Primary Cutaneous Aspergillosis in a Patient with CARD9 Deficiency and Aspergillus Susceptibility of Card9 Knockout Mice
Autor: | Chen Huang, Xiaowen Wang, Zhe Wan, Yi Zhang, Xuejun Zhu, Yinggai Song, Ruoyu Li, Yubo Ma |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Male medicine.medical_specialty Pathology Immunology Adaptive Immunity Peripheral blood mononuclear cell Aspergillus fumigatus Proinflammatory cytokine Pathogenesis 03 medical and health sciences symbols.namesake Mice 0302 clinical medicine Exome Sequencing medicine Immunology and Allergy Animals Aspergillosis Humans Genetic Predisposition to Disease Cells Cultured Sanger sequencing Inflammation Mice Knockout Aspergillus Mice Inbred BALB C biology business.industry Middle Aged medicine.disease biology.organism_classification Immunity Innate CARD Signaling Adaptor Proteins Mice Inbred C57BL 030104 developmental biology Mutation symbols Leukocytes Mononuclear Cytokines Histopathology Persistent Infection Primary cutaneous aspergillosis business 030215 immunology |
Zdroj: | Journal of clinical immunology. 41(2) |
ISSN: | 1573-2592 |
Popis: | 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. |
Databáze: | OpenAIRE |
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