Department of Dermatology and Venerology, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China.
Research Center for Medical Mycology, Peking University, Beijing, China.
J Clin Immunol. 2021 Feb;41(2):427-440. doi: 10.1007/s10875-020-00909-0. Epub 2020 Nov 12.
We describe a case of primary cutaneous aspergillosis caused by Aspergillus fumigatus, and elucidate the underlying genetic and immunological mechanisms.
Routine clinical and laboratory investigations were performed. Whole-exome sequencing of the patient's DNA suggested the presence of a CARD9 mutation, which was confirmed by Sanger sequencing. Innate and adaptive immunological responses of patient-derived CARD9-deficient cells were evaluated with ELISA and flow cytometry. Cutaneous and pulmonary aspergillosis models were established in Card9 knockout (KO) mice, which were compared with wild-type and immunosuppressed mice, to explore the pathogenesis and Aspergillus susceptibility.
A 45-year-old man presented with a 37-year history of skin lesions on his face. A diagnosis of primary cutaneous aspergillosis was made through histopathology, immunohistochemistry, and tissue culture. Sanger sequencing of CARD9 showed a homozygous frame-shift mutation (c.819_820insG, p.D274fsX60), which led to the lack of CARD9 expression. Peripheral blood mononuclear cells from the patient showed selective impairment of proinflammatory cytokines, and Th1-, Th17-, and Th22-associated responses upon fungus-specific stimulation. The cutaneous aspergillosis model established in Card9 KO mice presented with persistent infection, with fungal germs and short hyphae in tissue, consistent with the patient's lesions. Skin lesions in immunosuppressed mice were more severe, and led to death. Unlike our patient, Card9 KO mice were relatively susceptible to pulmonary aspergillosis, with reasons to be investigated.
This is, to our knowledge, the first report that links cutaneous aspergillosis to CARD9 mutation. This work enriches both the phenotypic spectrum of CARD9 deficiencies and the genetic background of cutaneous aspergillosis.
我们描述了一例由烟曲霉引起的原发性皮肤曲霉病，并阐明了潜在的遗传和免疫机制。
进行了常规的临床和实验室检查。对患者 DNA 的全外显子组测序提示存在 CARD9 突变，通过 Sanger 测序得到证实。通过 ELISA 和流式细胞术评估了患者来源的 CARD9 缺陷细胞的固有和适应性免疫反应。在 Card9 敲除 (KO) 小鼠中建立了皮肤和肺部曲霉病模型，并与野生型和免疫抑制型小鼠进行了比较，以探讨发病机制和曲霉易感性。
一名 45 岁男性，面部皮肤病变 37 年。通过组织病理学、免疫组织化学和组织培养诊断为原发性皮肤曲霉病。CARD9 的 Sanger 测序显示纯合移码突变 (c.819_820insG, p.D274fsX60)，导致 CARD9 表达缺失。患者外周血单核细胞在真菌特异性刺激下表现出促炎细胞因子和 Th1、Th17 和 Th22 相关反应的选择性受损。在 Card9 KO 小鼠中建立的皮肤曲霉病模型表现出持续性感染，组织中存在真菌芽和短菌丝，与患者的病变一致。免疫抑制小鼠的皮肤病变更严重，并导致死亡。与我们的患者不同，Card9 KO 小鼠对肺部曲霉病相对易感，原因有待进一步研究。
据我们所知，这是首例将皮肤曲霉病与 CARD9 突变联系起来的报告。这项工作丰富了 CARD9 缺陷的表型谱和皮肤曲霉病的遗传背景。
