Germinal centres: Role in B-cell physiology and malignancy

Nature Reviews Immunology

Volumn 8, Issue 1, 2008, Pages 22-33

  Klein, Ulf ^a   Dalla Favera, Riccardo ^a  

^a Och Spine at New York Presbyterian Hospitals   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

TRANSCRIPTION FACTOR;

B CELL LYMPHOMA; GENETIC TRANSCRIPTION; GERMINAL CENTER; LYMPHOCYTE STRUCTURE; MALIGNANT TRANSFORMATION; MEMORY CELL; NONHUMAN; PATHOGENESIS; PHENOTYPE; PLASMA CELL; PRIORITY JOURNAL; REVIEW; SOMATIC HYPERMUTATION; TRANSCRIPTION REGULATION;

ANIMALS; B-LYMPHOCYTES; CELL DIFFERENTIATION; GERMINAL CENTER; HUMANS; LYMPHOMA, B-CELL;

EID: 37549015263     PISSN: 14741733     EISSN: None     Source Type: Journal    
DOI: 10.1038/nri2217     Document Type: Review

References (135)

1. MacLennan, I. C. & Gray, D. Antigen-driven selection of virgin and memory B cells. Immunol. Rev. 91, 61-85 (1986).
2. Jacob, J., Kelsoe, G., Rajewsky, K. & Weiss, U. Intraclonal generation of antibody mutants in germinal centres. Nature 354, 389-392 (1991).
3. Berek, C., Berger, A. & Apel, M. Maturation of the immune response in germinal centers. Cell 67, 1121-1129 (1991).
4. MacLennan, I. C. Germinal centers. Annu. Rev. Immunol. 12, 117-139 (1994).
5. Küppers, R., Klein, U., Hansmann, M. L. & Rajewsky, K. Cellular origin of human B-cell lymphomas. N. Engl. J. Med. 341, 1520-1529 (1999).
6. Stevenson, F. et al. Insight into the origin and clonal history of B-cell tumors as revealed by analysis of immunoglobulin variable region genes. Immunol. Rev. 162, 247-259 (1998).
7. Camacho, S. A., Kosco-Vilbois, M. H. & Berek, C. The dynamic structure of the germinal center. Immunol. Today 19, 511-514 (1998).
8. Wang, Y. & Carter, R. H. CD19 regulates B cell maturation, proliferation, and positive selection in the FDC zone of murine splenic germinal centers. Immunity 22, 749-761 (2005).
9. Allen, C. D., Okada, T., Tang, H. L. & Cyster, J. G. Imaging of germinal center selection events during affinity maturation. Science 315, 528-531 (2007).
10. Schwickert, T. A. et al. In vivo imaging of germinal centres reveals a dynamic open structure. Nature 446, 83-87 (2007).
11. Hauser, A. E. et al. Definition of germinal-center B cell migration in vivo reveals predominant intrazonal circulation patterns. Immunity 26, 655-667 (2007).
12. Brink, R. Germinal-center B cells in the zone. Immunity 26, 552-554 (2007).
13. Hauser, A. E., Shlomchik, M. J. & Haberman, A. M. In vivo imaging studies shed light on germinal-centre development. Nature Rev. Immunol. 7, 499-504 (2007).
14. Allen, C. D. et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nature Immunol. 5, 943-952 (2004). This work provided insights into the trafficking of cells between the dark and light zones of GCs and is the first in an elegant series of studies (see references 9,10 and 11) that dissects the dynamics of GC B-cell differentiation using sophisticated experimental systems.
15. Klein, U. et al. Transcriptional analysis of the B cell germinal center reaction. Proc. Nat Acad. Sci. USA 100, 2639-2644 (2003).
16. Shaffer, A. L. et al. Signatures of the immune response. Immunity 15, 375-385 (2001).
17. Phan, R. T. & Dalla-Favera, R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 432, 635-639 (2004). This study shows that the p53-dependent response to DNA damage normally resulting in growth arrest and apoptotic responses is specifically suppressed in centroblasts by BCL-6.
18. Hu, B. T., Lee, S. C., Marin, E., Ryan, D. H. & Insel, R. A. Telomerase is up-regulated in human germinal center B cells in vivo and can be re-expressed in memory B cells activated in vitro. J. Immunol. 159, 1068-1071 (1997).
19. Liu, Y. J. et al. Mechanism of antigen-driven selection in germinal centres. Nature 342, 929-931 (1989). This is the first demonstration that GC B cells do not survive in vitro unless rescued by CD40 stimulation, thereby providing the first indication that centroblasts are characterized by a proapoptotic gene expression programme.
20. Feuillard, J., Taylor, D., Casamayor-Palleja, M., Johnson, G. D. & MacLennan, I. C. Isolation and characteristics of tonsil centroblasts with reference to Ig class switching. Int. Immunol. 7, 121-130 (1995).
21. + B cell subset with phenotypical and functional characteristics of germinal center B cells. Eur. J. Immunol. 26, 1712-1719 (1996).
22. Liu, Y. J. et al. Germinal center cells express BCL-2 protein after activation by signals which prevent their entry into apoptosis. Eur. J. Immunol. 21, 1905-1910 (1991).
23. Martinez-Valdez, H. et al. Human germinal center B cells express the apoptosis-inducing genes Fas, c-myc, P53, and Bax but not the survival gene bcl-2. J. Exp. Med. 183, 971-977 (1996).
24. Smith, K. G., Nossal, G. J. & Tarlinton, D. M. FAS is highly expressed in the germinal center but is not required for regulation of the B-cell response to antigen. Proc. Natl Acad. Sci. USA 92, 11628-11632 (1995).
25. Takahashi, Y., Ohta, H. & Takemori, T. Fas is required for clonal selection in germinal centers and the subsequent establishment of the memory B cell repertoire. Immunity 14, 181-192 (2001).
26. de Villartay, J. P., Fischer, A. & Durandy, A. The mechanisms of immune diversification and their disorders. Nature Rev. Immunol. 3, 962-972 (2003).
27. Han, S. et al. Cellular interaction in germinal centers. Roles of CD40 ligand and B7-2 in established germinal centers. J. Immunol. 155, 556-567 (1995).
28. Basso, K. et al. Tracking CD40 signaling during germinal center development. Blood 104, 4088-4096 (2004).
29. Kosco-Vilbois, M. H., Bonnefoy, J. Y. & Chvatchko, Y. The physiology of murine germinal center reactions. Immunol. Rev. 156, 127-136 (1997).
30. Su, G. H. et al. Defective B cell receptor-mediated responses in mice lacking the Ets protein, Spi-B. EMBO J. 16, 7118-7129 (1997).
31. Muto, A. et al. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 429, 566-571 (2004).
32. Lee, C. H. et al. Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein. J. Exp. Med. 203, 63-72 (2006).
33. Toyama, H. et al. Memory B cells without somatic hypermutation are generated from Bcl6-deficient B cells. Immunity 17, 329-339 (2002).
34. William, J., Euler, C., Christensen, S. & Shlomchik, M. J. Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science 297, 2066-2070 (2002).
35. Weller, S. et al. Human blood IgM "memory" B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire. Blood 104, 3647-3654 (2004).
36. Shen, H. M., Peters, A., Baron, B., Zhu, X. & Storb, U. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science 280, 1750-1752 (1998).
37. Pasqualucci, L. et al. BCL-6 mutations in normal germinal center B cells: evidence of somatic hypermutation acting outside Ig loci. Proc. Natl Acad. Sci. USA 95, 11816-11821 (1998). References 36 and 37 describe for the first time that the somatic hypermutation machinery can act outside the antibody gene loci.
38. Wagner, S. D. & Neuberger, M. S. Somatic hypermutation of immunoglobulin genes. Annu. Rev. Immunol. 14, 441-457 (1996).
39. Papavasiliou, F. N. & Schatz, D. G. Cell-cycle-regulated DNA double-stranded breaks in somatic hypermutation of immunoglobulin genes. Nature 408, 216-221 (2000).
40. Bross, L. et al. DNA double-strand breaks in immunoglobulin genes undergoing somatic hypermutation. Immunity 13, 589-597 (2000).
41. Muramatsu, M. et al. Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102, 553-563 (2000).
42. Revy, P. et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102, 565-575 (2000). References 41 and 42 identify AID as the enzyme required for SHM and CSR.
43. Petersen-Mahrt, S. K., Harris, R. S. & Neuberger, M. S. AID mutates E. coli suggesting a DNA deamination mechanism for antibody diversification. Nature 418, 99-103 (2002).
44. Bransteitter, R., Pham, P., Scharff, M. D. & Goodman, M. F. Activation-induced cytidine deaminase deaminates deoxycytidine on single-stranded DNA but requires the action of RNase. Proc. Natl Acad. Sci. USA 100, 4102-4107 (2003).
45. Chaudhuri, J. et al. Transcription-targeted DNA deamination by the AID antibody diversification enzyme. Nature 422, 726-730 (2003).
46. Di Noia, J. & Neuberger, M. S. Altering the pathway of immunoglobulin hypermutation by inhibiting uracil-DNA glycosylase. Nature 419, 43-48 (2002).
47. Dickerson, S. K., Market, E., Besmer, E. & Papavasiliou, F. N. AID mediates hypermutation by deaminating single stranded DNA. J. Exp. Med. 197, 1291-1296 (2003).
48. Ramiro, A. R., Stavropoulos, P., Jankovic, M. & Nussenzweig, M. C. Transcription enhances AID-mediated cytidine deamination by exposing single-stranded DNA on the nontemplate strand. Nature Immunol. 4, 452-456 (2003).
49. Di Noia, J. M. & Neuberger, M. S. Molecular mechanisms of antibody somatic hypermutation. Annu. Rev. Biochem. 76, 1-22 (2007).
50. Küppers, R., Zhao, M., Hansmann, M. L. & Rajewsky, K. Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J. 12, 4955-4967 (1993).
51. Pasqualucci, L. et al. Expression of the AID protein in normal and neoplastic B cells. Blood 104, 3318-3325 (2004).
52. Cattoretti, G. et al. Nuclear and cytoplasmic AID in extrafollicular and germinal center B cells. Blood 107, 3967-3975 (2006).
53. Sayegh, C. E., Quong, M. W., Agata, Y. & Murre, C. E-proteins directly regulate expression of activation-induced deaminase in mature B cells. Nature Immunol. 4, 586-593 (2003).
54. Gonda, H. et al. The balance between Pax5 and Id2 activities is the key to AID gene expression. J. Exp. Med. 198, 1427-1437 (2003).
55. Chaudhuri, J., Khuong, C. & Alt, F. W. Replication protein A interacts with AID to promote deamination of somatic hypermutation targets. Nature 430, 992-998 (2004).
56. Basu, U. et al. The AID antibody diversification enzyme is regulated by protein kinase A phosphorylation. Nature 438, 508-511 (2005).
57. Pasqualucci, L., Kitaura, Y., Gu, H. & Dalla-Favera, R. PKA-mediated phosphorylation regulates the function of activation-induced deaminase (AID) in B cells. Proc. Natl Acad. Sci. USA 103, 395-400 (2006).
58. McBride, K. M. et al. Regulation of hypermutation by activation-induced cytidine deaminase phosphorylation. Proc. Natl Acad. Sci. USA 103, 8798-8803 (2006).
59. Pasqualucci, L. et al. Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412, 341-346 (2001). This is the first demonstration that proto-oncogenes in a certain type of lymphoma are frequently hypermutated in their promoter region, and may contribute to lymphomagenesis by causing dysregulated expression.
60. Ye, B. H. et al. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 262, 747-750 (1993).
61. Cattoretti, G. et al. BCL-6 protein is expressed in germinal-center B cells. Blood 86, 45-53 (1995).
62. Allman, D. et al. BCL-6 expression during B-cell activation. Blood 87, 5257-5268 (1996).
63. Dent, A. L., Shaffer, A. L., Yu, X., Allman, D. & Staudt, L. M. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science 276, 589-592 (1997).
64. Ye, B. H. et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nature Genet. 16, 161-170 (1997). References 63 and 64 show that the BCL6 proto-oncogene is required for the formation of GCs in T-cell-dependent immune responses.
65. Cattoretti, G. et al. Deregulated BCL6 expression recapitulates the pathogenesis of human diffuse large B cell lymphomas in mice. Cancer Cell 7, 445-455 (2005).
66. Polo, J. M. et al. Specific peptide interference reveals BCL6 transcriptional and oncogenic mechanisms in B-cell lymphoma cells. Nature Med. 10, 1329-1335 (2004).
67. Fujita, N. et al. MTA3 and the Mi-2/NuRD complex regulate cell fate during B lymphocyte differentiation. Cell 119, 75-86 (2004).
68. Parekh, S. et al. BCL6 programs lymphoma cells for survival and differentiation through distinct biochemical mechanisms. Blood 110, 2067-2074 (2007).
69. Shaffer, A. L. et al. BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13, 199-212 (2000). This study employs an elegant global gene expression-profiling approach to identify BCL-6 target genes, providing novel insights into BCL-6 function.
70. Niu, H., Cattoretti, G. & Dalla-Favera, R. BCL6 controls the expression of the B7-1/CD80 costimulatory receptor in germinal center B cells. J. Exp. Med. 198, 211-221 (2003).
71. Phan, R. T., Saito, M., Basso, K., Niu, H. & Dalla-Favera, R. BCL6 interacts with the transcription factor Miz-1 to suppress the cyclin-dependent kinase inhibitor p21 and cell cycle arrest in germinal center B cells. Nature Immunol. 6, 1054-1060 (2005).
72. Ranuncolo, S. M. et al. Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR. Nature Immunol. 8, 705-714 (2007).
73. Phan, R. T., Saito, M., Kitagawa, Y., Means, A. & Dalla-Favera, R. Genotoxic stress regulates expression of the BCL6 proto-oncogene in germinal center B cells. Nature Immunol. 8, 1132-1139 (2007).
74. Tunyaplin, C. et al. Direct repression of prdm1 by Bcl-6 inhibits plasmacytic differentiation. J. Immunol. 173, 1158-1165 (2004).
75. Vasanwala, F. H., Kusam, S., Toney, L. M. & Dent, A. L. Repression of AP-1 function: a mechanism for the regulation of Blimp-1 expression and B lymphocyte differentiation by the B cell lymphoma-6 protooncogene. J. Immunol. 169, 1922-1929 (2002).
76. Turner, C. A. Jr, Mack, D. H. & Davis, M. M. Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 77, 297-306 (1994).
77. Shapiro-Shelef, M. et al. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19, 607-620 (2003). References 76 and 77 show that the transcriptional repressor BLIMP1 is essential for the terminal differentiation of a B cell into a plasma cell.
78. Kuo, T. C. et al. Repression of BCL-6 is required for the formation of human memory B cells in vitro. J. Exp. Med. 204, 819-830 (2007).
79. Niu, H., Ye, B. H. & Dalla-Favera, R. Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev. 12, 1953-1961 (1998).
80. Saito, M. et al. A signaling pathway mediating down-regulation of BCL6 in germinal center B-cells is blocked by BCL6 gene alterations in B-cell lymphoma. Cancer Cell 12, 280-292 (2007).
81. Bereshchenko, O. R., Gu, W. & Dalla-Favera, R. Acetylation inactivates the transcriptional repressor BCL6. Nature Genet. 32, 606-613 (2002).
82. Blink, E. J. et al. Early appearance of germinal center-derived memory B cells and plasma cells in blood after primary immunization. J. Exp. Med. 201, 545-554 (2005).
83. Shih, T. A., Meffre, E., Roederer, M. & Nussenzweig, M. C. Role of BCR affinity in T cell dependent antibody responses in vivo. Nature Immunol. 3, 570-575 (2002).
84. Phan, T. G. et al. High affinity germinal center B cells are actively selected into the plasma cell compartment. J. Exp. Med. 203, 2419-2424 (2006).
85. Barreto, V., Reina-San-Martin, B., Ramiro, A. R., McBride, K. M. & Nussenzweig, M. C. C-terminal deletion of AID uncouples class switch recombination from somatic hypermutation and gene conversion. Mol. Cell 12, 501-508 (2003).
86. Ta, V. T. et al. AID mutant analyses indicate requirement for class-switch-specific cofactors. Nature Immunol. 4, 843-848 (2003).
87. Rooney, S., Chaudhuri, J. & Alt, F. W. The role of the non-homologous end-joining pathway in lymphocyte development. Immunol. Rev. 200, 115-131 (2004).
88. Liu, Y. J. et al. Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity 4, 241-250 (1996).
89. Tafuri, A. et al. ICOS is essential for effective T-helper-cell responses. Nature 409, 105-109 (2001).
90. McAdam, A. J. et al. ICOS is critical for CD40-mediated antibody class switching. Nature 409, 102-105 (2001).
91. Castigli, E. et al. TACI and BAFF-R mediate isotype switching in B cells. J. Exp. Med. 201, 35-39 (2005).
92. Klein, U. et al. IRF4 controls plasma cell differentiation and class switch recombination. Nature Immunol. 7, 773-782 (2006).
93. Sciammas, R. et al. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity 25, 225-236 (2006).
94. Liu, Y. J. & Banchereau, J. Regulation of B-cell commitment to plasma cells or to memory B cells. Semin. Immunol. 9, 235-240 (1997).
95. Shan, H., Shlomchik, M. & Weigert, M. Heavy-chain class switch does not terminate somatic mutation. J. Exp. Med. 172, 531-536 (1990).
96. Cobaleda, C., Schebesta, A., Delogu, A. & Busslinger, M. Pax5: the guardian of B cell identity and function. Nature Immunol. 8, 463-470 (2007).
97. Delogu, A. et al. Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells. Immunity 24, 269-281 (2006).
98. Nera, K. P. et al. Loss of Pax5 promotes plasma cell differentiation. Immunity 24, 283-293 (2006).
99. Kallies, A. et al. Initiation of plasma-cell differentiation is independent of the transcription factor blimp-1. Immunity 26, 555-566 (2007). This study demonstrates that the earliest step in plasma-cell differentiation is mediated by the downregulation of PAX5, followed by BLIMP1 upregulation.
100. Falini, B. et al. A monoclonal antibody (MUM1p) detects expression of the MUM1/IRF4 protein in a subset of germinal center B cells, plasma cells, and activated T cells. Blood 95, 2084-2092 (2000).
101. Angelin-Duclos, C., Cattoretti, G., Lin, K. I. & Calame, K. Commitment of B lymphocytes to a plasma cell fate is associated with Blimp-1 expression in vivo. J. Immunol. 165, 5462-5471 (2000).
102. Reimold, A. M. et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature 412, 300-307 (2001).
103. Shaffer, A. L. et al. XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity 21, 81-93 (2004).
104. Mittrücker, H. W. et al. Requirement for the transcription factor LSIRF/IRF4 for mature B and T lymphocyte function. Science 275, 540-543 (1997).
105. Fornek, J. L. et al. Critical role for Stat3 in T-dependent terminal differentiation of IgG B cells. Blood 107, 1085-1091 (2006).
106. Scheeren, F. A. et al. STAT5 regulates the self-renewal capacity and differentiation of human memory B cells and controls Bcl-6 expression. Nature Immunol. 6, 303-313 (2005).
107. Reljic, R., Wagner, S. D., Peakman, L. J. & Fearon, D. T. Suppression of signal transducer and activator of transcription 3-dependent B lymphocyte terminal differentiation by BCL-6. J. Exp. Med. 192, 1841-1848 (2000).
108. Arpin, C. et al. Generation of memory B cells and plasma cells in vitro. Science 268, 720-722 (1995).
109. Stevenson, F. et al. Insight into the origin and clonal history of B-cell tumors as revealed by analysis of immunoglobulin variable region genes. Immunol. Rev. 162, 247-259 (1998).
110. Küppers, R. & Dalla-Favera, R. Mechanisms of chromosomal translocations in B cell lymphomas. Oncogene 20, 5580-5594 (2001).
111. Küppers, R. Mechanisms of B-cell lymphoma pathogenesis. Nature Rev. Cancer 5, 251-262 (2005).
112. Lenz, G. et al. Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma. J. Exp. Med. 204, 633-643 (2007).
113. Pasqualucci, L. et al. Mutations of the BCL6 proto-oncogene disrupt its negative autoregulation in diffuse large B-cell lymphoma. Blood 101, 2914-2923 (2003).
114. Okazaki, I. M. et al. Constitutive expression of AID leads to tumorigenesis. J. Exp. Med. 197, 1173-1181 (2003).
115. Ramiro, A. R. et al. AID is required for c-myc/IgH chromosome translocations in vivo. Cell 118, 431-438 (2004).
116. Unniraman, S., Zhou, S. & Schatz, D. G. Identification of an AID-independent pathway for chromosomal translocations between the Igh switch region and Myc. Nature Immunol. 5, 1117-1123 (2004).
117. Franco, S. et al. H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol. Cell 21, 201-214 (2006).
118. Kotani, A. et al. Activation-induced cytidine deaminase (AID) promotes B cell lymphomagenesis in Emu-cmyc transgenic mice. Proc. Natl Acad. Sci. USA 104, 1616-1620 (2007).
119. Pasqualucci, L. et al. Activation induced cytidine deaminase (AID) is required for germinal-center-derived lymphomagenesis. Nature Genet. 9 December 2007 (doi:10.1038/ng.2007.35) References 118 and 119 identify AID as being crucially involved in the pathogenesis of GC-derived B-cell lymphomas.
120. McDonnell, T. J. & Korsmeyer, S. J. Progression from lymphoid hyperplasia to high-grade malignant lymphoma in mice transgenic for the t(14;18). Nature 349, 254-256 (1991).
121. Iida, S. et al. The t(9;14)(p13;q32) chromosomal translocation associated with lymphoplasmacytoid lymphoma involves the PAX-5 gene. Blood 88, 4110-4117 (1996).
122. Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503-511 (2000).
123. Vafa, O. et al. c-Myc can induce DNA damage, increase reactive oxygen species, and mitigate p53 function: a mechanism for oncogene-induced genetic instability. Mol. Cell 9, 1031-1044 (2002).
124. Dominguez-Sola, D. et al. Non-transcriptional control of DNA replication by c-Myc. Nature 448, 445-451 (2007).
125. Tam, W. et al. Mutational analysis of PRDM1 indicates a tumor-suppressor role in diffuse large B-cell lymphomas. Blood 107, 4090-4100 (2006).
126. Pasqualucci, L. et al. Inactivation of the PRDM1/BLIMP1 gene in diffuse large B cell lymphoma. J. Exp. Med. 203, 311-317 (2006).
127. Davis, R. E., Brown, K. D., Siebenlist, U. & Staudt, L. M. Constitutive nuclear factor ?B activity is required for survival of activated B cell-like diffuse large B cell lymphoma cells. J. Exp. Med. 194, 1861-1874 (2001).
128. Thai, T. H. et al. Regulation of the germinal center response by microRNA-155. Science 316, 604-608 (2007).
129. Rodriguez, A. et al. Requirement of bic/microRNA-155 for normal immune function. Science 316, 608-611 (2007).
130. Goossens, T., Klein, U. & Küppers, R. Frequent occurrence of deletions and duplications during somatic hypermutation: implications for oncogene translocations and heavy chain disease. Proc. Natl Acad. Sci. USA 95, 2463-2468 (1998).
131. Toellner, K. M., Gulbranson-Judge, A., Taylor, D. R., Sze, D. M. & MacLennan, I. C. Immunoglobulin switch transcript production in vivo related to the site and time of antigen-specific B cell activation. J. Exp. Med. 183, 2303-2312 (1996).
132. Seki, M., Gearhart, P. J. & Wood, R. D. DNA polymerases and somatic hypermutation of immunoglobulin genes. EMBO Rep. 6, 1143-1148 (2005).
133. Martin, A. & Scharff, M. D. AID and mismatch repair in antibody diversification. Nature Rev. Immunol. 2, 605-614 (2002).
134. Shaffer, A. L. et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity 17, 51-62 (2002).
135. Lin, K. I., Angelin-Duclos, C., Kuo, T. C. & Calame, K. Blimp-1-dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol. Cell. Biol. 22, 4771-4780 (2002).