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

Humans STAT1 Transcription Factor / genetics Gain of Function Mutation Bacterial Infections / immunology Female Male Child Immunoglobulins, Intravenous / therapeutic use B-Lymphocytes / immunology Adult Immunoglobulin G / immunology Child, Preschool Adolescent Young Adult Immunity, Humoral
Antibody Affinity B cell Gain of Function IGH Immunoglobulin Replacement Therapy STAT1

Journal

Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137

Informations de publication

Date de publication:
17 May 2024
Historique:
received: 09 01 2024
accepted: 22 04 2024
medline: 17 5 2024
pubmed: 17 5 2024
entrez: 17 5 2024
Statut: epublish

Résumé

STAT1 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. Eleven 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. All 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. STAT1-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.

Identifiants

DOI: 10.1007/s10875-024-01720-x PMID: 38758476
pubmed: 38758476
doi: 10.1007/s10875-024-01720-x
pii: 10.1007/s10875-024-01720-x
doi:

Substances chimiques

STAT1 protein, human 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

124

Subventions

Organisme : National Natural Science Foundation of China
ID : 82071845
Organisme : National Natural Science Foundation of China
ID : 82070135
Organisme : National Key Research and Development Program of China
ID : 2021YFC2700804

Informations de copyright

© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Références

Villarino AV, Kanno Y, O’Shea JJ. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat Immunol. 2017;18(4):374–84. https://doi.org/10.1038/ni.3691 .
doi: 10.1038/ni.3691 pubmed: 28323260
Zhang W, Chen X, Gao G, et al. Clinical Relevance of Gain- and Loss-of-Function Germline Mutations in STAT1: A Systematic Review. Front Immunol. 2021;12:654406. https://doi.org/10.3389/fimmu.2021.654406 .
doi: 10.3389/fimmu.2021.654406 pubmed: 33777053 pmcid: 7991083
Toubiana J, Okada S, Hiller J, et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood. 2016;127(25):3154–64. https://doi.org/10.1182/blood-2015-11-679902 .
doi: 10.1182/blood-2015-11-679902 pubmed: 27114460 pmcid: 4920021
Chen X, Xu Q, Li X, et al. Molecular and Phenotypic Characterization of Nine Patients with STAT1 GOF Mutations in China. J Clin Immunol. 2020;40(1):82–95. https://doi.org/10.1007/s10875-019-00688-3 .
doi: 10.1007/s10875-019-00688-3 pubmed: 31686315
Asano T, Utsumi T, Kagawa R, Karakawa S, Okada S. Inborn errors of immunity with loss- and gain-of-function germline mutations in STAT1. Clin Exp Immunol. 2023;212(2):96–106. https://doi.org/10.1093/cei/uxac106 .
doi: 10.1093/cei/uxac106 pubmed: 36420581
Akkaya M, Kwak K, Pierce SK. B cell memory: building two walls of protection against pathogens. Nat Rev Immunol. 2020;20(4):229–38. https://doi.org/10.1038/s41577-019-0244-2 .
doi: 10.1038/s41577-019-0244-2 pubmed: 31836872
Laidlaw BJ, Cyster JG. Transcriptional regulation of memory B cell differentiation. Nat Rev Immunol. 2021;21(4):209–20. https://doi.org/10.1038/s41577-020-00446-2 .
doi: 10.1038/s41577-020-00446-2 pubmed: 33024284
Methot SP, Di Noia JM. Molecular Mechanisms of Somatic Hypermutation and Class Switch Recombination. Adv Immunol. 2017;133:37–87. https://doi.org/10.1016/bs.ai.2016.11.002 .
doi: 10.1016/bs.ai.2016.11.002 pubmed: 28215280
Gitlin AD, von Boehmer L, Gazumyan A, Shulman Z, Oliveira TY, Nussenzweig MC. Independent Roles of Switching and Hypermutation in the Development and Persistence of B Lymphocyte Memory. Immunity. 2016;44(4):769–81. https://doi.org/10.1016/j.immuni.2016.01.011 .
doi: 10.1016/j.immuni.2016.01.011 pubmed: 26944202 pmcid: 4838502
Viant C, Weymar GHJ, Escolano A, et al. Antibody Affinity Shapes the Choice between Memory and Germinal Center B Cell Fates. Cell. 2020;183(5):1298-1311.e11. https://doi.org/10.1016/j.cell.2020.09.063 .
doi: 10.1016/j.cell.2020.09.063 pubmed: 33125897 pmcid: 7722471
Roco JA, Mesin L, Binder SC, et al. Class-Switch Recombination Occurs Infrequently in Germinal Centers. Immunity. 2019;51(2):337-350.e7. https://doi.org/10.1016/j.immuni.2019.07.001 .
doi: 10.1016/j.immuni.2019.07.001 pubmed: 31375460 pmcid: 6914312
Kitaura K, Yamashita H, Ayabe H, Shini T, Matsutani T, Suzuki R. Different Somatic Hypermutation Levels among Antibody Subclasses Disclosed by a New Next-Generation Sequencing-Based Antibody Repertoire Analysis. Front Immunol. 2017;8:389. https://doi.org/10.3389/fimmu.2017.00389 .
doi: 10.3389/fimmu.2017.00389 pubmed: 28515723 pmcid: 5413556
Tangye SG, Pathmanandavel K, Ma CS. Cytokine-mediated STAT-dependent pathways underpinning human B-cell differentiation and function. Curr Opin Immunol. 2023;81:102286. https://doi.org/10.1016/j.coi.2023.102286 .
doi: 10.1016/j.coi.2023.102286 pubmed: 36764056
van Zelm MC, Bartol SJ, Driessen GJ, et al. Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation. J Allergy Clin Immunol. 2014;134(1):135–44. https://doi.org/10.1016/j.jaci.2013.11.015 .
doi: 10.1016/j.jaci.2013.11.015 pubmed: 24418477
Berkowska MA, Driessen GJ, Bikos V, et al. Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways. Blood. 2011;118(8):2150–8. https://doi.org/10.1182/blood-2011-04-345579 .
doi: 10.1182/blood-2011-04-345579 pubmed: 21690558 pmcid: 3342861
Macdonald RA, Hosking CS, Jones CL. The measurement of relative antibody affinity by ELISA using thiocyanate elution. J Immunol Methods. 1988;106(2):191–4. https://doi.org/10.1016/0022-1759(88)90196-2 .
doi: 10.1016/0022-1759(88)90196-2 pubmed: 3339255
Venselaar H, Te Beek TA, Kuipers RK, et al. Protein structure analysis of mutations causing inheritable diseases An e-Science approach with life scientist friendly interfaces. BMC Bioinformatics. 2010;11:548. https://doi.org/10.1186/1471-2105-11-548 .
doi: 10.1186/1471-2105-11-548 pubmed: 21059217 pmcid: 2992548
Kagawa R, Fujiki R, Tsumura M, et al. Alanine-scanning mutagenesis of human signal transducer and activator of transcription 1 to estimate loss- or gain-of-function variants. J Allergy Clin Immunol. 2017;140(1):232–41. https://doi.org/10.1016/j.jaci.2016.09.035 .
doi: 10.1016/j.jaci.2016.09.035 pubmed: 28011069
Itan Y, Shang L, Boisson B, et al. The mutation significance cutoff: gene-level thresholds for variant predictions. Nat Methods. 2016;13(2):109–10. https://doi.org/10.1038/nmeth.3739 .
doi: 10.1038/nmeth.3739 pubmed: 26820543 pmcid: 4980758
Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310–5. https://doi.org/10.1038/ng.2892 .
doi: 10.1038/ng.2892 pubmed: 24487276 pmcid: 3992975
Zhang P, Bigio B, Rapaport F, et al. PopViz: a webserver for visualizing minor allele frequencies and damage prediction scores of human genetic variations. Bioinformatics. 2018;34(24):4307–9. https://doi.org/10.1093/bioinformatics/bty536 .
doi: 10.1093/bioinformatics/bty536 pubmed: 30535305 pmcid: 6289133
Kitaura K, Yamashita H, Ayabe H, et al. Different Somatic Hypermutation Levels among Antibody Subclasses Disclosed by a New Next-Generation Sequencing-Based Antibody Repertoire Analysis. Front Immunol. 2017;8:389. https://doi.org/10.3389/fimmu.2017.00389 .
doi: 10.3389/fimmu.2017.00389 pubmed: 28515723 pmcid: 5413556
Ma CS, Wong N, Rao G, et al. Unique and shared signaling pathways cooperate to regulate the differentiation of human CD4+ T cells into distinct effector subsets. J Exp Med. 2016;213(8):1589–608. https://doi.org/10.1084/jem.20151467 .
doi: 10.1084/jem.20151467 pubmed: 27401342 pmcid: 4986526
Largent AD, Lambert K, Chiang K, et al. Dysregulated IFN-γ signals promote autoimmunity in STAT1 gain-of-function syndrome. Sci Transl Med. 2023;15(703):eade7028. https://doi.org/10.1126/scitranslmed.ade7028 .
doi: 10.1126/scitranslmed.ade7028 pubmed: 37406138
Ma CS, Wong N, Rao G, et al. Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies. J Allergy Clin Immunol. 2015;136(4):993-1006.e1. https://doi.org/10.1016/j.jaci.2015.05.036 .
doi: 10.1016/j.jaci.2015.05.036 pubmed: 26162572 pmcid: 5042203
Al Shehri T, Gilmour K, Gothe F, et al. Novel gain-of-function mutation in Stat1 sumoylation site leads to CMC/CID phenotype responsive to ruxolitinib. J Clin Immunol. 2019;39:776–85. https://doi.org/10.1007/s10875-019-00687-4 .
doi: 10.1007/s10875-019-00687-4 pubmed: 31512162
van Zelm MC, Bosco JJ, Aui PM, et al. Impaired STAT3-Dependent Upregulation of IL2Rα in B Cells of a Patient With a STAT1 Gain-of-Function Mutation. Front Immunol. 2019;10:768. https://doi.org/10.3389/fimmu.2019.00768 .
doi: 10.3389/fimmu.2019.00768 pubmed: 31068927 pmcid: 6491679
Smyth AE, Kaleviste E, Snow A, Kisand K, McMahon CJ, Cant AJ, et al. Aortic calcification in a patient with a gain-of-function STAT1 mutation. J Clin Immunol. 2018;38:468–70. https://doi.org/10.1007/s10875-018-0513-z .
doi: 10.1007/s10875-018-0513-z pubmed: 29804236
Marinelli L, Ristagno E, Fischer P, Abraham R, Joshi A. Cryptococcal pneumonia in an adolescent with a gain-of-function variant in signal transduction and activator of transcription 1 (STAT1). BMJ Case Rep. 2020;13:e234120. https://doi.org/10.1136/bcr-2019-234120 .
doi: 10.1136/bcr-2019-234120 pubmed: 32327459 pmcid: 7202788
Hartono SP, Vargas-Hernández A, Ponsford MJ, et al. Novel STAT1 Gain-of-Function Mutation Presenting as Combined Immunodeficiency. J Clin Immunol. 2018;38(7):753–6. https://doi.org/10.1007/s10875-018-0554-3 .
doi: 10.1007/s10875-018-0554-3 pubmed: 30317461
Delmonte OM, Bergerson JRE, Burbelo PD, et al. Antibody responses to the SARS-CoV-2 vaccine in individuals with various inborn errors of immunity. J Allergy Clin Immunol. 2021;148(5):1192–7. https://doi.org/10.1016/j.jaci.2021.08.016 .
doi: 10.1016/j.jaci.2021.08.016 pubmed: 34492260 pmcid: 8418380
Chi X, Li Y, Qiu X. V(D)J recombination, somatic hypermutation and class switch recombination of immunoglobulins: mechanism and regulation. Immunology. 2020;160(3):233–47. https://doi.org/10.1111/imm.13176 .
doi: 10.1111/imm.13176 pubmed: 32031242 pmcid: 7341547
Horiuchi K, Imai K, Mitsui-Sekinaka K, et al. Analysis of somatic hypermutations in the IgM switch region in human B cells. J Allergy Clin Immunol. 2014;134(2):411–9. https://doi.org/10.1016/j.jaci.2014.02.043 .
doi: 10.1016/j.jaci.2014.02.043 pubmed: 24836470
Cagigi A, Misasi J, Ploquin A, et al. Vaccine Generation of Protective Ebola Antibodies and Identification of Conserved B-Cell Signatures. J Infect Dis. 2018;218:S528–36. https://doi.org/10.1093/infdis/jiy333 .
doi: 10.1093/infdis/jiy333 pubmed: 30010811 pmcid: 6455927
Avery DT, Deenick EK, Ma CS, et al. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J Exp Med. 2010;207(1):155–71. https://doi.org/10.1084/jem.20091706 .
doi: 10.1084/jem.20091706 pubmed: 20048285 pmcid: 2812540
Kirkham PM, Schroeder HW Jr. Antibody structure and the evolution of immunoglobulin V gene segments. Semin Immunol. 1994;6(6):347–60. https://doi.org/10.1006/smim.1994.1 .
doi: 10.1006/smim.1994.1 pubmed: 7654992

Auteurs

Ran Chen (R)

National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China.

Huilin Mu (H)

National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China.

Xuemei Chen (X)

Department of Rheumatology and Immunology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.

Miyuki Tsumura (M)

Department of Pediatrics, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan.

Lina Zhou (L)

National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China.

Xinhui Jiang (X)

Department of Nephrology and Immunology, Guiyang Maternal & Child Health Care Hospital, Guiyang, China.

Zhiyong Zhang (Z)

National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China.
Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan 2nd Road, Yuzhong District, Chongqing, 400014, China.

Xuemei Tang (X)

National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China.
Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan 2nd Road, Yuzhong District, Chongqing, 400014, China.

Yongwen Chen (Y)

Institute of Immunology, PLA, Third Military Medical University, Chongqing, 400038, People's Republic of China.

Yanjun Jia (Y)

National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China.

Satoshi Okada (S)

Department of Pediatrics, Graduate School of Biomedical and Health Sciences, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551, Japan. sokada@hiroshima-u.ac.jp.
ORCID: 0000-0002-4622-5657

Xiaodong Zhao (X)

National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China. zhaoxd530@aliyun.com.
Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan 2nd Road, Yuzhong District, Chongqing, 400014, China. zhaoxd530@aliyun.com.
ORCID: 0000-0003-2054-8711

Yunfei An (Y)

National Clinical Research Center for Child Health and Disorders, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Rare Diseases in Infection and Immunity, Children's Hospital of Chongqing Medical University, Chongqing, China. anyf82@aliyun.com.
Department of Rheumatology and Immunology, Children's Hospital of Chongqing Medical University, No. 136, Zhongshan 2nd Road, Yuzhong District, Chongqing, 400014, China. anyf82@aliyun.com.
ORCID: 0000-0001-9664-1256

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Qualitative Immunoglobulin Deficiency Causes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription STAT › Facteur de transcription STAT-1 › Qualitative Immunoglobulin Deficiency Causes...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Mutation gain de fonction › Qualitative Immunoglobulin Deficiency Causes...
questionsmedicales.fr › Infection › Infections bactériennes et mycoses › Infections bactériennes › Qualitative Immunoglobulin Deficiency Causes...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Qualitative Immunoglobulin Deficiency Causes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Immunoglobulines par voie veineuse › Qualitative Immunoglobulin Deficiency Causes...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes B › Qualitative Immunoglobulin Deficiency Causes...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Qualitative Immunoglobulin Deficiency Causes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Globulines › Sérum-globulines › Immunoglobulines › Anticorps › Isotypes des immunoglobulines › Immunoglobuline G › Qualitative Immunoglobulin Deficiency Causes...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Enfant d'âge préscolaire › Qualitative Immunoglobulin Deficiency Causes...
questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › Qualitative Immunoglobulin Deficiency Causes...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Jeune adulte › Qualitative Immunoglobulin Deficiency Causes...
questionsmedicales.fr › Phénomènes du système immunitaire › Immunité › Immunité acquise › Immunité humorale › Qualitative Immunoglobulin Deficiency Causes...