Published online May 7, 2007
doi:10.1084/jem.20070087
The Journal of Experimental Medicine, Vol. 204, No. 5, 1207-1216
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Péron et al.
A primary immunodeficiency characterized by defective immunoglobulin class switch recombination and impaired DNA repair
Sophie Péron1,2,
Qiang Pan-Hammarström3,
Kohsuke Imai4,
Likun Du3,
Nadine Taubenheim1,2,
Ozden Sanal5,
Laszlo Marodi6,
Anne Bergelin-Besançon7,
Malika Benkerrou8,
Jean-Pierre de Villartay1,2,8,
Alain Fischer1,2,8,
Patrick Revy1,2, and
Anne Durandy1,2,8
1 Institut National de la Santé et de la Recherche Médicale, U768, Paris, F-75015, France
2 Université Paris-Descartes, Faculté de Médecine René Descartes, Site Necker, Institut Fédératif de Recherche, Paris, F-75015, France
3 Division of Clinical Immunology, F79, Department of Laboratory Medicine, Karolinska University Hospital, Huddinge, SE-141 86 Stockholm, Sweden
4 Department of Pediatrics, National Defense Medical College, Tokorozawa, 359-8516 Saitama, Japan
5 Immunology Division, Hacettepe University Children's Hospital, 06100 Ankara, Turkey
6 Department of Infectology and Paediatric Immunology, Medical and Health Science Centre, University of Debrecen, H-4012 Debrecen, Hungary
7 Centre Hospitalier du Mans, Le Mans, 72000, France
8 AP-HP, Hôpital Necker Enfants Malades, Service d'Immunologie et d'Hématologie Pédiatrique, Paris, F-75015, France
CORRESPONDENCE Anne Durandy: durandy{at}necker.fr
Immunoglobulin class switch recombination (CSR) deficiencies are rare primary immunodeficiencies, characterized by a lack of switched isotype (IgG, IgA, or IgE) production, variably associated with abnormal somatic hypermutation (SHM). Deficiencies in CD40 ligand, CD40, activation-induced cytidine deaminase, and uracil-N-glycosylase may account for this syndrome. We previously described another Ig CSR deficiency condition, characterized by a defect in CSR downstream of the generation of double-stranded DNA breaks in switch (S) µ regions. Further analysis performed with the cells of five affected patients showed that the Ig CSR deficiency was associated with an abnormal formation of the S junctions characterized by microhomology and with increased cell radiosensitivity. In addition, SHM was skewed toward transitions at G/C residues. Overall, these findings suggest that a unique Ig CSR deficiency phenotype could be related to an as-yet-uncharacterized defect in a DNA repair pathway involved in both CSR and SHM events.
Abbreviations used: AID, activation-induced cytidine deaminase; A-T, ataxia telangiectasia; ATM, A-T mutated; BCR, B cell receptor; CSR, class switch recombination; DSB, double-stranded break; EBV, Epstein-Barr virus; MDC1, mediator of DNA damage checkpoint 1; MMR, mismatch repair; NHEJ, nonhomologous end joining; SHM, somatic hypermutation; UNG, uracil-N-glycosylase; WCE, whole-cell extract; 53BP1, tumor.protein.p53-binding.protein.1.
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