CD1a promotes systemic manifestations of skin inflammation.
CD1a promotes systemic manifestations of skin inflammation.
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CD1a促进皮肤炎症的全身表现。
DOI：
10.1038/s41467-022-35071-1
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发表时间：
2022-12-07
影响因子：
16.6
通讯作者：
Ogg, Graham S.
中科院分区：
文献类型：
--
作者：
Hardman, Clare S.;Chen, Yi-Ling;Wegrecki, Marcin;Ng, Soo Weei;Murren, Robert;Mangat, Davinderpreet;Silva, John-Paul;Munro, Rebecca;Chan, Win Yan;O'Dowd, Victoria;Doyle, Carl;Mori, Prashant;Popplewell, Andy;Rossjohn, Jamie;Lightwood, Daniel;Ogg, Graham S.
炎症性皮肤病越来越多地被认为与全身炎症有关。连接皮肤和全身性疾病的机制还不清楚。CD 1a是一种几乎单形的主要组织相容性复合体（MHC）I类分子，由皮肤和粘膜朗格汉斯细胞高度表达，并将脂质抗原呈递给T细胞。在这里，我们显示了在两个实验性疾病模型中，CD 1a在连接皮肤和全身炎症中的重要作用。在人CD 1a转基因小鼠中，与野生型相比，toll样受体（TLR）7激动剂咪喹莫特诱导更明显的脾肿大、外周血和脾T细胞区室扩增以及增强的中性粒细胞和嗜酸性粒细胞应答，伴随皮肤和血浆细胞因子水平升高，包括IL-23、IL-1α、IL-1β、MCP-1和IL-17 A。在MC 903诱导的皮肤炎症中显示了类似的全身性升级。在我们的实验室中开发和筛选的CD 1a阻断抗体可以抵消恶化的炎症。有益的效果是表位依赖性的，我们进一步验证了五种性能最好的抗体调节CD 1a表达细胞和改善CD 1a依赖性全身炎症反应的能力。总之，我们表明，治疗靶向的CD 1a依赖性途径可能在皮肤炎症的全身传播中发挥作用。皮肤炎症通常伴有全身性疾病，但调节这种升级的途径却鲜为人知。在这里，作者表明，小鼠中人CD 1a的转基因表达导致实验性皮肤炎症和全身性炎症性疾病的升级，并且可以通过阻断针对CD 1a的抗体来缓解全身症状。
Inflammatory skin conditions are increasingly recognised as being associated with systemic inflammation. The mechanisms connecting the cutaneous and systemic disease are not well understood. CD1a is a virtually monomorphic major histocompatibility complex (MHC) class I-like molecule, highly expressed by skin and mucosal Langerhans cells, and presents lipid antigens to T-cells. Here we show an important role for CD1a in linking cutaneous and systemic inflammation in two experimental disease models. In human CD1a transgenic mice, the toll-like receptor (TLR)7 agonist imiquimod induces more pronounced splenomegaly, expansion of the peripheral blood and spleen T cell compartments, and enhanced neutrophil and eosinophil responses compared to the wild-type, accompanied by elevated skin and plasma cytokine levels, including IL-23, IL-1α, IL-1β, MCP-1 and IL-17A. Similar systemic escalation is shown in MC903-induced skin inflammation. The exacerbated inflammation could be counter-acted by CD1a-blocking antibodies, developed and screened in our laboratories. The beneficial effect is epitope dependent, and we further characterise the five best-performing antibodies for their capacity to modulate CD1a-expressing cells and ameliorate CD1a-dependent systemic inflammatory responses. In summary, we show that a therapeutically targetable CD1a-dependent pathway may play a role in the systemic spread of cutaneous inflammation. Skin inflammation is often accompanied by systemic disease, yet the pathways that regulate this escalation are little known. Here authors show that transgenic expression of human CD1a in mice leads to the escalation of experimental skin inflammation and systemic inflammatory disease, and the generalized symptoms could be alleviated by blocking antibodies developed against CD1a.
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