Impaired memory B-cell development and antibody maturation with a skewing toward IgE in patients with STAT3 hyper-IgE syndrome.
Adolescent
Adult
Antibody Formation
/ immunology
B-Lymphocytes
/ immunology
Biomarkers
Child
Child, Preschool
Disease Susceptibility
Female
Genotype
Humans
Immunoglobulin E
/ genetics
Immunoglobulin G
/ genetics
Immunoglobulin Heavy Chains
/ genetics
Immunoglobulin Variable Region
/ genetics
Immunologic Memory
Interleukins
/ biosynthesis
Job Syndrome
/ diagnosis
Lymphocyte Activation
/ genetics
Lymphoid Tissue
/ immunology
Male
Middle Aged
Mutation
Plasma Cells
/ immunology
STAT3 Transcription Factor
/ genetics
Signal Transduction
Young Adult
B cell maturation
IgE
STAT3 hyper-IgE syndrome
Journal
Allergy
ISSN: 1398-9995
Titre abrégé: Allergy
Pays: Denmark
ID NLM: 7804028
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
05
09
2018
revised:
10
04
2019
accepted:
22
05
2019
pubmed:
4
7
2019
medline:
10
9
2020
entrez:
4
7
2019
Statut:
ppublish
Résumé
Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is caused by heterozygous mutations in the STAT3 gene and is associated with eczema, elevated serum IgE, and recurrent infections resembling severe atopic dermatitis, while clinically relevant specific IgE is almost absent. To investigate the impact of STAT3 signaling on B-cell responses, we assessed lymph node and bone marrow, blood B and plasma cell subsets, somatic hypermutations in Ig genes, and in vitro proliferation and antibody production in STAT3-HIES patients and healthy controls. Lymph nodes of STAT3-HIES patients showed normal germinal center architecture and CD138 Despite impaired STAT3 signaling, STAT3-HIES patients can mount in vivo T-cell-dependent B-cell responses, while circulating memory B cells, except for those expressing IgG4 and IgE, were reduced. Reduced molecular maturation demonstrated the critical need of STAT3 signaling for optimal affinity maturation and B-cell differentiation, supporting the need for immunoglobulin substitution therapy and explaining the high IgE serum level in the majority with absent allergic symptoms.
Sections du résumé
BACKGROUND
Signal transducer and activator of transcription 3 hyper-IgE syndrome (STAT3-HIES) is caused by heterozygous mutations in the STAT3 gene and is associated with eczema, elevated serum IgE, and recurrent infections resembling severe atopic dermatitis, while clinically relevant specific IgE is almost absent.
METHODS
To investigate the impact of STAT3 signaling on B-cell responses, we assessed lymph node and bone marrow, blood B and plasma cell subsets, somatic hypermutations in Ig genes, and in vitro proliferation and antibody production in STAT3-HIES patients and healthy controls.
RESULTS
Lymph nodes of STAT3-HIES patients showed normal germinal center architecture and CD138
CONCLUSIONS
Despite impaired STAT3 signaling, STAT3-HIES patients can mount in vivo T-cell-dependent B-cell responses, while circulating memory B cells, except for those expressing IgG4 and IgE, were reduced. Reduced molecular maturation demonstrated the critical need of STAT3 signaling for optimal affinity maturation and B-cell differentiation, supporting the need for immunoglobulin substitution therapy and explaining the high IgE serum level in the majority with absent allergic symptoms.
Substances chimiques
Biomarkers
0
Immunoglobulin G
0
Immunoglobulin Heavy Chains
0
Immunoglobulin Variable Region
0
Interleukins
0
STAT3 Transcription Factor
0
Immunoglobulin E
37341-29-0
interleukin-21
MKM3CA6LT1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2394-2405Subventions
Organisme : Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
ID : 320030159870
Pays : International
Organisme : NHMRC Senior Research Fellowship
ID : GNT1117687
Pays : International
Organisme : Sophia Children's Hospital Fund
ID : S698
Pays : International
Organisme : Wilhelm-Sander foundation
ID : 2013.015.2
Pays : International
Organisme : Deutsche Forschungsgemeinschaft
ID : DFG 28869530
Pays : International
Organisme : Helmholtz-Gemeinschaft, Zukunftsthema "Immunology and Inflammation"
ID : ZT-0027
Pays : International
Organisme : Christine Kühne Center Allergy Research and Education Foundation
Pays : International
Informations de copyright
© 2019 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.
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