Defect in IgV gene somatic hypermutation in common variable immuno-deficiency syndrome

Abstract

Common Variable Immuno-Deficiency (CVID) is the most common symptomatic primary antibody-deficiency syndrome, but the basic immunologic defects underlying this syndrome are not well defined. We report here that among eight patients studied (six CVID and two hypogammaglobulinemic patients with recurrent infections), there is in two CVID patients a dramatic reduction in Ig V gene somatic hypermutation with 40-75% of IgG transcripts totally devoid of mutations in the circulating memory B cell compartment. Functional assays of the T cell compartment point to an intrinsic B cell defect in the process of antibody affinity maturation in these two cases.

Figure 1

Distribution of mutations along the JH4-JH5 intron in CD19⁺IgM⁻IgD⁻ memory B cells from normal donors. The number of mutations in 31 sequences obtained from controls is indicated. Mutation hotspots are indicated in a four-nucleotide context, with the mutated position underlined.

Figure 2

Sequences of JH4-JH5 intron from CD19⁺IgM⁻IgD⁻ memory B cells from normal donor and CVID patient LE. JH4-JH5 intronic sequences were compared with the sequence of the corresponding germline allele (15) (allelic variations are marked above the sequence). Nineteen sequences from ND1 (A) and 15 from patient LE (B) are shown. These sequences were checked by the criteria of their VDJH4 junction to be clonally unrelated. Asterisks represent deletions and insertions are indicated by vertical arrows. A slash indicates an incomplete sequence. 1/19 sequences (13) from ND1 and 10/15 sequences (1, 2, 4, 5, 8, 10–13, and 15) from patient LE displayed 0–1 mutation.

Figure 2

Sequences of JH4-JH5 intron from CD19⁺IgM⁻IgD⁻ memory B cells from normal donor and CVID patient LE. JH4-JH5 intronic sequences were compared with the sequence of the corresponding germline allele (15) (allelic variations are marked above the sequence). Nineteen sequences from ND1 (A) and 15 from patient LE (B) are shown. These sequences were checked by the criteria of their VDJH4 junction to be clonally unrelated. Asterisks represent deletions and insertions are indicated by vertical arrows. A slash indicates an incomplete sequence. 1/19 sequences (13) from ND1 and 10/15 sequences (1, 2, 4, 5, 8, 10–13, and 15) from patient LE displayed 0–1 mutation.

Figure 3

Frequency distribution of mutations within V3–23-Cγ transcripts from normal donors and CVID patients LE and SO. Each histogram represents the percentage of V3–23 sequences displaying the number of mutations in a given range.