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ARS Home » Midwest Area » Ames, Iowa » National Animal Disease Center » Infectious Bacterial Diseases Research » Research » Publications at this Location » Publication #203452
Title: Role for Msh5 in the Regulation of Ig Class Switch Recombination

Author
item SEKINE, HIDEHARU - MEDICAL UNIV. OF SC
item FERREIRA, RICARDO - UNIV. OF MN MED. SCHOOL
item PAN-HAMMARSTROM, QIANG - KAROLINSKA UNIV. HOSP.
item GRAHAM, ROBERT - BROAD INSTITUTE
item ZIEMBA, BETH - UNIV. OF MN MED. SCHOOL
item DE VRIES, SANDRA - NETHERLANDS CANCER INST.
item LIU, JIABIN - UNIV. OF MN MED. SCHOOL
item HIPPEN, KELI - UNIV. OF MN MED. SCHOOL
item KOEUTH, THEARITH - UNIV. OF MN MED. SCHOOL
item ORTMANN, WARD - UNIV. OF MN MED. SCHOOL
item IWAHORI, AKIKO - MEDICAL UNIV. OF SC
item Elliott, Margaret
item OFFER, STEVEN - UNIV. OF MN MED. SCHOOL
item SKON, CARA - UNIV. OF MN MED. SCHOOL
item DU, LIKUN - KAROLINSKA UNIV. HOSP.
item NOVITZKE, JILL - UNIV. OF MN MED. SCHOOL
item LEE, ANNETTE - FEINSTEIN INSTITUTE
item ZHAO, NIANXI - WASHINGTON STATE UNIV.
item TOMPKINS, JOSHUA - WASHINGTON STATE UNIV.
item ALTSHULER, DAVID - BROAD INSTITUTE
item GREGERSEN, PETER - FEINSTEIN INSTITUTE
item CUNNINGHAM-RUNDLES, CHARLOTTE - MOUNT SINAI SCHOOL OF M.
item HARRIS, REUBEN - UNIV. OF MN MED. SCHOOL
item HER, CHENGTAO - WASHINGTON STATE UNIV.
item NELSON, DAVID - NATIONAL CANCER INSTITUTE
item HAMMARSTROM, LENNART - KAROLINSKA UNIV. HOSPITAL
item GILKESON, GARY - MED. UNIV. OF S. CAROLINA
item BEHRENS, TIMOTHY - UNIV. OF MN MED. SCHOOL

Submitted to: Proceedings of the National Academy of Sciences (PNAS)
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 2/19/2007
Publication Date: 4/4/2007
Citation: Sekine, H., Ferreira, R., Pan-Hammarstrom, Q., Graham, R.R., Ziemba, B., De Vries, S.S., Liu, J., Hippen, K., Koeuth, T., Ortmann, W., Iwahori, A., Elliott, M.K., Offer, S., Skon, C., Du, L., Novitzke, J., Lee, A.T., Zhao, N., Tompkins, J.D., Altshuler, D., Gregersen, P.K., Cunningham-Rundles, C., Harris, R.S., Her, C., Nelson, D.L., Hammarstrom, L., Gilkeson, G.S., Behrens, T.W. 2007. Role for Msh5 in the Regulation of lg Class Switch Recombination. Proceedings of the National Academy of Sciences. 104(17):7193-7198.

Interpretive Summary: Antibody diversity is essential for an effective immune response. This processes is achieved by the breaking and re-joining of gene segments within antibody producing cells. A number of proteins are responsible to ensure correct assembly of the gene segment. In mammals, five of these proteins are designated Msh2, Msh3, Msh4, Msh5, and Msh6. In this study, we found that Msh5 is important for proper assembly of antibody genes. Msh5 comes in different forms. Mice inheriting a particular form of Msh5 with other immune genes fail to make all of the antibodies normal mice do. This is similar to a disease in humans where all of the normal antibodies are not produced, resulting in immunodeficiency and greater susceptibility to disease. Elucidation of the mechanisms involved in antibody diversity is important for understanding immunodeficiency and developing important treatments or therapies for persons and livestock with these diseases.

Technical Abstract: Immunoglobulin (Ig) class switch recombination (CSR) and somatic hypermutation serve to diversify antibody responses, and are orchestrated by the activity of activation-induced cytidine deaminase (AID) and a large number of proteins involved in DNA repair and genome surveillance. Here we show that lupus-prone MRL/lpr mice carrying a congenic H-2b/b major histocompatibility complex (MHC) interval exhibit several abnormalities relating to CSR, including a profound deficiency of IgG3 in most mice, and a relative deficiency of IgA in older animals. We discovered that the H-2b haplotype contains a hypomorphic allele for Msh5, a gene with a critical role in resolving Holliday junction crossovers during meiotic homologous recombination. Splenic B cells express Msh5, and both H-2b/b congenic MRL/lpr and FVB Msh5-gene knockout mice display increased donor/acceptor microhomology at Ig switch junctions, a phenotype found in mice lacking specific genes important for CSR. Increased microhomology at Ig switch junctions are also present in C57BL/6 mice deficient in Msh4, a heterodimeric partner of Msh5. These findings indicate that Msh5, a protein previously implicated only in homologous recombination, promotes efficiency of class switch to IgG3 and IgA, and possibly in suppressing microhomology-based CSR, likely in conjunction with Msh4.