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