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

总结 自身免疫性疾病显然与衰老有关，但自我耐受性的机制与衰老有关。 年龄不清楚。诱导T细胞变得自我耐受是胸腺的功能，并且被认为是 包括呈递（直接或通过交叉致敏）广谱外周自身抗原 （组织限制性抗原，TRA）。我们最近 显示TRA通过mTEC的表达随着年龄的增长而降低。进行性、年龄相关性TRA丢失 预期表达最终将导致中枢耐受性的进行性失败，并且释放 潜在的自我反应细胞进入外周。本申请中描述的实验是 来检验这个假设使用已发表的计算方法，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 相关的信息（身体图谱）和遗传（小鼠突变）资源，以及预测的MHC类 II-结合肽从这些TRA。这些将用于产生10-15名高优先级候选人， 肽的构建：可以检测潜在自身反应性T细胞的存在的MHC四聚体。等 将在年轻小鼠（其中耐受性应该是高效的）和逐渐减少的小鼠中定量细胞。 年龄增长。我们预计，衰老将导致T细胞的出现和逐渐积累 可以识别并潜在地对抗外周自身抗原。因此，这些研究具有 有可能为衰老与自身免疫的关系提供一个机制性的解释。 胸腺随着年龄的增长而迅速萎缩，在青春期左右达到高峰， 此后逐步。因此，胸腺周围自身抗原的丢失可能仅仅是一种免疫反应。 继发性萎缩反应。然而，胸腺是为数不多的具有新生胸腺的成年器官之一。 再生潜力，并可以完全再生（虽然短暂）使用刺激，如手术 阉割在上面提到的同一项研究中，我们发现，衰老对胸腺的大部分影响， 包括外周自身抗原表达的丧失，在再生胸腺中持续存在（从 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）。 因此，老化的、再生的胸腺不仅不能清除潜在的自反应细胞， 而且产生的数量更大，因为胸腺的T细胞输出量与其质量成正比。 由于药物雄激素阻断剂正在测试其恢复胸腺输出和免疫功能的能力， 老年人的衰老，包括健康的志愿者，我们认为重要的是要确定 事实上，再生的胸腺是否真的产生了更大的识别自身抗原的细胞库， 因此可能具有有害的潜力。这一点也将在拟议项目中得到检验。

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.