title: The defect in humoral immunity in patients with Nijmegen breakage syndrome is explained by defects in peripheral B lymphocyte maturation.
abstract: Patients with an immunodeficiency in the course of Nijmegen breakage syndrome (NBS) that is caused by mutations in the NBN/NBS1 gene are prone to recurrent infections and malignancies, due to a defective DNA double-strand breaks repair mechanism. Four-color flow cytometry was used to analyze changes in B lymphocyte subsets reflecting the most important stages of peripheral B cell maturation. It was demonstrated that the humoral immune defect observed in NBS patients was caused by reduced numbers of B lymphocytes, but also by their aberrant maturation. Reduced relative and absolute counts of naïve and memory B cells were accompanied by a significant accumulation of the natural effector B lymphocytes. The elevated proportion of IgM-only memory and reduced proportion of IgM-negative cells within the memory B cell pool suggests that there is class-switch recombination defect in this population of cells in NBS patients, resulting in inadequate production of immunoglobulins. Because of the reduced T-cell counts, the T-cell dependent antigen response is severely impaired resulting in a lower frequency of memory B-cells. The T-cell independent B-cell differentiation pathway seems less affected. The reduced IgG and IgA levels in patients with NBS are caused both by ineffective class switch, at least due to poor T cell help, and low number of memory B cells. This study illustrates that the NBN gene product nibrin plays an important role at different levels in the B-cell system.
authors.affiliation: Histocompatibility Laboratory, Children's Memorial Health Institute, Warsaw, Poland. b.piatosa@czd.pl
authors.forename: Barbara
authors.initials: B
authors.lastname: Piątosa
authors.forename: Mirjam
authors.initials: M
authors.lastname: van der Burg
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Siewiera
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Pac
authors.forename: Jacques J M
authors.initials: JJ
authors.lastname: van Dongen
authors.forename: Anton W
authors.initials: AW
authors.lastname: Langerak
authors.forename: Krystyna H
authors.initials: KH
authors.lastname: Chrzanowska
authors.forename: Ewa
authors.initials: E
authors.lastname: Bernatowska
mesh_terms: D000293:Adolescent; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D056724:Immunity, Humoral; D007070:Immunoglobulin A / Q000097:blood; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007156:Immunologic Memory; D016130:Immunophenotyping; D007223:Infant; D018655:Lymphocyte Count; D049932:Nijmegen Breakage Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D018797:Cell Cycle Proteins; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007075:Immunoglobulin M; C112156:NBN protein, human; D009687:Nuclear Proteins