pp 1-16 | Cite as

B Cells Carrying Antigen Receptors Against Microbes as Tools for Vaccine Discovery and Design

  • Deepika Bhullar
  • David NemazeeEmail author
Part of the Current Topics in Microbiology and Immunology book series


Can basic science improve the art of vaccinology? Here, we review efforts to understand immune responses with the aim to improve vaccine design and, eventually, to predict the efficacy of human vaccine candidates using the tools of transformed B cells and targeted transgenic mice carrying B cells with antigen receptors specific for microbes of interest.


  1. Alamyar E, Duroux P, Lefranc MP, Giudicelli V (2012) IMGT((R)) tools for the nucleotide analysis of immunoglobulin (IG) and T cell receptor (TR) V-(D)-J repertoires, polymorphisms, and IG mutations: IMGT/V-QUEST and IMGT/HighV-QUEST for NGS. Methods Mol Biol 882:569–604Google Scholar
  2. Arnold LW, Pennell CA, McCray SK, Clarke SH (1994) Development of B-1 cells: segregation of phosphatidyl choline-specific B cells to the B-1 population occurs after immunoglobulin gene expression. J Exp Med 179:1585–1595Google Scholar
  3. Berland R, Fernandez L, Kari E, Han JH, Lomakin I, Akira S, Wortis HH, Kearney JF, Ucci AA, Imanishi-Kari T (2006) Toll-like receptor 7-dependent loss of B cell tolerance in pathogenic autoantibody knockin mice. Immunity 25:429–440Google Scholar
  4. Betz AG, Rada C, Pannell R, Milstein C, Neuberger MS (1993) Passenger transgenes reveal intrinsic specificity of the antibody hypermutation mechanism: clustering, polarity, and specific hot spots. Proc Natl Acad Sci USA 90:2385–2388Google Scholar
  5. Bonsignori M, Montefiori DC, Wu X, Chen X, Hwang KK, Tsao CY, Kozink DM, Parks RJ, Tomaras GD, Crump JA, Kapiga SH, Sam NE, Kwong PD, Kepler TB, Liao HX, Mascola JR, Haynes BF (2012) Two distinct broadly neutralizing antibody specificities of different clonal lineages in a single HIV-1-infected donor: implications for vaccine design. J Virol 86:4688–4692Google Scholar
  6. Borrero M, Clarke SH (2002) Low-affinity anti-Smith antigen B cells are regulated by anergy as opposed to developmental arrest or differentiation to B-1. J Immunol 168:13–21Google Scholar
  7. Brink R, Goodnow CC, Crosbie J, Adams E, Eris J, Mason DY, Hartley SB, Basten A (1992) Immunoglobulin M and D antigen receptors are both capable of mediating B lymphocyte activation, deletion, or anergy after interaction with specific antigen. J Exp Med 176:991–1005Google Scholar
  8. Brinster RL, Ritchie KA, Hammer RE, O’Brien RL, Arp B, Storb U (1983) Expression of a microinjected immunoglobulin gene in the spleen of transgenic mice. Nature 306:332–336Google Scholar
  9. Bruggemann M, Osborn MJ, Ma B, Hayre J, Avis S, Lundstrom B, Buelow R (2015) Human antibody production in transgenic animals. Arch Immunol Ther Exp (Warsz) 63:101–108Google Scholar
  10. Cambier JC, Monroe JG (1984) B cell activation. V. Differentiation signaling of B cell membrane depolarization, increased I-A expression, G0 to G1 transition, and thymidine uptake by anti-IgM and anti-IgD antibodies. J Immunol 133:576–581Google Scholar
  11. Cambier JC, Gauld SB, Merrell KT, Vilen BJ (2007) B-cell anergy: from transgenic models to naturally occurring anergic B cells? Nat Rev Immunol 7:633–643Google Scholar
  12. Carmack CE, Shinton SA, Hayakawa K, Hardy RR (1990) Rearrangement and selection of VH11 in the Ly-1 B cell lineage. J Exp Med 172:371–374Google Scholar
  13. Carmack CE, Camper SA, Mackle JJ, Gerhard WU, Weigert Mg (1991) Influence of a V kappa 8 L chain transgene on endogenous rearrangements and the immune response to the HA(Sb) determinant on influenza virus. J Immunol 147, 2024–2033Google Scholar
  14. Carsetti R, Kohler G, Lamers MC (1995) Transitional B cells are the target of negative selection in the B cell compartment. J Exp Med 181:2129–2140Google Scholar
  15. Cascalho M, Ma A, Lee S, Masat L, Wabl M (1996) A quasi-monoclonal mouse. Science 272:1649–1652Google Scholar
  16. Casellas R, Shih TA, Kleinewietfeld M, Rakonjac J, Nemazee D, Rajewsky K, Nussenzweig MC (2001) Contribution of receptor editing to the antibody repertoire. Science 291:1541–1544Google Scholar
  17. Chen C, Nagy Z, Prak EL, Weigert M (1995) Immunoglobulin heavy chain gene replacement: a mechanism of receptor editing. Immunity 3:747–755Google Scholar
  18. Chen C, Prak EL, Weigert M (1997) Editing disease-associated autoantibodies. Immunity 6:97–105Google Scholar
  19. Chen Y, Zhang J, Hwang KK, Bouton-Verville H, Xia SM, Newman A, Ouyang YB, Haynes BF, Verkoczy L (2013) Common tolerance mechanisms, but distinct cross-reactivities associated with gp41 and lipids, limit production of HIV-1 broad neutralizing antibodies 2F5 and 4E10. J ImmunolGoogle Scholar
  20. Chumley MJ, Dal Porto JM, Kawaguchi S, Cambier JC, Nemazee D, Hardy RR (2000) A VH11 V kappa 9 B cell antigen receptor drives generation of CD5+ B cells both in vivo and in vitro. J Immunol 164:4586–4593Google Scholar
  21. Clarke SH, Staudt LM, Kavaler J, Schwartz D, Gerhard WU, Weigert MG (1990) V region gene usage and somatic mutation in the primary and secondary responses to influenza virus hemagglutinin. J Immunol 144:2795–2801Google Scholar
  22. Crews S, Griffin J, Huang H, Calame K, Hood L (1981) A single VH gene segment encodes the immune response to phosphorylcholine: somatic mutation is correlated with the class of the antibody. Cell 25:59–66Google Scholar
  23. Doores KJ, Huber M, Le KM, Wang SK, Doyle-Cooper C, Cooper A, Pantophlet R, Wong CH, Nemazee D, Burton DR (2013) 2G12-expressing B cell lines may aid in HIV carbohydrate vaccine design strategies. J Virol 87:2234–2241Google Scholar
  24. Dosenovic P, von Boehmer L, Escolano A, Jardine J, Freund NT, Gitlin AD, McGuire AT, Kulp DW, Oliveira T, Scharf L, Pietzsch J, Gray MD, Cupo A, van Gils MJ, Yao KH, Liu C, Gazumyan A, Seaman MS, Bjorkman PJ, Sanders RW, Moore JP, Stamatatos L, Schief WR, Nussenzweig MC (2015) Immunization for HIV-1 broadly neutralizing antibodies in human Ig knockin mice. Cell 161:1505–1515Google Scholar
  25. Dougan SK, Ogata S, Hu CC, Grotenbreg GM, Guillen E, Jaenisch R, Ploegh HL (2012) IgG1+ ovalbumin-specific B-cell transnuclear mice show class switch recombination in rare allelically included B cells. Proc Natl Acad Sci USA 109:13739–13744Google Scholar
  26. Doyle-Cooper C, Hudson KE, Cooper AB, Ota T, Skog P, Dawson PE, Zwick MB, Schief WR, Burton DR, Nemazee D (2013) Immune tolerance negatively regulates B cells in knock-in mice expressing broadly neutralizing HIV antibody 4E10. J ImmunolGoogle Scholar
  27. Dreyfus C, Laursen NS, Kwaks T, Zuijdgeest D, Khayat R, Ekiert DC, Lee JH, Metlagel Z, Bujny MV, Jongeneelen M, van der Vlugt R, Lamrani M, Korse HJ, Geelen E, Sahin O, Sieuwerts M, Brakenhoff JP, Vogels R, Li OT, Poon LL, Peiris M, Koudstaal W, Ward AB, Wilson IA, Goudsmit J, Friesen RH (2012) Highly conserved protective epitopes on influenza B viruses. Science 337:1343–1348Google Scholar
  28. Ekiert DC, Friesen RH, Bhabha G, Kwaks T, Jongeneelen M, Yu W, Ophorst C, Cox F, Korse HJ, Brandenburg B, Vogels R, Brakenhoff JP, Kompier R, Koldijk MH, Cornelissen LA, Poon LL, Peiris M, Koudstaal W, Wilson IA, Goudsmit J (2011) A highly conserved neutralizing epitope on group 2 influenza A viruses. Science 333:843–850Google Scholar
  29. Erikson J, Radic MZ, Camper SA, Hardy RR, Carmack C, Weigert M (1991) Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice. Nature 349:331–334Google Scholar
  30. Feeney AJ, Atkinson MJ, Cowan MJ, Escuro G, Lugo G (1996) A defective Vkappa A2 allele in Navajos which may play a role in increased susceptibility to haemophilus influenzae type b disease. J Clin Invest 97:2277–2282Google Scholar
  31. Finton KA, Larimore K, Larman HB, Friend D, Correnti C, Rupert PB, Elledge SJ, Greenberg PD, Strong RK (2013) Autoreactivity and exceptional CDR plasticity (but not unusual polyspecificity) hinder elicitation of the anti-HIV antibody 4E10. PLoS Pathog 9:e1003639Google Scholar
  32. Foster MH, Liu Q, Chen H, Nemazee D, Cooperstone BG (1997) Anti-laminin reactivity and glomerular immune deposition by in vitro recombinant antibodies. Autoimmunity 26:231–243Google Scholar
  33. Fulcher DA, Basten A (1994) Reduced life span of anergic self-reactive B cells in a double-transgenic model. J Exp Med 179:125–134Google Scholar
  34. Gaeta BA, Malming HR, Jackson KJ, Bain ME, Wilson P, Collins AM (2007) iHMMune-align: hidden Markov model-based alignment and identification of germline genes in rearranged immunoglobulin gene sequences. Bioinformatics 23:1580–1587Google Scholar
  35. Gay D, Saunders T, Camper S, Weigert M (1993) Receptor editing: an approach by autoreactive B cells to escape tolerance. J Exp Med 177:999–1008Google Scholar
  36. Gearhart PJ, Johnson ND, Douglas R, Hood L (1981) IgG antibodies to phosphorylcholine exhibit more diversity than their IgM counterparts. Nature 291:29–34Google Scholar
  37. Gerdes T, Wabl M (2004) Autoreactivity and allelic inclusion in a B cell nuclear transfer mouse. Nat Immunol 5:1282–1287Google Scholar
  38. Golub R, Martin D, Bertrand FE, Cascalho M, Wabl M, Wu GE (2001) VH gene replacement in thymocytes. J Immunol 166:855–860Google Scholar
  39. Goodnow CC, Crosbie J, Adelstein S, Lavoie TB, Smith-Gill SJ, Brink RA, Pritchard-Briscoe H, Wotherspoon JS, Loblay RH, Raphael K et al. (1988) Altered immunoglobulin expression and functional silencing of self-reactive B lymphocytes in transgenic mice. Nature 334, 676–682Google Scholar
  40. Goodnow CC, Sprent J, Fazekas de St GB, Vinuesa CG (2005) Cellular and genetic mechanisms of self tolerance and autoimmunity. Nature 435:590–597Google Scholar
  41. Green LL (2014) Transgenic mouse strains as platforms for the successful discovery and development of human therapeutic monoclonal antibodies. Curr Drug Discov Technol 11:74–84Google Scholar
  42. Hagman J, Lo D, Doglio LT, Hackett JJ, Rudin CM, Haasch D, Brinster R, Storb U (1989) Inhibition of immunoglobulin gene rearrangement by the expression of a lambda 2 transgene [published erratum appears in J Exp Med 1989 Aug 1;170(2):619]. J Exp Med 169, 1911–1929Google Scholar
  43. Hangartner L, Senn BM, Ledermann B, Kalinke U, Seiler P, Bucher E, Zellweger RM, Fink K, Odermatt B, Burki K, Zinkernagel RM, Hengartner H (2003) Antiviral immune responses in gene-targeted mice expressing the immunoglobulin heavy chain of virus-neutralizing antibodies. Proc Natl Acad Sci USA 100:12883–12888Google Scholar
  44. Hangartner L, Zellweger RM, Giobbi M, Weber J, Eschli B, McCoy KD, Harris N, Recher M, Zinkernagel RM, Hengartner H (2006) Nonneutralizing antibodies binding to the surface glycoprotein of lymphocytic choriomeningitis virus reduce early virus spread. J Exp Med 203:2033–2042Google Scholar
  45. Hara T, Jung LK, Bjorndahl JM, Fu SM (1986) Human T cell activation. III. Rapid induction of a phosphorylated 28 kD/32 kD disulfide-linked early activation antigen (EA 1) by 12-o-tetradecanoyl phorbol-13-acetate, mitogens, and antigens. J Exp Med 164:1988–2005Google Scholar
  46. Hayakawa K, Asano M, Shinton SA, Gui M, Allman D, Stewart CL, Silver J, Hardy RR (1999) Positive selection of natural autoreactive B cells. Science 285:113–116Google Scholar
  47. Hayakawa K, Asano M, Shinton SA, Gui M, Wen LJ, Dashoff J, Hardy RR (2003) Positive selection of anti-thy-1 autoreactive B-1 cells and natural serum autoantibody production independent from bone marrow B cell development. J Exp Med 197:87–99Google Scholar
  48. Haynes BF, Fleming J, St Clair EW, Katinger H, Stiegler G, Kunert R, Robinson J, Scearce RM, Plonk K, Staats HF, Ortel TL, Liao HX, Alam SM (2005) Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies. Science 308:1906–1908Google Scholar
  49. Hochedlinger K, Jaenisch R (2002) Monoclonal mice generated by nuclear transfer from mature B and T donor cells. Nature 415:1035–1038Google Scholar
  50. Hombach J, Tsubata T, Leclercq L, Stappert H, Reth M (1990) Molecular components of the B-cell antigen receptor complex of the IgM class. Nature 343:760–762Google Scholar
  51. Hoot S, McGuire AT, Cohen KW, Strong RK, Hangartner L, Klein F, Diskin R, Scheid JF, Sather DN, Burton DR, Stamatatos L (2013) Recombinant HIV envelope proteins fail to engage germline versions of anti-CD4bs bNAbs. PLoS Pathog 9:e1003106Google Scholar
  52. Hu L, Rezanka LJ, Mi QS, Lustig A, Taub DD, Longo DL, Kenny JJ (2002) T15-idiotype-negative B cells dominate the phosphocholine binding cells in the preimmune repertoire of T15i knockin mice. J Immunol 168:1273–1280Google Scholar
  53. Hur EM, Patel SN, Shimizu S, Rao DS, Gnanapragasam PN, An DS, Yang L, Baltimore D (2012) Inhibitory effect of HIV-specific neutralizing IgA on mucosal transmission of HIV in humanized mice. Blood 120:4571–4582Google Scholar
  54. Jardine J, Julien JP, Menis S, Ota T, Kalyuzhniy O, McGuire A, Sok D, Huang PS, Macpherson S, Jones M, Nieusma T, Mathison J, Baker D, Ward AB, Burton DR, Stamatatos L, Nemazee D, Wilson IA, Schief WR (2013) Rational HIV immunogen design to target specific germline B cell receptors. Science 340:711–716Google Scholar
  55. Jardine JG, Ota T, Sok D, Pauthner M, Kulp DW, Kalyuzhniy O, Skog PD, Thinnes TC, Bhullar D, Briney B, Menis S, Jones M, Kubitz M, Spencer S, Adachi Y, Burton DR, Schief WR, Nemazee D (2015) HIV-1 VACCINES. Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen. Science 349:156–161Google Scholar
  56. Kaartinen M, Griffiths GM, Markham AF, Milstein C (1983) mRNA sequences define an unusually restricted IgG response to 2-phenyloxazolone and its early diversification. Nature 304:320–324Google Scholar
  57. Karpel ME, Boutwell CL, Allen TM (2015) BLT humanized mice as a small animal model of HIV infection. Curr Opin Virol 13:75–80Google Scholar
  58. Kashyap AK, Steel J, Oner AF, Dillon MA, Swale RE, Wall KM, Perry KJ, Faynboym A, Ilhan M, Horowitz M, Horowitz L, Palese P, Bhatt RR, Lerner RA (2008) Combinatorial antibody libraries from survivors of the Turkish H5N1 avian influenza outbreak reveal virus neutralization strategies. Proc Natl Acad Sci USA 105:5986–5991Google Scholar
  59. Kenny JJ, Stall AM, Sieckmann DG, Lamers MC, Finkelman FD, Finch L, Longo DL (1991) Receptor-mediated elimination of phosphocholine-specific B cells in x-linked immune-deficient mice. J Immunol 146:2568–2577Google Scholar
  60. Kirak O, Frickel EM, Grotenbreg GM, Suh H, Jaenisch R, Ploegh HL (2010) Transnuclear mice with predefined T cell receptor specificities against Toxoplasma gondii obtained via SCNT. Science 328:243–248Google Scholar
  61. Kitamura D, Rajewsky K (1992) Targeted disruption of mu chain membrane exon causes loss of heavy-chain allelic exclusion [see comments]. Nature 356:154–156Google Scholar
  62. Klein F, Halper-Stromberg A, Horwitz JA, Gruell H, Scheid JF, Bournazos S, Mouquet H, Spatz LA, Diskin R, Abadir A, Zang T, Dorner M, Billerbeck E, Labitt RN, Gaebler C, Marcovecchio PM, Incesu RB, Eisenreich TR, Bieniasz PD, Seaman MS, Bjorkman PJ, Ravetch JV, Ploss A, Nussenzweig MC (2012) HIV therapy by a combination of broadly neutralizing antibodies in humanized mice. Nature 492:118–122Google Scholar
  63. Koralov SB, Novobrantseva TI, Konigsmann J, Ehlich A, Rajewsky K (2006) Antibody repertoires generated by VH replacement and direct VH to JH joining. Immunity 25:43–53Google Scholar
  64. Kumar R, Bach MP, Mainoldi F, Maruya M, Kishigami S, Jumaa H, Wakayama T, Kanagawa O, Fagarasan S, Casola S (2015) Antibody repertoire diversification through VH gene replacement in mice cloned from an IgA plasma cell. Proc Natl Acad Sci USA 112:E450–457Google Scholar
  65. Lenschow DJ, Sperling AI, Cooke MP, Freeman G, Rhee L, Decker DC, Gray G, Nadler LM, Goodnow CC, Bluestone JA (1994) Differential up-regulation of the B7-1 and B7-2 costimulatory molecules after Ig receptor engagement by antigen. J Immunol 153:1990–1997Google Scholar
  66. Lieberman R, Potter M, Mushinski EB, Humphrey W Jr, Rudikoff S (1974) Genetics of a new IgVH (T15 idiotype) marker in the mouse regulating natural antibody to phosphorylcholine. J Exp Med 139:983–1001Google Scholar
  67. Lingwood D, McTamney PM, Yassine HM, Whittle JR, Guo X, Boyington JC, Wei CJ, Nabel GJ (2012) Structural and genetic basis for development of broadly neutralizing influenza antibodies. NatureGoogle Scholar
  68. Litzenburger T, Bluthmann H, Morales P, Pham-Dinh D, Dautigny A, Wekerle H, Iglesias A (2000) Development of myelin oligodendrocyte glycoprotein autoreactive transgenic B lymphocytes: receptor editing in vivo after encounter of a self-antigen distinct from myelin oligodendrocyte glycoprotein. J Immunol 165:5360–5366Google Scholar
  69. Lucas AH, Reason DC (1999) Polysaccharide vaccines as probes of antibody repertoires in man. Immunol Rev 171:89–104Google Scholar
  70. Luning Prak E, Weigert M (1995) Light chain replacement: a new model for antibody gene rearrangement. J Exp Med 182:541–548Google Scholar
  71. Ma B, Osborn MJ, Avis S, Ouisse LH, Menoret S, Anegon I, Buelow R, Bruggemann M (2013) Human antibody expression in transgenic rats: comparison of chimeric IgH loci with human VH, D and JH but bearing different rat C-gene regions. J Immunol Methods 400–401:78–86Google Scholar
  72. Martin F, Oliver AM, Kearney JF (2001) Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 14:617–629Google Scholar
  73. McGuire AT, Hoot S, Dreyer AM, Lippy A, Stuart A, Cohen KW, Jardine J, Menis S, Scheid JF, West AP, Schief WR, Stamatatos L (2013) Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies. J Exp Med 210:655–663Google Scholar
  74. McGuire AT, Dreyer AM, Carbonetti S, Lippy A, Glenn J, Scheid JF, Mouquet H, Stamatatos L (2014a) HIV antibodies. Antigen modification regulates competition of broad and narrow neutralizing HIV antibodies. Science 346:1380–1383Google Scholar
  75. McGuire AT, Glenn JA, Lippy A, Stamatatos L (2014b) Diverse recombinant HIV-1 Envs fail to activate B cells expressing the germline B cell receptors of the broadly neutralizing anti-HIV-1 antibodies PG9 and 447-52D. J Virol 88:2645–2657Google Scholar
  76. Mi QS, Zhou L, Schulze DH, Fischer RT, Lustig A, Rezanka LJ, Donovan DM, Longo DL, Kenny JJ (2000) Highly reduced protection against Streptococcus pneumoniae after deletion of a single heavy chain gene in mouse. Proc Natl Acad Sci USA 97:6031–6036Google Scholar
  77. Nadel B, Tang A, Lugo G, Love V, Escuro G, Feeney AJ (1998) Decreased frequency of rearrangement due to the synergistic effect of nucleotide changes in the heptamer and nonamer of the recombination signal sequence of the V kappa gene A2b, which is associated with increased susceptibility of Navajos to Haemophilus influenzae type b disease. J Immunol 161:6068–6073Google Scholar
  78. Nemazee D (2006) Receptor editing in lymphocyte development and central tolerance. Nat Rev Immunol 6:728–740Google Scholar
  79. Nemazee DA, Burki K (1989) Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature 337:562–566Google Scholar
  80. Nisonoff A, Ju S (1976) Studies of a cross-reactive idiotype associated with anti-para-azophenylarsonate antibodies of A/J mice. Ann Immunol (Paris) 127:347–356Google Scholar
  81. Nussenzweig MC, Shaw AC, Sinn E, Danner DB, Holmes KL, Morse HC, Leder P (1987) Allelic exclusion in transgenic mice that express the membrane form of immunoglobulin mu. Science 236:816–819Google Scholar
  82. O’Brien RL, Brinster RL, Storb U (1987) Somatic hypermutation of an immunoglobulin transgene in kappa transgenic mice. Nature 326:405–409Google Scholar
  83. Osborn MJ, Ma B, Avis S, Binnie A, Dilley J, Yang X, Lindquist K, Menoret S, Iscache AL, Ouisse LH, Rajpal A, Anegon I, Neuberger MS, Buelow R, Bruggemann M (2013) High-affinity IgG antibodies develop naturally in Ig-knockout rats carrying germline human IgH/Igkappa/Iglambda loci bearing the rat CH region. J Immunol 190:1481–1490Google Scholar
  84. Ota T, Doyle-Cooper C, Cooper AB, Huber M, Falkowska E, Doores KJ, Hangartner L, Le K, Sok D, Jardine J, Lifson J, Wu X, Mascola JR, Poignard P, Binley JM, Chakrabarti BK, Schief WR, Wyatt RT, Burton DR, Nemazee D (2012) Anti-HIV B cell lines as candidate vaccine biosensors. J. Immunol. 189:4816–4824Google Scholar
  85. Ota T, Doyle-Cooper C, Cooper AB, Doores KJ, Aoki-Ota M, Le K, Schief WR, Wyatt RT, Burton DR, Nemazee D (2013) B cells from knock-in mice expressing broadly neutralizing HIV antibody b12 carry an innocuous B cell receptor responsive to HIV vaccine candidates. J ImmunolGoogle Scholar
  86. Parameswaran P, Liu Y, Roskin KM, Jackson KK, Dixit VP, Lee JY, Artiles KL, Zompi S, Vargas MJ, Simen BB, Hanczaruk B, McGowan KR, Tariq MA, Pourmand N, Koller D, Balmaseda A, Boyd SD, Harris E, Fire AZ (2013) Convergent antibody signatures in human dengue. Cell Host Microbe 13:691–700Google Scholar
  87. Pelanda R, Schaal S, Torres RM, Rajewsky K (1996) A prematurely expressed Ig(kappa) transgene, but not V(kappa)J(kappa) gene segment targeted into the Ig(kappa) locus, can rescue B cell development in lambda5-deficient mice. Immunity 5:229–239Google Scholar
  88. Pelanda R, Schwers S, Sonoda E, Torres RM, Nemazee D, Rajewsky K (1997) Receptor editing in a transgenic mouse model: site, efficiency, and role in B cell tolerance and antibody diversification. Immunity 7:765–775Google Scholar
  89. Pewzner-Jung Y, Friedmann D, Sonoda E, Jung S, Rajewsky K, Eilat D (1998) B cell deletion, anergy, and receptor editing in “knock in” mice targeted with a germline-encoded or somatically mutated anti-DNA heavy chain. J Immunol 161:4634–4645Google Scholar
  90. Phan TG, Amesbury M, Gardam S, Crosbie J, Hasbold J, Hodgkin PD, Basten A, Brink R (2003) B cell receptor-independent stimuli trigger immunoglobulin (Ig) class switch recombination and production of IgG autoantibodies by anergic self-reactive B cells. J Exp Med 197:845–860Google Scholar
  91. Pruzina S, Williams GT, Kaneva G, Davies SL, Martin-Lopez A, Bruggemann M, Vieira SM, Jeffs SA, Sattentau QJ, Neuberger MS (2011) Human monoclonal antibodies to HIV-1 gp140 from mice bearing YAC-based human immunoglobulin transloci. Protein Eng Des Sel 24:791–799Google Scholar
  92. Reth M (1989) Antigen receptor tail clue. Nature 338:383–384Google Scholar
  93. Reth M (1992) Antigen receptors on B lymphocytes. Annu Rev Immunol 10:97–121Google Scholar
  94. Ritchie KA, Brinster RL, Storb U (1984) Allelic exclusion and control of endogenous immunoglobulin gene rearrangement in kappa transgenic mice. Nature 312:517–520Google Scholar
  95. Rusconi S, Kohler G (1985) Transmission and expression of a specific pair of rearranged immunoglobulin mu and kappa genes in a transgenic mouse line. Nature 314:330–334Google Scholar
  96. Russ DE, Ho KY, Longo NS (2015) HTJoinSolver: human immunoglobulin VDJ partitioning using approximate dynamic programming constrained by conserved motifs. BMC Bioinformatics 16:170Google Scholar
  97. Russell DM, Dembic Z, Morahan G, Miller JF, Burki K, Nemazee D (1991) Peripheral deletion of self-reactive B cells. Nature 354:308–311Google Scholar
  98. Seiler P, Kalinke U, Rulicke T, Bucher EM, Bose C, Zinkernagel RM, Hengartner H (1998) Enhanced virus clearance by early inducible lymphocytic choriomeningitis virus-neutralizing antibodies in immunoglobulin-transgenic mice. J Virol 72:2253–2258Google Scholar
  99. Senn BM, Lopez-Macias C, Kalinke U, Lamarre A, Isibasi A, Zinkernagel RM, Hengartner H (2003) Combinatorial immunoglobulin light chain variability creates sufficient B cell diversity to mount protective antibody responses against pathogen infections. Eur J Immunol 33:950–961Google Scholar
  100. Sher A, Cohn M (1972) Inheritance of an idiotype associated with the immune response of inbred mice to phosphorylcholine. Eur J Immunol 2:319–326Google Scholar
  101. Shlomchik MJ (2008) Sites and stages of autoreactive B cell activation and regulation. Immunity 28:18–28Google Scholar
  102. Shlomchik MJ, Zharhary D, Saunders T, Camper SA, Weigert Mg (1993) A rheumatoid factor transgenic mouse model of autoantibody regulation. Int Immunol 5, 1329–1341Google Scholar
  103. Sigal NH, Pickard AR, Metcalf ES, Gearhart PJ, Klinman NR (1977) Expression of phosphorylcholine-specific B cells during murine development. J Exp Med 146:933–948Google Scholar
  104. Sonoda E, Pewzner-Jung Y, Schwers S, Taki S, Jung S, Eilat D, Rajewsky K (1997) B cell development under the condition of allelic inclusion. Immunity 6:225–233Google Scholar
  105. Storb U (1987) Transgenic mice with immunoglobulin genes. Annu Rev Immunol 5:151–174Google Scholar
  106. Storb U, Pinkert C, Arp B, Engler P, Gollahon K, Manz J, Brady W, Brinster RL (1986) Transgenic mice with mu and kappa genes encoding antiphosphorylcholine antibodies. J Exp Med 164:627–641Google Scholar
  107. Sui J, Hwang WC, Perez S, Wei G, Aird D, Chen LM, Santelli E, Stec B, Cadwell G, Ali M, Wan H, Murakami A, Yammanuru A, Han T, Cox NJ, Bankston LA, Donis RO, Liddington RC, Marasco WA (2009) Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol 16:265–273Google Scholar
  108. Taki S, Meiering M, Rajewsky K (1993) Targeted insertion of a variable region gene into the immunoglobulin heavy chain locus [see comments]. Science 262:1268–1271Google Scholar
  109. Taki S, Schwenk F, Rajewsky K (1995) Rearrangement of upstream DH and VH genes to a rearranged immunoglobulin variable region gene inserted into the DQ52-JH region of the immunoglobulin heavy chain locus. Eur J Immunol 25:1888–1896Google Scholar
  110. Thomson CA, Bryson S, McLean GR, Creagh AL, Pai EF, Schrader JW (2008) Germline V-genes sculpt the binding site of a family of antibodies neutralizing human cytomegalovirus. EMBO J 27:2592–2602Google Scholar
  111. Throsby M, van den Brink E, Jongeneelen M, Poon LL, Alard P, Cornelissen L, Bakker A, Cox F, van Deventer E, Guan Y, Cinatl J, ter Meulen J, Lasters I, Carsetti R, Peiris M, de Kruif J, Goudsmit J (2008) Heterosubtypic neutralizing monoclonal antibodies cross-protective against H5N1 and H1N1 recovered from human IgM + memory B cells. PLoS ONE 3:e3942Google Scholar
  112. Tiegs SL, Russell DM, Nemazee D (1993) Receptor editing in self-reactive bone marrow B cells. J Exp Med 177:1009–1020Google Scholar
  113. Venkitaraman AR, Williams GT, Dariavach P, Neuberger MS (1991) The B-cell antigen receptor of the five immunoglobulin classes. Nature 352:777–781Google Scholar
  114. Verkoczy L, Diaz M (2014) Autoreactivity in HIV-1 broadly neutralizing antibodies: implications for their function and induction by vaccination. Curr Opin HIV and AIDS 9:224–234Google Scholar
  115. Verkoczy L, Diaz M, Holl TM, Ouyang YB, Bouton-Verville H, Alam SM, Liao HX, Kelsoe G, Haynes BF (2010) Autoreactivity in an HIV-1 broadly reactive neutralizing antibody variable region heavy chain induces immunologic tolerance. Proc Natl Acad Sci USA 107:181–186Google Scholar
  116. Verkoczy L, Chen Y, Bouton-Verville H, Zhang J, Diaz M, Hutchinson J, Ouyang YB, Alam SM, Holl TM, Hwang KK, Kelsoe G, Haynes BF (2011) Rescue of HIV-1 broad neutralizing antibody-expressing B cells in 2F5 VH x VL knockin mice reveals multiple tolerance controls. J Immunol 187:3785–3797Google Scholar
  117. Verkoczy L, Chen Y, Zhang J, Bouton-Verville H, Newman A, Lockwood B, Scearce RM, Montefiori DC, Dennison SM, Xia SM, Hwang KK, Liao HX, Alam SM, Haynes BF (2013) Induction of HIV-1 broad neutralizing antibodies in 2F5 knock-in mice: selection against membrane proximal external region-associated autoreactivity limits T-dependent responses. J Immunol 191:2538–2550Google Scholar
  118. Villaudy J, Schotte R, Legrand N, Spits H (2014) Critical assessment of human antibody generation in humanized mouse models. J Immunol Methods 410:18–27Google Scholar
  119. Weaver D, Costantini F, Imanishi-Kari T, Baltimore D (1985) A transgenic immunoglobulin mu gene prevents rearrangement of endogenous genes. Cell 42:117–127Google Scholar
  120. Weaver GC, Villar RF, Kanekiyo M, Nabel GJ, Mascola JR, Lingwood D (2016) In vitro reconstitution of B cell receptor-antigen interactions to evaluate potential vaccine candidates. Nat Protoc 11:193–213Google Scholar
  121. Whittle JR, Zhang R, Khurana S, King LR, Manischewitz J, Golding H, Dormitzer PR, Haynes BF, Walter EB, Moody MA, Kepler TB, Liao HX, Harrison SC (2011) Broadly neutralizing human antibody that recognizes the receptor-binding pocket of influenza virus hemagglutinin. Proc Natl Acad Sci USA 108:14216–14221Google Scholar
  122. Whittle JR, Wheatley AK, Wu L, Lingwood D, Kanekiyo M, Ma SS, Narpala SR, Yassine HM, Frank GM, Yewdell JW, Ledgerwood JE, Wei CJ, McDermott AB, Graham BS, Koup RA, Nabel GJ (2014) Flow cytometry reveals that H5N1 vaccination elicits cross-reactive stem-directed antibodies from multiple Ig heavy-chain lineages. J Virol 88:4047–4057Google Scholar
  123. Wrammert J, Koutsonanos D, Li GM, Edupuganti S, Sui J, Morrissey M, McCausland M, Skountzou I, Hornig M, Lipkin WI, Mehta A, Razavi B, Del Rio C, Zheng NY, Lee JH, Huang M, Ali Z, Kaur K, Andrews S, Amara RR, Wang Y, Das SR, O’Donnell CD, Yewdell JW, Subbarao K, Marasco WA, Mulligan MJ, Compans R, Ahmed R, Wilson PC (2011) Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection. J Exp Med 208:181–193Google Scholar
  124. Wu X, Zhou T, Zhu J, Zhang B, Georgiev I, Wang C, Chen X, Longo NS, Louder M, McKee K, O’Dell S, Perfetto S, Schmidt SD, Shi W, Wu L, Yang Y, Yang ZY, Yang Z, Zhang Z, Bonsignori M, Crump JA, Kapiga SH, Sam NE, Haynes BF, Simek M, Burton DR, Koff WC, Doria-Rose NA, Connors M, Mullikin JC, Nabel GJ, Roederer M, Shapiro L, Kwong PD, Mascola JR (2011) Focused evolution of HIV-1 neutralizing antibodies revealed by structures and deep sequencing. Science 333:1593–1602Google Scholar
  125. Wysocki LJ, Margolies MN, Huang B, Nemazee DA, Wechsler DS, Sato VL, Smith JA, Gefter ML (1985) Combinational diversity within variable regions bearing the predominant anti-p-azophenylarsonate idiotype of strain A mice. J Immunol 134:2740–2747Google Scholar
  126. Yang G, Holl TM, Liu Y, Li Y, Lu X, Nicely NI, Kepler TB, Alam SM, Liao HX, Cain DW, Spicer L, Vandeberg JL, Haynes BF, Kelsoe G (2013) Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies. J Exp, MedGoogle Scholar
  127. Ye J, Ma N, Madden TL, Ostell JM (2013) IgBLAST: an immunoglobulin variable domain sequence analysis tool. Nucleic Acids Res 41:W34–40Google Scholar
  128. Zhang R, Verkoczy L, Wiehe K, Munir Alam S, Nicely NI, Santra S, Bradley T, Pemble CWt., Zhang J, Gao F, Montefiori DC, Bouton-Verville H, Kelsoe G, Larimore K, Greenberg PD, Parks R, Foulger A, Peel JN, Luo K, Lu X, Trama AM, Vandergrift N, Tomaras GD, Kepler TB, Moody MA, Liao HX, Haynes BF (2016) Initiation of immune tolerance-controlled HIV gp41 neutralizing B cell lineages. Sci Transl Med 8, 336ra362Google Scholar
  129. Zhou J, Lottenbach KR, Barenkamp SJ, Lucas AH, Reason DC (2002) Recurrent variable region gene usage and somatic mutation in the human antibody response to the capsular polysaccharide of Streptococcus pneumoniae type 23F. Infect Immun 70:4083–4091Google Scholar
  130. Zhou T, Georgiev I, Wu X, Yang ZY, Dai K, Finzi A, Kwon YD, Scheid JF, Shi W, Xu L, Yang Y, Zhu J, Nussenzweig MC, Sodroski J, Shapiro L, Nabel GJ, Mascola JR, Kwong PD (2010) Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 329:811–817Google Scholar
  131. Zhou T, Zhu J, Wu X, Moquin S, Zhang B, Acharya P, Georgiev IS, Altae-Tran HR, Chuang GY, Joyce MG, Do Kwon Y, Longo NS, Louder MK, Luongo T, McKee K, Schramm CA, Skinner J, Yang Y, Yang Z, Zhang Z, Zheng A, Bonsignori M, Haynes BF, Scheid JF, Nussenzweig MC, Simek M, Burton DR, Koff WC, Program NCS, Mullikin JC, Connors M, Shapiro L, Nabel GJ, Mascola JR, Kwong PD (2013) Multidonor analysis reveals structural elements, genetic determinants, and maturation pathway for HIV-1 neutralization by VRC01-class antibodies. Immunity 39:245–258Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Immunology and MicrobiologyThe Scripps Research InstituteLa JollaUSA

Personalised recommendations