The Journal of Experimental Medicine
Avanti Polar Lipids
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Published online 25 October 2004 doi:10.1084/jem.20041074
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 9, 1111-1121
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Immunoglobulin Class Switch Recombination Is Impaired in Atm-deficient Mice

Joanne M. Lumsden1, Thomas McCarty2, Lisa K. Petiniot1,3, Rhuna Shen1,3, Carrolee Barlow4, Thomas A. Wynn5, Herbert C. Morse, III2, Patricia J. Gearhart8, Anthony Wynshaw-Boris4, Edward E. Max6, and Richard J. Hodes1,7

1 Experimental Immunology Branch, National Cancer Institute
2 Laboratory of Immunopathology, National Institute of Allergy and Infectious Diseases (NIAID)
3 Howard Hughes Medical Institute - National Institutes of Health Research Scholars Program, National Center for Human Genome Research
4 Genetic Disease Research Branch, National Center for Human Genome Research
5 Laboratory of Parasitic Diseases, NIAID
6 Center for Drugs Evaluation and Research, Food and Drug Administration
7 National Institute on Aging, National Institutes of Health (NIH), Bethesda, MD 20892
8 Laboratory of Molecular Gerontology, National Institute on Aging, NIH, Baltimore, MD 21224

Address correspondence to Joanne Lumsden, Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bldg. 10, Room 4B10, 10 Center Dr., Bethesda, MD 20892. Phone: (301) 435-6462; Fax: (301) 496-0887; email: lumsdenj{at}mail.nih.gov

Immunoglobulin class switch recombination (Ig CSR) involves DNA double strand breaks (DSBs) at recombining switch regions and repair of these breaks by nonhomologous end-joining. Because the protein kinase ataxia telengiectasia (AT) mutated (ATM) plays a critical role in DSB repair and AT patients show abnormalities of Ig isotype expression, we assessed the role of ATM in CSR by examining ATM-deficient mice. In response to T cell–dependent antigen (Ag), Atm–/– mice secreted substantially less Ag-specific IgA, IgG1, IgG2b, and IgG3, and less total IgE than Atm+/+ controls. To determine whether Atm–/– B cells have an intrinsic defect in their ability to undergo CSR, we analyzed in vitro responses of purified B cells. Atm–/– cells secreted substantially less IgA, IgG1, IgG2a, IgG3, and IgE than wild-type (WT) controls in response to stimulation with lipopolysaccharide, CD40 ligand, or anti-IgD plus appropriate cytokines. Molecular analysis of in vitro responses indicated that WT and Atm–/– B cells produced equivalent amounts of germline IgG1 and IgE transcripts, whereas Atm–/– B cells produced markedly reduced productive IgG1 and IgE transcripts. The reduction in isotype switching by Atm–/– B cells occurs at the level of genomic DNA recombination as measured by digestion–circularization PCR. Analysis of sequences at CSR sites indicated that there is greater microhomology at the µ–{gamma}1 switch junctions in ATM B cells than in wild-type B cells, suggesting that ATM function affects the need or preference for sequence homology in the CSR process. These findings suggest a role of ATM in DNA DSB recognition and/or repair during CSR.

Key Words: ataxia telangiectasia • Ig class switching • B lymphocytes • DNA damage • DNA repair

J.M. Lumsden, T. McCarty, L.K. Petiniot, and R. Shen contributed equally to this work.

The present address of C. Barlow is Merck Research Laboratories, San Diego, CA 92121.

The present address of A. Wynshaw-Boris is UCSD School of Medicine, La Jolla, CA 92093.

Abbreviations used in this paper: Ag, antigen; AID, activation-induced cytidine deaminase; AT, ataxia telangiectasia; ATM, ataxia telangiectasia mutated; CD40L, CD40 ligand; CSR, class switch recombination; DC-PCR, digestion-circularization PCR; nAChR, nicotinic acetylcholine receptor; NHEJ, nonhomologous end-joining; PNA, peanut agglutinin; S, switch; TD, T cell–dependent.


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