Advertisement

Positive and Negative Selection of Natural Autoreactive B Cells

  • Richard R. HardyEmail author
  • Kyoko Hayakawa
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 750)

Abstract

Naturally occurring antibodies (NAbs) produced by CD5+ B-1 B cells include those with specificity for thymocytes (anti-thymocyte autoantibody, ATA). Here we describe a prototypic example, encoded by an unmutated immunoglobulin μ/κ heavy chain/light chain. Studies with ATA-μ (“heavy chain only”) transgenic mice demonstrated a critical requirement for self-antigen in the accumulation of B cells with this specificity and for the production of high levels of serum ATA NAb. Furthermore, analysis of B-cell development in ATA-μκ (“heavy and light chain”) transgenic mice revealed two distinct responses by B cells to expression of this B-cell receptor (BCR). (1) Most B cells developing from bone marrow of adult mice were blocked at an immature stage in spleen and only escaped apoptosis by editing their BCR to eliminate the ATA specificity. (2) Some B cells differentiated to antibody-forming cells without altering their specificity, produced high levels of serum ATA, and many ATA-secreting plasma cells were observed in spleen. Finally, examination of B-cell development and ATA NAb production in ATA-μκ transgenic mice with levels of Thy-1 autoantigen varying from very low to above physiologic reveals a clear relationship between BCR crosslinking by antigen and B-cell fate. Low levels of Thy-1 autoantigen resulted in diversion of ATA B cells into the marginal zone B-cell compartment, presumably because of reduced BCR signaling. Thus, our studies demonstrate a key positive selection step in the development of NAb-producing B cells and show that most of these cells in adult mice bearing such specificities fail to reach a mature stage. Importantly, because these specificities are isolated from B-1 B cells and, when expressed as transgenes, guide development into the B-1 or marginal zone B-cell pool, we identify these B cells as a major source of natural autoantibodies in mice.

Keywords

Marginal Zone Receptor Editing Natural Autoantibody Specific Light Chain Chain Transgenic Mouse 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Hayakawa K, Hardy RR, Parks DR et al. The “Ly-1 B” cell subpopulation in normal, immunodefective, and autoimmune mice. J Exp Med 1983; 157:202–18; PMID:6600267; http://dx.doi.org/10.1084/jem.157.1.202.PubMedCrossRefGoogle Scholar
  2. 2.
    Hayakawa K, Hardy RR, Honda M et al. Ly-1 B cells: functionally distinct lymphocytes that secrete IgM autoantibodies. Proc Natl Acad Sci USA 1984; 81:2494–8; PMID:6609363; http://dx.doi.org/10.1073/pnas.81.8.2494.PubMedCrossRefGoogle Scholar
  3. 3.
    Sidman CL, Shultz LD, Hardy RR et al. Production of immunoglobulin isotypes by Ly-1+ B cells in viable motheaten and normal mice. Science 1986; 232:1423–5; PMID:3487115; http://dx.doi.org/10.1126/science.3487115.PubMedCrossRefGoogle Scholar
  4. 4.
    Hayakawa K, Hardy RR, Herzenberg LA et al. Progenitors for Ly-1 B cells are distinct from progenitors for otherB cells. J Exp Med 1985; 161:1554–68; PMID:3874257; http://dx.doi.org/10.1084/jem.161.6.1554.PubMedCrossRefGoogle Scholar
  5. 5.
    Cunningham AJ. Large numbers of cells in normal mice produce antibody components of isologous erythrocytes. Nature 1974; 252:749–51; PMID:4140475; http://dx.doi.org/10.1038/252749a0.PubMedCrossRefGoogle Scholar
  6. 6.
    Cunningham AJ, Steele EJ. Ontogeny of the autoimmune reaction in normal mice to antigens in erythrocytes and gut. Clin Exp Immunol 1981; 44:38–48; PMID:7021025.PubMedGoogle Scholar
  7. 7.
    Hayakawa K, Carmack CE, Hyman R et al. Natural autoantibodies to thymocytes: origin, VH genes, fine specificities, and the role of Thy-1 glycoprotein. J Exp Med 1990; 172:869–78; PMID:1974916; http://dx.doi.org/10.1084/jem.l72.3.869.PubMedCrossRefGoogle Scholar
  8. 8.
    Gui M, Wiest DL, Li J et al. Peripheral CD4+ T cell maturation recognized by increased expression of Thy-1/CD90 bearing the 6C10 carbohydrate epitope. J Immunol 1999; 163:4796–804; PMID: 10528179.PubMedGoogle Scholar
  9. 9.
    Hayakawa K, Hardy RR. Murine CD4+T cell subsets defined. J Exp Med 1988; 168:1825–38; PMID:2903214; http://dx.doi.org/10.1084/jem.168.5.1825.PubMedCrossRefGoogle Scholar
  10. 10.
    Nosten-Bertrand M, Errington ML, Murphy KP et al. Normal spatial learning despite regional inhibition of LTP in mice lacking Thy-1. Nature 1996; 379:826–9; PMID:8587606; http://dx.doi.org/10.1038/379826a0.PubMedCrossRefGoogle Scholar
  11. 11.
    Hayakawa K, Asano M, Shinton SA et al. Positive selection of natural autoreactive B cells. Science 1999; 285:113–6; PMID: 10390361; http://dx.doi.org/10.1126/science.285.5424.113.PubMedCrossRefGoogle Scholar
  12. 12.
    Murakami M, Tsubata T, Okamoto M et al. Antigen-induced apoptotic death of Ly-1 B cells responsible for autoimmune disease in transgenic mice. Nature 1992; 357:77–80; PMID: 1574128; http://dx.doi.org/10.1038/357077a0.PubMedCrossRefGoogle Scholar
  13. 13.
    Okamoto M, Murakami M, Shimizu A et al. A transgenic model of autoimmune hemolytic anemia. J Exp Med 1992; 175:71–9; PMID:1730928; http://dx.doi.org/10.1084/jem.175.l.71.PubMedCrossRefGoogle Scholar
  14. 14.
    Hayakawa K, Asano M, Shinton SA et al. 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 2003; 197:87–99; PMID:12515816; http://dx.doi.org/10.1084/jem.20021459.PubMedCrossRefGoogle Scholar
  15. 15.
    Goodnow CC, Crosbie J, Jorgensen H et al. Induction of self-tolerance in mature peripheral B lymphocytes. Nature 1989; 342:385–91; PMID:2586609; http://dx.doi.org/10.1038/342385a0.PubMedCrossRefGoogle Scholar
  16. 16.
    Nemazee DA, Burki K. Clonal deletion of B lymphocytes in a transgenic mouse bearing anti-MHC class I antibody genes. Nature 1989; 337:562–6; PMID:2783762; http://dx.doi.org/10.1038/337562a0.PubMedCrossRefGoogle Scholar
  17. 17.
    Erikson J, Radic MZ, Camper SA et al. Expression of anti-DNA immunoglobulin transgenes in non-autoimmune mice. Nature 1991; 349:331–4; PMID:1898987; http://dx.doi.org/10.1038/349331a0.PubMedCrossRefGoogle Scholar
  18. 18.
    Gay D, Saunders T, Camper S et al. Receptor editing: an approach by autoreactive B cells to escape tolerance. J Exp Med 1993; 177:999–1008; PMID:8459227; http://dx.doi.org/10.1084/jem.177.4.999.PubMedCrossRefGoogle Scholar
  19. 19.
    Wen L, Brill-Dashoff J, Shinton SA et al. Evidence of marginal-zone B cell-positive selection in spleen. Immunity 2005; 23:297–308; PMID: 16169502; http://dx.doi.org/10.1016/j.immuni.2005.08.007.PubMedCrossRefGoogle Scholar
  20. 20.
    Tanigaki K, Han H, Yamamoto N et al. Notch-RBP-J signaling is involved in cell fate determination of marginal zone B cells. Nat Immunol 2002; 3:443–50; PMID: 11967543; http://dx.doi.org/10.1038/ni793.PubMedCrossRefGoogle Scholar
  21. 21.
    Schiemann B, Gommerman JL, Vora K et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 2001; 293:2111–4 PMID: 11509691; http://dx.doi.org/10.1126/science.l061964.PubMedCrossRefGoogle Scholar
  22. 22.
    Schneider P, Takatsuka H, Wilson A et al. Maturation of marginal zone and follicular B cells requires B cell activating factor of the tumor necrosis factor family and is independent of B cell maturation antigen. J Exp Med 2001; 194:1691–7; PMID: 11733583; http://dx.doi.org/10.1084/jem.194.11.1691.PubMedCrossRefGoogle Scholar
  23. 23.
    Hardy RR, Hayakawa K. A developmental switch in B lymphopoiesis. Proc Natl Acad Sci USA 1991; 88:11550–4; PMID:1722338; http://dx.doi.org/10.1073/pnas.88.24.11550.PubMedCrossRefGoogle Scholar
  24. 24.
    Casola S, Otipoby KL, Alimzhanov M et al. B cell receptor signal strength determines B cell fate. Nat Immunol 2004; 5:317–27; PMID: 14758357; http://dx.doi.org/10.1038/ni1036.PubMedCrossRefGoogle Scholar
  25. 25.
    Baumgarth N, Herman OC, Jager GC et al. B-1 and B-2 cell-derived immunoglobulin M antibodies are nonredundant components of the protective response to influenza virus infection. J Exp Med 2000; 192:271–80; PMID: 10899913; http://dx.doi.org/10.1084/jem.192.2.271.PubMedCrossRefGoogle Scholar
  26. 26.
    Choi YS, Baumgarth N. Dual role for B-1a cells in immunity to influenza virus infection. J Exp Med 2008; 205:3053–64; PMID: 19075288; http://dx.doi.org/10.1084/jem.20080979.PubMedCrossRefGoogle Scholar
  27. 27.
    Pennell CA, Arnold LW, Haughton G et al. Restricted Ig variable region gene expression among Ly-1+ B cell lymphomas. J Immunol 1988; 141:2788–96; PMID:3139765.PubMedGoogle Scholar
  28. 28.
    Haughton G, Arnold LW, Bishop GA et al. The CH series of murine B cell lymphomas: neoplastic analogues of Ly-1+ normal B cells. Immunol Rev 1986; 93:35–51; PMID:3491037; http://dx.doi.org/10.1111/j.l600-065X.1986.tb01501.x.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  1. 1.Fox Chase Cancer CenterPhiladelphiaUSA

Personalised recommendations