Human Immunoglobulin Heavy-Chain Variable Region Genes: Organization, Polymorphism, and Expression

Advances in Immunology

Volumn 49, Issue C, 1991, Pages 1-74

  Pascual, Virginia ^a   Capra, J Donald ^a  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ENDOGENOUS COMPOUND; IMMUNOGLOBULIN HEAVY CHAIN;

GENETIC ORGANIZATION; GENETIC POLYMORPHISM; HUMAN; IMMUNOGLOBULIN GENE; IMMUNOGLOBULIN VARIABLE REGION; MOUSE; PRIORITY JOURNAL; REVIEW;

ANIMAL; ANTIBODIES; ANTIBODY DIVERSITY; AUTOIMMUNE DISEASES; BASE SEQUENCE; CHROMOSOMES, HUMAN, PAIR 14; COMPARATIVE STUDY; ENHANCER ELEMENTS (GENETICS); GENE EXPRESSION REGULATION; GENE REARRANGEMENT, B-LYMPHOCYTE; GENES, IMMUNOGLOBULIN; HUMAN; IMMUNOGLOBULIN VARIABLE REGION; IMMUNOGLOBULINS, HEAVY-CHAIN; LEUKEMIA; LYMPHOMA; MICE; MOLECULAR SEQUENCE DATA; MULTIGENE FAMILY; POLYMORPHISM (GENETICS); PROMOTER REGIONS (GENETICS); PSEUDOGENES; SEQUENCE HOMOLOGY, NUCLEIC ACID; SUPPORT, NON-U.S. GOV'T; SUPPORT, U.S. GOV'T, P.H.S.;

EID: 0025900706     PISSN: 00652776     EISSN: 15578445     Source Type: Book Series    
DOI: 10.1016/S0065-2776(08)60774-9     Document Type: Article

References (179)

1. Agnello, V., Arbetter, A., de Kasep, G.I., Powell, R., Tan, E.M., Joslin, F., Evidence for a subset of rheumatoid factors that cross-react with DNA–hi stone and have a distinct cross-reactive idiotype. J. Exp. Med. 151 (1980), 1514–1527.
2. Aguado, M.T., Balderas, R.S., Rubin, R.L., Duchosal, M.A., Kofler, R., Birshtein, B.K., Secher, D.S., Dixon, F.J., Theofilopoulos, A., Specificity and molecular characteristics of monoclonal IgM rheumatoid factors from arthritic and non-arthritic mice. J. Immunol. 139 (1987), 1080–1088.
3. Alt, F.W., Blackwell, T.K., Yancopoulos, G.D., Development of the primary antibody repertoire. Science 238 (1988), 1079–1087.
4. Andrews, D.W., Capra, J.D., Complete amino acid sequence of variable domains from two monoclonal human anti-gammaglobulins of the Wa cross-idiotypic group: Suggestion that the J segments are involved in the structural correlate of the idiotype. Proc. Natl. Acad. Sci. U.S.A. 78 (1981), 3799–3803.
5. Baer, R., Chen, K.-C., Smith, S.D., Rabbitts, T.H., Fusion of an immunoglobulin variable gene and a T cell receptor constant gene in the chromosome 14 inversion associated with T cell tumours. Cell (Cambridge, Mass.), 43, 1985, 705.
6. Baer, R., Foster, A., Lavenir, I., Rabbitts, T.H., Immunoglobulin VH genes are transcribed by T cells in association with a new 5′ exon. J. Exp. Med. 167 (1988), 2011–2016.
7. Banerji, J., Olson, L., Schaffner, W., A lymphocyte-specific cellular enhancer is located downstream of the joining region in immunoglobulin heavy chain genes. Cell (Cambridge, Mass.), 33, 1983, 729.
8. Bentley, D.L., Rabbitts, T.H., Evolution of immunoglobulin V genes: Evidence indicating that recently duplicated human V sequences have diverged by gene conversion. Cell (Cambridge, Mass.) 32 (1983), 181–189.
9. Bergman, Y., Rice, D., Grosschedl, R., Baltimore, D., Two regulatory elements for immunoglobulin gene expression. Proc. Natl. Acad. Sci. U.S.A. 81 (1984), 7041–7045.
10. Berman, J.E., Alt, F.W., Human heavy chain variable region gene diversity, organization, and expression. Int. Rev. Immunol. 5 (1990), 203–214.
11. Berman, J.E., Mellis, S.J., Pollock, R., Smith, C.L., Suh, H., Heinke, B., Kowal, C., Surti, U., Chess, L., Cantor, C.R., Alt, F.W., Content and organization of the human Ig VH lcous: Definition of three new VH families and linkage to the Ig CH locus. EMBO J. 7 (1988), 727–738.
12. Bottaro, A., Gallina, R., DeMarchi, M., Carbonara, A.O., Genetic analysis of new restriction fragment length polymorphisms (RFLP) in the human IgH constant gene locus. Eur. J. Immunol. 19 (1989), 2151–2157.
13. Bottaro, A., DeMarchi, M., DeLange, G.G., Boccazzi, C., Fubini, L., Borra, C., Cappello, N., Carbonara, A.O., Human IGHC locus restriction fragment length polymorphisms in IgG4 deficiency: Evidence for a structural IGHC defect. Eur. J. Immunol. 19 (1989), 2159–2162.
14. Brodeur, P.D., Riblet, R., The immunoglobulin heavy chain variable region (Igh-V) locus in the mouse. I. One hundred Igh-V genes comprise seven families of homologous genes. Eur. J. Immunol. 14 (1984), 922–930.
15. Buluwela, L., Rabbitts, T.H., A VH gene is located within 95 Kb of the human immunoglobulin heavy chain constant region genes. Eur. J. Immunol. 18 (1988), 1843–1845.
16. Buluwela, L., Albertson, D.G., Sherrington, P., Rabbitts, P.H., Spurr, N., Rabbitts, T.H., The use of chromosomal translocations to study human immunoglobulin gene organization: Mapping DH segments within 35 kb of the Cμ gene and identification of the new DH locus. EMBO J. 7 (1988), 2003–2010.
17. Burastero, S.E., Casali, P., Characterization of human CD5 (Leu-1, OKT1)+ B lymphocytes and the antibodies they produce. Contrib. Microbiol. Immunol. 11 (1989), 231–262.
18. Cairns, E., Kwong, P.C., Misener, V., Ip, P., Bell, D.A., Siminovitch, K.A., Analysis of variable region genes encoding a human anti-DNA antibody of normal origin. J. Immunol. 143 (1989), 685–691.
19. Capra, J.D., A hypervariable region of human immunoglobulin heavy chains. Nature (London) 230 (1971), 61–63.
20. Capra, J.D., Kehoe, J.M., Structure of antibodies with shared idiotypy: The complete sequence of the heavy chain variable regions of two immunoglobulin M anti-gamma globulins. Proc. Natl. Acad. Sci. U.S.A. 71 (1974), 4032–4036.
21. Capra, J.D., Kehoe, J.M., Hypervariable regions, idiotypy and the antibody combining site. Adv. Immunol. 20 (1975), 1–40.
22. Capra, J.D., Tucker, P.W., Human immunoglobulin heavy chain genes. J. Biol. Chem. 264 (1989), 12745–12748.
23. Casali, P., Notkins, A.L., Probing the human B cell repertoire with EBV: Polyreactive antibodies and CD5+ B lymphocytes. Annu. Rev. Immunol. 7 (1989), 513–535.
24. Casali, P., Burastero, S.E., Nakamura, M., Inghirami, G., Notkins, A.L., Human lymphocytes making rheumatoid factor and antibody to ssDNA belong to the Leu-1+ B-cell subset. Science 23 (1987), 77–81.
25. Chen, P.P., Structural analyses of human developmentally regulated VH3 genes. Scand. J. Immunol. 31 (1990), 257–267.
26. Chen, P.P., Yang, P.-M., A segment of VH gene locus is duplicated. Scand. J. Immunol. 31 (1990), 593–599.
27. Chen, P.P., Liu, M.-F., Sinha, S., Carson, D.A., A 16/6 idiotype-positive anti-DNA antibody is encoded by a conserved VH gene with no somatic mutation. Arthritis Rheum. 31 (1988), 1429–1431.
28. Chen, P.P., Liu, M.F., Glass, C.A., Sinha, S., Kipps, T.J., Carson, D.A., Characterization of two immunoglobulin VH genes that are homologous to human rheumatoid factors. Arthritis Rheum. 32 (1989), 72–76.
29. Chen, P.P., Siminovitch, K.A., Olsen, N.J., Erger, R.A., Carson, D.A., A highly informative probe for two polymorphic VH gene regions that contain one or more autoantibody-associated VH genes. J. Clin. Invest. 84 (1989), 706–710.
30. Chen, P.P.R.W., Soto-Gil, R.W., Carson, D.A., The early expression of some human autoantibody-associated heavy chain variable region genes is controlled by specific regulatory elements. Scand. J. Immunol. 31 (1990), 673–678.
31. Chen, P.P., Silverman, G.J., Liu, M.-F., Carson, D.A., Idiotypic and molecular characterization of human rheumatoid factors. Chem. Immunol. 48 (1990), 63–81.
32. Chen, P.P., Olsen, N.J., Yang, P.-M., Soto-Gil, R.W., Olee, T., Siminovitch, K.A., Carson, D.A., From human autoantibodies to the fetal antibody repertoire to B cell malignancy: It's a small world after all. Int. Rev. Immunol. 5 (1990), 239–251.
33. Christoph, T., Krawinkel, U., Physical linkage of variable, diversity and joining gene segments in the immunoglobulin heavy chain locus of the mouse. Eur. J. Immunol. 19 (1989), 1521–1523.
34. Cleary, M.L., Galili, N., Trela, M., Levy, R., Sklar, J., Single cell origin of bigenotypic and biphenotypic B cell proliferations in human follicular lymphomas. J. Exp. Med. 167 (1988), 582–597.
35. Cox, D.W., Markovic, V.D., Teshisma, I.E., Genes for immunoglobulin heavy chains and for α1-antitrypsin are localized to specific regions of chromosome 14q. Nature (London) 297 (1982), 428–430.
36. Croce, C.M., Shander, M., Martinis, J., Cicurel, L., D'Ancora, G., Dolby, T.W., Koprowski, H., Chromosomal location of the genes for human immunoglobulin heavy chains. Proc. Natl. Acad. Sci. U.S.A. 76 (1979), 3416–3419.
37. Cuisinier, A.-M., Guigou, V., Boubli, L., Fougereau, M., Tonnelle, C., Preferential expression of VH5 and VH6 immunoglobulin genes in early human B-cell ontogeny. Scand. J. Immunol. 30 (1989), 493–497.
38. Cunningham, B.A., Pflumm, M.N., Rutishauser, U., Edelman, G.M., Subgroups of amino acid sequences in the variable regions of immunoglobulin heavy chains. Proc. Natl. Acad. Sci. U.S.A. 64 (1969), 997–1003.
39. Davidson, A., Smith, A., Katz, J., Preud'homme, J.-L., Soloman, A., Diamond, B., A cross-reactive idiotype on anti-DNA antibodies defines a H chain determinant present almost exclusively on IgG antibodies. J. Immunol. 143 (1989), 174–180.
40. Davidson, A., Manheimer-Lory, A., Aranow, C., Peterson, R., Hannigan, N., Diamond, B., Molecular characterization of a somatically mutated anti-DNA antibody bearing two systemic lupus erythematosus-related idiotypes. J. Clin. Invest. 85 (1990), 1401–1409.
41. Dersimonian, H., Schwartz, R.S., Barrett, K.J., Stollar, B.D., Relationship of human variable region heavy chain germline genes to genes encoding anti-DNA autoantibodies. J. Immunol. 139 (1987), 2496–2501.
42. Dersimonian, H., McAdam, K.P.W.J., Mackworth-Young, C., Stollar, B.D., The recurrent expression of variable region segments in human IgM anti-DNA autoantibodies. J. Immunol. 142 (1989), 4027–4033.
43. Dighiero, G., Lymberi, P., Holmberg, D., Lundquist, I., Coutinho, A., Avrameas, S., High frequency of natural autoantibodies in normal newborn mice. J. Immunol. 134 (1985), 765–771.
44. Dreyfuss, M., Doyen, N., Rougeon, F., The conserved decanucleotide from the immunoglobulin heavy chain promoter induces a very high transcriptional activity in B-cells when introduced into a heterolgous promoter. EMBO J. 6 (1987), 1685–1690.
45. Dunn, A.R., Gough, N., Tissue-specific enhancers. Trends Biochem. Sci. 9 (1984), 81–82.
46. Edelman, G.M., Cunningham, B.A., Gall, W.E., Gottlieb, P.D., Rutihauser, U., Waxdal, M.J., The covalent structure of the entire γG immunoglobulin molecule. Proc. Natl. Acad. Sci. U.S.A. 63 (1969), 78–85.
47. ElRoiey, A., Sela, O., Isenberg, D., Feldman, R., Colaco, C., Kennedy, R., Shoenfeld, Y., The sera of patients with Klebsiella infections contain a common anti-DNA idiotype (16/6 Id) and anti-polynucleotide activity. Clin. Exp. Immunol. 67 (1987), 507–515.
48. Falkner, F.G., Zachau, H.G., Correct transcription of an immunoglobulin K gene requires an upstream fragment containing conserved sequence elements. Nature (London) 310 (1984), 71–74.
49. Forre, O., Dobloug, J.H., Michaelsen, T.E., Natvig, J.B., Evidence of similar idiotypic determinants on different rheumatoid factor populations. Scand. J. Immunol. 9 (1979), 281–287.
50. Gathings, W.E., Lawton, A.R., Cooper, M.D., Immunofluorescent studies of the development of the pre-B cells, B lymphocytes and immunoglobulin isotype diversity in humans. Eur. J. Immunol., 7, 1977, 804.
51. Ghanem, N., Lefranc, M.-P., Lefranc, G., Definition of the RFLP alleles in the human immunoglobulin IGHG gene locus. Eur. J. Immunol. 18 (1988), 1059–1065.
52. Gillies, S.D., Morrison, S.L., Oi, V.T., Tonegawa, S., A tissue-specific transcription enhancer element is located in the major intron of a rearranged immunoglobulin heavy chain gene. Cell (Cambridge, Mass.) 33 (1983), 717–728.
53. Gimble, J.M., Flanagan, J.R., Recker, D., Max, E.E., Identification and partial purification of a protein binding to the human immunoglobulin kappa enhancer κE2 site. Nucleic Acids Res. 16 (1988), 4967–4988.
54. Gruss, P., Dhar, R., Khoury, G., Simian virus 40 tandem repeated sequences as an element of early promoter. Proc. Natl. Acad. Sci. U.S.A. 78 (1981), 943–947.
55. Guilbert, G., Dighiero, G., Avrameas, S., Naturally occurring antibodies against nine common antigens in human sera. I. Detection, isolation and characterization. J. Immunol., 128, 1982, 2779.
56. Guillaume, T., Rubinstein, D.B., Young, F., Tucker, L., Logtenberg, T., Schwartz, R.S., Barrett, K.J., Individual VH genes detected with oligonucleotide probes from the complementarity-determining regions. J. Immunol. 145 (1990), 1934–1945.
57. Hanke, J.H., Landolfi, N.F., Tucker, P.W., Tucker, J.D., Identification of murine nuclear proteins that bind to the conserved octamer sequence of the immunoglobulin promoter region. Proc. Natl. Acad. Sci. U.S.A. 85 (1988), 3560–3564.
58. Hasemann, C.A., Capra, J.D., Pedl, William E., (eds.) “Immunoglobulins: Structure and Function. Fundamental Immunology,”, 2nd ed., 1989, Raven Press, New York.
59. Hendriks, R.W., Van Tol, M.J.D., De Lange, G.G., Schuurman, R.K.B., Inheritance of a large deletion within the human immunoglobulin heavy chain constant region gene complex and immunological implications. Scand. J. Immunol. 29 (1989), 535–541.
60. Hillson, J.L., Perlmutter, R.M., Autoantibodies and the fetal antibody repertoire. Int. Rev. Immunol. 5 (1990), 215–229.
61. Hoch, S., Schwaber, J., Identification and sequence of the VH gene elements encoding a human anti-DNA antibody. J. Immunol. 139 (1987), 1689–1693.
62. Hofker, M.H., Walter, M.A., Cox, D.W., Complete physical map of the human immunoglobulin heavy chain constant region gene complex. Proc. Natl. Acad. Sci. U.S.A. 86 (1989), 5567–5571.
63. Honjo, T., Shimizu, A., Yaoita, Y., Constant-region genes of the immunoglobulin heavy chain and the molecular mechanism of class switching. Honjo, T., Alt, F.W., Rabbitts, T.H., (eds.) “Immunoglobulin Genes”, 1989, Academic Press, San Diego, California, 123–149.
64. Hope, T.J., Aguilera, R.J., Minie, M.E., Sakano, H., Endonucleolytic activity that cleaves immunoglobulin recombination sequences. Science 231 (1986), 1141–1145.
65. Huck, S., Lefranc, G., Lefranc, M.-P., A human immunoglobulin IGHG3 allele (Gmb0, b1, c3, c5, u) with an IGHG4 converted region and three hinge exons. Immunogenetics 30 (1989), 250–257.
66. Humphries, C.G., Shen, A., Kuziel, W.A., Capra, J.D., Blattner, F.R., Tucker, P.W., A new human immunoglobulin VH family preferentially rearranged in immature B-cell tumours. Nature (London) 331 (1988), 446–449.
67. Ichihara, Y., Abe, M., Yasui, H., Matsuoka, H., Kurosawa, Y., At least five DH genes of human immunoglobulin heavy chains are encoded in 9-kilobase DNA fragments. Eur. J. Immunol. 18 (1988), 649–652.
68. Ichihara, Y., Matsuoka, H., Kurosawa, Y., Organization of human immunoglobulin heavy chain diversity gene loci. EMBO J. 7 (1988), 4141–4150.
69. Isenberg, D.A., Collins, C., Detection of cross-reactive anti-DNA antibody idotypes on renal tissue-bound immunoglobulins from lupus patients. J. Clin. Invest. 76 (1985), 287–294.
70. Isenberg, D.A., Shoenfeld, Y., Madaio, M.P., Rauch, J., Reichlin, M., Stollar, B.D., Schwartz, R.S., Anti-DNA antibody idiotypes in systemic lupus erythematosus. Lancet 2 (1984), 417–422.
71. Johnson, M.J., Natali, A.M., Cann, H.M., Honjo, T., Cavalli-Sforza, L.L., Polymorphisms of human variable heavy chain gene showing linkage with constant heavy chain genes. Proc. Natl. Acad. Sci. U.S.A. 81 (1984), 7840–7844.
72. Kaartinen, M., Solin, M.-L., Makela, O., Allelic forms of immunoglobulin V genes in different strains of mice. EMBO J. 8 (1989), 1743–1748.
73. Kearney, J., Vakil, M., Nicholson, N., Non-random VH gene expression and idiotype anti-idiotype expression in early B cells. Kelso, G., Schulze, D., (eds.) “Evolution and Vertebrate Immunity: The Antigen Receptor and MHC Gene Families”, 1987, Univ. of Texas Press, Austin, 175–190.
74. Kehoe, J.M., Capra, J.D., Localization of two additional hypervariable regions in immunoglobulin heavy chains. Proc. Natl. Acad. Sci. U.S.A. 68 (1971), 2019–2021.
75. Kennedy, M.A., Morris, C.M., Hollings, P.E., Fitzgerald, P.H., Involvement of immunoglobulin heavy-and light-chain (kappa) gene clusters in a human B-cell translocation, t(2;14). Cytogenet. Cell Genet. 52 (1989), 50–56.
76. Keyeux, G., Ghanem, N., Lefranc, G., Lefranc, M.-P., Identification of the PvuII RFLPs from the switch human immunoglobulin alpha (IGSA) regions. Nucleic Acids Res., 17, 1989, 3623.
77. Keyeux, G., Lefranc, G., Lefranc, M.-P., A specific switch alpha probe of the human immunoglobulin IGHA locus. Nucleic Acids Res., 17, 1989, 3624.
78. Kipps, T.J., Immunoglobulin idiotypes in human B cell neoplasia: Implications for pathogenesis and therapy. Chem. Immunol. 48 (1990), 167–185.
79. Kipps, T.J., Tomhave, E., Pratt, L.F., Duffy, S., Chen, P.P., Carson, D.A., Developmentally restricted immunoglobulin heavy chain variable region gene expressed at high frequency in chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. U.S.A. 86 (1989), 5913–5917.
80. Kirsch, I.R., Morton, C.C., Nakahara, K., Leder, P., Human immunoglobulin heavy chain genes mapped to a region of translocations in malignant B lymphocytes. Science 216 (1982), 301–303.
81. Knight, K.L., Becker, R.S., Molecular basis of the allelic inheritance of rabbit immunoglobulin VH allotypes: Implications for the generation of antibody diversity. Cell (Cambridge, Mass.) 60 (1990), 963–970.
82. Ko, H.-S., Fast, P., McBride, W., Staudt, L.M., A human protein specific for the immunoglobulin octamer DNA motif contains a function homeobox domain. Cell (Cambridge, Mass.) 55 (1988), 135–144.
83. Kodaira, M., Kinashi, T., Umemura, I., Matsuda, F., Noma, T., Ono, Y., Honjo, T., Organization and evolution of variable region genes of the human immunoglobulin heavy chain. J. Mol. Biol. 190 (1986), 529–541.
84. Kunkel, H.G., Agnello, V., Joslin, F.G., Winchester, R.J., Capra, J.D., Cross-idiotypic specificity among monoclonal IgM proteins with anti-gamma globulin activity. J. Exp. Med. 137 (1973), 331–342.
85. Kunkel, H.G., Winchester, R.J., Joslin, F.G., Capra, J.D., Similarities in the light chains of anti-gamma globulins showing cross-idiotypic specificities. J. Exp. Med. 139 (1974), 128–136.
86. Kurosawa, Y., Tonegawa, S., Organization, structure, and assembly of immunoglobulin heavy chain diversity DNA segments. J. Exp. Med. 155 (1982), 201–218.
87. Kurosawa, Y., von Boehmer, H., Haas, W., Sakano, H., Traunecker, A., Tonegawa, S., Identification of D segments of immunoglobulin heavy-chain genes and their rearrangement in T lymphocytes. Nature (London), 290, 1981, 590.
88. Landolfi, N.F., Capra, J.D., Tucker, P.W., Interaction of cell-type-specific nuclear proteins with immunoglobulin VH promoter region sequences. Nature (London) 323 (1986), 548–551.
89. Lebowitz, J.H., Kobayashi, T., Staudt, L., Baltimore, D., Sharp, P.A., Octamer-binding proteins from B or HeLa cells stimulate transcription of the immunoglobulin heavy-chain promoter in vitro. Genes Dev. 2 (1988), 1227–1237.
90. Lee, K.H., Matsuda, F., Kinashi, T., Kodaira, M., Honjo, T., A novel family of variable region genes of the human immunoglobulin heavy chain. J. Mol. Biol. 195 (1987), 761–768.
91. Lefvert, A.K., James, R.W., Alloid, C., Fulpius, B.W., A monoclonal antiidiotypic antibody against anti-receptor antibodies from myasthenic sera. Eur. J. Immunol., 12, 1982, 790.
92. Lefvert, A.K., Sunden, H., Holm, G., Acetylcholine receptor antibodies and anti-idiotypic antibodies produced in blood lymphocyte cultures from patients with myasthenia gravis. Scand. J. Immunol., 23, 1986, 655.
93. Lefvert, A.K., Holm, G., Sunden, H., Pirskanen, R., Cellular production of antibodies related to the acetylcholine receptor in myasthenia gravis: Correlation with clinical stage. Scand. J. Immunol., 25, 1987, 265.
94. Levine, M., Hoey, T., Homeobox proteins as sequence-specific transcription factors. Cell (Cambridge, Mass.) 55 (1988), 537–540.
95. Logtenberg, T., Young, F.M., Van Es, J.H., Gmelig-Meyling, F.H.J., Alt, F.W., Autoantibodies encoded by the most JH-proximal human immunoglobulin heavy chain variable region gene. J. Exp. Med. 170 (1989), 1347–1355.
96. Loh, D.Y., Bothwell, A.L.M., White-Scharf, M.E., Imanishi-Kari, T., Baltimore, D., Molecular basis of a mouse strain-specific anti-hapten response. Cell (Cambridge, Mass.) 33 (1984), 85–93.
97. Mackworth-Young, C., Sabbaga, J., Schwartz, R.S., Idiotypic markers of polyclonal B cell activation: Public idiotypes shared by monoclonal antibodies derived from patients with systemic lupus erythematosus and leprosy. J. Clin. Invest. 79 (1987), 572–581.
98. Mageed, R.A., Jefferis, R., Analysis of rheumatoid factor autoantibodies in patients with essential mixed cryoglobulinemia and rheumatoid arthritis. Scand. J. Rheumatol., Suppl. 75 (1988), 172–178.
99. Mageed, R.A., Dearlove, M., Goodall, D.M., Jefferis, R., Immunogenic and antigenic epitopes of immunoglobulins. XVII. Monoclonal anti-idiotypes to the heavy chain of human rheumatoid factors. Rheumatol. Int. 6 (1986), 179–186.
100. Matsuda, F., Lee, K.H., Nakai, S., Sato, T., Kodaira, M., Zong, S.Q., Ohno, H., Fukuhara, S., Honjo, T., Dispersed localization of D segments in the human immunoglobulin heavy-chain locus. EMBO J. 7 (1988), 1047–1051.
101. Matsuda, F., Shin, E.K., Hirabayashi, Y., Nagaoka, H., Yoshida, M.C., Zong, S.Q., Honjo, T., Organization of variable region segments of the human immunoglobulin heavy chain: Duplication of the D5 cluster within the locus and interchromosomal translocation of variable region segments. EMBO J. 9 (1990), 2501–2506.
102. Matthyssens, G., Rabbitts, T.H., Structure and multiplicity of genes for the human immunoglobulin heavy chain variable region. Proc. Natl. Acad. Sci. U.S.A. 77 (1980), 6561–6565.
103. Meek, K.D., Hasemann, C.A., Capra, J.D., Novel rearrangement at the immunoglobulin D locus. J. Exp. Med. 170 (1989), 39–57.
104. Meek, K.D., Rathbun, G., Reininger, L., Jaton, J.-C., Kofler, R., Tucker, P.W., Capra, J.D., Organization of the murine immunoglobulin VH complex: Placement of two new VH families (VH10 and VH11) and analysis of VH family clustering and interdigitation. Mol. Immunol. 27 (1990), 1073–1081.
105. Meek, K. D., Eversole, T., and Capra, J. D. 1991. Conservation of the most JH proximal immunoglobulin VH gene segment (VHVI) throughout primate evolution. (Submitted for publication).
106. Moreau, P., Hen, R., Wasylyk, B., Everrett, R., Gaub, M., Chambon, P., The SV40 72-bp repeat has a striking effect on gene expression both in SV40 and other chimeric recombinations. Nucleic Acids Res. 9 (1981), 6047–6069.
107. Natvig, J.B., Munthe, E., Self-associating IgG rheumatoid factors represent a major response of plasma cells in rheumatoid inflammatory tissue. Ann. N.Y. Acad. Sci. 256 (1975), 88–95.
108. Newkirk, M.M., Mageed, R.A., Jefferis, R., Chen, P.P., Capra, J.D., Complete amino acid sequences of variable regions of two human IgM rheumatoid factors, BOR and KAS of the Wa idiotypic family, reveal restricted use of heavy and light chain variable and joining region segments. J. Exp. Med. 166 (1987), 550–564.
109. Nickerson, K.G., Berman, J., Glickman, E., Chess, L., Alt, F.W., Early human IgH gene assembly in Epstein–Barr virus-transformed fetal B cell lines: Preferential utilization of the most JH-proximal D segment (DQ52) and two unusual VH-related rearrangements. J. Exp. Med. 169 (1989), 1391–1403.
110. Ollier, P., Rocca-Serra, J., Somme, G., Theze, J., Fougereau, M., The idiotypic network and the internal image: Possible regulation of a germline network by paucigene encoded Ab2 (anti-idiotypic) antibodies in the GAT system. EMBO J., 3, 1985, 3681.
111. Parslow, T.G., Blair, D.L., Murphy, W.J., Granner, D.K., Structure of the 5′ ends of immunoglobulin genes: A novel conserved sequence. Proc. Natl. Acad. Sci. U.S.A. 81 (1984), 2650–2654.
112. Pascual, V., Randen, I., Thompson, K., Sould, M., Forre, C., Natvig, J.B., Capra, J.D., The complete nucleotide sequences of the heavy chain variable regions of six monospecific rheumatoid factors derived from EBV transformed B cells isolated from the synovial tissue of patients with rheumatoid arthritis: Further evidence that some autoantibodies are unmutated copies of germline genes. J. Clin. Invest. 86 (1990), 1320–1328.
113. Pascual, V., Andris, J., Capra, J.D., Int. Rev. Immunol. 5 (1990), 231–238.
114. Perlmutter, R.M., Berson, B., Griffin, J.A., Hood, L., Diversity in the germline antibody repertoire: Molecular evolution of the T15 VH gene family. J. Exp. Med. 162 (1985), 1998–2016.
115. Perlmutter, R.M., Kearney, J., Chang, S.P., Hood, L.E., Developmentally controlled expression of immunoglobulin VH genes. Science 227 (1985), 1597–1600.
116. Pincus, S.H., Human immunoglobulin heavy-chain-variable (VH) region gene families defined by hybridization with cloned human and murine VH-genes. Hum. Immunol. 22 (1988), 199–215.
117. Queen, C., Foster, J., Stauber, C., Stafford, J., Cell-type specific regulation of a κ immunoglobulin gene by promoter and enhancer elements. Immunol. Rev. 89 (1986), 49–68.
118. Rathbun, G.A., Capra, J.D., Tucker, P.W., Organization of the murine immunoglobulin VH complex in inbred strains. EMBO J. 6 (1987), 2931–2937.
119. Ravetch, J.V., Siebenlist, U., Korsmeyer, S., Waldmann, T., Leder, P., Structure of the human immunoglobulin μ locus: Characterization of embryonic and rearranged J and D genes. Cell (Cambridge, Mass.) 27 (1981), 583–591.
120. Rechavi, G., Bienz, B., Ram, D., Ben-Neriah, Y., Cohen, J.P., Zakut, R., Givol, D., Organization and evolution of immunoglobulin VH gene subgroup. Proc. Natl. Acad. Sci. U.S.A. 79 (1982), 4405–4409.
121. Rechavi, G., Ram, D., Glazer, L., Zakut, R., Givol, D., Evolutionary aspects of immunoglobulin heavy chain variable region (VH) gene subgroups. Proc. Natl. Acad. Sci. U.S.A. 80 (1983), 855–859.
122. Reynaud, C.-A., Anquez, V., Dahan, A., Weill, J.-C., A single rearrangement event generates most of the chicken immunoglobulin light chain diversity. Cell (Cambridge, Mass.) 40 (1985), 283–291.
123. Robbins, D.L., Kenny, T.P., Coloma, M.J., Gavilondo-Cowley, J.V., Soto-Gil, R.W., Chen, P.P., Larrick, J.W., Serologic and molecular characterization of a human rheumatoid factor derived from rheumatoid synovial cells. Arthritis Rheum. 33 (1990), 1188–1195.
124. Roudier, J., Silverman, G.J., Chen, P.P., Carson, D.A., Kipps, T.J., Intraclonal diversity in the VH genes expressed by CD5− chronic lymphocytic leukemia-producing pathologic IgM rheumatoid factor. J. Immunol. 144 (1990), 1526–1530.
125. Rubenstein, D., Guillaume, T., Tucker, L., Young, F., Logtenberg, T., Schwartz, R., and Barrett, K. J. 1989. Detection of germ line polymorphisms and preferentially expressed human V genes with oligonucleotide probes. Int. Congr. Immunol., 7th 1989 Abstract, p. 30.
126. Sakano, H., Maki, R., Kurosawa, Y., Roeder, W., Tonegawa, S., Two types of somatic recombination are necessary for the generation of complete immunoglobulin heavy chain genes. Nature (London) 286 (1980), 676–683.
127. Sakano, H., Kurosawa, Y., Weigert, M., Tonegawa, S., Identification and nucleotide sequence of a diversity DNA segment (D) of immunoglobulin heavy-chain genes. Nature (London) 290 (1981), 562–565.
128. Sanz, I., Kelly, P., Williams, C., Scholl, S., Tucker, P., Capra, J.D., The smaller human VH gene families display remarkably little polymorphism. EMBO J. 8 (1989), 3741–3748.
129. Sanz, I., Dang, H., Takei, M., Talal, N., Capra, J.D., VH sequence of a human anti-Sm autoantibody: Evidence that autoantibodies can be unmutated copies of germline genes. J. Immunol. 142 (1989), 883–887.
130. Sanz, I., Casali, P., Thomas, J.W., Notkins, A.L., Capra, J.D., Nucleotide sequences of eight human natural autoantibody VH regions reveal apparent restricted use of VH families. J. Immunol. 142 (1989), 4054–4061.
131. Sanz, I., Hwang, C., Hasemann, C., Thomas, J.W., Wasserman, R., Tucker, P., Capra, J.D., Polymorphisms of immunologically relevant loci in human disease: Autoimmunity and human heavy chain variable regions. Ann. N.Y. Acad. Sci. 546 (1989), 133–142.
132. Sasso, E.H., van Dijk, K.W., Milner, E.C.B., Prevalence and polymorphism of human VH3 genes. J. Immunol. 145 (1990), 2751–2757.
133. Sato, T., Matsuda, F., Lee, K.H., Shin, E.K., Honjo, T., Physical linkage of a variable region segment and the joining region segment of the human immunoglobulin heavy chain locus. Biochem. Biophys. Res. Commun. 154 (1988), 265–271.
134. Scheidereit, C., Heguy, A., Roeder, R.G., Identification and purification of a human lymphoid-specific octamer-binding protein (OTF-2) that activates transcription of an immunoglobulin promoter in vitro. Cell (Cambridge, Mass.) 51 (1987), 783–793.
135. Scheidereit, C., Cromlish, J.A., Gerster, T., Kawakami, K., Balmaceda, C.-G., Currie, R.A., Roeder, R.G., A human lymphoid-specific transcription factor that activates immunoglobulin genes is a homoeobox protein. Nature (London) 336 (1988), 551–557.
136. Schilling, J., Clevinger, B., Davie, J.M., Hood, L., Amino acid sequence of homogeneous antibodies to dextran and DNA rearrangements in heavy-chain V-region gene segments. Nature (London) 283 (1980), 35–40.
137. Schroeder, H.W. Jr., Wang, J.Y., Preferential utilization of conserved immunoglobulin heavy chain variable gene segments during human fetal life. Proc. Natl. Acad. Sci. U.S.A. 87 (1990), 6146–6150.
138. Schroeder, H. W., Jr., Hillson, J. L., and Perlmutter, R. M. 1987. Early restriction of the human antibody repertoire. Reports pp. 791–793.
139. Schroeder, H.W. Jr., Walter, M.A., Hofker, M.H., Ebens, A., van Dijk, K.W., Liao, L.C., Cox, D.W., Milner, E.C.B., Perlmutter, R.M., Physical linkage of a human immunoglobulin heavy chain variable region gene segment to diversity and joining region elements. Proc. Natl. Acad. Sci. U.S.A. 85 (1988), 8196–8200.
140. Schroeder, H.W. Jr., Hillson, J.L., Perlmutter, R.M., Structure and evolution of mammalian VH families. Int. Immunol. 2 (1990), 41–50.
141. Sen, R., Baltimore, D., Inducibility of κ immunoglobulin enhancer-binding proten NF-κB by a posttranslational mechanism. Cell (Cambridge, Mass.) 47 (1986), 921–928.
142. Shander, M., Martinis, J., Croce, C.M., Genetics of human immunoglobulins—Assignment of the genes of Mv-immunoglobulin, alpha-immunoglobulin, and gamma-immunoglobulin chains to human chromosome 14. Transplant. Proc. 10 (1980), 417–420.
143. Shen, A., Humphries, C., Tucker, P., Blattner, F., Human heavy-chain variable region gene family nonrandomly rearranged in familial chronic lymphocytic leukemia. Proc. Natl. Acad. Sci. U.S.A. 84 (1987), 8563–8567.
144. Shlomchik, M.J., Marshak-Rothstein, A., Wolfwicz, C.B., Rothstein, T.L., Weigert, M.G., The role of clonal selection and somatic mutation in autoimmunity. Nature (London) 328 (1987), 805–811.
145. Shlomchik, M.J., Aucoin, A.J., Pisetsky, D.S., Weigert, M.G., Structure and function of anti-DNA autoantibodies derived from a single autoimmune mouse. Proc. Natl. Acad. Sci. U.S.A. 84 (1987), 9150–9154.
146. Shoenfeld, Y., Isenberg, D.A., Rauch, J., Madaio, M., Stollar, B.D., Schwartz, R.S., Idiotypic cross-reactions of monoclonal human lupus autoantibodies. J. Exp. Med., 158, 1983, 718.
147. Shoenfeld, Y., Ben-Yehuda, O., Naparstek, Y., Wilner, Y., Frolichman, R., Schattner, A., Lavie, G., Joshua, H., Pinkhas, J., Kennedy, R.C., Schwartz, R.S., Pick, A.I., The detection of a common idiotype of anti-DNA antibodies in the sera of patients with monoclonal gammopathies. J. Clin. Immunol. 6 (1986), 194–204.
148. Shoenfeld, Y., Vilner, Y., Coates, A.R.M., Monoclonal anti-tuberculosis antibodies react with DNA and monoclonal anti-DNA antibodies react with Mycobacterium tuberculosis. Clin. Exp. Immunol. 66 (1986), 255–261.
149. Shokri, F., Mageed, R.A., Tunn, E., Bacon, P.A., Jefferis, R., Qualitative and quantitative expression of VHI associated cross-reactive idiotopes within IgM rheumatoid factor from patients with early synovitis. Ann. Rheum. Dis. 49 (1990), 150–154.
150. Siebenlist, U., Ravetch, J.V., Korsmeyer, S., Waldmann, T., Leder, P., Human immunoglobulin D segments encoded in tandem multigenic families. Nature (London) 294 (1981), 631–635.
151. Silberstein, L.E., Litwin, S., Carmack, C.E., Relationship of variable region genes expressed by a human B cell lymphoma secreting pathologic anti-PR2 erythrocyte autoantibodies. J. Exp. Med. 169 (1989), 1631–1643.
152. Silverman, G.J., Carson, D.A., Structural characterization of human monoclonal cold agglutinins: Evidence for a distinct primary sequence-defined VH4 idiotype. Eur. J. Immunol. 20 (1990), 351–356.
153. Silverman, G.J., Chen, P.P., Carson, D.A., Cold agglutinins: Specificity, idiotypy and structural analysis. Chem. Immunol. 48 (1990), 109–125.
154. Silverman, G.J., Schrohenloher, R.E., Achavitti, M.A., Koopman, W.J., Carson, D.A., Structural characterization of the second major cross-reactive idiotype group of human rheumatoid factors: Association with the VH4 gene family. Arthritis Rheum. 33 (1990), 1347–1360.
155. Silvestris, F., Searles, R.A., Capra, J.D., Williams, R.C. Jr., Studies of anti-F (ab')2 antibodies and VH region distribution among SLE kindreds. J. Autoimmun. 2 (1989), 395–401.
156. Siminovitch, K.A., Misener, V., Kwong, P.C., Song, Q.-L., Chen, P.P., A natural autoantibody is encoded by germline heavy and lambda light chain variable region genes without somatic mutation. J. Clin. Invest. 84 (1989), 1675–1678.
157. Sonntag, D., Weingartner, B., Grutzmann, R., A member of a novel human DH gene family: DHFL16. Nucleic Acids Res., 17, 1989, 1267.
158. Soua, Z., Ghanem, N., Salem, M.B., Lefranc, G., Lefranc, M.-P., Frequencies of the human immunoglobulin IGHA2M1 and IGHA2*M2 alleles corresponding to the A2m(1) and A2m(2) allotypes in the French, Lebanese, Tunisian, and Black African populations. Nucleic Acids Res., 17, 1989, 3625.
159. Souroujon, M.C., Rubinstein, D.B., Schwartz, R.S., Barrett, K.J., Polymorphisms in human H chain V region genes from the VHIII gene family. J. Immunol. 143 (1989), 706–711.
160. Spatz, L.A., Wong, K.K., Williams, M., Desai, R., Golier, J., Berman, J.E., Alt, F.W., Latov, N., Cloning and sequence analysis of the VH and VL regions of an anti-myelin/DNA antibody from a patient with peripheral neuropathy and chronic lymphocytic leukemia. J. Immunol. 144 (1990), 2821–2828.
161. Stevenson, F.K., Wrightham, M., Glennie, M.J., Jones, D.B., Cattan, A.R., Feizi, T., Hamblin, T.J., Stevenson, G.T., Antibodies to shared idiotypes as agents for analysis and therapy for human B cell tumors. Blood 68 (1986), 430–436.
162. Stevenson, F.K., Smith, G.J., North, J., Hamblin, T.G., Glennie, J.J., Identification of normal B-cell counterparts of neoplastic cells which secrete cold agglutinins of anti-I and anti-I specificity. Br. J. Haematol. 72 (1989), 9–15.
163. Takahashi, N., Ueda, S., Obata, M., Nikaido, T., Nikai, S., Honjo, T., Structure of human immunoglobulin gamma genes. Implications for evolution of a gene family. Cell (Cambridge, Mass.) 29 (1982), 671–679.
164. Takahashi, N., Noma, T., Honjo, T., Rearranged immunoglobulin heavy chain variable region (VH) pseudogene that deletes the second complementarity-determining region. Proc. Natl. Acad. Sci. U.S.A. 81 (1984), 5194–5198.
165. Trepicchio, W. Jr., Maruya, M., Barrett, K.J., The heavy chain genes of a lupus anti-DNA autoantibody are encoded in the germ line of a nonautoimmune strain of mouse and conserved in strains of mice polymorphic for this gene locus. J. Immunol. 139 (1987), 3139–3145.
166. Turnbull, I.F., Bernard, O., Sriprakash, K.S., Matthews, J.D., Human immunoglobulin variable region genes: A new VH sequence used to detect polymorphism. Immunogenetics 25 (1987), 184–192.
167. van der Heijden, R.W.J., Bunschoten, H., Pascual, V., Uytdehaag, F.G.C.M., Osterhaus, A.D.M.E., Capra, J.D., Nucleotide sequence of a human monoclonal anti-idiotypic antibody specific for a rabies virus-neutralizing monoclonal antibody reveals extensive somatic variability suggestive of an antigen-driven immune response. J. Immunol. 144 (1990), 2835–2839.
168. Van Dijk, K.W., Schroeder, H.W. Jr., Perlmutter, R.M., Milner, E.C.B., Heterogeneity in the human Ig VH locus. J. Immunol. 142 (1989), 2547–2554.
169. Walter, M.A., Cox, D.W., Analysis of genetic variation reveals human immunoglobulin VH region gene organization. Am. J. Hum. Genet. 42 (1988), 446–451.
170. Walter, M.A., Cox, D.W., A method for two-dimensional DNA electrophoresis (2D-DE): Application to the immunoglobulin heavy chain variable region. Genomics 5 (1989), 157–159.
171. Walter, M.A., Surti, U., Hofker, M.H., Cox, D.W., The physical organization of the human immunoglobulin heavy chain gene complex. EMBO J. 9 (1990), 3303–3313.
172. Wang, A.-C., Pink, J.R.L., Fudenberg, H.H., Ohms, J., A variable region subclass of heavy chains common to immunoglobulins G, A, and M and characterized by an unblocked amino-terminal residue. Proc. Natl. Acad. Sci. U.S.A. 66 (1970), 657–663.
173. Wang, X.-F., Calame, K., The endogenous immunoglobulin heavy chain enhancer can activate tandem VH promoters separated by a large distance. Cell (Cambridge, Mass.) 43 (1985), 659–665.
174. Wikler, M., Kohler, H., Sinoda, T., Putnam, F.W., Macroglobulin structure: Homology of μ and γ-heavy chains of human immunoglobulins. Science 163 (1969), 75–78.
175. Williams, R., Kunkel, H.G., Capra, J.D., Antigenic specificities related to the cold agglutinin activity of IgM globulins. Science 161 (1968), 379–381.
176. Wood, C., Tonegawa, S., Diversity and joining segments of mouse immunoglobulin heavy chain genes are closely linked and in the same orientation: Implications for the joining mechanisms. Proc. Natl. Acad. Sci. U.S.A. 80 (1983), 3030–3034.
177. Yancopoulos, G.D., Desiderio, S.V., Paskin, M., Kearney, J.F., Baltimore, D., Alt, F.W., Preferential utilization of the most VH proximal VH gene segments in pre-B-cell lines. Nature (London), 311, 1984, 727.
178. Zachau, H.G., Immunoglobulin light-chain genes of the κ type in man and mouse. Honjo, T., Alt, F.W., Rabbitts, T.H., (eds.) “Immunoglobulin Genes”, 1989, Academic Press, San Diego, California, 91–109.
179. Zong, S.Q., Naki, S., Matsuda, F., Lee, K.H., Honjo, T., Human immunoglobulin D segments: Isolation of a new D segment and polymorphic deletion of the D1 segment. Immunol. Lett., 17, 1988, 329.