Hyper-IgM syndrome type 4 with a B lymphocyte–intrinsic selective deficiency in Ig class-switch recombination
Kohsuke Imai, … , Alain Fischer, Anne Durandy
Kohsuke Imai, … , Alain Fischer, Anne Durandy
Published July 1, 2003
Citation Information: J Clin Invest. 2003;112(1):136-142. https://doi.org/10.1172/JCI18161.
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Article Immunology

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

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 μ 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.

Authors

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

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Detection of double-strand DNA breaks (DSBs) during CSR in HIGM4. (a) Po...
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).