Dysregulated STAT1 gain-of-function:Pathogen-free autoimmunity and fungal infection  

作　　者：Liping Guo Dongli Lian Yuchen Gu Xiaoyu Lu Ying Zhang Xiaohe Li Tatyana Aleksandrovna Khrustaleva Jianfeng Lan Yanhua Liang Vladislav Victorovich Khrustalev Yanyan Mao Yafan Chen Hongzhou Lu Jing Yuan 

机构地区：[1]Shenzhen Key Laboratory of Pathogen and Immunity,National Clinical Research Center for Infectious Disease,State Key Discipline of Infectious Disease,Shenzhen Third People’s Hospital,Second Hospital Affiliated to Southern University of Science and Technology,Guangdong,China [2]Department of Microbiology,Basic Medical College,Guangxi Medical University,Guangxi,China [3]School of Public Health(Shenzhen),Shenzhen Campus of Sun Yat-Sen University,Guangdong,China [4]Multidisciplinary Diagnostic Laboratory,Institute of Physiology of the National Academy of Sciences of Belarus,Minsk,Belarus [5]Department of General Chemistry,Belarusian State Medical University,Minsk,Belarus [6]Health Science Center,Shenzhen University,Guangdong,China

出　　处：《hLife》2024年第8期397-418,共22页健康科学（英文）

基　　金：supported in part by the National Science and Technology Major Project(No.2021 YFC2301803);Shenzhen Fund for Guangdong Provincial High-Level Clinical Key Specialties(No.SZGSP011);Science and Technology Program of Shenzhen,China(No.JCYJ 20230807143411023);the clinical research project of Shenzhen Third Peoples Hospital(No.G2022044);the Teaching Quality and Teaching Reform Project of Education Department of Guangdong Province:Experimental Teaching Demonstration Center of Emerging Infectious Diseases(Y01411846).

摘　　要：Inborn errors of the signal transducer and activator of transcription 1(STAT1)result in four types of immunodeficiency disease with varying degrees of impaired STAT1 function:autosomal recessive(AR)complete STAT1 deficiency,AR partial STAT1 deficiency,autosomal dominant(AD)STAT1 deficiency,and AD STAT1 gain-of-function(STAT1-GOF).Of which,the STAT1-GOF mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections,especially chronic mucocutaneous candidiasis(CMC)and Talaromyces marneffei infection and predisposition to humoral autoimmunity.STAT1-GOF mutations lead to enhanced phosphorylation of STAT1(pSTAT1),delayed dephosphorylation,and impaired nuclear dephosphorylation.As a result,the development of T helper(Th)17 cells is impaired,limiting the production of interleukin(IL)-17,which plays an important role in antifungal immunity.Additionally,mutations can also cause a decrease in the proportion of CD4^(+),CD8^(+),and natural killer(NK)cells.Recent research demonstrated that in the absence of overt infection,STAT-GOF mice can disrupt naïve CD4^(+)T cell homeostasis and promote expansion and differentiation of abnormal T-follicular helper/T-helper 1-like(Tfh/Th1-like)T cells and germinal center-like(GC-like)B cells,and thus reminds us of the complex molecular mechanism of autoimmune disease with/without fungal infection,which may further involve specific clinical treatment including antifungal and anti-autoimmunity therapies.In addition,sex and location of mutation were also associated with the clinical phenotype.Individuals with DNA binding domain(DBD)mutations had a higher prevalence of autoimmunity and aberrant B cell activation.Disrupted CD4^(+)T cell homeostasis occurred sooner and more robustly in females,highlighting the importance of specific treatment to normalize STAT1 expression and restore immune tolerance in patients with STAT1-GOF syndrome.Herein,we provide a comprehensive review of STAT1-GOF aiming to further clarify the regulatory mechanism of cellular and hu

关 键 词：signal transducer and activator of transcription 1 gain-of-function(STAT-GOF)mutation fungal infection chronic mucocutaneous candidiasis(CMC) Talaromyces marneffei treatment 

分 类 号：R392[医药卫生—免疫学]