过敏的起源：一种由外而内的生物能量学假说。

文献信息

中文摘要

背景： 过敏性疾病的增长过快，遗传易感性无法解释，迄今报道的风险变异位于上皮屏障和2型免疫中。我们提出一个五层模型，其中上皮屏障和生物能量功能障碍可能先于并促进2型免疫偏移，而非仅作为其结果出现，其进展从（1）屏障和生物能量功能障碍、线粒体DNA逃逸至胞质开始，经过（2）危险感知和（3）上皮-免疫通讯，到（4）2型免疫放大和（5）由循环IgE、神经源性放大和特应性进程组成的全身层，并伴有相互的炎症反馈。第1层也是测量最少的：标准免疫panel几乎不包含这些基因，且没有任何全基因组关联研究涉及线粒体基因组或其核调控因子。从1856个编目的转录组系列中，其中985个为表达系列，我们从110个系列中提取了116个病例对照队列，包括3776例患者和2164例对照，第1层预先设定为19个结构域中的350个基因。在212个模块估计中，有9个在错误发现校正后存活：两个2型阳性对照、两个胞质感知和炎症小体模块，在食管组织（Hedges' g +1.70）和特应性皮肤（+1.27）中升高，以及食管组织中的五个生物能量模块。在嗜酸性食管炎中，线粒体清除分支在全部13个队列中均降低（HIF1A -1.94，BNIP3 -1.98）。STING1在所有测量它的13个皮肤队列中均升高，而MAVS在13个食管队列中的10个下降，且STING1减去MAVS的对比无一例外地将过敏性上皮与银屑病、慢性阻塞性肺疾病和哮喘区分开来（精确p 0.029）。在一个临床未受累特应性皮肤的系列中，KEAP1升高而NFE2L2、claudin-1和filaggrin降低（p < 0.001），且该组织并未发炎；在九个系列中汇总时，方向大体保持但未达到显著性。不支持过敏性组织中线粒体程序的广泛抑制：该表型具有组织依赖性，存在于嗜酸性食管炎和特应性皮炎中，在鼻息肉病和已确立的哮喘中不存在，在过敏性鼻炎中为条件性。前瞻性和实验性研究必须确立时间性和因果性关系。

英文摘要

Allergic disease has risen too rapidly for inherited susceptibility to explain it, and the risk variants so far reported lie in the epithelial barrier and in type-2 immunity. We propose a five-layer model in which epithelial barrier and bioenergetic dysfunction may precede and promote type-2 immune deviation rather than arise solely as its consequence, progressing from (1) barrier and bioenergetic dysfunction, with mitochondrial DNA escaping into the cytosol, through (2) danger sensing and (3) epithelial-immune communication, to (4) type-2 immune amplification and (5) a systemic layer of circulating IgE, neurogenic amplification and the atopic march, with reciprocal inflammatory feedback. Layer 1 is also the least measured: standard immune panels carry almost none of these genes, and no genome-wide association study has implicated the mitochondrial genome or its nuclear regulators. From 1856 catalogued transcriptomic series, 985 of them expression series, we drew 116 case-control cohorts from 110 series, 3776 patients and 2164 controls, with Layer 1 prespecified as 350 genes across 19 domains. Of 212 module estimates nine survived false-discovery correction: two type-2 positive controls, two cytosolic sensing and inflammasome modules, raised in oesophageal tissue (Hedges' g +1.70) and atopic skin (+1.27), and five bioenergetic modules in oesophageal tissue. In eosinophilic oesophagitis the mitochondrial clearance limb was reduced in every one of thirteen cohorts (HIF1A -1.94, BNIP3-1.98). STING1 increased in all thirteen skin cohorts that measured it while MAVS fell in ten of thirteen oesophageal cohorts, and a STING1 minus MAVS contrast separated the allergic epithelia from psoriasis, chronic obstructive pulmonary disease and asthma without exception (exact p 0.029). In one series of clinically uninvolved atopic skin KEAP1 increased while NFE2L2, claudin-1 and filaggrin decreased (p < 0.001), in tissue that is not inflamed; pooled across nine series the directions largely hold without reaching significance. Broad suppression of mitochondrial programmes across allergic tissues was not supported: the phenotype is tissue-dependent, present in eosinophilic oesophagitis and atopic dermatitis, absent in nasal polyposis and established asthma and conditional in allergic rhinitis. Prospective and experimental studies must establish temporal and causal relationships.