title: Deficiency of somatic hypermutation of the antibody light chain is associated with increased frequency of severe respiratory tract infection in common variable immunodeficiency.
abstract: Reduced levels of somatic hypermutation (SHM) have recently been described in IgG-switched immunoglobulin genes in a minority of patients with common variable immunodeficiency (CVID), demonstrating a disruption of the normal linkage between isotype switch and SHM. To see if, irrespective of isotype, there is a tendency to use unmutated immunoglobulin genes in CVID, we studied SHM in kappa light-chain transcripts using a VkappaA27-specific restriction enzyme-based hot-spot mutation assay (IgkappaREHMA). Hot-spot mutations were found in 48% (median; reference interval, 28%-62%) of transcripts from 53 healthy controls. Values were significantly lower in 31 patients (median, 7.5%; range, 0%-73%; P < .0000001) of whom 24 (77%) had levels below the reference interval. Low levels of SHM correlated with increased frequency of severe respiratory tract infection (SRTI; P < .005), but not with diarrhea (P = .8). Mannose-binding lectin (MBL) deficiency also correlated with SRTI score (P = .009). However, the correlation of SHM and SRTI was also seen when only patients with normal MBL genotypes were analyzed (n = 18, P = .006). A slight decline of mutated fractions over years was noted (P = .01). This suggests that most patients with CVID fail to recruit affinity-maturated B cells, adding a qualitative deficiency to the quantitative deficiency characterizing these patients.
authors.affiliation: Department of Clinical Immunology, Blood Bank, University Hospital, Copenhagen, Copenhagen, Denmark. pernille.andersen@dadlnet.dk
authors.forename: Pernille
authors.initials: P
authors.lastname: Andersen
authors.forename: Henrik
authors.initials: H
authors.lastname: Permin
authors.forename: Vagn
authors.initials: V
authors.lastname: Andersen
authors.forename: Lone
authors.initials: L
authors.lastname: Schejbel
authors.forename: Peter
authors.initials: P
authors.lastname: Garred
authors.forename: Arne
authors.initials: A
authors.lastname: Svejgaard
authors.forename: Torben
authors.initials: T
authors.lastname: Barington
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003001:Cloning, Molecular; D017074:Common Variable Immunodeficiency / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D005260:Female; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D007145:Immunoglobulin kappa-Chains / Q000235:genetics* / Q000276:immunology; D007156:Immunologic Memory; D015994:Incidence; D008297:Male; D037601:Mannose-Binding Lectin / Q000172:deficiency; D012141:Respiratory Tract Infections / Q000453:epidemiology / Q000235:genetics* / Q000276:immunology; D012720:Severity of Illness Index; D027041:Somatic Hypermutation, Immunoglobulin / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism
chemical_list: D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D037601:Mannose-Binding Lectin; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7