Qualitative Immunoglobulin Deficiency Causes Bacterial Infections in Patients with STAT1 Gain-of-Function Mutations

作者全名：Chen, Ran; Mu, Huilin; Chen, Xuemei; Tsumura, Miyuki; Zhou, Lina; Jiang, Xinhui; Zhang, Zhiyong; Tang, Xuemei; Chen, Yongwen; Jia, Yanjun; Okada, Satoshi; Zhao, Xiaodong; An, Yunfei

作者地址：[Chen, Ran; Mu, Huilin; Zhou, Lina; Zhang, Zhiyong; Tang, Xuemei; Jia, Yanjun; Zhao, Xiaodong; An, Yunfei] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Chongqing Key Lab Child Rare Dis Infect & Immun,Ch, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing 400014, Peoples R China; [Zhang, Zhiyong; Tang, Xuemei; Zhao, Xiaodong; An, Yunfei] Chongqing Med Univ, Dept Rheumatol & Immunol, Childrens Hosp, 136 Zhongshan 2nd Rd, Chongqing 400014, Peoples R China; [Chen, Xuemei] Chongqing Med Univ, Dept Rheumatol & Immunol, Affiliated Hosp 2, Chongqing, Peoples R China; [Tsumura, Miyuki; Okada, Satoshi] Grad Sch Biomed & Hlth Sci, Dept Pediat, 1-2-3 Kasumi,Minami Ku, Hiroshima 7348551, Japan; [Jiang, Xinhui] Guiyang Maternal & Child Hlth Care Hosp, Dept Nephrol & Immunol, Guiyang, Peoples R China; [Chen, Yongwen] Third Mil Med Univ, PLA, Inst Immunol, Chongqing 400038, Peoples R China

通信作者：Zhao, XD; An, YF (通讯作者)，Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Chongqing Key Lab Child Rare Dis Infect & Immun,Ch, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing 400014, Peoples R China.; Zhao, XD; An, YF (通讯作者)，Chongqing Med Univ, Dept Rheumatol & Immunol, Childrens Hosp, 136 Zhongshan 2nd Rd, Chongqing 400014, Peoples R China.; Okada, S (通讯作者)，Grad Sch Biomed & Hlth Sci, Dept Pediat, 1-2-3 Kasumi,Minami Ku, Hiroshima 7348551, Japan.

来源：JOURNAL OF CLINICAL IMMUNOLOGY

ESI学科分类：IMMUNOLOGY

WOS号：WOS:001227231000005

JCR分区：Q1

影响因子：7.2

年份：2024

卷号：44

期号：5

开始页：　

结束页：　

文献类型：Article

关键词：STAT1; Gain of Function; Immunoglobulin Replacement Therapy; B cell; Antibody Affinity; IGH

摘要：PurposesSTAT1 is a transduction and transcriptional regulator that functions within the classical JAK/STAT pathway. In addition to chronic mucocutaneous candidiasis, bacterial infections are a common occurrence in patients with STAT1 gain-of-function (GOF) mutations. These patients often exhibit skewing of B cell subsets; however, the impact of STAT1-GOF mutations on B cell-mediated humoral immunity remains largely unexplored. It is also unclear whether these patients with IgG within normal range require regular intravenous immunoglobulin (IVIG) therapy.MethodsEleven patients (harboring nine different STAT1-GOF mutations) were enrolled. Reporter assays and immunoblot analyses were performed to confirm STAT1 mutations. Flow cytometry, deep sequencing, ELISA, and ELISpot were conducted to assess the impact of STAT1-GOF on humoral immunity.ResultsAll patients exhibited increased levels of phospho-STAT1 and total STAT1 protein, with two patients carrying novel mutations. In vitro assays showed that these two novel mutations were GOF mutations. Three patients with normal total IgG levels received regular IVIG infusions, resulting in effective control of bacterial infections. Four cases showed impaired affinity and specificity of pertussis toxin-specific antibodies, accompanied by reduced generation of class-switched memory B cells. Patients also had a disrupted immunoglobulin heavy chain (IGH) repertoire, coupled with a marked reduction in the somatic hypermutation frequency of switched Ig transcripts.ConclusionSTAT1-GOF mutations disrupt B cell compartments and skew IGH characteristics, resulting in impaired affinity and antigen-specificity of antibodies and recurrent bacterial infections. Regular IVIG therapy can control these infections in patients, even those with normal total IgG levels.

基金机构：National Natural Science Foundation of China

基金资助正文：The authors thank all the patients, their families, and healthy volunteers for their participation in the study.