title: Impaired antibody affinity maturation process characterizes a subset of patients with common variable immunodeficiency.
abstract: Common variable immunodeficiency (CVID) is an heterogeneous syndrome characterized by decreased levels of serum Ig and recurrent bacterial infection. Here, we were interested to study whether a qualitative defect of the affinity Ab maturation process could be combined to the low level of serum Ig in a cohort of 38 CVID patients. For this, we designed a novel and rapid screening test for the detection of hypomutated V gene expressed by memory B cells. This test delineated a subset of 9/38 (23%) CVID patients with an abnormal pattern of Ig V gene mutation. The mean frequency of V gene mutation of this subset was significantly lower (1.74%) compared with other CVID patients (5.46%) and normal donors (6.5%) (p<0.0001). The mean age of this subgroup was significantly higher than other hypogammaglobulinemic patients with normal levels of V gene mutation (p<0.02), whereas no difference in the duration of symptoms was noted between the two groups. This suggests that hypomutation characterizes patients who began CVID late in life. Recently, it was shown that non-Ig sequences, such as the intronic BCL-6 gene, could be the target of the somatic hypermutation process in normal memory B cells. Our finding of a normal mutation frequency of the BCL-6 gene in two hypomutated CVID point to a defect of the Ig targeting of hypermutation machinery in these cases.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unit 474. Hôpital Henri Mondor, Créteil, France.
authors.forename: D
authors.initials: D
authors.lastname: Bonhomme
authors.forename: L
authors.initials: L
authors.lastname: Hammarström
authors.forename: D
authors.initials: D
authors.lastname: Webster
authors.forename: H
authors.initials: H
authors.lastname: Chapel
authors.forename: O
authors.initials: O
authors.lastname: Hermine
authors.forename: F
authors.initials: F
authors.lastname: Le Deist
authors.forename: E
authors.initials: E
authors.lastname: Lepage
authors.forename: P H
authors.initials: PH
authors.lastname: Romeo
authors.forename: Y
authors.initials: Y
authors.lastname: Levy
mesh_terms: D000328:Adult; D000368:Aged; D000409:Alanine / Q000235:genetics; D000915:Antibody Affinity / Q000235:genetics*; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D002999:Clone Cells; D003062:Codon; D017074:Common Variable Immunodeficiency / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D016384:Consensus Sequence; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000097:blood / Q000235:genetics; D005803:Genes, Immunoglobulin; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000235:genetics; D007074:Immunoglobulin G / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007156:Immunologic Memory / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000097:blood / Q000235:genetics; D051560:Proto-Oncogene Proteins c-bcl-6; D012694:Serine / Q000235:genetics; D014157:Transcription Factors / Q000097:blood / Q000235:genetics; D014158:Transcription, Genetic / Q000276:immunology
chemical_list: D003062:Codon; D004268:DNA-Binding Proteins; D007127:Immunoglobulin Constant Regions; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D014157:Transcription Factors; D012694:Serine; D000409:Alanine