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Circulating human B cells that express surrogate light chains and edited receptors

Abstract

Immunoglobulin gene recombination can result in the assembly of self-reactive antibodies. Deletion, anergy or receptor editing normally silence B cells that produce these autoantibodies. Receptor editing is highly efficient in mouse B cells that carry pre-recombined autoantibody transgenes or gene “knock-ins”. However, it has been difficult to identify cells that have edited receptors in unmanipulated mice and humans. To try to identify such cells we isolated and characterized B cells that coexpress surrogate and conventional light chains (V-preB+L+) from the blood of normal human donors. V-preB+L+ B cells express RAG mRNA, display an unusual heavy and light chain antibody repertoire consistent with antiself reactivity, and show evidence of receptor editing. These cells accumulate in the joints of patients with rheumatoid arthritis, consistent with a role for V-preB+L+ B cells and receptor editing in autoimmune disease.

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Figure 1: Surrogate light chain cell-surface expression on peripheral blood B cells.
Figure 2: RAG, TdT, V-preB and λ-like gene expression in human peripheral B cell subsets measured by semiquantitative RT-PCR.
Figure 3: RAG-1, RAG-2, TdT and surrogate light chain gene expression in newly emigrated B cells.
Figure 4: Characterization of VH5(D)JH expression in conventional and V-preB+L+ B cells.
Figure 5: κ light chain repertoire in V-preB+L+ and conventional B cells.
Figure 6: V-preB+L+ B cells are overrepresented in rheumatoid synovia.

References

  1. Goodnow, C. C. Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires . Proc. Natl Acad. Sci. USA 93, 2264– 71 (1996).

    Article  CAS  Google Scholar 

  2. Nemazee, D. Does immunological tolerance explain the waste in the B-lymphocyte immune system? Experiment and theory. Ann. NY Acad. Sci. 764 , 397–401 (1995).

    Article  CAS  Google Scholar 

  3. Radic, M. Z. & Weigert, M. Origins of anti-DNA antibodies and their implications for B-cell tolerance. Ann. NY Acad. Sci. 764, 384–96 (1995).

    Article  CAS  Google Scholar 

  4. Hertz, M. & Nemazee, D. BCR ligation induces receptor editing in IgM+IgD bone marrow B cells in vitro. Immunity 6, 429– 436 (1997).

    Article  CAS  Google Scholar 

  5. Melamed, D., Benschop, R. J., Cambier, J. C. & Nemazee, D. Developmental regulation of B lymphocyte immune tolerance compartmentalizes clonal selection from receptor selection. Cell 92, 173–82 (1998).

    Article  CAS  Google Scholar 

  6. Gay, D., Saunders, T., Camper, S. & Weigert, M. Receptor editing: an approach by autoreactive B cells to escape tolerance. J. Exp. Med. 177, 999–1008 ( 1993).

    Article  CAS  Google Scholar 

  7. Radic, M.Z., Erickson, J., Litwin, S. & Weigert, M. B lymphocytes may escape tolerance by revising their antigen receptors. J. Exp. Med. 177, 1165–1173 ( 1993).

    Article  CAS  Google Scholar 

  8. Tiegs, S. L., Russell, D. M. & Nemazee, D. Receptor editing in self-reactive bone marrow B cells . J. Exp. Med. 177, 1009– 1020 (1993).

    Article  CAS  Google Scholar 

  9. Chen, C., Prak, E. L. & Weigert, M. Editing disease-associated autoantibodies. Immunity 6, 97–105 ( 1997).

    Article  Google Scholar 

  10. Pelanda, R. et al. Receptor editing in a transgenic mouse model: site, efficiency, and role in B cell tolerance and antibody diversification. Immunity 7, 765–75 ( 1997).

    Article  CAS  Google Scholar 

  11. Xu, H., Li, H., Suri-Payer, E., Hardy, R. R. & Weigert, M. Regulation of anti-DNA B cells in recombination-activating gene-deficient mice. J. Exp. Med. 188, 1247 –54 (1998).

    Article  CAS  Google Scholar 

  12. Reth, M., Gehrmann, P., Petrac, E. & Wiese, P. A novel VH to VH(D)JH joining mechanism in heavy-chain-negative (null) pre-B cells results in heavy-chain production. Nature 322, 840–2 (1986).

    Article  CAS  Google Scholar 

  13. Chen, C., Nagy, Z., Prak, E. L. & Weigert, M. Immunoglobulin heavy chain gene replacement: a mechanism of receptor editing. Immunity 3, 747–55 ( 1995).

    Article  CAS  Google Scholar 

  14. Taki, S., Schwenk, F. & Rajewsky, K. 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– 96 (1995).

    Article  CAS  Google Scholar 

  15. Prak, E. L. & Weigert, M. Light chain replacement: a new model for antibody gene rearrangement. J. Exp. Med. 182, 541–8 (1995).

    Article  CAS  Google Scholar 

  16. Retter, M. W. & Nemazee, D. Receptor editing occurs frequently during normal B cell development. J. Exp. Med. 188, 1231–8 (1998).

    Article  CAS  Google Scholar 

  17. Wilson, P. C. et al. Receptor revision of immunoglobulin heavy chain variable region genes in normal human B lymphocytes. J. Exp. Med. 191 ,1881–94 (2000).

    Article  CAS  Google Scholar 

  18. Klein, U., Rajewsky, K. & Kuppers, R. Phenotypic and molecular characterization of human peripheral blood B-cell subsets with special reference to N-region addition and J κ-usage in Vκ Jκ-joints and κ/λ ratios in naive versus memory B-cell subsets to identify traces of receptor editing processes. Curr. Top. Microbiol. Immunol. 246 , 141–6 (1999).

    CAS  PubMed  Google Scholar 

  19. Giachino, C., Padovan, E. & Lanzavecchia, A. Re-expression of RAG-1 and RAG-2 genes and evidence for secondary rearrangements in human germinal center B lymphocytes. Eur. J. Immunol. 28, 3506–13 (1998).

    Article  CAS  Google Scholar 

  20. de Wildt, R. M., Hoet, R. M. A., van Venrooij, W. J., Tomlinson, I. M. & Winter, G. Analysis of heavy and light chain pairings indicates that receptor editing shapes the human antibody repertoire. J. Mol. Biol. 285, 895–901 (1999).

    Article  CAS  Google Scholar 

  21. Brard, F., Shannon, M., Prak, E. L., Litwin, S. & Weigert, M. Somatic mutation and light chain rearrangement generate autoimmunity in anti-single-stranded DNA transgenic MRL/lpr mice. J. Exp. Med. 190, 691–704 (1999).

    Article  CAS  Google Scholar 

  22. Dorner, T., Foster, S.J., Farner, N.L. & Lipsky, P.E. Immunoglobulin κ chain receptor editing in systemic lupus erythematosus . J. Clin. Invest. 102, 688– 94 (1998).

    Article  CAS  Google Scholar 

  23. Dorner, T., Farner, N. L. & Lipsky, P. E. Ig λ and heavy chain gene usage in early untreated systemic lupus erythematosus suggests intensive B cell stimulation. J. Immunol. 163, 1027–36 (1999).

    CAS  PubMed  Google Scholar 

  24. Meffre, E. et al. Antigen receptor engagement turns off the V(D)J recombination machinery in human tonsil B cells. J. Exp. Med. 188 , 765–72 (1998).

    Article  CAS  Google Scholar 

  25. Wang, Y. H., Nomura, J., Faye-Petersen, O. M. & Cooper, M. D. Surrogate light chain production during B cell differentiation: differential intracellular versus cell surface expression. J. Immunol. 161, 1132–9 (1998).

    CAS  PubMed  Google Scholar 

  26. Lemmers, B., Gauthier, L., Guelpa-Fonlupt, V., Fougereau, M. & Schiff, C. The human (PsiL+mu) proB complex: cell surface expression and biochemical structure of a putative transducing receptor. Blood 93, 4336–46 (1999).

    CAS  PubMed  Google Scholar 

  27. Uckun, F. M. Regulation of human B-cell ontogeny. Blood 76, 1908–23 (1990).

    CAS  PubMed  Google Scholar 

  28. Pascual, V. et al. Analysis of somatic mutation in five B cell subsets of human tonsil. J. Exp. Med. 180, 329– 339 (1994).

    Article  CAS  Google Scholar 

  29. Liu, Y. J. et al. Normal human IgD+IgM germinal center B cells can express up to 80 mutations in the variable region of their IgD transcripts. Immunity 4, 603 –13 (1996).

    Article  CAS  Google Scholar 

  30. Klein, U., Rajewsky, K. & Kuppers, R. Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J. Exp. Med. 188, 1679–89 (1998).

    Article  CAS  Google Scholar 

  31. Yu, W. et al. Continued RAG expression in late stages of B cell development and no apparent re–induction after immunization. Nature 400, 682–7 (1999).

    Article  CAS  Google Scholar 

  32. Monroe, R. et al. RAG2:GFP knockin mice reveal novel aspects of RAG2 expression in primary and peripheral lymphoid tissues. Immunity 11, 201–212 (1999).

    Article  CAS  Google Scholar 

  33. Tangye, S. G., Liu, Y. J., Aversa, G., Phillips, J. H. & de Vries, J. E. Identification of functional human splenic memory B cells by expression of CD148 and CD27. J. Exp. Med. 188, 1691–703 (1998).

    Article  CAS  Google Scholar 

  34. Conley, M. E. B cells in patients with X-linked agammaglobulinemia. J. Immunol. 134, 3070–4 ( 1985).

    CAS  PubMed  Google Scholar 

  35. Lassoued, K. et al. Expression of surrogate light chain receptors is restricted to a late stage in pre-B cell differentiation. Cell 73, 73–86 (1993).

    Article  CAS  Google Scholar 

  36. Guelpa-Fonlupt, V., Tonnelle, C., Blaise, D., Fougereau, M. & Fumoux, F. Discrete early pro-B and pre-B stages in normal human bone marrow as defined by surface pseudo-light chain expression. Eur. J. Immunol. 24, 257–64 (1994).

    Article  CAS  Google Scholar 

  37. Ghia, P. et al. Ordering of human bone marrow B lymphocyte precursors by single-cell polymerase chain reaction analyses of the rearrangement status of the immunoglobulin H and L chain loci. J. Exp. Med. 184, 2217 –2229 (1996).

    Article  CAS  Google Scholar 

  38. Sanz, I. et al. The smaller human VH gene families display remarkably little polymorphism. EMBO J. 8, 3741– 8 (1989).

    Article  CAS  Google Scholar 

  39. Yamada, M. et al. Preferential utilization of specific immunoglobulin heavy chain diversity and joining segments in adult human peripheral blood B lymphocytes . J. Exp. Med. 173, 395– 407 (1991).

    Article  CAS  Google Scholar 

  40. Brezinschek, H. P. et al. Analysis of the human VH gene repertoire. Differential effects of selection and somatic hypermutation on human peripheral CD5(+)/IgM+ and CD5()/IgM+ B cells. J. Clin. Invest. 99, 2488–501 (1997).

    Article  CAS  Google Scholar 

  41. Corbett, S. J., Tomlinson, I. M., Sonnhammer, E. L. L., Buck, D. & Winter, G. Sequence of the human immunoglobulin diversity (D) segment locus: a systematic analysis provides no evidence for the use of DIR segments, inverted D segments, “minor” D segments or D-D recombination. J. Mol. Biol. 270, 587–97 (1997).

    Article  CAS  Google Scholar 

  42. Meek, K. D., Hasemann, C. A. & Capra, J. D. Novel rearrangements at the immunoglobulin D locus. Inversions and fusions add to IgH somatic diversity. J. Exp. Med. 170, 39–57 ( 1989).

    Article  CAS  Google Scholar 

  43. Klonowski, K. D., Primiano, L. L. & Monestier, M. Atypical VH-D-JH rearrangements in newborn autoimmune MRL mice. J. Immunol. 162, 1566–72 (1999).

    CAS  PubMed  Google Scholar 

  44. Ichiyoshi, Y. & Casali, P. Analysis of the structural correlates for antibody polyreactivity by multiple reassortments of chimeric human immunoglobulin heavy and light chain V segments. J. Exp. Med. 180, 885–95 (1994).

    Article  CAS  Google Scholar 

  45. Crouzier, R., Martin, T. & Pasquali, J. L. Heavy chain variable region, light chain variable region, and heavy chain CDR3 influences on the mono- and polyreactivity and on the affinity of human monoclonal rheumatoid factors. J. Immunol. 154, 4526–35 ( 1995).

    CAS  PubMed  Google Scholar 

  46. Han, S., Zheng, B., Schatz, D. G., Spanopoulou, E. & Kelsoe, G. Neoteny in lymphocytes: Rag1 and Rag2 expression in germinal center B cells. Science 274, 2094 –7 (1996).

    Article  CAS  Google Scholar 

  47. Hikida, M. et al. Reexpression of RAG-1 and RAG-2 Genes in Activated Mature Mouse B cells. Science 274, 2092– 2094 (1996).

    Article  CAS  Google Scholar 

  48. Han, S. et al. V(D)J recombinase activity in a subset of germinal center B lymphocytes . Science 278, 301–305 (1997).

    Article  CAS  Google Scholar 

  49. Hikida, M., Mori, M., Kawabata, T., Takai, T. & Ohmori, H. Characterization of B cells expressing Recombination Activating Genes in germinal centers of immunized mouse lymph nodes. J. Immunol. 158, 2509–2512 ( 1997).

    CAS  PubMed  Google Scholar 

  50. Papavasiliou, F. et al. V(D)J Recombination in Mature B cells a New Mechanism for Diversification of Antibody Responses. Science 278, 298–301 (1997).

    Article  CAS  Google Scholar 

  51. Hertz, M., Kouskoff, V., Nakamura, T. & Nemazee, D. V(D)J recombinase induction in splenic B lymphocytes is inhibited by antigen-receptor signaling. Nature 394, 292– 5 (1998).

    Article  CAS  Google Scholar 

  52. Foster, S. J., Brezinschek, H. P., Brezinschek, R. I. & Lipsky, P. E. Molecular mechanisms and selective influences that shape the κ gene repertoire of IgM+ B cells. J. Clin. Invest. 99, 1614–27 (1997).

    Article  CAS  Google Scholar 

  53. Schable, K. F. & Zachau, H. G. The variable genes of the human immunoglobulin kappa locus. Biol. Chem. Hoppe Seyler 374, 1001–22 ( 1993).

    Article  CAS  Google Scholar 

  54. Victor, K. D. et al. Rheumatoid factors isolated from patients with autoimmune disorders are derived from germline genes distinct from those encoding the Wa, Po, and Bla cross-reactive idiotypes. J. Clin. Invest. 87, 1603–13 (1991).

    Article  CAS  Google Scholar 

  55. Bridges, S.L. Jr et al. Somatic mutation and CDR3 lengths of immunoglobulin kappa light chains expressed in patients with rheumatoid arthritis and in normal individuals. J. Clin. Invest. 96, 831–41 (1995).

    Article  CAS  Google Scholar 

  56. Randen, I., Mellbye, O. J., Forre, O. & Natvig, J. B. The identification of germinal centres and follicular dendritic cell networks in rheumatoid synovial tissue. Scand J. Immunol. 41 , 481–6 (1995).

    Article  CAS  Google Scholar 

  57. Gauthier, L., Lemmers, B., Guelpa-Fonlupt, V., Fougereau, M. & Schiff, C. Mu-surrogate light chain physicochemical interactions of the human preB cell receptor: implications for VH repertoire selection and cell signaling at the preB cell stage. J. Immunol. 162, 41–50 ( 1999).

    CAS  PubMed  Google Scholar 

  58. Mian, I. S., Bradwell, A. R. & Olson, A. J. Structure, function and properties of antibody binding sites. J. Mol. Biol. 217, 133– 51 (1991).

    Article  CAS  Google Scholar 

  59. Manheimer-Lory, A. J., Zandman-Goddard, G., Davidson, A., Aranow, C. & Diamond, B. Lupus-specific antibodies reveal an altered pattern of somatic mutation. J. Clin. Invest. 100, 2538–46 (1997).

    Article  CAS  Google Scholar 

  60. Erikson, J. et al. Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice. Nature 349, 331–4 (1991).

    Article  CAS  Google Scholar 

  61. Goodnow, C. C., Crosbie, J., Jorgensen, H., Brink, R. A. & Basten, A. Induction of self-tolerance in mature peripheral B lymphocytes. Nature 342, 385 –391 (1989).

    Article  CAS  Google Scholar 

  62. Paramithiotis, E. & Cooper, M. D. Memory B lymphocytes migrate to bone marrow in humans. Proc. Natl Acad. Sci. USA 94, 208–12 (1997).

    Article  CAS  Google Scholar 

  63. Meffre, E. et al. A human non-XLA immunodeficiency disease characterized by blockage of B cell development at an early proB cell stage. J. Clin. Invest. 98, 1519–26 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the Nussenzweig lab for comments and discussions; G. Michel, H. Chambost and C. Fossat for blood samples; W. Muller and K. Tai for tonsil and joint samples and P. Wilson, J. D. Capra and N. Chiorazzi for sharing unpublished data. Supported by grants from the NIH (to M.C.N. and J.W.Y.) and the Leukemia and Lymphoma Society (to J.W.Y.). M.C.N. is based at the Howard Hughes Medical Institute.

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Meffre, E., Davis, E., Schiff, C. et al. Circulating human B cells that express surrogate light chains and edited receptors. Nat Immunol 1, 207–213 (2000). https://doi.org/10.1038/79739

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