Drummond Rebecca A, Lionakis Michail S
Fungal Pathogenesis Unit, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health Bethesda, MD, USA.
Front Cell Infect Microbiol. 2016 Apr 5;6:39. doi: 10.3389/fcimb.2016.00039. eCollection 2016.
Human CARD9 deficiency is an autosomal recessive primary immunodeficiency disorder caused by biallelic mutations in the gene CARD9, which encodes a signaling protein that is found downstream of many C-type lectin receptors (CLRs). CLRs encompass a large family of innate recognition receptors, expressed predominantly by myeloid and epithelial cells, which bind fungal carbohydrates and initiate antifungal immune responses. Accordingly, human CARD9 deficiency is associated with the spontaneous development of persistent and severe fungal infections that primarily localize to the skin and subcutaneous tissue, mucosal surfaces and/or central nervous system (CNS). In the last 3 years, more than 15 missense and nonsense CARD9 mutations have been reported which associate with the development of a wide spectrum of fungal infections caused by a variety of fungal organisms. The mechanisms by which CARD9 provides organ-specific protection against these fungal infections are now emerging. In this review, we summarize recent immunological and clinical advances that have provided significant mechanistic insights into the pathogenesis of human CARD9 deficiency. We also discuss how genetic mutations in CARD9-coupled receptors (Dectin-1, Dectin-2) and CARD9-binding partners (MALT1, BCL10) affect human antifungal immunity relative to CARD9 deficiency, and we highlight major understudied research questions which merit future investigation.
人类CARD9缺陷是一种常染色体隐性原发性免疫缺陷疾病，由CARD9基因的双等位基因突变引起，该基因编码一种信号蛋白，位于许多C型凝集素受体（CLR）的下游。CLR是一个庞大的天然识别受体家族，主要由髓样细胞和上皮细胞表达，可结合真菌碳水化合物并启动抗真菌免疫反应。因此，人类CARD9缺陷与持续性严重真菌感染的自发发展有关，这些感染主要定位于皮肤和皮下组织、粘膜表面和/或中枢神经系统（CNS）。在过去3年中，已报道了15种以上的错义突变和无义CARD9突变，这些突变与多种真菌病原体引起的广泛真菌感染的发生有关。CARD9针对这些真菌感染提供器官特异性保护的机制正在逐渐明晰。在本综述中，我们总结了最近的免疫学和临床进展，这些进展为人类CARD9缺陷的发病机制提供了重要的机制性见解。我们还讨论了CARD9偶联受体（Dectin-1、Dectin-2）和CARD9结合伴侣（MALT1、BCL10）中的基因突变相对于CARD9缺陷如何影响人类抗真菌免疫，并且我们强调了一些主要的研究不足问题，值得未来进行研究。
