Spontaneous Loss of Tolerance of Autoreactive B Cells in Act1-Deficient Rheumatoid Factor Transgenic Mice

被引:11
作者
Giltiay, Natalia V. [1 ]
Lu, Yi [1 ]
Cullen, Jaime L. [2 ]
Jorgensen, Trine N. [1 ]
Shlomchik, Mark J. [2 ]
Li, Xiaoxia [1 ]
机构
[1] Cleveland Clin, Lerner Res Inst, Dept Immunol, Cleveland, OH 44195 USA
[2] Yale Univ, Sch Med, Dept Lab Med, Immunol Sect, New Haven, CT 06520 USA
基金
美国国家卫生研究院;
关键词
LYN-DEFICIENT MICE; MRL-LPR/LPR MICE; SOMATIC HYPERMUTATION; AUTOIMMUNE-DISEASE; GERMINAL-CENTERS; SELF-TOLERANCE; T-CELLS; NEGATIVE REGULATOR; ADAPTER ACT1; MOUSE MODEL;
D O I
10.4049/jimmunol.1300152
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Self-reactive B cells in BALB/c AM14 transgenic (Tg) rheumatoid factor mice are not subject to central or peripheral tolerization. Instead, they remain at a stage of "clonal ignorance"; that is, they do not proliferate and differentiate into Ab-forming cells. However, the immunoregulatory mechanisms that prevent autoantibody production in these mice remain unclear. In this study, we show that crossing AM14 Tg mice to a mouse strain deficient in Act1, a molecule involved in the regulation of BAFF-R and CD40-signaling in B cells, results in spontaneous activation of AM14 Tg B cells and production of AM14-specific Abs. Three- to 5-mo-old AM14 Tg Act1(-/-) mice showed significant expansion of AM14 Tg B cells, including a 2- to 3-fold increase in the spleen and cervical lymph nodes compared with AM14 Tg Act1(+/+) mice. Furthermore, in the presence of endogenous self-Ag (IgH(a) congenic background), AM14 Tg Act1(-/-) B cells were spontaneously activated and differentiated into Ab-forming cells. In contrast with previous studies using AM14 Tg MLR. Fas(lpr) mice, we found that a significant number of AM14 Tg cells AM14 Tg Act1(-/-) mice displayed phenotypic characteristics of germinal center B cells. Anti-CD40L treatment significantly limited the expansion and activation of AM14 Tg Act1(-/-) B cells, suggesting that CD40L-mediated signals are required for the retention of these cells. Our results support the important role of Act1 in the regulation of self-reactive B cells and reveal how Act1 functions to prevent the production of autoantibodies.
引用
收藏
页码:2155 / 2163
页数:9
相关论文
共 60 条
[1]   Resolution of three nonproliferative immature splenic B cell subsets reveals multiple selection points during peripheral B cell maturation [J].
Allman, D ;
Lindsley, RC ;
DeMuth, W ;
Rudd, K ;
Shinton, SA ;
Hardy, RR .
JOURNAL OF IMMUNOLOGY, 2001, 167 (12) :6834-6840
[2]   SELF TOLERANCE IN THE B-CELL REPERTOIRE [J].
BASTEN, A ;
BRINK, R ;
PEAKE, P ;
ADAMS, E ;
CROSBIE, J ;
HARTLEY, S ;
GOODNOW, CC .
IMMUNOLOGICAL REVIEWS, 1991, 122 :5-19
[3]  
Biancone L, 1999, INT J MOL MED, V3, P343
[4]   Regulation of B cell self-tolerance by BAFF [J].
Brink, Robert .
SEMINARS IN IMMUNOLOGY, 2006, 18 (05) :276-283
[5]   TRANSITIONAL B-CELLS ARE THE TARGET OF NEGATIVE SELECTION IN THE B-CELL COMPARTMENT [J].
CARSETTI, R ;
KOHLER, G ;
LAMERS, MC .
JOURNAL OF EXPERIMENTAL MEDICINE, 1995, 181 (06) :2129-2140
[6]   Selection of anti-double-stranded DNA B cells in autoimmune MRL-lpr/lpr mice [J].
Chen, Ching ;
Li, Hui ;
Tian, Qi ;
Beardall, Michael ;
Xu, Yang ;
Casanova, Nina ;
Weigert, Martin .
JOURNAL OF IMMUNOLOGY, 2006, 176 (09) :5183-5190
[7]   Positive and negative roles of the tyrosine kinase Lyn in B cell function [J].
DeFranco, AL ;
Chan, VWF ;
Lowell, CA .
SEMINARS IN IMMUNOLOGY, 1998, 10 (04) :299-307
[8]   EXPRESSION OF ANTI-DNA IMMUNOGLOBULIN TRANSGENES IN NON-AUTOIMMUNE MICE [J].
ERIKSON, J ;
RADIC, MZ ;
CAMPER, SA ;
HARDY, RR ;
CARMACK, C ;
WEIGERT, M .
NATURE, 1991, 349 (6307) :331-334
[9]   The Adaptor Molecule Act1 Regulates BAFF Responsiveness and Self-Reactive B Cell Selection during Transitional B Cell Maturation [J].
Giltiay, Natalia V. ;
Lu, Yi ;
Allman, David ;
Jorgensen, Trine N. ;
Li, Xiaoxia .
JOURNAL OF IMMUNOLOGY, 2010, 185 (01) :99-109
[10]   ALTERED IMMUNOGLOBULIN EXPRESSION AND FUNCTIONAL SILENCING OF SELF-REACTIVE LYMPHOCYTES-B IN TRANSGENIC MICE [J].
GOODNOW, CC ;
CROSBIE, J ;
ADELSTEIN, S ;
LAVOIE, TB ;
SMITHGILL, SJ ;
BRINK, RA ;
PRITCHARDBRISCOE, H ;
WOTHERSPOON, JS ;
LOBLAY, RH ;
RAPHAEL, K ;
TRENT, RJ ;
BASTEN, A .
NATURE, 1988, 334 (6184) :676-682