Purpose

We describe a case of primary cutaneous aspergillosis caused by Aspergillus fumigatus, and elucidate the underlying genetic and immunological mechanisms.

Materials and Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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患有 CARD9 缺陷的患者的原发性皮肤曲霉病和 Card9 基因敲除小鼠的曲霉易感性

目的

我们描述了一个由烟曲霉引起的原发性皮肤曲霉病病例，并阐明了潜在的遗传和免疫机制。

材料和方法

进行了常规临床和实验室调查。患者 DNA 的全外显子组测序表明存在CARD9突变，Sanger 测序证实了这一点。用 ELISA 和流式细胞术评估源自患者的 CARD9 缺陷细胞的先天性和适应性免疫反应。建立Card9基因敲除(KO)小鼠的皮肤和肺曲霉病模型，并与野生型和免疫抑制小鼠进行比较，探讨其发病机制和对曲霉菌的易感性。

结果

一名 45 岁男子，因面部皮肤损伤 37 年就诊。原发性皮肤曲霉病的诊断是通过组织病理学、免疫组织化学和组织培养进行的。CARD9的Sanger 测序显示纯合移码突变（c.819_820insG，p.D274fsX60），导致 CARD9 缺乏表达。来自患者的外周血单个核细胞在真菌特异性刺激下显示出促炎细胞因子以及 Th1、Th17 和 Th22 相关反应的选择性损伤。Card9建立的皮肤曲霉病模型KO小鼠出现持续感染，组织中有真菌细菌和短菌丝，与患者的病变一致。免疫抑制小鼠的皮肤损伤更严重，并导致死亡。与我们的患者不同，Card9 KO 小鼠对肺曲霉病相对易感，原因有待调查。

结论

据我们所知，这是第一份将皮肤曲霉病与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。