Menno C van Zelm1, Sophinus J W Bartol2, Gertjan J Driessen3, Françoise Mascart4, Ismail Reisli5, Jose L Franco6, Beata Wolska-Kusnierz7, Hirokazu Kanegane8, Louis Boon9, Jacques J M van Dongen2, Mirjam van der Burg2. 1. Department of Immunology, Erasmus MC, Rotterdam, The Netherlands. Electronic address: m.vanzelm@erasmusmc.nl. 2. Department of Immunology, Erasmus MC, Rotterdam, The Netherlands. 3. Department of Immunology, Erasmus MC, Rotterdam, The Netherlands; Department of Pediatrics, Erasmus MC, Rotterdam, The Netherlands. 4. Immunobiology Clinic, Hôpital Erasme, and Laboratory of Vaccinology and Mucosal Immunity, Université Libre de Bruxelles, Brussels, Belgium. 5. Meram Medical Faculty, Department of Pediatric Immunology and Allergy, Necmettin Erbakan University, Konya, Turkey. 6. Group of Primary Immunodeficiencies, University of Antioquia, Medellín, Colombia. 7. Department of Immunology, Children's Memorial Health Institute, Warsaw, Poland. 8. Department of Pediatrics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan. 9. Bioceros B.V., Utrecht, The Netherlands.
Abstract
BACKGROUND: Individuals with genetic defects in CD40 ligand (CD40L) or B-cell antigen receptor coreceptor molecules CD19 and CD81 suffer from an antibody deficiency. Still, these patients carry low levels of memory B cells and serum antibodies. OBJECTIVE: We sought to assess why the remaining memory B cells and antibodies in the blood of these patients do not provide functional immunity. METHODS: We included CD19-deficient patients (n = 8), CD40L-deficient patients (n = 8), and healthy controls (n = 50) to perform detailed flow cytometry on blood B cells, molecular analysis of IgA and IgG transcripts, as well as functional analysis of B-cell activation. RESULTS: CD19-deficient and CD40L-deficient patients carried reduced numbers of all memory B-cell subsets except CD27(-)IgA(+) B cells. Their immunoglobulin heavy chain class-switched transcripts contained less somatic mutations and reduced usage of IgM-distal IgG2 and IgA2 subclasses. The selection strength of mutations for antigen binding was significantly lower than in controls, whereas selection to maintain superantigen binding was normal. Furthermore, the patients showed impaired selection against inherently autoreactive properties of their immunoglobulins. Somatic hypermutation analysis revealed decreased activation-induced cytidine deaminase and uracil-DNA glycosylase 2 activity in CD40L deficiency and increased uracil-DNA glycosylase 2 but decreased mismatch repair in CD19 deficiency. B-cell activation studies revealed that this was at least in part due to transcriptional regulation of DNA repair genes. CONCLUSIONS: This study on CD19 and CD40L deficiencies illustrates that both the B-cell antigen receptor and CD40 signaling pathways are required for the selection of immunoglobulin reactivity. Still, they differentially mediate DNA repair pathways during somatic hypermutation, thereby together shaping the human in vivo antigen-experienced B-cell repertoire.
BACKGROUND: Individuals with genetic defects in CD40 ligand (CD40L) or B-cell antigen receptor coreceptor molecules CD19 and CD81 suffer from an antibody deficiency. Still, these patients carry low levels of memory B cells and serum antibodies. OBJECTIVE: We sought to assess why the remaining memory B cells and antibodies in the blood of these patients do not provide functional immunity. METHODS: We included CD19-deficientpatients (n = 8), CD40L-deficientpatients (n = 8), and healthy controls (n = 50) to perform detailed flow cytometry on blood B cells, molecular analysis of IgA and IgG transcripts, as well as functional analysis of B-cell activation. RESULTS:CD19-deficient and CD40L-deficientpatients carried reduced numbers of all memory B-cell subsets except CD27(-)IgA(+) B cells. Their immunoglobulin heavy chain class-switched transcripts contained less somatic mutations and reduced usage of IgM-distal IgG2 and IgA2 subclasses. The selection strength of mutations for antigen binding was significantly lower than in controls, whereas selection to maintain superantigen binding was normal. Furthermore, the patients showed impaired selection against inherently autoreactive properties of their immunoglobulins. Somatic hypermutation analysis revealed decreased activation-induced cytidine deaminase and uracil-DNA glycosylase 2 activity in CD40L deficiency and increased uracil-DNA glycosylase 2 but decreased mismatch repair in CD19 deficiency. B-cell activation studies revealed that this was at least in part due to transcriptional regulation of DNA repair genes. CONCLUSIONS: This study on CD19 and CD40L deficiencies illustrates that both the B-cell antigen receptor and CD40 signaling pathways are required for the selection of immunoglobulin reactivity. Still, they differentially mediate DNA repair pathways during somatic hypermutation, thereby together shaping the human in vivo antigen-experienced B-cell repertoire.
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