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. 2003 Jul;112(1):136-42.
doi: 10.1172/JCI18161.

Hyper-IgM syndrome type 4 with a B lymphocyte-intrinsic selective deficiency in Ig class-switch recombination

Kohsuke Imai  1 , Nadia Catalan, Alessandro Plebani, László Maródi, Ozden Sanal, Satoru Kumaki, Vasantha Nagendran, Philip Wood, Catherine Glastre, Françoise Sarrot-Reynauld, Olivier Hermine, Monique Forveille, Patrick Revy, Alain Fischer, Anne Durandy
Affiliations

Hyper-IgM syndrome type 4 with a B lymphocyte-intrinsic selective deficiency in Ig class-switch recombination

Kohsuke Imai et al. J Clin Invest. 2003 Jul.

Abstract

Hyper-IgM syndrome (HIGM) is a heterogeneous condition characterized by impaired Ig class-switch recombination (CSR). The molecular defects that have so far been associated with this syndrome - which affect the CD40 ligand in HIGM type 1 (HIGM1), CD40 in HIGM3, and activation-induced cytidine deaminase (AID) in HIGM2 - do not account for all cases. We investigated the clinical and immunological characteristics of 15 patients with an unidentified form of HIGM. Although the clinical manifestations were similar to those observed in HIGM2, these patients exhibited a slightly milder HIGM syndrome with residual IgG production. We found that B cell CSR was intrinsically impaired. However, the generation of somatic hypermutations was observed in the variable region of the Ig heavy chain gene, as in control B lymphocytes. In vitro studies showed that the molecular defect responsible for this new HIGM entity (HIGM4) occurs downstream of the AID activity, as the AID gene was induced normally and AID-induced DNA double-strand breaks in the switch micro region of the Ig heavy chain locus were detected during CSR as normal. Thus, HIGM4 is probably the consequence of a selective defect either in a CSR-specific factor of the DNA repair machinery or in survival signals delivered to switched B cells.

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Figures

Figure 1
Figure 1
Serum Ig levels in HIGM4 and HIGM2 patients. Horizontal bars indicate the mean levels for each group of patients. Levels from age-matched controls are indicated.
Figure 2
Figure 2
B cell responses to sCD40L+rIL-4 activation. (a) Normal B cell proliferative response to sCD40L+rIL-4 stimulation in HIGM4 patients. PBMCs from age-matched controls (n = 24), HIGM2 patients (n = 16), and HIGM4 patients (n = 13) were stimulated with sCD40L and rIL-4 for 5 days. White bars, no stimulation; black bars, 12-day stimulation with sCD40L+IL-4. Mean uptakes of [3H]thymidine (cpm) are shown. Error bars show the SD. (b) Defective IgE and IgG CSR following stimulation by sCD40L+rIL-4 in HIGM4 patients. PBMCs from normal controls (n = 20 for IgE, n = 5 for IgG), HIGM2 patients (n = 20), and HIGM4 patients (n = 13 for IgE, n = 4 for IgG) were stimulated with sCD40L+rIL-4 for 12 days. White bars, no stimulation; black bars, 12-day stimulation with sCD40L+IL-4. Concentrations of IgE and IgG in the culture supernatants were quantified by ELISA. Mean values are shown. Error bars show the SD.
Figure 3
Figure 3
Detection of RNA transcripts of CSR-related genes. (a) RNA transcripts of the CD19 (as control), AID, germ-line (εGLTs), circular (εCTs), and functional (εFTs) transcripts for IgE, and of the functional transcripts for IgG (γFTs) were detected by RT-PCR after stimulation with sCD40L+rIL-4 for 5 days in control subjects (C) and in HIGM4 patients (P1, P2, P5, P7, P8, P11, P15). (b) CD19 transcripts and εGLTs levels were analyzed using different quantities of cDNA (1:1, 1:10, 1:100, and 1:1,000 dilution) in RT-PCR for selected cases (P1, P5, P7, P15).
Figure 4
Figure 4
Detection of double-strand DNA breaks (DSBs) during CSR in HIGM4. (a) Positions of primers and probe used in DSB assay. Directions and positions of the primers and radioactive Sμ-specific probe used in the DSB assay are shown. The asterisk shows the putative position of DSBs in the Sμ region. (b) DSBs were detected by LM-PCR in activated B cells of HIGM4 patients. Genomic DNA of sCD40L+rIL-4–activated B cells (2 × 103, 5 × 103, or 25 × 103 cells per lane) from controls (C1, C2, C3) or HIGM4 patients (n = 6, P1, P2, P4, P6–P8) was ligated with a double-stranded linker and amplified by a semi-nested PCR using the linker (Bw1) as a primer as well as two specific primers in the Sμ region (Sμext and Sμint). The PCR products were subjected to electrophoresis and transferred onto a membrane before being incubated with a radiolabeled Sμ-specific probe. Radioactivity was detected by use of a PhosphorImager. The negative control consisted of anti-CD3+rIL-2–activated T cells (25 × 103 cells per lane, C3).
Figure 5
Figure 5
Generation of SHMs in the VH region of IgM in HIGM4. (a) The frequency of SHMs in the VH region of IgM is normal in HIGM4 patients. SHMs in the VH3-23 region of the IgM were analyzed using cDNA from CD19+CD27+ B cells from controls (n = 7), HIGM2 patients (n = 9), and HIGM4 patients (n = 6, P2, P5–P9). Horizontal bars indicate the mean values. (b) The pattern of SHMs in the VH region of IgM is normal in HIGM4 patients. Mean percentages of nucleotide changes and targets of SHMs in the VH3-23 region of IgM in controls (n = 7) and HIGM4 patients (n = 6, P2, P5–P9) are shown.
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