Immune Tolerance and Signalling Laboratory, Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra 0200, Australia.
Proc Natl Acad Sci U S A. 2010 Aug 17;107(33):14709-14. doi: 10.1073/pnas.1009209107. Epub 2010 Jul 28.
Autoimmune polyendocrinopathy syndrome type 1 (APS1) results from homozygous Aire mutations that cripple thymic deletion of organ-specific T cells. The clinical course in man and mouse is characterized by high variability both in the latent period before onset of autoimmune disease and in the specific organs affected, but the reasons for this are unknown. Here we test the hypothesis that the latent period reflects the failsafe action of discrete postthymic mechanisms for imposing self-tolerance in peripheral T cells. Aire-deficient mice were crossed with mice of a uniform major histocompatibility complex (MHC) haplotype and genetic background carrying specific genetic defects in one of four distinct peripheral tolerance mechanisms: activation-induced cell death (Fasl(gld/gld)), anergy and requirement for CD28 costimulation (Cblb(-/-)), inhibition of ICOS and T(FH) cells (Rc3h1(san/san)), or decreased numbers of Foxp3(+) T regulatory cells (Card11(unm/unm)). Cblb-deficiency was unique among these four in precipitating rapid clinical autoimmune disease when combined with Aire-deficiency, resulting in autoimmune exocrine pancreatitis with median age of survival of only 25 d. Massive lymphocytic infiltration selectively destroyed most of the exocrine acinar cells of the pancreas and submandibular salivary gland, and CD4(+) and CD8(+) subsets were necessary and sufficient to transfer the disease. Intrinsic regulation of peripheral T cells by CBL-B thus serves a uniquely critical role as a failsafe against clinical onset of autoimmune disease in AIRE deficiency, and multiple peripheral tolerance mechanisms may need to fail before onset of clinical autoimmunity to many organs.
自身免疫性多内分泌腺病综合征 1 型（APS1）是由 Aire 基因纯合突变引起的，该突变使胸腺中器官特异性 T 细胞的删除受损。人和小鼠的临床病程特征是在自身免疫性疾病发作前的潜伏期和受影响的特定器官方面具有高度可变性，但原因尚不清楚。在这里，我们检验了这样一个假设，即潜伏期反映了离散的胸腺后机制在周围 T 细胞中施加自身耐受的失效保护作用。Aire 缺陷型小鼠与具有统一主要组织相容性复合体（MHC）单倍型和遗传背景的小鼠交配，这些小鼠在四个不同的外周耐受机制中的一个中具有特定的遗传缺陷：激活诱导的细胞死亡（Fasl(gld/gld)）、无能和对 CD28 共刺激的需求（Cblb(-/-)）、ICOS 和 T(FH)细胞的抑制（Rc3h1(san/san)）或 Foxp3(+)T 调节细胞数量减少（Card11(unm/unm)）。在与 Aire 缺陷结合时，Cblb 缺陷是这四种缺陷中唯一会引发快速临床自身免疫性疾病的，导致自身免疫性外分泌性胰腺炎，中位生存时间仅为 25 天。大量淋巴细胞浸润选择性地破坏了胰腺和颌下唾液腺的大部分外分泌腺泡细胞，CD4(+)和 CD8(+)亚群是转移疾病所必需且充分的。因此，CBL-B 对周围 T 细胞的内在调节在 Aire 缺陷中作为临床自身免疫病发作的失效保护作用具有独特的关键作用，并且在许多器官发生临床自身免疫之前，可能需要多个外周耐受机制失效。
