Somatic hypermutation in normal and transformed human B cells

Immunological Reviews

Volumn 162, Issue , 1998, Pages 261-280

  Klein, Ulf ^a   Goossens, Tina ^a   Fischer, Matthias ^a   Kanzler, Holger ^a   Braeuninger, Andreas ^b   Rajewsky, Klaus ^a   Küppers, Ralf ^a,c  

^a UNIVERSITY OF COLOGNE   (Germany)

^b GOETHE UNIVERSITY   (Germany)

^c UNIVERSITY HOSPITAL OF COLOGNE   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

CD27 ANTIGEN; CD5 ANTIGEN; IMMUNOGLOBULIN HEAVY CHAIN; IMMUNOGLOBULIN M; LYMPHOCYTE ANTIGEN RECEPTOR;

B CELL LYMPHOMA; B LYMPHOCYTE; CHROMOSOME TRANSLOCATION; CONTROLLED STUDY; GENE AMPLIFICATION; GENE DELETION; GENE INSERTION; GENE LOCUS; GENE REARRANGEMENT; HEAVY CHAIN DISEASE; HODGKIN DISEASE; HUMAN; HUMAN CELL; IMMUNOGLOBULIN GENE; IMMUNOGLOBULIN VARIABLE REGION; LYMPHOCYTE TRANSFORMATION; MEMORY CELL; NONHODGKIN LYMPHOMA; ONCOGENE; PRIORITY JOURNAL; REVIEW; SEQUENCE ANALYSIS; SOMATIC MUTATION; STEM CELL;

ANIMALS; ANTIBODY DIVERSITY; B-LYMPHOCYTES; CELL TRANSFORMATION, NEOPLASTIC; GENES, IMMUNOGLOBULIN; HUMANS; IMMUNOGLOBULIN VARIABLE REGION; LYMPHOCYTE SUBSETS; LYMPHOMA, B-CELL; MUTATION; POINT MUTATION; POLYMERASE CHAIN REACTION;

EID: 0031897511     PISSN: 01052896     EISSN: None     Source Type: Journal    
DOI: 10.1111/j.1600-065X.1998.tb01447.x     Document Type: Review

References (163)

1. Rajewsky K. Clonal selection and learning in the antibody system. Nature 1996;381:751-758.
2. Liu YJ, et al. Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. Immunity 1996;4:241-250.
3. Jacob J, Kelsoe G, Rajewsky K, Weiss U. Intraclonal generation of antibody mutants in germinal centres. Nature 1991;354:389-392.
4. Berek C, Berger A, Apel M. Maturation of the immune response in germinal centers. Cell 1991;67:1121-1129.
5. Küppers R, Zhao M, Hansmann ML, Rajewsky K. Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J 1993;12:4955-4967.
6. Küppers R, Roers A, Kanzler H. Molecular single cell studies of normal and transformed lymphocytes. Cancer Surv 1997;30:45-58.
7. Huang C, Stewart AK, Schwartz RS, Stollar BD. Immunoglobulin heavy chain gene expression in peripheral blood B lymphocytes. J Clin Invest 1992;89:1331-1343.
8. van Es JH, Meyling EH, Logtenberg T. High frequency of somatically mutated IgM molecules in the human adult blood B cell repertoire. Eur J Immunol 1992;22:2761-2764.
9. Chapple MR, MacLennan IC, Johnson GD. A phenotypic study of B lymphocyte subpopulations in human bone marrow. Clin Exp Immunol 1990;81:166-172.
10. Jelinek DF, Splawski JB, Lipsky PE. Human peripheral blood B lymphocyte subpopulations: functional and phenotypic analysis of surface IgD positive and negative subsets. J Immunol 1986;136:83-92.
11. Klein U, Küppers R, Rajewsky K. Human IgM+IgD+ B cells, the major B cell subset in the peripheral blood, express V kappa genes with no or little somatic mutation throughout life. Eur J Immunol 1993;23:3272-3277.
12. Klein U, Küppers R, Rajewsky K. Evidence for a large compartment of IgM-expressing memory B cells in humans. Blood 1997;89:1288-1298.
13. Pascual V, Liu YJ, Magalski A, de Bouteiller O, Banchereau J, Capra JD. Analysis of somatic mutation in five B cell subsets of human tonsil. J Exp Med 1994;180:329-339.
14. Klein U, Küppers R, Rajewsky K. Variable region gene analysis of B cell subsets derived from a 4-year- old child: somatically mutated memory B cells accumulate in the peripheral blood already at young age. J Exp Med 1994;180:1383-1393.
15. Agematsu K, et al. B cell subpopulations separated by CD27 and crucial collaboration of CD27+ B cells and helper T cells in immunoglobulin production. Eur J Immunol 1997;27:2073-2079.
16. Brezinschek HP, Brezinschek RI, Lipsky PE. Analysis of the heavy chain repertoire of human peripheral B cells using single-cell polymerase chain reaction. J Immunol 1995;155:190-202.
17. Maurer D, et al. IgM and IgG but not cytokine secretion is restricted to the CD27+ B lymphocyte subset. J Immunol 1992;148:3700-3705.
18. Fischer M, Klein U, Küppers R. Molecular single-cell analysis reveals that CD5-positive peripheral blood B cells in healthy humans are characterized by rearranged V kappa genes lacking somatic mutation. J Clin Invest 1997;100:1667-1676.
19. Ebeling SB, Schutte ME, Logtenberg T. Peripheral human CD5+ and CD5- B cells may express somatically mutated VH5- and VH6-encoded IgM receptors. J Immunol 1993;151:6891-6899.
20. Bridges SL Jr, et al. Somatic mutation and CDR3 lengths of immunoglobulin kappa light chains expressed in patients with rheumatoid arthritis and in normal individuals. J Clin Invest 1995;96:831-841.
21. Huang C, Stollar BD. A majority of Ig H chain cDNA of normal human adult blood lymphocytes resembles cDNA for fetal Ig and natural autoantibodies. J Immunol 1993;151:5290-5300.
22. Insel RA, Varade WS, Marin E. Human splenic IgM immunoglobulin transcripts are mutated at high frequency. Mol Immunol 1994;31:383-392.
23. Klein R, Jaenichen R, Zachau HG. Expressed human immunoglobulin kappa genes and their hypermutation. Eur J Immunol 1993;23:3248-3262.
24. Kipps TJ. The CD5 B cell. Adv Immunol 1989;47:117-185.
25. Ebeling SB. Schutte ME, Logtenberg T. The majority of human tonsillar CD5+ B cells express somatically mutated V kappa 4 genes. Eur J Immunol 1993;23:1405-1408.
26. Weber JC, Blaison G, Martin T, Knapp AM, Pasquali JL. Evidence that the V kappa III gene usage is nonstochastic in both adult and newborn peripheral B cells and that peripheral CD5+ adult B cells are oligoclonal. J Clin Invest 1994;93:2093-2105.
27. Irsch J, Irlenbusch S, Radl J, Burrows PD, Cooper MD, Radbruch AH. Switch recombination in normal IgA1 + B lymphocytes. Proc Natl Acad Sci USA 1994;91:1323-1327.
28. van Oers MH, et al. Expression and release of CD27 in human B-cell malignancies. Blood 1993;82:3430-3436.
29. Brezinschek HP, Foster SJ, Brezinschek RI, Dorner T, Domiati-Saad R, Lipsky PE. Analysis of the human VH gene repertoire. Differential effects of selection and somatic hypermutation on human peripheral CD5(+)/IgM+ and CD5(-)/IgM+ B cells. J Clin Invest 1997;99:2488-2501.
30. Foster SJ, Brezinschek HP, Brezinschek RI, Lipsky PE. Molecular mechanisms and selective influences that shape the kappa gene repertoire of IgM+ B cells. J Clin Invest 1997;99:1614-1627.
31. Gadol N, Ault KA. Phenotypic and functional characterization of human Leu1 (CD5) B cells. Immunol Rev 1986;93:23-34.
32. Bhat NM, Kantor AB, Bieber MM, Stall AM, Herzenberg LA, Teng NN. The ontogeny and functional characteristics of human B-1 (CD5+ B) cells. Int Immunol 1992;4:243-252.
33. Liu YJ, Johnson GD, Gordon J, MacLennan IC. Germinal centres in T-cell-dependent antibody responses. Immunol Today 1992;13:17-21.
34. Andris JS, Ehrlich PH, Ostberg L, Capra JD. Probing the human antibody repertoire to exogenous antigens. Characterization of the H and L chain V region gene segments from anti-hepatitis B virus antibodies. J Immunol 1992;149:4053-4059.
35. Bye JM, et al. Germline variable region gene segment derivation of human monoclonal anti-Rh(D) antibodies. Evidence for affinity maturation by somatic hypermutation and repertoire shift. J Clin Invest 1992;90:2481-2490.
36. Ikematsu H, Harindranath N, Ueki Y, Notkins AL, Casali P. Clonal analysis of a human antibody response. II. Sequences of the VH genes of human IgM, IgG, and IgA to rabies virus reveal preferential utilization of VHIII segments and somatic hypermutation. J Immunol 1993;150:1325-1337.
37. Mortari F, Wang JY, Schroeder HW Jr. Human cord blood antibody repertoire. Mixed population of VH gene segments and CDR3 distribution in the expressed C alpha and C gamma repertoires. J Immunol 1993;150:1348-1357.
38. Kindler V, Zubler RH. Memory, but not naive, peripheral blood B lymphocytes differentiate into Ig-secreting cells after CD40 ligation and costimulation with IL-4 and the differentiation factors IL-2, IL-10, and IL-3. J Immunol 1997;159:2085-2090.
39. Varade WS, Insel RA. Isolation of germinal centerlike events from human spleen RNA. Somatic hypermutation of a clonally related VH6DJH rearrangement expressed with IgM, IgG, and IgA. J Clin Invest 1993;91:1838-1842.
40. Notarangelo LD, Duse M, Ugazio AG. Immunodeficiency with hyper-IgM (HIM). Immunodefic Rev 1992;3:101-121.
41. Chu YW, et al. Somatic mutation of human immunoglobulin V genes in the X-linked HyperIgM syndrome. J Clin Invest 1995;95:1389-1393.
42. Razanajaona D, et al. Somatic mutations in human Ig variable genes correlate with a partially functional CD40-ligand in the X-linked hyper-IgM syndrome. J Immunol 1996;157:1492-1498.
43. Nossal GJ, Austin CM, Ada GL. Antigens in immunity. VII. Analysis of immunological memory. Immunology 1965;9:333-348.
44. Valentova V, Cerny J, Ivanyi J. Immunological memory of IgM and IgG type antibodies. I. Requirements of antigen dose for induction and of time interval for development of memory. Folia Biol 1967;13:100-108.
45. Schirrmacher V, Rajewsky K. Determination of antibody class in a system of cooperating antigenic determinants. J Exp Med 1970;132:1019-1034.
46. Paramithiotis E, Cooper MD. Memory B lymphocytes migrate to bone marrow in humans. Proc Natl Acad Sci USA 1997;94:208-212.
47. Lens SM, Keehnen RM, van Oers MH, van Lier RA, Pals ST, Koopman G. Identification of a novel subpopulation of germinal center B cells characterized by expression of IgD and CD70. Eur J Immunol 1996;26:1007-1011.
48. Reynaud CA, Garcia C, Hein WR, Weill JC. Hypermutation generating the sheep immunoglobulin repertoire is an antigen-independent process. Cell 1995;80:115-125.
49. Bos NA, et al. Serum immunoglobulin levels and naturally occurring antibodies against carbohydrate antigens in germ-free BALB/c mice fed chemically defined ultrafiltered diet. Eur J Immunol 1989;19:2335-2339.
50. Stall AM, Wells SM, Lam KP. B-1 cells: unique origins and functions. Semin Immunol 1996;8:45-59.
51. Kroese FG, Ammerlaan WA, Deenen GJ, Adams S, Herzenberg LA, Kantor AB. A dual origin for IgA plasma cells in the murine small intestine. Adv Exp Med Biol 1995;371A:435-440.
52. Kroese FG, Butcher EC, Stall AM, Lalor PA, Adams S, Herzenberg LA. Many of the IgA producing plasma cells in murine gut are derived from self-replenishing precursors in the peritoneal cavity. Int Immunol 1989;1:75-84.
53. Brandtzaeg P, et al. Immunobiology and immunopathology of human gut mucosa: humoral immunity and intraepithelial lymphocytes. Gastroenterology 1989;97:1562-1584.
54. Brandtzaeg P. Distribution and characteristics of mucosal immunoglobulin-producing cells. In: Ogra PL, ed. Handbook of mucosal immunology. San Diego: Academic Press; 1994. p. 251-262.
55. Dunn-Walters DK, Isaacson PG, Spencer J. Sequence analysis of human IgVH genes indicates that ileal lamina propria plasma cells are derived from Peyer's patches. Eur J Immunol 1997;27:463-467.
56. Dunn-Walters DK, Boursier L, Spencer J. Hypermutation, diversity and dissemination of human lamina propria plasma cells. Eur J Immunol 1997;27:2959-2964.
57. Baker BW, Deane M, Gilleece MH, Johnston D, Scarffe JH, Norton JD. Distinctive features of immunoglobulin heavy chain variable region gene rearrangement in multiple myeloma. Leuk Lymphoma 1994;14:291-301.
58. Bakkus MH, Heirman C, Van Riet I, Van Camp B, Thielemans K. Evidence that multiple myeloma Ig heavy chain VDJ genes contain somatic mutations but show no intraclonal variation. Blood 1992;80:2326-2335.
59. Sahota S, Hamblin T, Oscier DG, Stevenson FK. Assessment of the role of clonogenic B lymphocytes in the pathogenesis of multiple myeloma. Leukemia 1994;8:1285-1289.
60. Vescio RA, et al. Myeloma Ig heavy chain V region sequences reveal prior antigenic selection and marked somatic mutation but no intraclonal diversity. J Immunol 1995;155:2487-2497.
61. Klein U, Klein G, Ehlin-Henriksson B, Rajewsky K, Küppers R. Burkitt's lymphoma is a malignancy of mature B cells expressing somatically mutated V region genes. Mol Med 1995;1:495-505.
62. Küppers R, Hajadi M, Plank L, Rajewsky K, Hansmann ML. Molecular Ig gene analysis reveals that monocytoid B cell lymphoma is a malignancy of mature B cells carrying somatically mutated V region genes and suggests that rearrangement of the kappa-deleting element (resulting in deletion of the Ig kappa enhancers) abolishes somatic hypermutation in the human. Eur J Immunol 1996;26:1794-1800.
63. Küppers R, Rajewsky K, Hansmann ML. Diffuse large cell lymphomas are derived from mature B cells carrying V region genes with a high load of somatic mutation and evidence of selection for antibody expression. Eur J Immunol 1997;27:1398-1405.
64. Harris NL, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994;84:1361-1392.
65. Chapman CJ, Mockridge CI, Rowe M, Rickinson AB, Stevenson FK. Analysis of VH genes used by neoplastic B cells in endemic Burkitt's lymphoma shows somatic hypermutation and intraclonal heterogeneity. Blood 1995;85:2176-2181.
66. Chapman CJ, Zhou JX, Gregory C, Rickinson AB, Stevenson FK. VH and VL gene analysis in sporadic Burkitt's lymphoma shows somatic hypermutation, intraclonal heterogeneity, and a role for antigen selection. Blood 1996;88:3562-3568.
67. Hsu FJ, Levy R. Preferential use of the VH4 Ig gene family by diffuse large-cell lymphoma. Blood 1995;86:3072-3082.
68. van Belzen N, Hupkes PE, Doekharan D, Hoogeveen-Westerveld M, Dorssers LCJ, van't Veer MB. Detection of minimal disease using rearranged immunoglobulin heavy chain genes from intermediate- and high-grade malignant B cell non-Hodgkin's lymphoma. Leukemia 1997;11:1742-1752.
69. Stiernholm N, Kuzniar B, Berinstein NL. Absence of immunoglobulin variable region hypermutation in a large cell lymphoma after in vivo and in vitro propagation. Blood 1992;80:738-743.
70. Bahler DW, Campbell MJ, Hart S, Miller RA, Levy S, Levy R. Ig VH gene expression among human follicular lymphomas. Blood 1991;78:1561-1568.
71. Cleary ML, et al. Clustering of extensive somatic mutations in the variable region of an immunoglobulin heavy chain gene from a human B cell lymphoma. Cell 1986;44:97-106.
72. Bahler DW, Miklos JA, Swerdlow SH. Ongoing Ig gene hypermutation in salivary gland mucosa-associated lymphoid tissue-type lymphomas. Blood 1997;89:3335-3344.
73. Qin Y, Greiner A, Trunk MJ, Schmausser B, Ott MM, Müller-Hermelink HK. Somatic hypermutation in low-grade mucosa-associated lymphoid tissue-type B-cell lymphoma. Blood 1995;86:3528-3534.
74. Qin Y, Greiner A, Hallas C, Haedicke W, Müller-Hermelink HK. Intraclonal offspring expansion of gastric low-grade MALT-type lymphoma: evidence for the role of antigen-driven high-affinity mutation in lymphomagenesis. Lab Invest 1997;76:477-185.
75. Du M, Diss TC, Xu C, Peng H, Isaacson PG, Pan L. Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion. Leukemia 1996;10:1190-1197.
76. Riboldi P, et al. Two acquired immunodeficiency syndrome-associated Burkitt's lymphomas produce specific anti-i IgM cold agglutinins using somatically mutated VH4-21 segments. Blood 1994;83:2952-2961.
77. Ng VL, et al. IgMs produced by two acquired immune deficiency syndrome lymphoma cell lines: Ig binding specificity and VH-gene putative somatic mutation analysis. Blood 1994;83:1067-1078.
78. Davi F, et al. High frequency of somatic mutations in the VH genes expressed in prolymphocytic leukemia. Blood 1996;88:3953-3961.
79. Wagner SD, Martinelli V, Luzzatto L. Similar patterns of V kappa gene usage but different degrees of somatic mutation in hairy cell leukemia, prolymphocytic leukemia, Waldenstrom's macroglobulinemia, and myeloma. Blood 1994;83:3647-3653.
80. Cai J, Humphries C, Richardson A, Tucker PW. Extensive and selective mutation of a rearranged VH5 gene in human B cell chronic lymphocytic leukemia. J Exp Med 1992;176:1073-1081.
81. Hashimoto S, et al. Somatic diversification and selection of immunoglobulin heavy and light chain variable region genes in IgG+ CD5+ chronic lymphocytic leukemia B cells. J Exp Med 1995;181:1507-1517.
82. Hummel M, Tamaru J, Kalvelage B, Stein H. Mantle cell (previously centrocytic) lymphomas express VH genes with no or very little somatic mutations like the physiologic cells of the follicle mantle. Blood 1994;84:403-407.
83. Johnson TA, Rassenti LZ, Kipps TJ. Ig VH1 genes expressed in B cell chronic lymphocytic leukemia exhibit distinctive molecular features. J Immunol 1997;158:235-246.
84. Rassenti LZ, Kipps TJ. Lack of extensive mutations in the VH5 genes used in common B cell chronic lymphocytic leukemia. J Exp Med 1993;177:1039-1046.
85. Caligaris-Cappio F. B-chronic lymphocytic leukemia: a malignancy of anti-self B cells. Blood 1996;87:2615-2620.
86. Kantor AB, Stall AM, Adams K, Watanabe K, Herzenberg LA. De novo development and self-replenishment of B cells. Int Immunol 1995;7:55-68.
87. Hayakawa K, Hardy RR, Stall AM, Herzenberg LA, Herzenberg LA. Immunoglobulin-bearing B cells reconstitute and maintain the murine Ly-1 B cell lineage. Eur J Immunol 1986;16:1313-1316.
88. Förster I, Gu H, Rajewsky K. Germline antibody V regions as determinants of clonal persistence and malignant growth in the B cell compartment. EMBO J 1988;7:3693-3703.
89. Tarlinton D, Stall AM, Herzenberg LA. Repetitive usage of immunoglobulin VH and D gene segments in CD5+ Ly-1 B clones of (NZBxNZW)F1 mice. EMBO J 1988;7:3705-3710.
90. Haughton G, Arnold LW, Bishop GA, Mercelino TJ. The CH series of murine B cell lymphomas: neoplastic analogues of Ly-1+ normal B cells. Immunol Rev 1986;93:35-49.
91. Schroeder HW, Dighiero G. The pathogenesis of chronic lymphocytic leukemia: analysis of the antibody repertoire. Immunol Today 1994;15:288-294.
92. Burke JS. Hodgkin's disease: histopathology and differential diagnosis. In: Knowles DM, ed. Neoplastic hematopathology. Baltimore: Williams and Wilkins; 1992. p. 497-533.
93. Küppers R, Rajewsky K. The origin of Hodgkin and Reed/Sternberg cells in Hodgkin's disease. Annu Rev Immunol 1998 (In press).
94. Delabie J, Tierens A, Wu G, Weisenburger DD, Chan WC. Lymphocyte predominance Hodgkin's disease: lineage and clonality determination using a single-cell assay. Blood 1994;84:3291-3298.
95. Hummel M, Ziemann K, Lammert H, Pileri S, Sabattini E, Stein H. Hodgkin's disease with monoclonal and polyclonal populations of Reed-Sternberg cells. N Engl J Med 1995;333:901-906.
96. Delabie J, Tierens A, Gavriil T, Wu G, Weisenburger DD, Chan WC. Phenotype, genotype and clonality of Reed-Sternberg cells in nodular sclerosis Hodgkin's disease: results of a single-cell study. Br J Haematol 1996;94:198-205.
97. Hummel M, Marafioti T, Stein H. Immunoglobulin V genes in Reed-Sternberg cells. N Engl J Med 1996;334:405-406 (Letter).
98. Ohno T, Stribley JA, Wu G, Hinrichs SH, Weisenburger DD, Chan WC. Clonality in nodular lymphocyte-predominant Hodgkin's disease. N Engl J Med 1997;337:459-465.
99. Küppers R, et al. Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc Natl Acad Sci USA 1994;91:10962-10966.
100. Kanzler H, Küppers R, Hansmann ML, Rajewsky K. Hodgkin and Reed-Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor done derived from (crippled) germinal center B cells. J Exp Med 1996;184:1495-1505.
101. Kanzler H, et al. Molecular single cell analysis demonstrates the derivation of a peripheral blood-derived cell line (L1236) from the Hodgkin/Reed-Sternberg cells of a Hodgkin's lymphoma patient. Blood 1996;87:3429-3436.
102. Braeuninger A, Küppers R, Strickler JG, Wacker HH, Rajewsky K, Hansmann ML. Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells. Proc Natl Acad Sci USA 1997;94:9337-9342.
103. Marafioti T, et al. Origin of nodular lymphocyte-predominant Hodgkin's disease from a clonal expansion of highly mutated germinal-center B cells. N Engl J Med 1997;337:453-458.
104. Liu YJ, Grouard G, de Bouteiller O, Banchereau J. Follicular dendritic cells and germinal centers. Int Rev Cytol 1996;166:139-179.
105. Weiss U, Zoebelein R, Rajewsky K. Accumulation of somatic mutants in the B cell compartment after primary immunization with a T cell-dependent antigen. Eur J Immunol 1992;22:511-517.
106. Betz AG, Neuberger MS, Milstein C. Discriminating intrinsic and antigen-selected mutational hotspots in immunoglobulin V genes. Immunol Today 1993;14:405-411.
107. Neuberger MS, Milstein C. Somatic hypermutation. Curr Opin Immunol 1995;7:248-254.
108. Wagner SD, Neuberger MS. Somatic hypermutation of immunoglobulin genes. Annu Rev Immunol 1996;14:441-457.
109. Rogozin IB, Kolchanov NA. Somatic hypermutagenesis in immunoglobulin genes. II. Influence of neighbouring base sequence on mutagensis. Biochim Biophys Acta 1992;1171:11-18.
110. Dörner T, Brezinschek HP, Brezinschek RI, Foster SJ, Domiati-Saad R, Lipsky PE. Analysis of the frequency and pattern of somatic mutations within nonproductively rearranged human variable heavy chain genes. J Immunol 1997;158:2779-2789.
111. Betz AG, Milstein C, Gonzalez-Fernandez A, Pannell R, Larson T, Neuberger MS. Elements regulating somatic hypermutation of an immunoglobulin kappa gene: critical role for the intron enhancer/matrix attachment region. Cell 1994;77:239-248.
112. Goyenechea B, et al. Cells strongly expressing Ig(kappa) transgenes show clonal recruitment of hypermutation: a role for both MAR and the enhancers. EMBO J 1997;16:3987-3994.
113. Feddersen RM, Martin DJ, Van Ness BG. The frequency of multiple recombination events occurring at the human Ig kappa L chain locus. J Immunol 1990;144:1088-1093.
114. Klobeck HG. The human Ck gene segment and the kappa deleting element are closely linked. Nucleic Acids Res 1986;14:4591-4603.
115. Graninger WB, Goldman PL, Morton CC, O'Brien SJ, Korsmeyer SJ. The kappa-deleting element. J Exp Med 1988;167:488-501.
116. Siminovitch KA, Bakhshi A, Goldman P, Korsmeyer SJ. A uniform deleting element mediates the loss of kappa genes in human B cells. Nature 1985;316:260-262.
117. Allen D, et al. Timing, genetic requirements and functional consequences of somatic hypermutation during B-cell development. Immunol Rev 1987;96:5-22.
118. Shlomchik MJ, Aucoin AH, Pisetsky DS, Weigert MG. Structure and function of anti-DNA autoantibodies derived from a single autoimmune mouse. Proc Natl Acad Sci USA 1987;84:9150-9154.
119. Allen D, Simon T, Sablitzky F, Rajewsky K, Cumano A. Antibody engineering for the analysis of affinity maturation of an anti-hapten response. EMBO J 1988;7:1995-2001.
120. Shlomchik MJ, Nemazee DA, Sato VL, Van Snick J, Carson DA, Weigert MG. Variable region sequences of murine IgM anti-IgG monoclonal autoantibodies (rheumatoid factors). A structural explanation for the high frequency of IgM anti-IgG B cells. J Exp Med 1986;164:407-427.
121. Chang B, Casali P. The CDR1 sequence of a major proportion of human Ig VH genes are inherently susceptible to amino acid replacement. Immunol Today 1994;15:367-373.
122. 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 1998;95:2463-2468.
123. Close PM, Pringle JH, Ruprai AK, West KP, Lauder I. Zonal distribution of immunoglobulin-synthesizing cells within the germinal centre: an in situ hybridization and immunohistochemical study. J Pathol 1990;162:209-216.
124. Aoufouchi S, Yélamos J, Milstein C. Nonsense mutations inhibit RNA splicing in a cell-free system: recognition of mutant codon is independent of protein synthesis. Cell 1996;85:415-422.
125. Shokat KM, Goodnow CC. Antigen-induced B-cell death and elimination during germinal-centre immune responses. Nature 1995;375:334-338.
126. Pulendran B, Kannourakis G, Nouri S, Smith KGC, Nossal GJV. Soluble antigen can cause enhanced apoptosis of germinal-centre B cells. Nature 1995;375:331-334.
127. Nakamura M, et al. Death of germinal center B cells without DNA fragmentation. Eur J Immunol 1996;26:1211-1216.
128. Bahler DW, Levy R. Clonal evolution of a follicular lymphoma: evidence for antigen selection. Proc Natl Acad Sci USA 1992;89:6770-6774.
129. Kocks C, Rajewsky K. Stable expression and somatic hypermutation of antibody V regions in B-cell developmental pathways. Annu Rev Immunol 1989;7:537-559.
130. Andris JS, Johnson S, Zolla-Pazner S, Capra JD. Molecular characterization of five human anti-human immunodeficiency virus type 1 antibody heavy chains reveals extensive somatic mutation typical of an antigen-driven immune response. Proc Natl Acad Sci USA 1991;88:7783-7787.
131. Andris JS, Brodeur BR, Capra JD. Molecular characterization of human antibodies to bacterial antigens: utilization of the less frequently expressed VH2 and VH6 heavy chain variable region gene families. Mol Immunol 1993;30:1601-1616.
132. Deftos M, Olee T, Carson DA, Chen PP. Defining the genetic origins of three rheumatoid synovium-derived IgG rheumatoid factors. J Clin Invest 1994;93:2545-2553.
133. Harindranath N, et al. Complete sequence of the genes encoding the VH and VL regions of low- and high-affinity monoclonal IgM and IgA1 rheumatoid factors produced by CD5+ B cells from a rheumatoid arthritis patient. Int Immunol 1991;3:865-875.
134. Pinchuk GV, Nottenburg C, Milner EC. Predominant V-region gene configurations in the human antibody response to Haemophilus influenzae capsule polysaccharide. Scand J Immunol 1995;41:324-330.
135. Cardona A, Pritsch O, Dumas G, Bach JF, Dighiero G. Evidence for an antigen-driven selection process in human autoantibodies against acetylcholine receptor. Mol Immunol 1995;32:1215-1223.
136. Wu HY, Kaartinen M. The somatic hypermutation activity of a follicular lymphoma links to large insertions and deletions of immunoglobulin genes. Scand J Immunol 1995;42:52-59.
137. Przybylski GK, et al. Evidence for early B-cell activation preceding the development of Epstein-Barr virus-negative acquired immunodeficiency syndrome-related lymphoma. Blood 1996;88:4620-4629.
138. Cogne M, Guglielmi P. Exon skipping without splice site mutation accounting for abnormal immunoglobulin chains in nonsecretory human myeloma. Eur J Immunol 1993;23:1289-1293.
139. Papavasiliou F, et al. V(D)J recombination in mature B cells: a mechanism for altering antibody responses. Science 1997;278:298-301.
140. Han S, Dillon SR, Zheng B, Shimoda M, Schlissel MS, Kelsoe G. V(D)J recombinase activity in a subset of germinal center B lymphocytes. Science 1997;278:301-305.
141. Steele EJ, Pollard JW. Hypothesis: somatic hypermutation by gene conversion via the error prone DNA-RNA-DNA information loop. Mol Immunol 1987;24:667-673.
142. Cogne M, Silvain C, Khamlichi AA, Preud'homme JL. Structurally abnormal immunoglobulins in human immunoproliferative disorders. Blood 1992;79:2181-2195.
143. Alexander A, Anicito I, Buxbaum J. Gamma heavy chain disease in man. Genomic sequence reveals two noncontiguous deletions in a single gene. J Clin Invest 1988;82:1244-1252.
144. Bakhshi A, Guglielmi P, Siebenlist U, Ravetch JV, Jensen JP, Korsmeyer SJ. A DNA insertion/deletion necessitates an aberrant RNA splice accounting for a mu heavy chain disease protein. Proc Natl Acad Sci USA 1986;83:2689-2693.
145. Bentaboulet M, Mihaesco E, Gendron MC, Brouet JC, Tsapis A. Genomic alterations in a case of alpha heavy chain disease leading to the generation of composite exons from the JH region. Eur J Immunol 1989;19:2093-2098.
146. Haluska FG, Finver S, Tsujimoto Y, Croce CM. The t(8;14) chromosomal translocation occurring in B-cell malignancies results from mistakes in V-D-J joining. Nature 1986;324:158-161.
147. Hartl P, Lipp M. Generation of a variant t(2;8) translocation of Burkitt's lymphoma by site-specific recombination via the kappa light-chain joining signals. Mol Cell Biol 1987;7:2037-2045.
148. Klein G. Multistep evolution of B-cell-derived tumors in humans and rodents. Gene 1993;135:189-196.
149. Cotter FE. The role of bcl-2 gene in lymphoma. Br J Haematol 1990;75:449-453.
150. Rimokh R, et al. Detection of the chromosomal translocation t(11;14) by polymerase chain reaction in mantle cell lymphomas. Blood 1994;83:1871-1875.
151. Henglein B, Synovzik H, Groitl P, Bornkamm GW, Hard P, Lipp M. Three breakpoints of variant t(2;8) translocations in Burkitt's lymphoma cells fall within a region 140 kilobases distal from c-myc. Mol Cell Biol 1989;9:2105-2113.
152. Kato S, Tachibana K, Takayama N, Kataoka H, Yoshida MC, Takano T. Genetic recombination in a chromosomal translocation t(2;8) (p11; q24) of a Burkitt's lymphoma cell line, KOBK101. Gene 1991;97:239-244.
153. Dyomin VG, Rao PH, Dalla-Favera R, Chaganti RSK. BCL8, a novel gene involved in translocations affecting band 15q11-13 in diffuse large-cell lymphoma. Proc Natl Acad Sci USA 1997;94:5728-5732.
154. Dunn-Walters DK, Isaacson PG, Spencer J. Analysis of mutations in immunoglobulin heavy chain variable region genes of microdissected marginal zone (MGZ) B cells suggests that the MGZ of human spleen is a reservoir of memory B cells. J Exp Med 1995;182:559-566.
155. Dunn-Walters DK, Isaacson PG, Spencer J. Sequence analysis of rearranged IgVH genes from microdissected human Peyer's patch marginal zone B cells. Immunology 1996;88:618-624.
156. Dono M, Zupo S, Groosi CE, Chiorazzi N. Subepithelial B cells of the human tonsil. Chem Immunol 1997;6:58-69.
157. Liu YJ, Barthelemy C, de Bouteiller O, Arpin C, Durand I, Banchereau J. Memory B cells from human tonsils colonize mucosal epithelium and directly present antigen to T cells by rapid up-regulation of B7-1 and B7-2. Immunity 1995;2:239-248.
158. Maloum K, et al. Analysis of VH gene expression in CD5+ and CD5- B-cell chronic lymphocytic leukemia. Blood 1995;86:3883-3890.
159. Oscier DG, Thompsett A, Zhu D, Stevenson FK. Differential rates of somatic hypermutation in V(H) genes among subsets of chronic lymphocytic leukemia defined by chromosomal abnormalities. Blood 1997;89:4153-4160.
160. Pritsch O, Magnac C, Dumas G, Egile C, Dighiero G. V gene usage by seven hybrids derived from CD5+ B-cell chronic lymphocytic leukemia and displaying autoantibody activity. Blood 1993;82:3103-3112.
161. Zelenetz AD, Chen TT, Levy R. Clonal expansion in follicular lymphoma occurs subsequent to antigenic selection. J Exp Med 1992;176:1137-1148.
162. Zhu D, Hawkins RE, Hamblin TJ, Stevenson FK. Clonal history of a human follicular lymphoma as revealed in the immunoglobulin variable region genes. Br J Haematol 1994;86:505-512.
163. Küppers R, Hansmann ML, Rajewsky K. Micromanipulation and PCR analysis of single cells from tissue sections. In: Herzenberg LA, Herzenberg LA, Weir DM, Blackwell C, eds. Handbook of experimental immunology. 5th ed. Malden (MA): Blackwell Science; 1997. p. 206.1-206.4.