Reduced Isotype Switching in Splenic B Cells from Mice Deficient in Mismatch Repair Enzymes

doi:10.1084/jem.190.3.323

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J. Exp. Med., Volume 190, Number 3, August 2, 1999 323-330
Copyright © 1999 by The Rockefeller University Press.

Reduced Isotype Switching in Splenic B Cells from Mice Deficient in Mismatch Repair Enzymes

Carol E. Schrader^a, Winfried Edelmann^b, Raju Kucherlapati^c, and Janet Stavnezer^a
^a From the Department of Molecular Genetics and Microbiology, Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts 01655-0122
^b Department of Cell Biology, Albert Einstein Medical College, Bronx, New York 10461
^c Department of Molecular Genetics, Albert Einstein Medical College, Bronx, New York 10461

Correspondence to: Carol E. Schrader, Department of Molecular Genetics and Microbiology, University of Massachusetts Medical School, 55 Lake Ave. No., Worcester, MA 01655-0122., carol.schrader{at}banyan.ummed.edu (E-mail), 508-856-3914 (phone), 508-856-5920 (fax)

Mice deficient in various mismatch repair (MMR) enzymes wereexamined to determine whether this repair pathway is involvedin antibody class switch recombination. Splenic B cells frommice deficient in Msh2, Mlh1, Pms2, or Mlh1 and Pms2 were stimulatedin culture with lipopolysaccharide (LPS) to induce immunoglobulin(Ig)G2b and IgG3, LPS and interleukin (IL)-4 to induce IgG1,or LPS, anti– ${delta}$ -dextran, IL-4, IL-5, and transforming growthfactor (TGF)-ß1 to induce IgA. After 4 d in culture, cellswere surface stained for IgM and non-IgM isotypes and analyzedby FACS^®. B cells from MMR-deficient mice show a 35–75%reduction in isotype switching, depending on the isotype andon the particular MMR enzyme missing. IgG2b is the most affected,reduced by 75% in Mlh1-deficient animals. The switching defectis not due to a lack of maturation of the B cells, as purifiedIgM⁺IgD⁺ B cells show the same reduction. MMR deficiency hadno effect on cell proliferation, viability, or apoptosis, asdetected by [³H]thymidine incorporation and by propidium iodidestaining. The reduction in isotype switching was demonstratedto be at the level of DNA recombination by digestion-circularizationpolymerase chain reaction (DC-PCR). A model of the potentialrole for MMR enzymes in class switch recombination is presented.

Key Words: class switch recombination, msh2, mlh1, pms2

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