Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting

被引:54
作者
Longo, Nancy S. [1 ]
Lugar, Patricia L. [1 ]
Yavuz, Sule [1 ]
Zhang, Wen [1 ]
Krijger, Peter H. L. [1 ]
Russ, Daniel E. [2 ]
Jima, Dereje D. [3 ]
Dave, Sandeep S. [3 ,4 ]
Grammer, Amrie C. [1 ]
Lipsky, Peter E. [1 ]
机构
[1] NIAMSD, Autoimmun Branch, Bethesda, MD 20892 USA
[2] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA
[3] Duke Univ, Duke Inst Genome Sci & Policy, Durham, NC USA
[4] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
关键词
INDUCED CYTIDINE DEAMINASE; MEMORY B-CELLS; CLASS-SWITCH RECOMBINATION; DNA-POLYMERASE-ETA; HEAVY-CHAIN REPERTOIRE; GERMINAL-CENTERS; CD40; LIGAND; IMMUNOGLOBULIN GENES; ANTIBODY DIVERSIFICATION; RGYW MOTIFS;
D O I
10.1182/blood-2008-10-183632
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Subjects with X-linked hyper-IgM syndrome (X-HIgM) have a markedly reduced frequency of CD27(+) memory B cells, and their Ig genes have a low level of somatic hypermutation (SHM). To analyze the nature of SHM in X-HIgM, we sequenced 209 nonproductive and 926 productive Ig heavy chain genes. In nonproductive rearrangements that were not subjected to selection, as well as productive rearrangements, most of the mutations were within targeted RGYW, WRCY, WA, or TW motifs (R = purine, Y = pyrimidine, and W = A or T). However, there was significantly decreased targeting of the hypermutable G in RGYW motifs. Moreover, the ratio of transitions to transversions was markedly increased compared with normal. Microarray analysis documented that specific genes involved in SHM, including activation-induced cytidine deaminase (AICDA) and uracil-DNA glycosylase (UNG2), were up-regulated in normal germinal center (GC) B cells, but not induced by CD40 ligation. Similar results were obtained from light chain rearrangements. These results indicate that in the absence of CD40-CD154 interactions, there is a marked reduction in SHM and, specifically, mutations of AICDA-targeted G residues in RGYW motifs along with a decrease in transversions normally related to UNG2 activity. (Blood. 2009; 113: 3706-3715)
引用
收藏
页码:3706 / 3715
页数:10
相关论文
共 80 条
[1]   Absence of IgD-CD27+ memory B cell population in X-linked hyper-IgM syndrome [J].
Agematsu, K ;
Nagumo, H ;
Shinozaki, K ;
Hokibara, S ;
Yasui, K ;
Terada, K ;
Kawamura, N ;
Toba, T ;
Nonoyama, S ;
Ochs, HD ;
Komiyama, A .
JOURNAL OF CLINICAL INVESTIGATION, 1998, 102 (04) :853-860
[2]   CD27: a memory B-cell marker [J].
Agematsu, K ;
Hokibara, S ;
Nagumo, H ;
Komiyama, A .
IMMUNOLOGY TODAY, 2000, 21 (05) :204-206
[3]   Repair of U/G and U/A in DNA by UNG2-associated repair complexes takes place predominantly by short-patch repair both in proliferating and growth-arrested cells [J].
Akbari, M ;
Otterlei, M ;
Peña-Diaz, J ;
Aas, PA ;
Kavli, B ;
Liabakk, NB ;
Hagen, L ;
Imai, K ;
Durandy, A ;
Slupphaug, G ;
Krokan, HE .
NUCLEIC ACIDS RESEARCH, 2004, 32 (18) :5486-5498
[4]   CD40 LIGAND GENE DEFECTS RESPONSIBLE FOR X-LINKED HYPER-IGM SYNDROME [J].
ALLEN, RC ;
ARMITAGE, RJ ;
CONLEY, ME ;
ROSENBLATT, H ;
JENKINS, NA ;
COPELAND, NG ;
BEDELL, MA ;
EDELHOFF, S ;
DISTECHE, CM ;
SIMONEAUX, DK ;
FANSLOW, WC ;
BELMONT, J ;
SPRIGGS, MK .
SCIENCE, 1993, 259 (5097) :990-993
[5]   Altered somatic hypermutation and reduced class-switch recombination in exonuclease 1-mutant mice [J].
Bardwell, PD ;
Woo, CJ ;
Wei, KC ;
Li, ZQ ;
Martin, A ;
Sack, SZ ;
Parris, T ;
Edelmann, W ;
Scharff, MD .
NATURE IMMUNOLOGY, 2004, 5 (02) :224-229
[6]   Gut IgA class switch recombination in the absence of CD40 does not occur in the lamina propria and is independent of germinal centers [J].
Bergqvist, Peter ;
Gardby, Eva ;
Stensson, Anneli ;
Bemark, Mats ;
Lycke, Nils Y. .
JOURNAL OF IMMUNOLOGY, 2006, 177 (11) :7772-7783
[7]   The influence of CD40-CD154 interactions on the expressed human VH repertoire:: analysis of VH genes expressed by individual B cells of a patient with X-linked hyper-IgM syndrome [J].
Brezinschek, HP ;
Dörner, T ;
Monson, NL ;
Brezinschek, RI ;
Lipsky, PE .
INTERNATIONAL IMMUNOLOGY, 2000, 12 (06) :767-775
[8]  
BREZINSCHEK HP, 1995, J IMMUNOL, V155, P190
[9]   Analysis of the human V-H gene repertoire - Differential effects of selection and somatic hypermutation on human peripheral CD5(+)/IgM(+) and CD5(-)/IgM(+) B cells [J].
Brezinschek, HP ;
Foster, SJ ;
Brezinschek, RI ;
Dorner, T ;
DomiatiSaad, R ;
Lipsky, PE .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 99 (10) :2488-2501
[10]   DNA repair in antibody somatic hypermutation [J].
Casali, Paolo ;
Pal, Zsuzsanna ;
Xu, Zhenming ;
Zan, Hong .
TRENDS IN IMMUNOLOGY, 2006, 27 (07) :313-321