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Assembly and Function of the Precursor B-Cell Receptor

  • Rudolf Übelhart
  • Markus Werner
  • Hassan JumaaEmail author
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 393)

Abstract

During early stages of development, precursor B lymphocytes express a characteristic type of antigen receptor known as the pre-B-cell receptor (pre-BCR). This receptor differs from conventional BCRs in that it possesses a germ line-encoded surrogate light chain (SLC), which is associated with the signal transduction machinery via heavy chain (HC) proteins that have been generated by productive rearrangement of the immunoglobulin HC genes. The pre-BCR marks a key step of B-cell commitment, as it activates the B-cell-specific signaling cascade and mediates the selection, expansion, and differentiation of cells expressing a productively rearranged HC protein. Another difference between the pre-BCR and conventional BCR might be the initial event that triggers receptor activation, as the pre-BCR is activated in the absence of external ligands, while conventional BCRs require antigen for activation. Nonetheless, the pre-BCR downstream signaling cascade is largely similar to that of the BCR suggesting that the characteristic LC of the pre-BCR mediates important receptor interactions thereby providing distinctive, germ line-encoded features to the pre-BCR. In fact, the SLC enables the pre-BCR to act as a surrogate autoreactive receptor. Here, we outline the structure and function of the pre-BCR and how the autonomous signaling capacity might be a direct consequence of pre-BCR assembly. In addition to its role in early B-cell development, we discuss how the ordered activation of downstream signaling cascades enables the pre-BCR to activate seemingly opposing cellular programs such as proliferation and differentiation.

Keywords

Bone Marrow Stromal Cell Conserve Arginine Residue Surrogate Light Chain Unique Tail VpreB Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Aiba Y, Kameyama M, Yamazaki T, Tedder TF, Kurosaki T (2008) Regulation of B-cell development by BCAP and CD19 through their binding to phosphoinositide 3-kinase. Blood 111(3):1497–1503PubMedGoogle Scholar
  2. Alkhatib A, Werner M, Hug E, Herzog S, Eschbach C, Faraidun H et al (2012) FoxO1 induces Ikaros splicing to promote immunoglobulin gene recombination. J Exp Med 209(2):395–406PubMedPubMedCentralGoogle Scholar
  3. Amin RH, Schlissel MS (2008) Foxo1 directly regulates the transcription of recombination-activating genes during B cell development. Nat Immunol 9(6):613–622PubMedPubMedCentralGoogle Scholar
  4. Amzel LM, Poljak RJ (1979) Three-dimensional structure of immunoglobulins. Annu Rev Biochem 48:961–997PubMedGoogle Scholar
  5. Bankovich AJ, Raunser S, Juo ZS, Walz T, Davis MM, Garcia KC (2007) Structural insight into pre-B cell receptor function. Science 316(5822):291–294PubMedGoogle Scholar
  6. Bossy D, Milili M, Zucman J, Thomas G, Fougereau M, Schiff C (1991) Organization and expression of the lambda-like genes that contribute to the mu-psi light chain complex in human pre-B cells. Int Immunol 3(11):1081–1090PubMedGoogle Scholar
  7. Bradl H, Jack HM (2001) Surrogate light chain-mediated interaction of a soluble pre-B cell receptor with adherent cell lines. J Immunol 167(11):6403–6411PubMedGoogle Scholar
  8. Bradl H, Wittmann J, Milius D, Vettermann C, Jack HM (2003) Interaction of murine precursor B cell receptor with stroma cells is controlled by the unique tail of lambda 5 and stroma cell-associated heparan sulfate. J Immunol 171(5):2338–2348PubMedGoogle Scholar
  9. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS et al (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96(6):857–868PubMedGoogle Scholar
  10. Calamito M, Juntilla MM, Thomas M, Northrup DL, Rathmell J, Birnbaum MJ et al (2010) Akt1 and Akt2 promote peripheral B-cell maturation and survival. Blood 115(20):4043–4050PubMedPubMedCentralGoogle Scholar
  11. Chiu CW, Dalton M, Ishiai M, Kurosaki T, Chan AC (2002) BLNK: molecular scaffolding through ‘cis’-mediated organization of signaling proteins. EMBO J 21(23):6461–6472PubMedPubMedCentralGoogle Scholar
  12. Coffer PJ, Burgering BM (2004) Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol 4(11):889–899PubMedGoogle Scholar
  13. Conley ME, Dobbs AK, Quintana AM, Bosompem A, Wang YD, Coustan-Smith E et al (2012) Agammaglobulinemia and absent B lineage cells in a patient lacking the p85alpha subunit of PI3K. J Exp Med 209(3):463–470PubMedPubMedCentralGoogle Scholar
  14. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y et al (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91(2):231–241PubMedGoogle Scholar
  15. del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G (1997) Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278(5338):687–689PubMedGoogle Scholar
  16. Dengler HS, Baracho GV, Omori SA, Bruckner S, Arden KC, Castrillon DH et al (2008) Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation. Nat Immunol 9(12):1388–1398PubMedPubMedCentralGoogle Scholar
  17. Dijkers PF, Birkenkamp KU, Lam EW, Thomas NS, Lammers JW, Koenderman L et al (2002) FKHR-L1 can act as a critical effector of cell death induced by cytokine withdrawal: protein kinase B-enhanced cell survival through maintenance of mitochondrial integrity. J Cell Biol 156(3):531–542PubMedPubMedCentralGoogle Scholar
  18. Dolmetsch RE, Lewis RS, Goodnow CC, Healy JI (1997) Differential activation of transcription factors induced by Ca2+ response amplitude and duration. Nature 386(6627):855–858PubMedGoogle Scholar
  19. Dul JL, Argon Y, Winkler T, ten Boekel E, Melchers F, Martensson IL (1996) The murine VpreB1 and VpreB2 genes both encode a protein of the surrogate light chain and are co-expressed during B cell development. Eur J Immunol 26(4):906–913PubMedGoogle Scholar
  20. Elantak L, Espeli M, Boned A, Bornet O, Bonzi J, Gauthier L et al (2012) Structural basis for galectin-1-dependent pre-B cell receptor (pre-BCR) activation. J Biol Chem 287(53):44703–44713PubMedPubMedCentralGoogle Scholar
  21. Eschbach C, Bach MP, Fidler I, Pelanda R, Kohler F, Rajewsky K et al (2011) Efficient generation of B lymphocytes by recognition of self-antigens. Eur J Immunol 41(8):2397–2403PubMedPubMedCentralGoogle Scholar
  22. Espeli M, Mancini SJ, Breton C, Poirier F, Schiff C (2009) Impaired B-cell development at the pre-BII-cell stage in galectin-1-deficient mice due to inefficient pre-BII/stromal cell interactions. Blood 113(23):5878–5886PubMedGoogle Scholar
  23. Feske S (2007) Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol 7(9):690–702PubMedGoogle Scholar
  24. Flaswinkel H, Reth M (1994) Dual role of the tyrosine activation motif of the Ig-alpha protein during signal transduction via the B cell antigen receptor. The EMBO J 13(1):83–89PubMedGoogle Scholar
  25. Fleming HE, Paige CJ (2002) Cooperation between IL-7 and the pre-B cell receptor: a key to B cell selection. Semin Immunol 14(6):423–430PubMedGoogle Scholar
  26. Fruman DA, Snapper SB, Yballe CM, Davidson L, Yu JY, Alt FW et al (1999) Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha. Science 283(5400):393–397PubMedGoogle Scholar
  27. Gauthier L, Rossi B, Roux F, Termine E, Schiff C (2002) Galectin-1 is a stromal cell ligand of the pre-B cell receptor (BCR) implicated in synapse formation between pre-B and stromal cells and in pre-BCR triggering. Proc Natl Acad Sci USA 99(20):13014–13019PubMedGoogle Scholar
  28. Guloglu FB, Roman CA (2006) Precursor B cell receptor signaling activity can be uncoupled from surface expression. J Immunol 176(11):6862–6872PubMedPubMedCentralGoogle Scholar
  29. Guo B, Kato RM, Garcia-Lloret M, Wahl MI, Rawlings DJ (2000) Engagement of the human pre-B cell receptor generates a lipid raft-dependent calcium signaling complex. Immunity 13(2):243–253PubMedGoogle Scholar
  30. Hardy RR, Hayakawa K (2001) B cell development pathways. Annu Rev Immunol 19:595–621PubMedGoogle Scholar
  31. Herzog S, Jumaa H (2012) Self-recognition and clonal selection: autoreactivity drives the generation of B cells. Curr Opin Immunol 24(2):166–172PubMedGoogle Scholar
  32. Herzog S, Hug E, Meixlsperger S, Paik JH, DePinho RA, Reth M et al (2008) SLP-65 regulates immunoglobulin light chain gene recombination through the PI(3)K-PKB-Foxo pathway. Nat Immunol 9(6):623–631PubMedGoogle Scholar
  33. Herzog S, Reth M, Jumaa H (2009) Regulation of B-cell proliferation and differentiation by pre-B-cell receptor signalling. Nat Rev Immunol 9(3):195–205PubMedGoogle Scholar
  34. Huang J, Manning BD (2009) A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans 37(Pt 1):217–222PubMedPubMedCentralGoogle Scholar
  35. Johnson K, Hashimshony T, Sawai CM, Pongubala JM, Skok JA, Aifantis I et al (2008) Regulation of immunoglobulin light-chain recombination by the transcription factor IRF-4 and the attenuation of interleukin-7 signaling. Immunity 28(3):335–345PubMedGoogle Scholar
  36. Jou ST, Carpino N, Takahashi Y, Piekorz R, Chao JR, Carpino N et al (2002) Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol 22(24):8580–8591PubMedPubMedCentralGoogle Scholar
  37. Jumaa H, Wollscheid B, Mitterer M, Wienands J, Reth M, Nielsen PJ (1999) Abnormal development and function of B lymphocytes in mice deficient for the signaling adaptor protein SLP-65. Immunity 11(5):547–554PubMedGoogle Scholar
  38. Karasuyama H, Kudo A, Melchers F (1990) The proteins encoded by the VpreB and lambda 5 pre-B cell-specific genes can associate with each other and with mu heavy chain. J Exp Med 172(3):969–972PubMedGoogle Scholar
  39. Karasuyama H, Rolink A, Melchers F (1993) A complex of glycoproteins is associated with VpreB/lambda 5 surrogate light chain on the surface of mu heavy chain-negative early precursor B cell lines. J Exp Med 178(2):469–478PubMedGoogle Scholar
  40. Keenan RA, De Riva A, Corleis B, Hepburn L, Licence S, Winkler TH et al (2008) Censoring of autoreactive B cell development by the pre-B cell receptor. Science 321(5889):696–699PubMedGoogle Scholar
  41. Knoll M, Yanagisawa Y, Simmons S, Engels N, Wienands J, Melchers F et al (2012) The non-Ig parts of the VpreB and lambda5 proteins of the surrogate light chain play opposite roles in the surface representation of the precursor B cell receptor. J Immunol 188(12):6010–6017PubMedGoogle Scholar
  42. Kohler F, Storch B, Kulathu Y, Herzog S, Kuppig S, Reth M et al (2005) A leucine zipper in the N terminus confers membrane association to SLP-65. Nat Immunol 6(2):204–210PubMedGoogle Scholar
  43. Kohler F, Hug E, Eschbach C, Meixlsperger S, Hobeika E, Kofer J et al (2008) Autoreactive B cell receptors mimic autonomous pre-B cell receptor signaling and induce proliferation of early B cells. Immunity 29(6):912–921PubMedGoogle Scholar
  44. Koretzky GA, Abtahian F, Silverman MA (2006) SLP76 and SLP65: complex regulation of signalling in lymphocytes and beyond. Nat Rev Immunol 6(1):67–78PubMedGoogle Scholar
  45. Kudo A, Melchers F (1987) A second gene, VpreB in the lambda 5 locus of the mouse, which appears to be selectively expressed in pre-B lymphocytes. The EMBO J 6(8):2267–2272PubMedGoogle Scholar
  46. Kurosaki T (2000) Functional dissection of BCR signaling pathways. Curr Opin Immunol 12(3):276–281PubMedGoogle Scholar
  47. Lanig H, Bradl H, Jack HM (2004) Three-dimensional modeling of a pre-B-cell receptor. Mol Immunol 40(17):1263–1272PubMedGoogle Scholar
  48. Lu R, Medina KL, Lancki DW, Singh H (2003) IRF-4,8 orchestrate the pre-B-to-B transition in lymphocyte development. Genes Dev 17(14):1703–1708PubMedPubMedCentralGoogle Scholar
  49. Ma S, Turetsky A, Trinh L, Lu R (2006) IFN regulatory factor 4 and 8 promote Ig light chain kappa locus activation in pre-B cell development. J Immunol 177(11):7898–7904PubMedGoogle Scholar
  50. Ma S, Pathak S, Trinh L, Lu R (2008) Interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to down-regulate pre-B-cell receptor and promote cell-cycle withdrawal in pre-B-cell development. Blood 111(3):1396–1403PubMedPubMedCentralGoogle Scholar
  51. Ma S, Pathak S, Mandal M, Trinh L, Clark MR, Lu R (2010) Ikaros and Aiolos inhibit pre-B-cell proliferation by directly suppressing c-Myc expression. Mol Cell Biol 30(17):4149–4158PubMedPubMedCentralGoogle Scholar
  52. Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129(7):1261–1274PubMedPubMedCentralGoogle Scholar
  53. Marshall AJ, Fleming HE, Wu GE, Paige CJ (1998) Modulation of the IL-7 dose-response threshold during pro-B cell differentiation is dependent on pre-B cell receptor expression. J Immunol 161(11):6038–6045PubMedGoogle Scholar
  54. Meixlsperger S, Kohler F, Wossning T, Reppel M, Muschen M, Jumaa H (2007) Conventional light chains inhibit the autonomous signaling capacity of the B cell receptor. Immunity 26(3):323–333PubMedGoogle Scholar
  55. Melchers F, Karasuyama H, Haasner D, Bauer S, Kudo A, Sakaguchi N et al (1993) The surrogate light chain in B-cell development. Immunol Today 14(2):60–68PubMedGoogle Scholar
  56. Milne CD, Paige CJ (2006) IL-7: a key regulator of B lymphopoiesis. Semin Immunol 18(1):20–30PubMedGoogle Scholar
  57. Minegishi Y, Hendershot LM, Conley ME (1999a) Novel mechanisms control the folding and assembly of lambda5/14.1 and VpreB to produce an intact surrogate light chain. Proc Natl Acad Sci USA 96(6):3041–3046PubMedGoogle Scholar
  58. Minegishi Y, Rohrer J, Coustan-Smith E, Lederman HM, Pappu R, Campana D et al (1999b) An essential role for BLNK in human B cell development. Science 286(5446):1954–1957PubMedGoogle Scholar
  59. Nagasawa T (2006) Microenvironmental niches in the bone marrow required for B-cell development. Nat Rev Immunol 6(2):107–116PubMedGoogle Scholar
  60. Ochiai K, Maienschein-Cline M, Mandal M, Triggs JR, Bertolino E, Sciammas R et al (2012) A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation. Nat Immunol 13(3):300–307PubMedPubMedCentralGoogle Scholar
  61. Ohnishi K, Melchers F (2003) The nonimmunoglobulin portion of lambda5 mediates cell-autonomous pre-B cell receptor signaling. Nat Immunol 4(9):849–856PubMedGoogle Scholar
  62. Ohnishi K, Shimizu T, Karasuyama H, Melchers F (2000) The identification of a nonclassical cadherin expressed during B cell development and its interaction with surrogate light chain. J Biol Chem 275(40):31134–31144PubMedGoogle Scholar
  63. Ohnishi K, Melchers F, Shimizu T (2005) Lymphocyte-expressed BILL-cadherin/cadherin-17 contributes to the development of B cells at two stages. Eur J Immunol 35(3):957–963PubMedGoogle Scholar
  64. Okkenhaug K (2013) Signaling by the phosphoinositide 3-kinase family in immune cells. Annu Rev Immunol 31:675–704PubMedPubMedCentralGoogle Scholar
  65. Okkenhaug K, Vanhaesebroeck B (2003) PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol 3(4):317–330PubMedGoogle Scholar
  66. Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E et al (2002) Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297(5583):1031–1034PubMedGoogle Scholar
  67. Pappu R, Cheng AM, Li B, Gong Q, Chiu C, Griffin N et al (1999) Requirement for B cell linker protein (BLNK) in B cell development. Science 286(5446):1949–1954PubMedGoogle Scholar
  68. 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(6):765–775PubMedGoogle Scholar
  69. Puel A, Ziegler SF, Buckley RH, Leonard WJ (1998) Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nat Genet 20(4):394–397PubMedGoogle Scholar
  70. Ramadani F, Bolland DJ, Garcon F, Emery JL, Vanhaesebroeck B, Corcoran AE et al (2010) The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development. Sci Signal 3(134):ra60PubMedPubMedCentralGoogle Scholar
  71. Reth M (1989) Antigen receptor tail clue. Nature 338(6214):383–384PubMedGoogle Scholar
  72. Reth M (1992) Antigen receptors on B lymphocytes. Annu Rev Immunol 10:97–121PubMedGoogle Scholar
  73. Rolink AG, Winkler T, Melchers F, Andersson J (2000) Precursor B cell receptor-dependent B cell proliferation and differentiation does not require the bone marrow or fetal liver environment. J Exp Med 191(1):23–32PubMedPubMedCentralGoogle Scholar
  74. Rolli V, Gallwitz M, Wossning T, Flemming A, Schamel WW, Zurn C et al (2002) Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop. Mol Cell 10(5):1057–1069PubMedGoogle Scholar
  75. Rossi B, Espeli M, Schiff C, Gauthier L (2006) Clustering of pre-B cell integrins induces galectin-1-dependent pre-B cell receptor relocalization and activation. J Immunol 177(2):796–803PubMedGoogle Scholar
  76. Rowley RB, Burkhardt AL, Chao HG, Matsueda GR, Bolen JB (1995) Syk protein-tyrosine kinase is regulated by tyrosine-phosphorylated Ig alpha/Ig beta immunoreceptor tyrosine activation motif binding and autophosphorylation. J Biol Chem 270(19):11590–11594PubMedGoogle Scholar
  77. Sabbattini P, Lundgren M, Georgiou A, Chow C, Warnes G, Dillon N (2001) Binding of Ikaros to the lambda5 promoter silences transcription through a mechanism that does not require heterochromatin formation. EMBO J 20(11):2812–2822PubMedPubMedCentralGoogle Scholar
  78. Sakaguchi N, Melchers F (1986) Lambda 5, a new light-chain-related locus selectively expressed in pre-B lymphocytes. Nature 324(6097):579–582PubMedGoogle Scholar
  79. Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, Bolon B et al (2000) Function of PI3K gamma in thymocyte development, T cell activation, and neutrophil migration. Science 287(5455):1040–1046PubMedGoogle Scholar
  80. ten Boekel E, Melchers F, Rolink AG (1997) Changes in the V(H) gene repertoire of developing precursor B lymphocytes in mouse bone marrow mediated by the pre-B cell receptor. Immunity 7(3):357–368PubMedGoogle Scholar
  81. Thompson EC, Cobb BS, Sabbattini P, Meixlsperger S, Parelho V, Liberg D et al (2007) Ikaros DNA-binding proteins as integral components of B cell developmental-stage-specific regulatory circuits. Immunity 26(3):335–344PubMedGoogle Scholar
  82. Trinh DL, Scott DW, Morin RD, Mendez-Lago M, An J, Jones SJ et al (2013) Analysis of FOXO1 mutations in diffuse large B-cell lymphoma. Blood 121(18):3666–3674PubMedPubMedCentralGoogle Scholar
  83. Tsubata T, Reth M (1990) The products of pre-B cell-specific genes (lambda 5 and VpreB) and the immunoglobulin mu chain form a complex that is transported onto the cell surface. J Exp Med 172(3):973–976PubMedGoogle Scholar
  84. Turner M, Mee PJ, Costello PS, Williams O, Price AA, Duddy LP et al (1995) Perinatal lethality and blocked B-cell development in mice lacking the tyrosine kinase Syk. Nature 378(6554):298–302PubMedGoogle Scholar
  85. Ubelhart R, Bach MP, Eschbach C, Wossning T, Reth M, Jumaa H (2010) N-linked glycosylation selectively regulates autonomous precursor BCR function. Nat Immunol 11(8):759–765PubMedGoogle Scholar
  86. Venigalla RK, McGuire VA, Clarke R, Patterson-Kane JC, Najafov A, Toth R et al (2013) PDK1 regulates VDJ recombination, cell-cycle exit and survival during B-cell development. EMBO J 32(7):1008–1022PubMedPubMedCentralGoogle Scholar
  87. Vettermann C, Herrmann K, Albert C, Roth E, Bosl MR, Jack HM (2008) A unique role for the lambda5 nonimmunoglobulin tail in early B lymphocyte development. J Immunol 181(5):3232–3242PubMedGoogle Scholar
  88. Waisman A, Kraus M, Seagal J, Ghosh S, Melamed D, Song J et al (2007) IgG1 B cell receptor signaling is inhibited by CD22 and promotes the development of B cells whose survival is less dependent on Ig alpha/beta. J Exp Med 204(4):747–758PubMedPubMedCentralGoogle Scholar
  89. Watanabe D, Hashimoto S, Ishiai M, Matsushita M, Baba Y, Kishimoto T et al (2001) Four tyrosine residues in phospholipase C-gamma 2, identified as Btk-dependent phosphorylation sites, are required for B cell antigen receptor-coupled calcium signaling. J Biol Chem 276(42):38595–38601PubMedGoogle Scholar
  90. Werner M, Hobeika E, Jumaa H (2010) Role of PI3K in the generation and survival of B cells. Immunol Rev 237(1):55–71PubMedGoogle Scholar
  91. Zhang X, Tang N, Hadden TJ, Rishi AK (2011) Akt, FoxO and regulation of apoptosis. Biochim Biophys Acta 1813(11):1978–1986PubMedGoogle Scholar

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Authors and Affiliations

  • Rudolf Übelhart
    • 1
  • Markus Werner
    • 1
  • Hassan Jumaa
    • 1
    • 2
    Email author
  1. 1.Department of ImmunologyUlm UniversityUlmGermany
  2. 2.Department of Molecular Immunology, Faculty of BiologyUniversity of FreiburgFreiburg im BreisgauGermany

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