Willem van de Veen1,2, Carolin E Krätz1,2,3, Craig I McKenzie4,5, Pei M Aui4,5, Jens Neumann6, Carel J M van Noesel7, Oliver F Wirz1, Beate Hagl3,8, Carolin Kröner3, Benedikt D Spielberger3,8, Cezmi A Akdis1,2, Menno C van Zelm4,5,9, Mübeccel Akdis1, Ellen D Renner2,8,10. 1. Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland. 2. Christine Kühne Center for Allergy Research and Education (CK-CARE), Davos, Switzerland. 3. University Children's Hospital at Dr. von Haunersches Kinderspital, Ludwig Maximilian University, Munich, Germany. 4. Department of Immunology and Pathology, Monash University, Melbourne, Victoria, Australia. 5. The Jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies in Melbourne, Melbourne, Victoria, Australia. 6. Pathology Department, Ludwig Maximilian University, Munich, Germany. 7. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. 8. Environmental Medicine, UNIKA-T Augsburg, Technische Universität München and Helmholtz Zentrum, München, Germany. 9. Department of Allergy, Immunology and Respiratory Medicine, Alfred Hospital, Melbourne, Victoria, Australia. 10. Hochgebirgsklinik Davos, Davos, Switzerland.
Abstract
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+ plasma cells residing in the paracortex, which expressed IgE, IgG, and IgM but not IgA. IgE+ plasma cells were abundantly present in STAT3-HIES bone marrow. Proliferation of naive B cells upon stimulation with CD40L and IL-4 was similar in patients and controls, while patient cells showed reduced responses to IL-21. IgE, IgG1, IgG3 and IgA1 transcripts showed reduced somatic hypermutations. Peripheral blood IgE+ memory B-cell frequencies were increased in STAT3-HIES, while other memory B-cell frequencies except for IgG4+ cells were decreased. 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.
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-HIESpatients and healthy controls. RESULTS: Lymph nodes of STAT3-HIESpatients showed normal germinal center architecture and CD138+ plasma cells residing in the paracortex, which expressed IgE, IgG, and IgM but not IgA. IgE+ plasma cells were abundantly present in STAT3-HIES bone marrow. Proliferation of naive B cells upon stimulation with CD40L and IL-4 was similar in patients and controls, while patient cells showed reduced responses to IL-21. IgE, IgG1, IgG3 and IgA1 transcripts showed reduced somatic hypermutations. Peripheral blood IgE+ memory B-cell frequencies were increased in STAT3-HIES, while other memory B-cell frequencies except for IgG4+ cells were decreased. CONCLUSIONS: Despite impaired STAT3 signaling, STAT3-HIESpatients 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.
Authors: D Ferastraoaru; H J Bax; C Bergmann; M Capron; M Castells; D Dombrowicz; E Fiebiger; H J Gould; K Hartmann; U Jappe; G Jordakieva; D H Josephs; F Levi-Schaffer; V Mahler; A Poli; D Rosenstreich; F Roth-Walter; M Shamji; E H Steveling-Klein; M C Turner; E Untersmayr; S N Karagiannis; E Jensen-Jarolim Journal: Clin Transl Allergy Date: 2020-07-17 Impact factor: 5.871
Authors: Peter-Paul A Unger; Niels J M Verstegen; Casper Marsman; Tineke Jorritsma; Theo Rispens; Anja Ten Brinke; S Marieke van Ham Journal: Cells Date: 2021-05-12 Impact factor: 6.600