不能消除潜在的自反应细胞，而且会产生更多的自反应细胞，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剂正在测试其恢复老年人胸腺输出和免疫衰老的能力，包括在其他健康志愿者中，我们认为重要的是要确定再生的胸腺是否确实产生了更大的识别自身抗原的细胞库，因此可能有害。这一点也将在拟议项目中得到检验。

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.