Deficiency of somatic hypermutation of the antibody light chain is associated with increased frequency of severe respiratory tract infection in common variable immunodeficiency.
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.
Andersen
Pernille
P
Department of Clinical Immunology, Blood Bank, University Hospital, Copenhagen, Copenhagen, Denmark. pernille.andersen@dadlnet.dk
Permin
Henrik
H
Andersen
Vagn
V
Schejbel
Lone
L
Garred
Peter
P
Svejgaard
Arne
A
Barington
Torben
T
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
D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D037601:Mannose-Binding Lectin; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7