Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut national de la santé et de la recherche médicale, Necker Hospital for Sick Children, Paris, France.
Imagine Institute, Paris Cité University, Paris, France.
J Exp Med. 2022 Apr 4;219(4). doi: 10.1084/jem.20211387. Epub 2022 Mar 23.
The vast interindividual clinical variability observed in any microbial infection-ranging from silent infection to lethal disease-is increasingly being explained by human genetic and immunological determinants. Autoantibodies neutralizing specific cytokines underlie the same infectious diseases as inborn errors of the corresponding cytokine or response pathway. Autoantibodies against type I IFNs underlie COVID-19 pneumonia and adverse reactions to the live attenuated yellow fever virus vaccine. Autoantibodies against type II IFN underlie severe disease caused by environmental or tuberculous mycobacteria, and other intra-macrophagic microbes. Autoantibodies against IL-17A/F and IL-6 are less common and underlie mucocutaneous candidiasis and staphylococcal diseases, respectively. Inborn errors of and autoantibodies against GM-CSF underlie pulmonary alveolar proteinosis; associated infections are less well characterized. In individual patients, autoantibodies against cytokines preexist infection with the pathogen concerned and underlie the infectious disease. Human antibody-driven autoimmunity can interfere with cytokines that are essential for protective immunity to specific infectious agents but that are otherwise redundant, thereby underlying specific infectious diseases.
在任何微生物感染中，个体间的临床差异巨大，从无症状感染到致命疾病都有，这种差异越来越多地可以用人类遗传和免疫决定因素来解释。中和特定细胞因子的自身抗体是导致相同感染性疾病的原因，就像相应细胞因子或反应途径的先天性错误一样。针对 I 型 IFNs 的自身抗体是导致 COVID-19 肺炎和减毒活黄热病疫苗不良反应的基础。针对 II 型 IFN 的自身抗体是导致由环境或结核分枝杆菌以及其他巨噬细胞内微生物引起的严重疾病的基础。针对 IL-17A/F 和 IL-6 的自身抗体则较为少见，分别与粘膜皮肤念珠菌病和葡萄球菌病有关。GM-CSF 的先天性错误和针对 GM-CSF 的自身抗体是导致肺泡蛋白沉积症的基础；相关感染的特征尚不明确。在个别患者中，针对细胞因子的自身抗体先于相关病原体感染存在，并导致感染性疾病。人类抗体驱动的自身免疫可以干扰对特定病原体保护性免疫至关重要但在其他方面是多余的细胞因子，从而导致特定的传染病。
