Bc110和PLCγ1在B细胞发育和功能中的作用
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摘要
B细胞是淋巴细胞中通过分泌抗体而参与体液免疫的一类重要的细胞亚群。B细胞的发育是一个多步骤,循序渐进并且受到严格调控的过程。胚胎阶段的B细胞的发育最初在胚胎肝脏中完成,随后转移至成年个体的骨髓中。在骨髓中,B细胞经历pro-B细胞,pre-B细胞,immature B细胞阶段后发育成熟进入外周淋巴器官脾脏中,继续经历transitional B细胞阶段发育至成熟B细胞。成熟B细胞在遭遇抗原后发生抗原和B细胞受体结合并激活B细胞,活化的B细胞在B细胞受体信号引发的一系列生化和分子生物学水平的调控后成为具有强大抗体分泌能力的效应细胞浆细胞,另一部分活化的B细胞则转化为记忆B细胞,为提供快速的二次免疫应答提供帮助。
为保证B细胞在能快速识别外源抗原从而有效地启动免疫应答反应的同时不会对机体自身的组成部分展开攻击而造成损伤,免疫系统采取了克隆删除、受体重新编辑和B细胞无反应性等一系列针对自身反应B细胞的阴性选择机制保证自身免疫耐受得以实现。在这个过程中,B细胞受体与自身抗原结合引发的BCR信号通路在决定B细胞进入阴性选择的方式中起到了重要的调控作用。
本论文的第一部分即研究Bcl10在自身反应性B细胞的阴性选择机制方面所起到的决定性作用。通过考察Bc110缺陷小鼠脾脏中无应答B细胞的数量和体内细胞凋亡水平,我们发现在Bcl10缺失条件下,无应答B细胞数量显著减少,并且在脾脏所有B细胞类群中仅无应答B细胞在缺失Bcl10表现细胞凋亡水平上升,显示在Bcl10缺失条件下自身反应性B细胞无法保持无应答B细胞类群,而是进入细胞凋亡程序而被克隆删除。在IgHELtgsHELtg这样一种研究自身反应性B细胞的诱导无应答过程的小鼠模型中我们也观察到了同样的表型。在体外培养条件下利用自身抗原HEL或anti-IgM刺激B细胞,在缺少Bcl10条件下B细胞呈高水平细胞凋亡。分子水平的实验证明,Bcl10缺失后BCR受体交联不能有效诱导B细胞表达促细胞存活蛋白Bcl-XL和A1,导致自身反应性B细胞因缺乏生存信号而被克隆删除。因此,Bcl10通过调节自身反应性B细胞的细胞存活和凋亡决定了自身反应性B细胞的阴性选择机制。
本论文第二部分为研究一个BCR信号通路中非常重要的信号蛋白PLCγ2的异构体：PLCγ1在B细胞的发育和功能中所起的作用。尽管现有研究认为PLCγ1主要参与TCR和其他生长因子受体的信号通路传导,PLCyl在B细胞发育早期的高表达量显示它对于B细胞发育早期可能起到了重要调控作用。利用造血系统特异性Cre表达系统MxCre和PLCγ1flox杂交小鼠的骨髓细胞移植入μMT小鼠后的嵌合小鼠作为研究对象,我们考察了B细胞特异性PLCγ1敲除对于各个B细胞类群的影响。实验结果显示,B细胞特异性的PLCγ1敲除导致嵌合小鼠脾脏和骨髓中mature B细胞在淋巴细胞中的比例和数量显著下降,然而在脾脏中生发中心的B细胞的比例增加。后者导致B细胞特异性PLCγ1缺失的嵌合小鼠在参与免疫应答反应中反应增强,小鼠血清中抗体水平增加。另外,B细胞特异性PLCγ1缺失的嵌合小鼠表现出一定水平的自身抗体的增加和自身免疫性疾病的倾向。因此,B细胞特异性PLCγ1缺失影响了mature B细胞的产生和natureB细胞所参与的免疫应答反应。
B cells are an important population of lymphocytes that can secrete antibody and thus play a critical role in humoral immune response. The development of B cells is a multi-step, gradually-progressed and strictly-regulated process. The embryonic B cell development occurs in the fetal liver, while in the adult the majority of B cells come from bone marrow. In the bone marrow, B cells undergo three developmental stages: pro-B, pre-B, immature B cells and then migrate into peripheral lymphoid organs, such as spleen. In the spleen, immature B cells further transit into transitional B cells and finally become mature naive B cells. Mature B cells are capable of binding to antigen and then become activated. Activated B cells undergo a serial of molecular up-regulation or down-regulation and fully differentiate into the powerful antibody-secreting cells:plasma cells. While another proportion of activated B cells will differentiate into memory B cells, which are responsible for the rapid immune response after secondary challenge.
How do B cells avoid attacking the "self" while at the same time do not compromise the ability to take rapid response to foreign pathogens? Clonal deletion, receptor edition and anergy serve as the three major mechanisms for negative selection to ensure the self-tolerance is effectively launched.It is generally thought that the signals from self-antigen binding to BCR provide the decision-making choice.
In the first party of my thesis, we studied the role of Bcl10in regulating the negative selection mechanisms. Bcl10deficient mice have less anergic B cell in the spleen. Within all the splenic B cell populations, anergic B cells specifically show a higher level of cell apoptosis with Bcl10, indicating that the deficiency of Bcl10selectively affect the survival of anergic B cell population. Moreover, using IgHELtgsHELtg mice model to study self-reactive B cells, we observed the total B cell loss and higher cell apoptosis in Bcl10deficient IgHELtgsHELtg mice, further demonstrating that Bcl10is involved in regulating the survival of self-reactive B cells. Bcl10-null B cells also displayed higher apoptosis level under in vitro stimulation with anti-IgM or HEL. Moreover, while wild type B cells can successfully induce the up-regulation of pro-survival molecules:BcI-XL and Al, but Bcl10deficient B cell failed to do so. Therefore, all our data demonstrated that Bcl10plays a decisive role in the negative selection mechanisms of self-reactive B cells.
The second part of my thesis is focusing on the role of PLCyl in B cell development and function. As one of the two isoforms of PLCy, PLCyl is generally thought be involved in TCR and growth factor receptor signaling. However, high expression level could be detected in early developmental stages of B cells, implying its possible role in regulating B cell development. Using the mixed bone marrow cells from PLCglf/-MxCre mice and μMT mice as bone marrow donor, we generated chimera mice that possess B cell specific deletion of PLCγ1. After examine the development of different stages of B cells, we found that both the number and percentage of mature B cells in bone marrow and spleen are reduced after PLCγ1is deleted. However, within the mature B cell population, the ratio of GC B cells is increased in PLCyl deficient mice. Challenged with ARS-CGG antigen, PLCyl B-cell-specific deficient mice displayed an overactive response to ARS, possibly due to the increase of GC B cells in the spleen. Moreover, Hep2cells staining for detecting anti-ANA antibody and IgH chain CDR3sequencing results demonstrate that PLCγ1B-cell-specific mice displayed a higher tendency of autoantibody production and autoimmune symptoms.
为保证B细胞在能快速识别外源抗原从而有效地启动免疫应答反应的同时不会对机体自身的组成部分展开攻击而造成损伤,免疫系统采取了克隆删除、受体重新编辑和B细胞无反应性等一系列针对自身反应B细胞的阴性选择机制保证自身免疫耐受得以实现。在这个过程中,B细胞受体与自身抗原结合引发的BCR信号通路在决定B细胞进入阴性选择的方式中起到了重要的调控作用。
本论文的第一部分即研究Bcl10在自身反应性B细胞的阴性选择机制方面所起到的决定性作用。通过考察Bc110缺陷小鼠脾脏中无应答B细胞的数量和体内细胞凋亡水平,我们发现在Bcl10缺失条件下,无应答B细胞数量显著减少,并且在脾脏所有B细胞类群中仅无应答B细胞在缺失Bcl10表现细胞凋亡水平上升,显示在Bcl10缺失条件下自身反应性B细胞无法保持无应答B细胞类群,而是进入细胞凋亡程序而被克隆删除。在IgHELtgsHELtg这样一种研究自身反应性B细胞的诱导无应答过程的小鼠模型中我们也观察到了同样的表型。在体外培养条件下利用自身抗原HEL或anti-IgM刺激B细胞,在缺少Bcl10条件下B细胞呈高水平细胞凋亡。分子水平的实验证明,Bcl10缺失后BCR受体交联不能有效诱导B细胞表达促细胞存活蛋白Bcl-XL和A1,导致自身反应性B细胞因缺乏生存信号而被克隆删除。因此,Bcl10通过调节自身反应性B细胞的细胞存活和凋亡决定了自身反应性B细胞的阴性选择机制。
本论文第二部分为研究一个BCR信号通路中非常重要的信号蛋白PLCγ2的异构体：PLCγ1在B细胞的发育和功能中所起的作用。尽管现有研究认为PLCγ1主要参与TCR和其他生长因子受体的信号通路传导,PLCyl在B细胞发育早期的高表达量显示它对于B细胞发育早期可能起到了重要调控作用。利用造血系统特异性Cre表达系统MxCre和PLCγ1flox杂交小鼠的骨髓细胞移植入μMT小鼠后的嵌合小鼠作为研究对象,我们考察了B细胞特异性PLCγ1敲除对于各个B细胞类群的影响。实验结果显示,B细胞特异性的PLCγ1敲除导致嵌合小鼠脾脏和骨髓中mature B细胞在淋巴细胞中的比例和数量显著下降,然而在脾脏中生发中心的B细胞的比例增加。后者导致B细胞特异性PLCγ1缺失的嵌合小鼠在参与免疫应答反应中反应增强,小鼠血清中抗体水平增加。另外,B细胞特异性PLCγ1缺失的嵌合小鼠表现出一定水平的自身抗体的增加和自身免疫性疾病的倾向。因此,B细胞特异性PLCγ1缺失影响了mature B细胞的产生和natureB细胞所参与的免疫应答反应。
B cells are an important population of lymphocytes that can secrete antibody and thus play a critical role in humoral immune response. The development of B cells is a multi-step, gradually-progressed and strictly-regulated process. The embryonic B cell development occurs in the fetal liver, while in the adult the majority of B cells come from bone marrow. In the bone marrow, B cells undergo three developmental stages: pro-B, pre-B, immature B cells and then migrate into peripheral lymphoid organs, such as spleen. In the spleen, immature B cells further transit into transitional B cells and finally become mature naive B cells. Mature B cells are capable of binding to antigen and then become activated. Activated B cells undergo a serial of molecular up-regulation or down-regulation and fully differentiate into the powerful antibody-secreting cells:plasma cells. While another proportion of activated B cells will differentiate into memory B cells, which are responsible for the rapid immune response after secondary challenge.
How do B cells avoid attacking the "self" while at the same time do not compromise the ability to take rapid response to foreign pathogens? Clonal deletion, receptor edition and anergy serve as the three major mechanisms for negative selection to ensure the self-tolerance is effectively launched.It is generally thought that the signals from self-antigen binding to BCR provide the decision-making choice.
In the first party of my thesis, we studied the role of Bcl10in regulating the negative selection mechanisms. Bcl10deficient mice have less anergic B cell in the spleen. Within all the splenic B cell populations, anergic B cells specifically show a higher level of cell apoptosis with Bcl10, indicating that the deficiency of Bcl10selectively affect the survival of anergic B cell population. Moreover, using IgHELtgsHELtg mice model to study self-reactive B cells, we observed the total B cell loss and higher cell apoptosis in Bcl10deficient IgHELtgsHELtg mice, further demonstrating that Bcl10is involved in regulating the survival of self-reactive B cells. Bcl10-null B cells also displayed higher apoptosis level under in vitro stimulation with anti-IgM or HEL. Moreover, while wild type B cells can successfully induce the up-regulation of pro-survival molecules:BcI-XL and Al, but Bcl10deficient B cell failed to do so. Therefore, all our data demonstrated that Bcl10plays a decisive role in the negative selection mechanisms of self-reactive B cells.
The second part of my thesis is focusing on the role of PLCyl in B cell development and function. As one of the two isoforms of PLCy, PLCyl is generally thought be involved in TCR and growth factor receptor signaling. However, high expression level could be detected in early developmental stages of B cells, implying its possible role in regulating B cell development. Using the mixed bone marrow cells from PLCglf/-MxCre mice and μMT mice as bone marrow donor, we generated chimera mice that possess B cell specific deletion of PLCγ1. After examine the development of different stages of B cells, we found that both the number and percentage of mature B cells in bone marrow and spleen are reduced after PLCγ1is deleted. However, within the mature B cell population, the ratio of GC B cells is increased in PLCyl deficient mice. Challenged with ARS-CGG antigen, PLCyl B-cell-specific deficient mice displayed an overactive response to ARS, possibly due to the increase of GC B cells in the spleen. Moreover, Hep2cells staining for detecting anti-ANA antibody and IgH chain CDR3sequencing results demonstrate that PLCγ1B-cell-specific mice displayed a higher tendency of autoantibody production and autoimmune symptoms.
引文
1. Charles A. Janeway. Jr., P. T., Mark Walport, Mark J. Shlomchik.2005. Immunobiology:the immune system in health disease.6th ed. Garl Science Publishing, New York London.
2. Galli, S. J., J. Kalesnikoff, M. A. Grimbaldeston, A. M. Piliponsky, C. M. Williams, M. Tsai.2005. Mast cells as "tunable" effector immunoregulatory cells:recent advances. Ann. Rev. Immunol.23:749-786.
3. Fuxa M., Skok J. A.2007. Transcriptional regulation in early B cell development. Curr. Opi. Immunol.19:129-136.
4. Riblet R.2004. Immunoglobulin heavy chain genes of mouse. In Molecular Biology of B Cells, ed. T Honjo, FW Alt, MS Neuberger, pp.19-26. London: Elsevier Acad.
5. http://www.ncbi.nlm.nih.gov/igblast
6. Boekel E., Melchers F., Rolink A.G.1997. Changes in V(H) gene repertoire of cell receptor. Immunity 7:357-368.
7. Kurosaki T., Shinohara H., Baba Y.2010. B cell signaling and fate decision. Annu. Rev. Immunol.28:21-55
8. Hardy RR., Hayakawa K.2001.B cell development pathways. Annu. Rev. Immunol.19:595-621.
9. Allman D.M.1993. Peripheral B cell maturation.Ⅱ Heat-stable antigen(hi) splenic B cell are immature developmental intermediate in the production of long-lived marrow-derived B cells. J. Immunol.151:4431-4444.
10. Rolink A. G.1998. Characterization of immature B cells by a novel monoclonal antibody, by turnover and by mitogen reactivity. Eur. J. Immunol. 28:3738-3748.
11. Allman D. M.1992. Peripheral B cell maturation. Ⅰ. Immature peripheral B cells in adults are heat-stable antigenhi and exhibit unique signaling characteristics. J. Immunol.149:2533-2540.
12.Norvell A., Monroe J. G.1996. Acquisition of surface IgD fails to protect from tolerance-induction. Both surface IgM-and surface IgD-mediated signals induce apoptosis of immature murine B lymphocytes. J. Immunol.156:1328-1332.
13. Chung J.B.2002. CD23 defines two distinct subsets of immature B cells which differ in their responses to T cell help signals. Int. Immunol.14:157-166.
14. Siechmann D.G.1978. Activation of mouse lymphocytes by anti-immunoglobulin. Ⅰ. Parameters of the proliferative response. J. Exp. Med. 147:814-829.
15.Goodnow C. C.1988. Altered immunoglobulin expression and function silencing of self-reactive B lymphocytes in transgenic mice. Nature.334:676-682.
16. Norvell A.1995. Engagement of the antigen-receptor on immature murine B lymphocytes results in death by apoptosis. J. Immunol.154:4404-4413.
17. Loder F.1999. B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals. J. Exp. Med.190:75-89.
18. Allman D.2001 Resolution of three nonproliferative immature splenic B cell subsets reveals multiple selection points during peripheral B cell maturation. J. Immunol.167:6834-6840.
19. Su T.T., Rawlings, D. J.2002. Transitional B lymphocyte subsets operate as distinct checkpoints in murine splenic B cell development. J. Immunol. 168:2101-2110.
20. Merrell K., Benschop R., Gauld S., Aviszus K., Ricardo D., Wysocki L. Cambier J.2006. Identification of anergic B cells within a wild-type repertoire. Immunity 25:953-962.
21. Chung J., Silverman M., Monroe J.2003 Transitional B cells:Step by step towards immune competence. TRENDS in Immunlogy.24:342-348.
22. Mebius R.E., Kraal G.,2005. Structure and function of the spleen. Nat. Rev. Immunol.5:606-616.
23. Martin F., Kearney JF.2002. Marginal-zone B cells. Nat Rev Immunol 2:323-335.
24. Pillai S., Cariappa A., Moran ST.2005. Marginal zone B cells. Annu Rev Immunol 23:161-196.
25. Lane PJ, Gray D, Oldfield S, MacLennan IC.1986. Differences in the recruitment of virgin B cells into antibody responses to thymusdependent and thymus-independent type-2 antigens. Eur J Immunol 16:1569-1575.
26. Paus D, Phan TG, Chan TD, Gardam S, Basten A, Brink R.2006. Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. J Exp Med 203:1081-1091.
27. Reif K, et al.2002. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 416:94-99.
28. Garside P, Ingulli E, Merica RR, Johnson JG, Noelle RJ, Jenkins MK.1998. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281:96-99.
29. Mohr E, et al.2009.Dendritic cells and monocyte/macrophages that create the IL-6/APRIL-rich lymph node microenvironments where plasmablasts mature. J Immunol 182:2113-2123.
30. Smith KG, Hewitson TD, Nossal GJ, Tarlinton DM.1996. The phenotype and fate of the antibody-forming cells of the splenic foci. Eur J Immunol 26:444-448.
31. Manz RA, Lohning M, Cassese G, Thiel A, Radbruch A.1998. Survival of long-lived plasma cells is independent of antigen. Int Immunol 10:1703-1711.
32. Lalor PA, Nossal GJ, Serson RD, McHeyzer-Williams MG.1992. Functional and molecular characterization of single, (4-hydroxy-3-nitrophenyl) acetyl (NP)-specific, IgGl+ B cells from antibody-secreting memory B cell pathways in the C57BL/6 immune response to NP. Eur J Immunol.22:3001-3011.
33. Shaffer AL, et al.2002. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17:51-62.
34. Kallies A, et al.2004. Plasma cell ontogeny defined by quantitative changes in Blimp-1 expression. J Exp Med 200:967-977.
35.Oracki S. Walker J. Hibbs M. Corcoran L. Tarlinton D.2010. Plasma cell development and survival. Immunol. Rev.237:140-159.
36. Jacobson D.L. Gange SJ. Rose NR.1997. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin. Immunol. Immunopathol.84:223-243.
37. Goodnow CC. Sprent J. Groth B. Vinuesa C.2005 Celluar and genetic mechanisms of self tolerance and autoimmunity. Nature 435:590-597.
38. Nemazee D. Hogquist K.2003 Antigen receptor selection by editing or downregulation of V(D)J recombination. Curr. Opin. Immunol.15:182-189.
39. Hartley SB.1993. Elimination of self-reactive B lymphocytes proceeds in two stages:arrested development and cell death. Cell 72:325-335.
40. Fields M. Erikson J.2003. The regulation of lupus-associated autoantibodies: immunoglobulin transgenic models. Curr. Opin. Immunol.15:709-717
41. Machay F. Schneider P. Rennert P.2003. BAFF and APRIL:a tutorial on B cell survival. Annu. Rev. Immunol.21:231-264.
42. Strasser A. Bouillet P.2003. The control of apoptosis in lymphocyte selection. Immunol. Rev.193:82-92.
43. Wardemann H.2003. Predominant autoantibody production by early human B cell precursors. Science 301:1374-1377.
44. Akkaraju S. Canann K. Goodnow CC.1997. Self-reactive B cells are not eliminated or inactivated by autoantigen expressed on thyroid epithelial cells. J. Exp. Med.186:2005-2012.
45. Bell SE. Goodnow CC.1994. A selective defect in IgM antigen receptor synthesis and transport causes loss of cell surface IgM expression on tolerant B lymphocytes. EMBOj.13:816-826.
46. Lesley R.2004. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 20:441-453.
47. Ravetch JV. Laniea LL.2000. Immune inhibitory receptors. Science 290:84-89.
48. Hippen KL. Tze LE. Behrens TW.2000 CD5 maintains tolerance in angeric B cells. J. Exp. Med.191:883-890.
49. Cyster JG. Hartley SB. Goodnow CC.1994. Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire. Nature 371:389-395.
50. Fox. CJ.2003. The serine/threonine kinase Pim-2 is a transcriptional regulated apoptotic inhibitor. Genes. Dev.17:1841-1854.
51.Foy TM. Aruffo A. Bajorath J. Buhlmann Je. Noelle RJ.1996. Immune regulation by CD40 and its ligand gp39. Annu. Rev. Immunol.14:591-617.
52. Kovanen PE. Leonard WJ.2004. Cytokines and immunodeficiency diseases: critical roles of the gamma(c)-dependent cytokines interleukins 2,4,7,9,15 21 their signaling pathways. Immunol. Rev.202:67-83.
53. Ang CW. Jacobs BC. Laman JD.2004. The Guillain-Barre syndrome:a true case of molecular mimicry. Trends. Immunol.25:61-66.
54. Mackay F. Figgett W. Saulep D. Lepage M. Hibbs M.2010. B-cell stage and context-dependent requirement for survival signals from BAFF and the B-cell receptor.237:205-225.
55. Gold MR. Law D. DeFranco AL.1990. Stimulation of protein tyrosine phosphorylation by the B-lymphocyte antigen receptor. Nature 345:810-813.
56. Campbell MA. Sefton BM.1990. Protein tyrosine phosphorylation is induced in murine B lymphocytes in response to stimulation with anti-immunoglobulin. EMBO J.9:2125-2131.
57. Brunswick M. Samelson LE. Mond JJ.1991. Surface immunoglobulin crosslinking activates a tyrosine kinase pathway in B cells that is independent of protein kinase C. Proc. Natl. Acad. Sci. USA 88:1311-1314.
58. Xu Y. Harder KW. Huntington ND.2005. Lyn tyrosine kinase;accentuating the positive and the negative. Immunity 22:9-18.
59. Hutchcroft JE. Harrison MI. Geahlen RI.1992. Association of the 72-kDa protein-tyrosine kinase PTK72 with the B cell antigen receptor. J. Biol. Chem. 267:8613-8619.
60. Rawlings DJ.1996. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science 271:822-825.
61. Ishiai M. Sugawara H. Kurosaki M. Kurosaki T.1999. Cutting edge: association of phospholipase C-gamma 2 Src homology 2 domains with BLNK is crutial for B cell antigen receptor signaling. J. Immunol.163:1746-1749.
62. Takata M. Kurosaki T.1996. A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2. J. Exp. Med.184:31-40.
63. Fu C. Turck CW. Kurosaki T. Chan AC.1998. BLNK:a central linker protein in B cell activation. Immunity 9:93-103.
64. King LB. Freedman BD.2009. B-lymphocyte calcium influx. Immunol. Rev. 231:265-277.
65. Ogawa Y. Takai Y. Kawahara Y. Kimura S.1981. A new possible regulatory system for protein phosphorylation in human peripheral lymphocytes. I. Characterization of a calcium-activated, phospholipid-dependent protein kinase. J. Immunol.127:1369-1374.
66. Ku Y. Kishimoto A. Takai Y. Ogawa Y. Kimura S. Nishizuka Y.1981. A new possible regulatory system for protein phosphorylation in human peripheral lymphocytes. Ⅱ. Possible relation to phosphatidylinositol turnover induced by mitogens. J. Immunol.127:1375-1379
67. Wu M. et al.1996. Inhibition of NF-kappaB/Rel induces apoptosis of murine B cells. EMBO J.15:4682-4690.
68. Grossman M. O'Reilly LA. Gugasyan R. Strasser A. Adams JM. Gerondakis S. 2000. The anti-apoptotic activities of Rel and RelA required and during B-cell maturation involve the regulation of Bcl-2 expression. EMBO J.19:6351-6360.
69. Grumont RJ. Rourke IJ. Gerondakis S.1999. Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes. Dev.13:400-411.
70. Glassford J. et al.2001. Vav is required for cyclin D2 induction and proliferation of mouse B lymphocytes activated via the antigen receptor. J. Biol. Chem.276:41040-41048.
71.Ishiura N. et al.2010. Differential phosphorylation of CD19 in pre-B and mature B cells. EMBO J.40:1192-1204.
72. Carter RH. Fearon DT.1992. CD19:lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256:105-107.
73. Okada T. Maeda A. Iwamatsu A. Gotoh K. Kurosaki T.2000. BCAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation. Immunity 12:817-827.
74. Aiba Y. Kameyama M. Yamazaki T. Tedder TF. Kurosaki T.2008. Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase. Blood 111:1497-1503.
75. Falasca M. Logan SK. Lehto VP. Baccante G. Lemmon MA. Schlessinger J. 1998. Activation of phospholipase C gamma by PI 3-kinase-induced PH domain-mediated membrane targeting. EMBO J.17:414-422.
76. Buhl AM. Cambier JC.1999. Phosphorylation of CD19 Y484 and Y515, linked activation of phosphadylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase. J. Immunol. 162:4438-4446.
77. Gold MR. et al.1999. The B cell antigen receptor activates the Akt (protein kinase B)/glycogen synthase kinase-3 signaling pathway via phosphatidylinositol 3-kinase. J. Immunol.163:894-905.
78. Dijkers PF. Medema RH. Lammers JW. Koenderman L. Coffer PJ.2000. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr. Biol.10:1201-1204.
79. Dijkers PF. et al.2000. Forkhead transcription factor FKHR-L1 modulated cytokine-dependent transcriptional regulation of p27(KIP1). Mol. Cell Biol. 20:9138-9148.
80. Chen J. Yusuf I. ersen HM. Fruman DA.2006. FOXO transcription factors cooperate with delta EF1 to activate growth suppressive genes in B lymphocytes. J. Immunol.176:2711-2721.
81. Birkenkamp KU. Coffer PJ.2003. FOXO transcription factors as regulators of immune homeostasis:molecules to die for? J. Immunol.171:1623-1629.
82. Hinman RM. Bushanam JN. Nichols WA. Satterhwaite AB.2007 B cell receptor signaling down-regulates forkhead box transcription factor class O 1 mRNA expression via phosphatidylinositol 3-kinase Bruton's tyrosine kinase. J. Immunol.178:740-747.
83. O'Rourke LM. Et al.1998. CD 19 as a membrane anchored adaptor protein of B lymphocytes:costimulation of lipid and protein kinases by recruitment of Vav. Immunity 8:635-645.
84. Batista FD. Iber D, Neuberger MS.2001. B cells aquire antigen from target cells after synapse formation. Nature 411:489-494.
85. Arana E. et al.2008. Activation of the small GTPase Rac2 via the B cell receptor regulates B cell adhesion and immunological-synapse formation. Immunity 28:88-99.
86. Fujikawa K. et al.2003. Vavl/2/3-null mice define as essential role for Vav family proteins in lymphocyte development and activation but a differential requirement in MAPK signaling in T and B cells. J. Exp. Med.198:1595-1608.
87. Saxton TM. Van OI. Bowtell D.1994 B cell antigen receptor crosslinking induces phosphorylation of the p21ras oncoprotein activators SHC and Msosl as well as assembly of complexes containing SHC, GRB-2, MSOS1, a 145KD tyrosine-phosphorylated protein. J. Immunol.153:623-636.
88. Smit L. Vries-Smits AM. Bos JL. Borst J.1994. B cell antigen receptor stimulation induces formation of a Shc-Grb2 complex containing multiple tyrosine-phosphorylated proteins. J. Biol. Chem.269:20209-20212.
89. Aiba Y. et al.2004. Activation of RasGRP3 by phosphorylation of Thr-133 is required for B cell receptor-mediated and Ras activation. Proc. Natl. Acad. Sci. USA 101:16612-16617.
90. Bell SE. et al.2004. PLCgamma2 regulates Bcl-2 levels and is required for survival rather than differentiation of marginal zone and follicular B cells. Eur. J. Immunol.34:2237-2247.
91.Mebratu Y. Tesfaigzi Y.2009. How ERK1/2 activation controls cell proliferation and cell death:is subcellular and localization the answer? Cell Cycle.8:1168-1175.
92. Day ES. Et al.2005. Selectivity of BAFF/BlyS and APRIL for binding to the TNF family receptors BAFFR/BR3 and BCMA. Biochemitry.44:1919-1931.
93. Lopez-Fraga M. Fernez R. Hahne M.2001. Biologically active APRIL is secreted following intracellular processing in the Golgi apparatus by furin convertase. EMBO J.2:945-951.
94. Schiemann B. et al.2001. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293:2111-2114.
95. Mackay F. et al.1999. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J. Exp. Med.190:1697-1710.
96. Groom J. et al. Association of BAFF/BlyS overexpression and altered B cell differentiation with Sjogren's syndrome. J. Clin. Invest.109:59-68.
97. Szodoray P. Jonsson R.2005. The BAFF/APRIL system is systemic autoimmune diseases with a special emphasisi on Sjogren's syndrome. Sc J. Immunol.62:421-428.
98. Ratner M.2009. Human Genome Sciences trial data wow lupus community. Nat. Biotechnol.27:779-780.
99. O' Connor BP, et al.2004. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med.199:91-97.
100. Moreaux J. et al.2005. The level of TACI gene expression in myeloma cells is acssociated with a signature of microenvironment dependence versus a plasmablastic signature. Blood.106:1021-1030.
101. Yan M. et al.2001. Activation and accumulation of B cells in TACI-deficient mice. Nat. Immunol.2:638-643.
102. Mackay F. Schneider P.2008. TACI, an enimatic BAFF/APRIL receptor, with new unappreciated biochemical and biological properties. Cytokine Grwoth Factor Rev.19:263-276.
103. Liao G. Zhang M. Harhaj EW. Sun SC.2004. Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-inducing kinase. J. Biol. Chem.279:26243-26250.
104. Gardam S. Sierro F. Basten A. Mackay F. Brink R.2008. TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signaling delivered to B cells by the BAFF receptor. Immunity 28:391-401.
105. Patke A. Mecklenbrauker Ⅰ. Erdjument-Bromage H. Tempst P. Tarakhovsky A.2006. BAFF controls B cell metabolic fitness through a PCK beta-and AKT-dependent mechanism. J. Exp. Med.203:2551-2562.
106. Woodl RT. Et al.2008. Multiple signaling dependent B-cell growth and survival. Blood 111:750-760.
107. Sitalo LA. Tibudan SS. Denning MF.2006. The protein kinase C delta catalytic fragment targets Mcl-1 for degradation to trigger apoptosis. J. Biol. Chem.281:29703-29710.
108. Grumnont RJ. Strasser A. Gerondakis S.2002. B cell growth is controlled by phosphatidylinositol 3-kinase-dependent induction of Rel/NF-kappaB regulated c-myc transcription. Mol. Cell 10:1283-1294.
109. Benson MJ. Elgueta R. Noelle R.2008. B cell survival:An unexpected mechanism of lymphocyte vitality. Immunol. Cell Bio.86:485-486.
110. Willis TG. Dalal MJ. Du. M. Peng H. Perry A. Abdul-Rauf. M. Price H. et al.1999. Bcl10 is involved in t (1;14) (p22;q32) of MALT B cell lymphoma mutated in multiple tumor types. Cell 96:35-45.
111. Li, Q., I. M. Verma.2002. NF-kappaB regulation in the immune system. Nature Reviews Immunology 2:725-734.
112. Suh RG. Park JI. Manzoli L. Cocco L. Peak JC. Katan M. Fukami K. Kataoka T. Yun S. Ryu S.2008. Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB 415-434.
113. Choi JH. Ryu SH. Suh PG.2007. On/Off-regulation of phospholipase C-yl-mediated signal transduction.47:104-116.
114. Yan, M., J. Lee, S. Schilbach, A. Goddard, V. Dixit.1999. mE10, a novel caspase recruitment domain-containing proapoptotic molecule. The Journal of Biological Chemistry 274:10287-10292.
115. Du, M. Q., H. Peng, H. Liu, R. A. Hamoudi, T. C. Diss, T. G. Willis, H. Ye, A. Dogan, A. C. Wotherspoon, M. J. Dyer, P. G. Isaacson.2000. BCL10 gene mutation in lymphoma. Blood 95:3885-3890.
116. Fakruddin, J. M., R. S. Chaganti, V. V. Murty.1999. Lack of BCL10 mutations in germ cell tumors and B cell lymphomas. Cell 97:683-684; discussion 686-688.
117. Apostolou, S., A. De Rienzo, S. S. Murthy, S. C. Jhanwar, J. R. Testa. 1999. Absence of BCL10 mutations in human malignant mesothelioma. Cell 97:684-686; discussion 686-688.
118. Ruland J. Duncan GS. Elia A, Barrantes IB. Nguyen L, Plyte S. Millar DG. Bouchard D. Wakeham A. Ohashi PS. Mak WT 2001 Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure. Cell 104:33-42.
119. Xue L. Morris SW. Orihuela C. Tuomanen E. Cui X. Ren W. Wang D. 2003. Defective development and function of Bcl10-deficient follicular, marginal zone and B1 B cells. Nature Immunol.4:857-865.
120. Grossmann M. et al.1999. The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects. Proc. Natl. Acad. Sci. USA 96:11848-11853.
121. Feng B. Cheng S. Pear WS. Liou HC.2004. NF-kappaB inhibitor and blocks B cell development at two checkpoints. Med. Immunol.3:1
122. Saijo K et al.2003. Essential role of Scr-family protein tyrosine kinases in NF-kappaB activation during B cell development. Nat. Immunol. 4:274-279.
123. Kirillov A. et al.1996. A role of nuclear NF-κB B-cell-specific demethylation of the Igκ locus. Nature. Genet.4:435-441.
124. Bendall HH. Sikes ML. Oitz EM.2001. Transcription factor NF-κB regulates Igλ light chain gene rearrangement. J. Immunol.167:264-269.
125. King LB. Monroe JG.2000. Immunolbiology of the immature B cell: plasticity in the B-cell antigen receptor-induced response fine tunes negative selection. Immunol. Rev.176:86-104.
126. Wu M. et al.1996. Inhibition of NF-κB/Rel induces apoptosis of murine B cells. EMBO J.15:4682-4690.
127. Benerji L. et al.2001. BCRsignals targets p27(Kipl) cyclin D2 via the PI3K signaling pathway to mediate cell cycle arrest apoptosis of WEHI231 B cells. Oncogene 20:7352-7367.
128. Saijo K. et al.2002. Protein kinase Cβ controls nuclear factor κB activation in B cells through selective regulation of the IκB kinase a. J. Exp. Med.195:1647-1652.
129. Cancro MP.2004. Peripheral B-cell maturation:the intersection of selection and homeostasis. Immunol. Rev.197:89-101.
130. Gerondakis S. Strasser A.2003. The role of Rel/NF-κB transcription in B lymphocytes survival. Semin. Immunol.15:159-166.
131. Claudio E. Brown K. Park S. Wang H. Siebenlist U.2002. BAFF-induced NEMO-independent processing of NF-κB2 in maturing B cells. Nature Immunol.10:958-965.
132. Grossmann M. et al.2000. The anti-apoptotic activities of Rel and Re1A required during B-cell maturation involve the regulation of Bcl-2 expression. EMBO J.19:6351-6360.
133. Grumont RJ. Et al.1998. B lymphocytes differentially use the Rel and nuclear factor κB1 transcription factors to regulate cell cycle progression apoptosis in quiescent mitogen-activated cells. J. Exp. Med.187:663-674.
134. Prendes M. Zheng Y. Beg AA.2003. Regulation of developing B cell survival by Re1A-containing NF-κB complexes. J. Immunol.171:3963-3969.
135. Hokin, M. R. Hokin, L. E.1953. Enzyme secretion and the incorporation of P32 into phospholipides of pancreas slices. J Biol. Chem. 203:967-977.
136. Takenawa, T. Nagai, Y.1981. Purification of phosphatidylinositol-specific phospholipase C from rat liver. J.Biol. Chem.256:6769-6775.
137. Suh, P. G., Ryu, S. H., Moon, K. H., Suh, H. W. Rhee, S. G.1988. Cloning and sequence of multiple forms of phospholipase C. Cell 54:161-169.
138. Essen, L. O., Perisic, O., Cheung, R., Katan, M. Williams, R. L.1996. Crystal structure of a mammalian phosphoinositide-specific phospholipase C delta. Nature 380:595-602.
139. Ellis, M. V., U, S. Katan, M.1995. Mutations within a highly conserved sequence present in the X region of phosphoinositide-specific phospholipase C-delta 1. Biochem.J.307:69-75.
140. Wang, T., Dowal, L., E1-Maghrabi, M. R., Rebecchi, M. Scarlata, S. 2000. The pleckstrin homology domain of phospholipase C-beta (2) links the binding of gbetagamma to activati activation of the catalytic core. J. Biol. Chem.275:7466-7469.
141. Wen, W., Yan, J. Zhang, M.2006. Structural characterization of the split pleckstrin homology domain in phospholipase C-gammal its interaction with TRPC3. J. Biol. Chem.281:12060-12068.
142. Mizuguchi, M, Yamada, M., Kim, S. U. Rhee, S. G.1991. Phospholipase C isozymes in neurons glial cells in culture: an immunocytochemical and immunochemical study. Brain Res.548:35-40.
143. Tanaka, O. Kondo, H.1994. Localization of mRNAs for three novel members (beta 3, beta 4 gamma 2) of phospholipase C family in mature rat brain. Neurosci. Lett.182:17-20.
144. Ji, Q. S., Ermini, S., Baulida, J., Sun, F. L. Carpenter, G.1998. Epidermal growth factor signaling mitogenesis in PLCγ1 null mouse embryonic fibroblasts. Mol. Biol. Cell.9:749-757.
145. Wang, D., Feng, J., Wen, R., Marine, J. C., Sangster, M. Y., Parganas, E., Hoffmeyer, A., Jackson, C. W., Clevel, J. L., Murray, P. J. Ihle, J. N.2000. Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors. Immunity 13:25-35.
146. Hashimoto, A., Takeda, K., Inaba, M., Sekimata, M., Kaisho, T., Ikehara, S., Homma, Y., Akira, S. Kurosaki, T.2000. Cutting edge:essential role of phospholipase C-gamma 2 in B cell development function. J. Immunol. 165:1738-1742.
147. Carpenter, G. Ji, Q.1999. Phospholipase C-gamma as a signal-transducing element. Exp. Cell Res.253:15-24.
148. Sekiya, F., Poulin, B., Kim, Y. J. Rhee, S. G.2004. Mechanism of tyrosine phosphorylation and activation of phospholipase C-gamma 1. Tyrosine 783 phosphorylation is not sufficient for lipase activation. J. Biol. Chem.279:32181-32190.
149. Kurosaki, T., Maeda, A., Ishiai, M., Hashimoto, A., Inabe, K. Takata, M.2000. Regulation of the phospholipase C-gamma2 pathway in B cells. Immunol. Rev.176,19-29.
150. Wen, R., Jou, S. T., Chen, Y., Hoffmeyer, A. Wang, D.2002. Phospholipase C gamma 2 is essential for specific functions of Fc epsilon R and Fc gamma R. J. Immunol.169:6743-6752.
151. Wilde, J. I., Watson, S. P.2001. Regulation of phospholipase C gamma isoforms in haematopoietic cells:why one, not the other? Cell. Signal. 13:691-701.
152. Jones, N. P. Katan, M.2007. Role of Phospholipase Cyl in Cell Spreading Requires Association with a β-Pix/GIT1-Containing Complex, Leading to Activation of Cdc42 and Racl. Mol. Cell. Biol.27:5790-5805.
153. Bar-Sagi, D., Rotin, D., Batzer, A., Miyan, V. Schlessinger, J.1993. SH3 domains direct cellular localization of signaling molecules. Cell 74:83-91.
154. Satterthwaite, A. B., Li, Z. Witte, O. N.1998. Btk function in B cell development and response. Semin. Immunol.10:309-316.
155. Yu, P., Constien, R., Dear, N., Katan, M., Hanke, P., Bunney, T. D., Kunder, S., Quintanilla-Martinez, L., Huffstadt, U., Schroder, A., Jones, N. P., Peters, T., Fuchs, H., de Angelis, M. H., Nehls, M., Grosse, J., Wabnitz, P., Meyer, T. P., Yasuda, K., Schiemann, M., Schneider-Fresenius, C., Jagla, W., Russ, A., Popp, A., Josephs, M., Marquardt, A., Laufs, J., Schmittwolf, C. Wagner, H., Pfeffer, K. Mudde, G. C.2005. Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry. Immunity 22:451-465.
156. Ji, Q. S., Winnier, G. E., Niswender, K. D., Horstman, D., Wisdom, R., Magnuson, M. A. Carpenter, G.1997. Essential role of the tyrosine kinase substrate phospholipase C-gammal in mammalian growth development. Proc. Natl. Acad. Sci. U. S. A.94:2999-3003.
157. Smith, M. R., Liu, Y. L., Kim, H., Rhee, S. G. Kung, H. F.1990. Inhibition of serum-ras-stimulated DNA synthesis by antibodies to phospholipase C. Science 247:1074-1077.
158. Kassis, J., Moellinger, J., Lo, H., Greenberg, N. M., Kim, H. G. Wells, A.1999. A role for phospholipase C-gamma-mediated signaling in tumor cell invasion. Clin. Cancer Res.5:2251-2260.
159. Irvin, B. J., Williams, B. L., Nilson, A. E., Maynor, H. O. Abraham, R. T.2000 Pleiotropic contributions of phospholipase C-gammal (PLC-gammal) to T-cell antigen receptor-mediated signaling:reconstitution studies of a PLC-gammal-deficient Jurkat T-cell line. Mol. Cell. Biol.20:9149-9161.
160. Bae, S. S., Lee, Y. H., Chang, J. S., Galadari, S. H., Kim, Y. S., Ryu, S. H. Suh, P. G.1998. Src homology domains of phospholipase C gammal inhibit nerve growth factor-induced differentiation of PC12 cells. J. Neurochem.71:178-185.
161. Patterson, R. L., van Rossum, D. B., Ford, D. L., Hurt, K. J., Bae, S. S., Suh, P. G., Kurosaki, T., Snyder, S. H. Gill, D. L. (2002) Phospholipase C-gamma is required for agonist-induced Ca2+ entry. Cell 111:529-541.
162. Huang, P. S., Davis, L., Huber, H., Goodhart, P. J., Wegrzyn, R. E., Oliff, A. Heimbrook, D. C.1995. An SH3 domain is required for the mitogenic activity of microinjected phospholipase C-gamma 1. FEBS Lett. 358287-292.
163. Ye, K.2005. PIKE/nuclear PI 3-kinase signaling in preventing programmed cell death. J. Cell Biochem.96:463-472.
164. Ye, K. Snyder, S. H.2004. PIKE GTPase:a novel mediator of phosphoinositide signaling. J. Cell Sci.117:155-161.
165. Choi, J. H., Yang, Y. R., Lee, S. K., Kim, I. S., Ha, S. H., Kim, E. K., Bae, Y. S., Ryu, S. H. Suh, P. G.2007 Phospholipase C-gammal potentiates integrin-dependent cell spreading and migration through Pyk2/paxillin activation. Cell. Signal.19:1784-1796.
166. Kanner, S. B., Grosmaire, L. S., Ledbetter, J. A. Damle, N. K.1993. Beta 2-integrin LFA-1 signaling through phospholipase C-gamma 1 activation. Proc. Natl. Acad. Sci. U. S. A.90:-7103.
167. Mackay F. Browning JL.2002. BAFF:A fundamental factor for B cells. Nature Rev. Immunol.2:465-475.
1. Willis TG. Dalal MJ. Du. M. Peng H. Perry A. Abdul-Rauf. M. Price H. et al. 1999. Bcl10 is involved in t (1;14) (p22;q32) of MALT B cell lymphoma mutated in multiple tumor types. Cell 96:35-45.
2. Du, M. Q., H. Peng, H. Liu, R. A. Hamoudi, T. C. Diss, T. G. Willis, H. Ye, A. Dogan, A. C. Wotherspoon, M. J. Dyer, P. G. Isaacson.2000. BCL10 gene mutation in lymphoma. Blood 95:3885-3890.
3. Ruland J. Duncan GS. Elia A. Barrantes I. Nguyen L. Plyte S. Millar DG. Bouchard D. Wakeham A. Ohashi P. Mak TW.2001. Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure. Cell 104:33-42.
4. Xue L. Morris SW. Orihuela C. Tuomanen E. Cui X. Ren W. Wang D.2003. Defective development and function of Bcl10-deficient follicular, marginal zone and B1 B cells. Nature Immunol.4:857-865.
5. Ferch U. Buschenfelde M. Gewies A. Wegener E. Rauser S. Peschel C. Krappmann D. Ruland J.2007 MALT1 directs B cell receptor-induced canonical nuclear factor-KB signaling selectively to the c-Rel subunit. Nature Immunol.8:984-991.
6. Siebenlist U. Brown K. Claudio E.2005. Control of lymphocyte development by nuclear factor-κB. Nat. Rev. Immunol.5:435-445.
7. Hayden MS. Ghosh S.2004. Signaling to NF-kappaB. Genes Dev.18:2195-2224.
8. Gerondakis S. Strasser A.2003. The role of Rel/NF-B transcription factors in B lymphocytes survival. Seminars Immunol.15:159-166.
9. Goodnow CC. Sprent J. Groth B. Vinuesa C.2005. Celluar and genetic mechanisms of self tolerance and autoimmunity. Nature 435:590-597.
10. Lesley R.2004. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 20:441-453.
11. Goodnow CC. Crosbie J. Adelstein S. Lavoie TB. Smith-Gill SJ. Brink RA. Pritchard-Briscoe H. Wotherspoon JS. Loblay RH. Raphael K.1988. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334:676-682.
12. Healy JI. Goodnow CC.1998. Positive versus negative signaling by lymphocyte antigen receptors. Annu. Rev. Immunol.16:645-670.
13. Schiemann B. et al.2001. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293:2111-2114.
14. Groom J. et al. Association of BAFF/BlyS overexpression and altered B cell differentiation with Sjogren's syndrome. J. Clin. Invest.109:59-68.
15. Gardam S. Sierro F. Basten A. Mackay F. Brink R.2008. TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signaling delivered to B cells by the BAFF receptor. Immunity 28:391-401.
16. Merrell KT. Benschop RJ. Gauld SB. Aviszus K. Decote-Ricardo D. Wysocki LJ. Cambier JC.2006. Identification of anergic B cells within a wild-type repertoire. Immunity 25:953-962.
1.Rhee SG. Bae YS.1997. Regulation of phosphoinositide-specific phospholipase C isozymes. J. Biol. Chem.272:'5045-15048.
2.Suh PG. Park J. Manzoli L. Cocco L. Peak J. Katan M. Fukami K. Kataoka T. Yun S. Ryu SH.2008. Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB reports.415-434.
3. Miura O. Nakamura N. Ihle JN. Aoki N.1994. Erythropoietin-dependent association of phosphatidylinositol 3-kinase with tyrosine-phosphorylated erythropoietin receptor. J. Biol. Chem.269:614-620.
4. Noh DY. Shin SH. Rhee SG.1995. Phosphoinositide-specific phospholipase C and mitogenic signaling. Biochim Biophys Acta.1242:99-113.
5. Ji QS. Ermini S. Baulida J. Sun F. Carpenter G.2007. Epidermal growth factor signaling and mitogenesis is PLCyl null mouse embryonic fibroblasts. Mol. Biol. Cell 9:749-757.
6. Wang D. Feng J. Wen R. Marine JC. Sangster MY. Parganas E. Hoffmeyer A. Jackson CW. Cleverland JL. Murray Pi. Ihle JN.2000. Phospholipase Cγ2 is essential in the functions of B cells and several Fc receptors. Immunity 13:25-35.
7. Fu G. Chen Y. Yu M. Podd A. Schuman J. He Y. Di L. Yassai M. Haribhai D. North PE. Gorski J. Williams CB. Wang D. Wen R.2010. Phospholipase Cyl is essential for T cell development, activation and tolerance. J. Exp. Med. 207:309-318.
8. Ji QS. Winnier GE. Niswender KD. Horstman D. Wisdom R. Magnuson MA. Carpenter G.1997. Essential role of the tyrosine kinase substrate phospholipase C-gammal in mammalian growth and development. Proc. Natl. Acad. Sci.94:2999-3002.
9. Srinivas S. Watanabe T.Lin CS. William CM. Tanabe Y. Jessell TM. Constantini F.2001. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol.1:1-4.
10. Wen R. Chen Y. Schuman J. Fu G. Yang S. Zhang W. Newman D. Wang D. 2004. An important role of phospholipase Cγ1 in pre-B-cell development and allelic exclusion.23:4007-4017.
11. Carter RH. Fearon DT.1992. CD19:lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256:105-107.
12. Kuhn R. Schwenk F. Aguet M. Rajewsky K.1995. Inducible gene targeting in mice. Science 269:1427-1429.
13. Kitamuar D. Roes J. Kuhn R. Rajewsky K.1991. A B cell deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature.350:423-426.
14. Randall K. et al.2009. Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nature Immunol.10:1283-1291.
15. Tavares RM, Turer EE, Liu CL, Advincula R, Scapini P, Rhee L, Barrera J, Lowell CA, Utz PJ, Malynn BA, Ma A.2010. The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity. Immunity. 33:181-91.
16. Tiller T. Kofer J. Kreschel C. Busse CE. Riebel S. Wichert S. Oden F. Mertes MM. Ehlers M. Wardemann H.2010. Development of self-reactive germinal center B cells and plasma cells in autoimmune FcyRIIB-deficient mice. J. Exp. Med.12:2767-2778.
17. Jacobi and Diamond,2005 A.M. Jacobi AM. Diamond B.2005. Balancing diversity and tolerance:Lessons from patients with systemic lupus erythematosus. J. Exp. Med.202:341-344.
18. Shlomchik MJ.2008. Sites and stages of autoreactive B cell activation and regulation. Immunity 28:18-28.
19. Yurasov S. Nussenzweig MC.2007. Regulation of autoreactive antibodies. Curr. Opin. Rheumatol.19:421-426.
20. Cappione et al.,2005 A. Cappione A. Anolik JH. Pugh-Bernard A. Barnard J. Dutcher P. Silverman G. Sanz I. Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus. J. Clin. Invest. 115:3205-3216.
2. Galli, S. J., J. Kalesnikoff, M. A. Grimbaldeston, A. M. Piliponsky, C. M. Williams, M. Tsai.2005. Mast cells as "tunable" effector immunoregulatory cells:recent advances. Ann. Rev. Immunol.23:749-786.
3. Fuxa M., Skok J. A.2007. Transcriptional regulation in early B cell development. Curr. Opi. Immunol.19:129-136.
4. Riblet R.2004. Immunoglobulin heavy chain genes of mouse. In Molecular Biology of B Cells, ed. T Honjo, FW Alt, MS Neuberger, pp.19-26. London: Elsevier Acad.
5. http://www.ncbi.nlm.nih.gov/igblast
6. Boekel E., Melchers F., Rolink A.G.1997. Changes in V(H) gene repertoire of cell receptor. Immunity 7:357-368.
7. Kurosaki T., Shinohara H., Baba Y.2010. B cell signaling and fate decision. Annu. Rev. Immunol.28:21-55
8. Hardy RR., Hayakawa K.2001.B cell development pathways. Annu. Rev. Immunol.19:595-621.
9. Allman D.M.1993. Peripheral B cell maturation.Ⅱ Heat-stable antigen(hi) splenic B cell are immature developmental intermediate in the production of long-lived marrow-derived B cells. J. Immunol.151:4431-4444.
10. Rolink A. G.1998. Characterization of immature B cells by a novel monoclonal antibody, by turnover and by mitogen reactivity. Eur. J. Immunol. 28:3738-3748.
11. Allman D. M.1992. Peripheral B cell maturation. Ⅰ. Immature peripheral B cells in adults are heat-stable antigenhi and exhibit unique signaling characteristics. J. Immunol.149:2533-2540.
12.Norvell A., Monroe J. G.1996. Acquisition of surface IgD fails to protect from tolerance-induction. Both surface IgM-and surface IgD-mediated signals induce apoptosis of immature murine B lymphocytes. J. Immunol.156:1328-1332.
13. Chung J.B.2002. CD23 defines two distinct subsets of immature B cells which differ in their responses to T cell help signals. Int. Immunol.14:157-166.
14. Siechmann D.G.1978. Activation of mouse lymphocytes by anti-immunoglobulin. Ⅰ. Parameters of the proliferative response. J. Exp. Med. 147:814-829.
15.Goodnow C. C.1988. Altered immunoglobulin expression and function silencing of self-reactive B lymphocytes in transgenic mice. Nature.334:676-682.
16. Norvell A.1995. Engagement of the antigen-receptor on immature murine B lymphocytes results in death by apoptosis. J. Immunol.154:4404-4413.
17. Loder F.1999. B cell development in the spleen takes place in discrete steps and is determined by the quality of B cell receptor-derived signals. J. Exp. Med.190:75-89.
18. Allman D.2001 Resolution of three nonproliferative immature splenic B cell subsets reveals multiple selection points during peripheral B cell maturation. J. Immunol.167:6834-6840.
19. Su T.T., Rawlings, D. J.2002. Transitional B lymphocyte subsets operate as distinct checkpoints in murine splenic B cell development. J. Immunol. 168:2101-2110.
20. Merrell K., Benschop R., Gauld S., Aviszus K., Ricardo D., Wysocki L. Cambier J.2006. Identification of anergic B cells within a wild-type repertoire. Immunity 25:953-962.
21. Chung J., Silverman M., Monroe J.2003 Transitional B cells:Step by step towards immune competence. TRENDS in Immunlogy.24:342-348.
22. Mebius R.E., Kraal G.,2005. Structure and function of the spleen. Nat. Rev. Immunol.5:606-616.
23. Martin F., Kearney JF.2002. Marginal-zone B cells. Nat Rev Immunol 2:323-335.
24. Pillai S., Cariappa A., Moran ST.2005. Marginal zone B cells. Annu Rev Immunol 23:161-196.
25. Lane PJ, Gray D, Oldfield S, MacLennan IC.1986. Differences in the recruitment of virgin B cells into antibody responses to thymusdependent and thymus-independent type-2 antigens. Eur J Immunol 16:1569-1575.
26. Paus D, Phan TG, Chan TD, Gardam S, Basten A, Brink R.2006. Antigen recognition strength regulates the choice between extrafollicular plasma cell and germinal center B cell differentiation. J Exp Med 203:1081-1091.
27. Reif K, et al.2002. Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature 416:94-99.
28. Garside P, Ingulli E, Merica RR, Johnson JG, Noelle RJ, Jenkins MK.1998. Visualization of specific B and T lymphocyte interactions in the lymph node. Science 281:96-99.
29. Mohr E, et al.2009.Dendritic cells and monocyte/macrophages that create the IL-6/APRIL-rich lymph node microenvironments where plasmablasts mature. J Immunol 182:2113-2123.
30. Smith KG, Hewitson TD, Nossal GJ, Tarlinton DM.1996. The phenotype and fate of the antibody-forming cells of the splenic foci. Eur J Immunol 26:444-448.
31. Manz RA, Lohning M, Cassese G, Thiel A, Radbruch A.1998. Survival of long-lived plasma cells is independent of antigen. Int Immunol 10:1703-1711.
32. Lalor PA, Nossal GJ, Serson RD, McHeyzer-Williams MG.1992. Functional and molecular characterization of single, (4-hydroxy-3-nitrophenyl) acetyl (NP)-specific, IgGl+ B cells from antibody-secreting memory B cell pathways in the C57BL/6 immune response to NP. Eur J Immunol.22:3001-3011.
33. Shaffer AL, et al.2002. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17:51-62.
34. Kallies A, et al.2004. Plasma cell ontogeny defined by quantitative changes in Blimp-1 expression. J Exp Med 200:967-977.
35.Oracki S. Walker J. Hibbs M. Corcoran L. Tarlinton D.2010. Plasma cell development and survival. Immunol. Rev.237:140-159.
36. Jacobson D.L. Gange SJ. Rose NR.1997. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin. Immunol. Immunopathol.84:223-243.
37. Goodnow CC. Sprent J. Groth B. Vinuesa C.2005 Celluar and genetic mechanisms of self tolerance and autoimmunity. Nature 435:590-597.
38. Nemazee D. Hogquist K.2003 Antigen receptor selection by editing or downregulation of V(D)J recombination. Curr. Opin. Immunol.15:182-189.
39. Hartley SB.1993. Elimination of self-reactive B lymphocytes proceeds in two stages:arrested development and cell death. Cell 72:325-335.
40. Fields M. Erikson J.2003. The regulation of lupus-associated autoantibodies: immunoglobulin transgenic models. Curr. Opin. Immunol.15:709-717
41. Machay F. Schneider P. Rennert P.2003. BAFF and APRIL:a tutorial on B cell survival. Annu. Rev. Immunol.21:231-264.
42. Strasser A. Bouillet P.2003. The control of apoptosis in lymphocyte selection. Immunol. Rev.193:82-92.
43. Wardemann H.2003. Predominant autoantibody production by early human B cell precursors. Science 301:1374-1377.
44. Akkaraju S. Canann K. Goodnow CC.1997. Self-reactive B cells are not eliminated or inactivated by autoantigen expressed on thyroid epithelial cells. J. Exp. Med.186:2005-2012.
45. Bell SE. Goodnow CC.1994. A selective defect in IgM antigen receptor synthesis and transport causes loss of cell surface IgM expression on tolerant B lymphocytes. EMBOj.13:816-826.
46. Lesley R.2004. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 20:441-453.
47. Ravetch JV. Laniea LL.2000. Immune inhibitory receptors. Science 290:84-89.
48. Hippen KL. Tze LE. Behrens TW.2000 CD5 maintains tolerance in angeric B cells. J. Exp. Med.191:883-890.
49. Cyster JG. Hartley SB. Goodnow CC.1994. Competition for follicular niches excludes self-reactive cells from the recirculating B-cell repertoire. Nature 371:389-395.
50. Fox. CJ.2003. The serine/threonine kinase Pim-2 is a transcriptional regulated apoptotic inhibitor. Genes. Dev.17:1841-1854.
51.Foy TM. Aruffo A. Bajorath J. Buhlmann Je. Noelle RJ.1996. Immune regulation by CD40 and its ligand gp39. Annu. Rev. Immunol.14:591-617.
52. Kovanen PE. Leonard WJ.2004. Cytokines and immunodeficiency diseases: critical roles of the gamma(c)-dependent cytokines interleukins 2,4,7,9,15 21 their signaling pathways. Immunol. Rev.202:67-83.
53. Ang CW. Jacobs BC. Laman JD.2004. The Guillain-Barre syndrome:a true case of molecular mimicry. Trends. Immunol.25:61-66.
54. Mackay F. Figgett W. Saulep D. Lepage M. Hibbs M.2010. B-cell stage and context-dependent requirement for survival signals from BAFF and the B-cell receptor.237:205-225.
55. Gold MR. Law D. DeFranco AL.1990. Stimulation of protein tyrosine phosphorylation by the B-lymphocyte antigen receptor. Nature 345:810-813.
56. Campbell MA. Sefton BM.1990. Protein tyrosine phosphorylation is induced in murine B lymphocytes in response to stimulation with anti-immunoglobulin. EMBO J.9:2125-2131.
57. Brunswick M. Samelson LE. Mond JJ.1991. Surface immunoglobulin crosslinking activates a tyrosine kinase pathway in B cells that is independent of protein kinase C. Proc. Natl. Acad. Sci. USA 88:1311-1314.
58. Xu Y. Harder KW. Huntington ND.2005. Lyn tyrosine kinase;accentuating the positive and the negative. Immunity 22:9-18.
59. Hutchcroft JE. Harrison MI. Geahlen RI.1992. Association of the 72-kDa protein-tyrosine kinase PTK72 with the B cell antigen receptor. J. Biol. Chem. 267:8613-8619.
60. Rawlings DJ.1996. Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases. Science 271:822-825.
61. Ishiai M. Sugawara H. Kurosaki M. Kurosaki T.1999. Cutting edge: association of phospholipase C-gamma 2 Src homology 2 domains with BLNK is crutial for B cell antigen receptor signaling. J. Immunol.163:1746-1749.
62. Takata M. Kurosaki T.1996. A role for Bruton's tyrosine kinase in B cell antigen receptor-mediated activation of phospholipase C-gamma 2. J. Exp. Med.184:31-40.
63. Fu C. Turck CW. Kurosaki T. Chan AC.1998. BLNK:a central linker protein in B cell activation. Immunity 9:93-103.
64. King LB. Freedman BD.2009. B-lymphocyte calcium influx. Immunol. Rev. 231:265-277.
65. Ogawa Y. Takai Y. Kawahara Y. Kimura S.1981. A new possible regulatory system for protein phosphorylation in human peripheral lymphocytes. I. Characterization of a calcium-activated, phospholipid-dependent protein kinase. J. Immunol.127:1369-1374.
66. Ku Y. Kishimoto A. Takai Y. Ogawa Y. Kimura S. Nishizuka Y.1981. A new possible regulatory system for protein phosphorylation in human peripheral lymphocytes. Ⅱ. Possible relation to phosphatidylinositol turnover induced by mitogens. J. Immunol.127:1375-1379
67. Wu M. et al.1996. Inhibition of NF-kappaB/Rel induces apoptosis of murine B cells. EMBO J.15:4682-4690.
68. Grossman M. O'Reilly LA. Gugasyan R. Strasser A. Adams JM. Gerondakis S. 2000. The anti-apoptotic activities of Rel and RelA required and during B-cell maturation involve the regulation of Bcl-2 expression. EMBO J.19:6351-6360.
69. Grumont RJ. Rourke IJ. Gerondakis S.1999. Rel-dependent induction of A1 transcription is required to protect B cells from antigen receptor ligation-induced apoptosis. Genes. Dev.13:400-411.
70. Glassford J. et al.2001. Vav is required for cyclin D2 induction and proliferation of mouse B lymphocytes activated via the antigen receptor. J. Biol. Chem.276:41040-41048.
71.Ishiura N. et al.2010. Differential phosphorylation of CD19 in pre-B and mature B cells. EMBO J.40:1192-1204.
72. Carter RH. Fearon DT.1992. CD19:lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256:105-107.
73. Okada T. Maeda A. Iwamatsu A. Gotoh K. Kurosaki T.2000. BCAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation. Immunity 12:817-827.
74. Aiba Y. Kameyama M. Yamazaki T. Tedder TF. Kurosaki T.2008. Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase. Blood 111:1497-1503.
75. Falasca M. Logan SK. Lehto VP. Baccante G. Lemmon MA. Schlessinger J. 1998. Activation of phospholipase C gamma by PI 3-kinase-induced PH domain-mediated membrane targeting. EMBO J.17:414-422.
76. Buhl AM. Cambier JC.1999. Phosphorylation of CD19 Y484 and Y515, linked activation of phosphadylinositol 3-kinase, are required for B cell antigen receptor-mediated activation of Bruton's tyrosine kinase. J. Immunol. 162:4438-4446.
77. Gold MR. et al.1999. The B cell antigen receptor activates the Akt (protein kinase B)/glycogen synthase kinase-3 signaling pathway via phosphatidylinositol 3-kinase. J. Immunol.163:894-905.
78. Dijkers PF. Medema RH. Lammers JW. Koenderman L. Coffer PJ.2000. Expression of the pro-apoptotic Bcl-2 family member Bim is regulated by the forkhead transcription factor FKHR-L1. Curr. Biol.10:1201-1204.
79. Dijkers PF. et al.2000. Forkhead transcription factor FKHR-L1 modulated cytokine-dependent transcriptional regulation of p27(KIP1). Mol. Cell Biol. 20:9138-9148.
80. Chen J. Yusuf I. ersen HM. Fruman DA.2006. FOXO transcription factors cooperate with delta EF1 to activate growth suppressive genes in B lymphocytes. J. Immunol.176:2711-2721.
81. Birkenkamp KU. Coffer PJ.2003. FOXO transcription factors as regulators of immune homeostasis:molecules to die for? J. Immunol.171:1623-1629.
82. Hinman RM. Bushanam JN. Nichols WA. Satterhwaite AB.2007 B cell receptor signaling down-regulates forkhead box transcription factor class O 1 mRNA expression via phosphatidylinositol 3-kinase Bruton's tyrosine kinase. J. Immunol.178:740-747.
83. O'Rourke LM. Et al.1998. CD 19 as a membrane anchored adaptor protein of B lymphocytes:costimulation of lipid and protein kinases by recruitment of Vav. Immunity 8:635-645.
84. Batista FD. Iber D, Neuberger MS.2001. B cells aquire antigen from target cells after synapse formation. Nature 411:489-494.
85. Arana E. et al.2008. Activation of the small GTPase Rac2 via the B cell receptor regulates B cell adhesion and immunological-synapse formation. Immunity 28:88-99.
86. Fujikawa K. et al.2003. Vavl/2/3-null mice define as essential role for Vav family proteins in lymphocyte development and activation but a differential requirement in MAPK signaling in T and B cells. J. Exp. Med.198:1595-1608.
87. Saxton TM. Van OI. Bowtell D.1994 B cell antigen receptor crosslinking induces phosphorylation of the p21ras oncoprotein activators SHC and Msosl as well as assembly of complexes containing SHC, GRB-2, MSOS1, a 145KD tyrosine-phosphorylated protein. J. Immunol.153:623-636.
88. Smit L. Vries-Smits AM. Bos JL. Borst J.1994. B cell antigen receptor stimulation induces formation of a Shc-Grb2 complex containing multiple tyrosine-phosphorylated proteins. J. Biol. Chem.269:20209-20212.
89. Aiba Y. et al.2004. Activation of RasGRP3 by phosphorylation of Thr-133 is required for B cell receptor-mediated and Ras activation. Proc. Natl. Acad. Sci. USA 101:16612-16617.
90. Bell SE. et al.2004. PLCgamma2 regulates Bcl-2 levels and is required for survival rather than differentiation of marginal zone and follicular B cells. Eur. J. Immunol.34:2237-2247.
91.Mebratu Y. Tesfaigzi Y.2009. How ERK1/2 activation controls cell proliferation and cell death:is subcellular and localization the answer? Cell Cycle.8:1168-1175.
92. Day ES. Et al.2005. Selectivity of BAFF/BlyS and APRIL for binding to the TNF family receptors BAFFR/BR3 and BCMA. Biochemitry.44:1919-1931.
93. Lopez-Fraga M. Fernez R. Hahne M.2001. Biologically active APRIL is secreted following intracellular processing in the Golgi apparatus by furin convertase. EMBO J.2:945-951.
94. Schiemann B. et al.2001. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293:2111-2114.
95. Mackay F. et al.1999. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J. Exp. Med.190:1697-1710.
96. Groom J. et al. Association of BAFF/BlyS overexpression and altered B cell differentiation with Sjogren's syndrome. J. Clin. Invest.109:59-68.
97. Szodoray P. Jonsson R.2005. The BAFF/APRIL system is systemic autoimmune diseases with a special emphasisi on Sjogren's syndrome. Sc J. Immunol.62:421-428.
98. Ratner M.2009. Human Genome Sciences trial data wow lupus community. Nat. Biotechnol.27:779-780.
99. O' Connor BP, et al.2004. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med.199:91-97.
100. Moreaux J. et al.2005. The level of TACI gene expression in myeloma cells is acssociated with a signature of microenvironment dependence versus a plasmablastic signature. Blood.106:1021-1030.
101. Yan M. et al.2001. Activation and accumulation of B cells in TACI-deficient mice. Nat. Immunol.2:638-643.
102. Mackay F. Schneider P.2008. TACI, an enimatic BAFF/APRIL receptor, with new unappreciated biochemical and biological properties. Cytokine Grwoth Factor Rev.19:263-276.
103. Liao G. Zhang M. Harhaj EW. Sun SC.2004. Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-inducing kinase. J. Biol. Chem.279:26243-26250.
104. Gardam S. Sierro F. Basten A. Mackay F. Brink R.2008. TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signaling delivered to B cells by the BAFF receptor. Immunity 28:391-401.
105. Patke A. Mecklenbrauker Ⅰ. Erdjument-Bromage H. Tempst P. Tarakhovsky A.2006. BAFF controls B cell metabolic fitness through a PCK beta-and AKT-dependent mechanism. J. Exp. Med.203:2551-2562.
106. Woodl RT. Et al.2008. Multiple signaling dependent B-cell growth and survival. Blood 111:750-760.
107. Sitalo LA. Tibudan SS. Denning MF.2006. The protein kinase C delta catalytic fragment targets Mcl-1 for degradation to trigger apoptosis. J. Biol. Chem.281:29703-29710.
108. Grumnont RJ. Strasser A. Gerondakis S.2002. B cell growth is controlled by phosphatidylinositol 3-kinase-dependent induction of Rel/NF-kappaB regulated c-myc transcription. Mol. Cell 10:1283-1294.
109. Benson MJ. Elgueta R. Noelle R.2008. B cell survival:An unexpected mechanism of lymphocyte vitality. Immunol. Cell Bio.86:485-486.
110. Willis TG. Dalal MJ. Du. M. Peng H. Perry A. Abdul-Rauf. M. Price H. et al.1999. Bcl10 is involved in t (1;14) (p22;q32) of MALT B cell lymphoma mutated in multiple tumor types. Cell 96:35-45.
111. Li, Q., I. M. Verma.2002. NF-kappaB regulation in the immune system. Nature Reviews Immunology 2:725-734.
112. Suh RG. Park JI. Manzoli L. Cocco L. Peak JC. Katan M. Fukami K. Kataoka T. Yun S. Ryu S.2008. Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB 415-434.
113. Choi JH. Ryu SH. Suh PG.2007. On/Off-regulation of phospholipase C-yl-mediated signal transduction.47:104-116.
114. Yan, M., J. Lee, S. Schilbach, A. Goddard, V. Dixit.1999. mE10, a novel caspase recruitment domain-containing proapoptotic molecule. The Journal of Biological Chemistry 274:10287-10292.
115. Du, M. Q., H. Peng, H. Liu, R. A. Hamoudi, T. C. Diss, T. G. Willis, H. Ye, A. Dogan, A. C. Wotherspoon, M. J. Dyer, P. G. Isaacson.2000. BCL10 gene mutation in lymphoma. Blood 95:3885-3890.
116. Fakruddin, J. M., R. S. Chaganti, V. V. Murty.1999. Lack of BCL10 mutations in germ cell tumors and B cell lymphomas. Cell 97:683-684; discussion 686-688.
117. Apostolou, S., A. De Rienzo, S. S. Murthy, S. C. Jhanwar, J. R. Testa. 1999. Absence of BCL10 mutations in human malignant mesothelioma. Cell 97:684-686; discussion 686-688.
118. Ruland J. Duncan GS. Elia A, Barrantes IB. Nguyen L, Plyte S. Millar DG. Bouchard D. Wakeham A. Ohashi PS. Mak WT 2001 Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure. Cell 104:33-42.
119. Xue L. Morris SW. Orihuela C. Tuomanen E. Cui X. Ren W. Wang D. 2003. Defective development and function of Bcl10-deficient follicular, marginal zone and B1 B cells. Nature Immunol.4:857-865.
120. Grossmann M. et al.1999. The combined absence of the transcription factors Rel and RelA leads to multiple hemopoietic cell defects. Proc. Natl. Acad. Sci. USA 96:11848-11853.
121. Feng B. Cheng S. Pear WS. Liou HC.2004. NF-kappaB inhibitor and blocks B cell development at two checkpoints. Med. Immunol.3:1
122. Saijo K et al.2003. Essential role of Scr-family protein tyrosine kinases in NF-kappaB activation during B cell development. Nat. Immunol. 4:274-279.
123. Kirillov A. et al.1996. A role of nuclear NF-κB B-cell-specific demethylation of the Igκ locus. Nature. Genet.4:435-441.
124. Bendall HH. Sikes ML. Oitz EM.2001. Transcription factor NF-κB regulates Igλ light chain gene rearrangement. J. Immunol.167:264-269.
125. King LB. Monroe JG.2000. Immunolbiology of the immature B cell: plasticity in the B-cell antigen receptor-induced response fine tunes negative selection. Immunol. Rev.176:86-104.
126. Wu M. et al.1996. Inhibition of NF-κB/Rel induces apoptosis of murine B cells. EMBO J.15:4682-4690.
127. Benerji L. et al.2001. BCRsignals targets p27(Kipl) cyclin D2 via the PI3K signaling pathway to mediate cell cycle arrest apoptosis of WEHI231 B cells. Oncogene 20:7352-7367.
128. Saijo K. et al.2002. Protein kinase Cβ controls nuclear factor κB activation in B cells through selective regulation of the IκB kinase a. J. Exp. Med.195:1647-1652.
129. Cancro MP.2004. Peripheral B-cell maturation:the intersection of selection and homeostasis. Immunol. Rev.197:89-101.
130. Gerondakis S. Strasser A.2003. The role of Rel/NF-κB transcription in B lymphocytes survival. Semin. Immunol.15:159-166.
131. Claudio E. Brown K. Park S. Wang H. Siebenlist U.2002. BAFF-induced NEMO-independent processing of NF-κB2 in maturing B cells. Nature Immunol.10:958-965.
132. Grossmann M. et al.2000. The anti-apoptotic activities of Rel and Re1A required during B-cell maturation involve the regulation of Bcl-2 expression. EMBO J.19:6351-6360.
133. Grumont RJ. Et al.1998. B lymphocytes differentially use the Rel and nuclear factor κB1 transcription factors to regulate cell cycle progression apoptosis in quiescent mitogen-activated cells. J. Exp. Med.187:663-674.
134. Prendes M. Zheng Y. Beg AA.2003. Regulation of developing B cell survival by Re1A-containing NF-κB complexes. J. Immunol.171:3963-3969.
135. Hokin, M. R. Hokin, L. E.1953. Enzyme secretion and the incorporation of P32 into phospholipides of pancreas slices. J Biol. Chem. 203:967-977.
136. Takenawa, T. Nagai, Y.1981. Purification of phosphatidylinositol-specific phospholipase C from rat liver. J.Biol. Chem.256:6769-6775.
137. Suh, P. G., Ryu, S. H., Moon, K. H., Suh, H. W. Rhee, S. G.1988. Cloning and sequence of multiple forms of phospholipase C. Cell 54:161-169.
138. Essen, L. O., Perisic, O., Cheung, R., Katan, M. Williams, R. L.1996. Crystal structure of a mammalian phosphoinositide-specific phospholipase C delta. Nature 380:595-602.
139. Ellis, M. V., U, S. Katan, M.1995. Mutations within a highly conserved sequence present in the X region of phosphoinositide-specific phospholipase C-delta 1. Biochem.J.307:69-75.
140. Wang, T., Dowal, L., E1-Maghrabi, M. R., Rebecchi, M. Scarlata, S. 2000. The pleckstrin homology domain of phospholipase C-beta (2) links the binding of gbetagamma to activati activation of the catalytic core. J. Biol. Chem.275:7466-7469.
141. Wen, W., Yan, J. Zhang, M.2006. Structural characterization of the split pleckstrin homology domain in phospholipase C-gammal its interaction with TRPC3. J. Biol. Chem.281:12060-12068.
142. Mizuguchi, M, Yamada, M., Kim, S. U. Rhee, S. G.1991. Phospholipase C isozymes in neurons glial cells in culture: an immunocytochemical and immunochemical study. Brain Res.548:35-40.
143. Tanaka, O. Kondo, H.1994. Localization of mRNAs for three novel members (beta 3, beta 4 gamma 2) of phospholipase C family in mature rat brain. Neurosci. Lett.182:17-20.
144. Ji, Q. S., Ermini, S., Baulida, J., Sun, F. L. Carpenter, G.1998. Epidermal growth factor signaling mitogenesis in PLCγ1 null mouse embryonic fibroblasts. Mol. Biol. Cell.9:749-757.
145. Wang, D., Feng, J., Wen, R., Marine, J. C., Sangster, M. Y., Parganas, E., Hoffmeyer, A., Jackson, C. W., Clevel, J. L., Murray, P. J. Ihle, J. N.2000. Phospholipase Cgamma2 is essential in the functions of B cell and several Fc receptors. Immunity 13:25-35.
146. Hashimoto, A., Takeda, K., Inaba, M., Sekimata, M., Kaisho, T., Ikehara, S., Homma, Y., Akira, S. Kurosaki, T.2000. Cutting edge:essential role of phospholipase C-gamma 2 in B cell development function. J. Immunol. 165:1738-1742.
147. Carpenter, G. Ji, Q.1999. Phospholipase C-gamma as a signal-transducing element. Exp. Cell Res.253:15-24.
148. Sekiya, F., Poulin, B., Kim, Y. J. Rhee, S. G.2004. Mechanism of tyrosine phosphorylation and activation of phospholipase C-gamma 1. Tyrosine 783 phosphorylation is not sufficient for lipase activation. J. Biol. Chem.279:32181-32190.
149. Kurosaki, T., Maeda, A., Ishiai, M., Hashimoto, A., Inabe, K. Takata, M.2000. Regulation of the phospholipase C-gamma2 pathway in B cells. Immunol. Rev.176,19-29.
150. Wen, R., Jou, S. T., Chen, Y., Hoffmeyer, A. Wang, D.2002. Phospholipase C gamma 2 is essential for specific functions of Fc epsilon R and Fc gamma R. J. Immunol.169:6743-6752.
151. Wilde, J. I., Watson, S. P.2001. Regulation of phospholipase C gamma isoforms in haematopoietic cells:why one, not the other? Cell. Signal. 13:691-701.
152. Jones, N. P. Katan, M.2007. Role of Phospholipase Cyl in Cell Spreading Requires Association with a β-Pix/GIT1-Containing Complex, Leading to Activation of Cdc42 and Racl. Mol. Cell. Biol.27:5790-5805.
153. Bar-Sagi, D., Rotin, D., Batzer, A., Miyan, V. Schlessinger, J.1993. SH3 domains direct cellular localization of signaling molecules. Cell 74:83-91.
154. Satterthwaite, A. B., Li, Z. Witte, O. N.1998. Btk function in B cell development and response. Semin. Immunol.10:309-316.
155. Yu, P., Constien, R., Dear, N., Katan, M., Hanke, P., Bunney, T. D., Kunder, S., Quintanilla-Martinez, L., Huffstadt, U., Schroder, A., Jones, N. P., Peters, T., Fuchs, H., de Angelis, M. H., Nehls, M., Grosse, J., Wabnitz, P., Meyer, T. P., Yasuda, K., Schiemann, M., Schneider-Fresenius, C., Jagla, W., Russ, A., Popp, A., Josephs, M., Marquardt, A., Laufs, J., Schmittwolf, C. Wagner, H., Pfeffer, K. Mudde, G. C.2005. Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry. Immunity 22:451-465.
156. Ji, Q. S., Winnier, G. E., Niswender, K. D., Horstman, D., Wisdom, R., Magnuson, M. A. Carpenter, G.1997. Essential role of the tyrosine kinase substrate phospholipase C-gammal in mammalian growth development. Proc. Natl. Acad. Sci. U. S. A.94:2999-3003.
157. Smith, M. R., Liu, Y. L., Kim, H., Rhee, S. G. Kung, H. F.1990. Inhibition of serum-ras-stimulated DNA synthesis by antibodies to phospholipase C. Science 247:1074-1077.
158. Kassis, J., Moellinger, J., Lo, H., Greenberg, N. M., Kim, H. G. Wells, A.1999. A role for phospholipase C-gamma-mediated signaling in tumor cell invasion. Clin. Cancer Res.5:2251-2260.
159. Irvin, B. J., Williams, B. L., Nilson, A. E., Maynor, H. O. Abraham, R. T.2000 Pleiotropic contributions of phospholipase C-gammal (PLC-gammal) to T-cell antigen receptor-mediated signaling:reconstitution studies of a PLC-gammal-deficient Jurkat T-cell line. Mol. Cell. Biol.20:9149-9161.
160. Bae, S. S., Lee, Y. H., Chang, J. S., Galadari, S. H., Kim, Y. S., Ryu, S. H. Suh, P. G.1998. Src homology domains of phospholipase C gammal inhibit nerve growth factor-induced differentiation of PC12 cells. J. Neurochem.71:178-185.
161. Patterson, R. L., van Rossum, D. B., Ford, D. L., Hurt, K. J., Bae, S. S., Suh, P. G., Kurosaki, T., Snyder, S. H. Gill, D. L. (2002) Phospholipase C-gamma is required for agonist-induced Ca2+ entry. Cell 111:529-541.
162. Huang, P. S., Davis, L., Huber, H., Goodhart, P. J., Wegrzyn, R. E., Oliff, A. Heimbrook, D. C.1995. An SH3 domain is required for the mitogenic activity of microinjected phospholipase C-gamma 1. FEBS Lett. 358287-292.
163. Ye, K.2005. PIKE/nuclear PI 3-kinase signaling in preventing programmed cell death. J. Cell Biochem.96:463-472.
164. Ye, K. Snyder, S. H.2004. PIKE GTPase:a novel mediator of phosphoinositide signaling. J. Cell Sci.117:155-161.
165. Choi, J. H., Yang, Y. R., Lee, S. K., Kim, I. S., Ha, S. H., Kim, E. K., Bae, Y. S., Ryu, S. H. Suh, P. G.2007 Phospholipase C-gammal potentiates integrin-dependent cell spreading and migration through Pyk2/paxillin activation. Cell. Signal.19:1784-1796.
166. Kanner, S. B., Grosmaire, L. S., Ledbetter, J. A. Damle, N. K.1993. Beta 2-integrin LFA-1 signaling through phospholipase C-gamma 1 activation. Proc. Natl. Acad. Sci. U. S. A.90:-7103.
167. Mackay F. Browning JL.2002. BAFF:A fundamental factor for B cells. Nature Rev. Immunol.2:465-475.
1. Willis TG. Dalal MJ. Du. M. Peng H. Perry A. Abdul-Rauf. M. Price H. et al. 1999. Bcl10 is involved in t (1;14) (p22;q32) of MALT B cell lymphoma mutated in multiple tumor types. Cell 96:35-45.
2. Du, M. Q., H. Peng, H. Liu, R. A. Hamoudi, T. C. Diss, T. G. Willis, H. Ye, A. Dogan, A. C. Wotherspoon, M. J. Dyer, P. G. Isaacson.2000. BCL10 gene mutation in lymphoma. Blood 95:3885-3890.
3. Ruland J. Duncan GS. Elia A. Barrantes I. Nguyen L. Plyte S. Millar DG. Bouchard D. Wakeham A. Ohashi P. Mak TW.2001. Bcl10 is a positive regulator of antigen receptor-induced activation of NF-κB and neural tube closure. Cell 104:33-42.
4. Xue L. Morris SW. Orihuela C. Tuomanen E. Cui X. Ren W. Wang D.2003. Defective development and function of Bcl10-deficient follicular, marginal zone and B1 B cells. Nature Immunol.4:857-865.
5. Ferch U. Buschenfelde M. Gewies A. Wegener E. Rauser S. Peschel C. Krappmann D. Ruland J.2007 MALT1 directs B cell receptor-induced canonical nuclear factor-KB signaling selectively to the c-Rel subunit. Nature Immunol.8:984-991.
6. Siebenlist U. Brown K. Claudio E.2005. Control of lymphocyte development by nuclear factor-κB. Nat. Rev. Immunol.5:435-445.
7. Hayden MS. Ghosh S.2004. Signaling to NF-kappaB. Genes Dev.18:2195-2224.
8. Gerondakis S. Strasser A.2003. The role of Rel/NF-B transcription factors in B lymphocytes survival. Seminars Immunol.15:159-166.
9. Goodnow CC. Sprent J. Groth B. Vinuesa C.2005. Celluar and genetic mechanisms of self tolerance and autoimmunity. Nature 435:590-597.
10. Lesley R.2004. Reduced competitiveness of autoantigen-engaged B cells due to increased dependence on BAFF. Immunity 20:441-453.
11. Goodnow CC. Crosbie J. Adelstein S. Lavoie TB. Smith-Gill SJ. Brink RA. Pritchard-Briscoe H. Wotherspoon JS. Loblay RH. Raphael K.1988. Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334:676-682.
12. Healy JI. Goodnow CC.1998. Positive versus negative signaling by lymphocyte antigen receptors. Annu. Rev. Immunol.16:645-670.
13. Schiemann B. et al.2001. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293:2111-2114.
14. Groom J. et al. Association of BAFF/BlyS overexpression and altered B cell differentiation with Sjogren's syndrome. J. Clin. Invest.109:59-68.
15. Gardam S. Sierro F. Basten A. Mackay F. Brink R.2008. TRAF2 and TRAF3 signal adapters act cooperatively to control the maturation and survival signaling delivered to B cells by the BAFF receptor. Immunity 28:391-401.
16. Merrell KT. Benschop RJ. Gauld SB. Aviszus K. Decote-Ricardo D. Wysocki LJ. Cambier JC.2006. Identification of anergic B cells within a wild-type repertoire. Immunity 25:953-962.
1.Rhee SG. Bae YS.1997. Regulation of phosphoinositide-specific phospholipase C isozymes. J. Biol. Chem.272:'5045-15048.
2.Suh PG. Park J. Manzoli L. Cocco L. Peak J. Katan M. Fukami K. Kataoka T. Yun S. Ryu SH.2008. Multiple roles of phosphoinositide-specific phospholipase C isozymes. BMB reports.415-434.
3. Miura O. Nakamura N. Ihle JN. Aoki N.1994. Erythropoietin-dependent association of phosphatidylinositol 3-kinase with tyrosine-phosphorylated erythropoietin receptor. J. Biol. Chem.269:614-620.
4. Noh DY. Shin SH. Rhee SG.1995. Phosphoinositide-specific phospholipase C and mitogenic signaling. Biochim Biophys Acta.1242:99-113.
5. Ji QS. Ermini S. Baulida J. Sun F. Carpenter G.2007. Epidermal growth factor signaling and mitogenesis is PLCyl null mouse embryonic fibroblasts. Mol. Biol. Cell 9:749-757.
6. Wang D. Feng J. Wen R. Marine JC. Sangster MY. Parganas E. Hoffmeyer A. Jackson CW. Cleverland JL. Murray Pi. Ihle JN.2000. Phospholipase Cγ2 is essential in the functions of B cells and several Fc receptors. Immunity 13:25-35.
7. Fu G. Chen Y. Yu M. Podd A. Schuman J. He Y. Di L. Yassai M. Haribhai D. North PE. Gorski J. Williams CB. Wang D. Wen R.2010. Phospholipase Cyl is essential for T cell development, activation and tolerance. J. Exp. Med. 207:309-318.
8. Ji QS. Winnier GE. Niswender KD. Horstman D. Wisdom R. Magnuson MA. Carpenter G.1997. Essential role of the tyrosine kinase substrate phospholipase C-gammal in mammalian growth and development. Proc. Natl. Acad. Sci.94:2999-3002.
9. Srinivas S. Watanabe T.Lin CS. William CM. Tanabe Y. Jessell TM. Constantini F.2001. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol.1:1-4.
10. Wen R. Chen Y. Schuman J. Fu G. Yang S. Zhang W. Newman D. Wang D. 2004. An important role of phospholipase Cγ1 in pre-B-cell development and allelic exclusion.23:4007-4017.
11. Carter RH. Fearon DT.1992. CD19:lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256:105-107.
12. Kuhn R. Schwenk F. Aguet M. Rajewsky K.1995. Inducible gene targeting in mice. Science 269:1427-1429.
13. Kitamuar D. Roes J. Kuhn R. Rajewsky K.1991. A B cell deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature.350:423-426.
14. Randall K. et al.2009. Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nature Immunol.10:1283-1291.
15. Tavares RM, Turer EE, Liu CL, Advincula R, Scapini P, Rhee L, Barrera J, Lowell CA, Utz PJ, Malynn BA, Ma A.2010. The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity. Immunity. 33:181-91.
16. Tiller T. Kofer J. Kreschel C. Busse CE. Riebel S. Wichert S. Oden F. Mertes MM. Ehlers M. Wardemann H.2010. Development of self-reactive germinal center B cells and plasma cells in autoimmune FcyRIIB-deficient mice. J. Exp. Med.12:2767-2778.
17. Jacobi and Diamond,2005 A.M. Jacobi AM. Diamond B.2005. Balancing diversity and tolerance:Lessons from patients with systemic lupus erythematosus. J. Exp. Med.202:341-344.
18. Shlomchik MJ.2008. Sites and stages of autoreactive B cell activation and regulation. Immunity 28:18-28.
19. Yurasov S. Nussenzweig MC.2007. Regulation of autoreactive antibodies. Curr. Opin. Rheumatol.19:421-426.
20. Cappione et al.,2005 A. Cappione A. Anolik JH. Pugh-Bernard A. Barnard J. Dutcher P. Silverman G. Sanz I. Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus. J. Clin. Invest. 115:3205-3216.