Mahmoud Tamer I, Wang Jingya, Karnell Jodi L, Wang Qiming, Wang Shu, Naiman Brian, Gross Phillip, Brohawn Philip Z, Morehouse Chris, Aoyama Jordan, Wasserfall Clive, Carter Laura, Atkinson Mark A, Serreze David V, Braley-Mullen Helen, Mustelin Tomas, Kolbeck Roland, Herbst Ronald, Ettinger Rachel
Respiratory, Inflammation, and Autoimmunity Group, MedImmune LLC, Gaithersburg, MD 20878, USA.
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
Sci Transl Med. 2016 Oct 19;8(361):361ra137. doi: 10.1126/scitranslmed.aag0367.
Autoantibodies can be present years to decades before the onset of disease manifestations in autoimmunity. This finding suggests that the initial autoimmune trigger involves a peripheral lymphoid component, which ultimately drives disease pathology in local tissues later in life. We show that Sjögren's syndrome manifestations that develop in aged NOD.H-2h4 mice were driven by and dependent on peripheral dysregulation that arose in early life. Specifically, elimination of spontaneous germinal centers in spleens of young NOD.H-2h4 mice by transient blockade of CD40 ligand (CD40L) or splenectomy abolished Sjögren's pathology of aged mice. Strikingly, a single injection of anti-CD40L at 4 weeks of age prevented tertiary follicle neogenesis and greatly blunted the formation of key autoantibodies implicated in glandular pathology, including anti-muscarinic receptor antibodies. Microarray profiling of the salivary gland characterized the expression pattern of genes that increased with disease progression and showed that early anti-CD40L greatly repressed B cell function while having a broader effect on multiple biological pathways, including interleukin-12 and interferon signaling. A single prophylactic treatment with anti-CD40L also inhibited the development of autoimmune thyroiditis and diabetes in NOD.H-2h4 and nonobese diabetic mice, respectively, supporting a key role for CD40L in the pathophysiology of several autoimmune models. These results strongly suggest that early peripheral immune dysregulation gives rise to autoimmune manifestations later in life, and for diseases predated by autoantibodies, early prophylactic intervention with biologics may prove efficacious.
自身抗体可能在自身免疫性疾病临床表现出现前数年至数十年就已存在。这一发现表明，最初的自身免疫触发涉及外周淋巴成分，最终在生命后期驱动局部组织的疾病病理过程。我们发现，老年NOD.H-2h4小鼠出现的干燥综合征表现是由生命早期出现的外周失调所驱动且依赖于此。具体而言，通过短暂阻断CD40配体（CD40L）或脾切除术消除年轻NOD.H-2h4小鼠脾脏中的自发生发中心，可消除老年小鼠的干燥综合征病理表现。引人注目的是，在4周龄时单次注射抗CD40L可预防三级滤泡新生，并极大地抑制与腺体病理相关的关键自身抗体的形成，包括抗毒蕈碱受体抗体。唾液腺的微阵列分析表征了随疾病进展而增加的基因的表达模式，并表明早期抗CD40L处理极大地抑制了B细胞功能，同时对包括白细胞介素-12和干扰素信号传导在内的多种生物学途径具有更广泛的影响。单次预防性给予抗CD40L还分别抑制了NOD.H-2h4和非肥胖糖尿病小鼠自身免疫性甲状腺炎和糖尿病的发展，支持CD40L在几种自身免疫模型病理生理学中的关键作用。这些结果有力地表明，早期外周免疫失调会导致生命后期出现自身免疫表现，对于由自身抗体引发的疾病，早期使用生物制剂进行预防性干预可能证明是有效的。
