Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Confounding B-cell defences: lessons from a staphylococcal superantigen

Key Points

  • Superantigens are microbial toxins that target large sets of lymphocytes through conserved variable-region sites on antigen receptors. Studies of superantigens for B cells, produced by common pathogens like Staphylococcus aureus, S. magnus and HIV-1, are revealing new perspectives on the mechanisms responsible for B-cell-receptor-mediated clonal fates.

  • Recently developed mouse models have shown that superantigens induce antigen-receptor-mediated B-cell apoptosis through a form of activation-induced cell death that follows a CD95- and tumour-necrosis-factor receptor 1-independent intrinsic pathway.

  • Marginal zone B cells, which are important for defence from blood-borne infection, are especially susceptible to B-cell superantigens that induce more rapid and efficient apoptotic deletion than do follicular B cells.

  • Superantigen-induced death of the innate-like B cells, B1 cell and marginal zone B cells, can result in long lasting supraclonal defects in the repertoire and functional defects in immune responsiveness, that are especially relevant to T-cell-independent responses.

  • Recent studies in an infection model suggest that in vivo bacterial production of SpA can affect the immune system by superantigen-induced modulation of the B-cell compartment.

  • In naive non-autoimmune mice, large B-cell superantigen doses induce limited proliferation and more rapid larger-scale deletion, whereas small doses (even in the microgram range) generally induce greater initial proliferation and expansion followed by delayed small-scale deletion.

  • Lessons from B-cell superantigens are providing new insights into how BCR-mediated pathways for positive and negative supraclonal selection can be co-opted by common microbial pathogens.

Abstract

Studies of microbial superantigens that target large clonal sets of B cells through conserved antigen-receptor-variable-region sites are providing new insights into the mechanisms of B-cell activation-induced cell death. These investigations have shown differences between the clonal regulation of follicular B cells (B2 cells) and the innate-like marginal-zone B cells and B1 cells, and have also shown how B-cell superantigens can affect specialized host defences against infection. Agents designed to emulate the properties of B-cell superantigens might also provide new approaches for the treatment of B-cell-mediated autoimmune and neoplastic diseases.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Superantigens interact with conserved variable region sites on antibodies.
Figure 2: The in vivo susceptibility of B cells to superantigen exposure and subsequent outcomes.
Figure 3: Superantigen-induced cell death through B-cell receptor engagement.

Similar content being viewed by others

References

  1. Huber, B. T. Current Communications in Cell and Molecular Biology Vol. 182 (Cold Spring Harbor Laboratory Press, 1993).

    Google Scholar 

  2. Graille, M. et al. Crystal structure of a Staphylococcus aureus protein A domain complexed with the Fab fragment of a human IgM antibody: structural basis for recognition of B-cell receptors and superantigen activity. Proc. Natl Acad. Sci. USA 97, 5399–5404 (2000). The first solved structure for a B-cell superantigen, also characterized in complex with an antibody.

    CAS  PubMed  Google Scholar 

  3. Graille, M. et al. Complex between Peptostreptococcus magnus protein L and a human antibody reveals structural convergence in the interaction modes of Fab binding proteins. Structure 9, 679–687 (2001).

    CAS  PubMed  Google Scholar 

  4. Tutter, A. & Riblet, R. Conservation of an immunoglobulin variable-region gene family indicates a specific, noncoding function. Proc. Natl Acad. Sci. USA 86, 7460–7464 (1989).

    CAS  PubMed  Google Scholar 

  5. Schroeder, H. W. J., Hillson, J. L. & Perlmutter, R. M. Structure and evolution of mammalian VH families. Int. Immunol. 2, 41–50 (1990).

    PubMed  Google Scholar 

  6. Roben, P., Salem, A. & Silverman, G. J. VH3 antibodies bind domain D of staphylococcal protein A. J. Immunol. 154, 6437–6446 (1995).

    CAS  PubMed  Google Scholar 

  7. Silverman, G. J., Pirès, R. & Bouvet, J. P. An endogenous sialoprotein and a bacterial B-cell superantigen compete in their VH family-specific binding interactions with human immunoglobulins. J. Immunol. 157, 4496–4502 (1996).

    CAS  PubMed  Google Scholar 

  8. Sasso, E. H., Silverman, G. J. & Mannik, M. Human IgM molecules that bind staphylococcal protein A contain VHIII H chains. J. Immunol. 142, 2778–2783 (1989). First demonstration of V-gene family restriction for the Fab-mediated binding interactions of SpA, which has become the prototypic B-cell superantigen.

    CAS  PubMed  Google Scholar 

  9. Sasso, E. H., Silverman, G. J. & Mannik, M. Human IgA and IgG F(ab')2 that bind to staphylococcal protein A belong to the VHIII subgroup. J. Immunol. 147, 1877–1883 (1991).

    CAS  PubMed  Google Scholar 

  10. Hillson, J. L., Karr, N. S., Oppliger, I. R., Mannik, M. & Sasso, E. H. The structural basis of germline-encoded VH3 immunoglobulin binding to staphylococcal protein A. J. Exp. Med. 178, 331–336 (1993).

    CAS  PubMed  Google Scholar 

  11. Sasano, M., Burton, D. R. & Silverman, G. J. Molecular selection of human antibodies with an unconventional bacterial B cell antigen. J. Immunol. 151, 5822–5839 (1993).

    CAS  PubMed  Google Scholar 

  12. Silverman, G. J., Sasano, M. & Wormsley, S. B. Age-associated changes in binding of human B lymphocytes to a VH3-restricted unconventional bacterial antigen. J. Immunol. 151, 5840–5855 (1993).

    CAS  PubMed  Google Scholar 

  13. Bjorck, L. Protein L. A novel bacterial cell wall protein with affinity for Ig L chains. J. Immunol. 140, 1194–1197 (1988).

    CAS  PubMed  Google Scholar 

  14. Beckingham, J. A., Bottomley, S. P., Hinton, R., Sutton, B. J. & Gore, M. G. Interactions between a single immunoglobulin-binding domain of protein L from Peptostreptococcus magnus and a human κ light chain. Biochem. J. 340, 193–199 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Axcrona, K., Bjorck, L. & Leanderson, T. Multiple ligand interactions for bacterial immunoglobulin-binding proteins on human and murine cells of the hematopoetic lineage. Scand. J. Immunol. 42, 359–367 (1995).

    CAS  PubMed  Google Scholar 

  16. Goodyear, C. S., Narita, M. & Silverman, G. J. In vivo VL-targeted activation-induced apoptotic supraclonal deletion by a microbial B cell toxin. J. Immunol. 172, 2870–2877 (2004). First demonstration of the in vivo properties of a V L -specific superantigen.

    CAS  PubMed  Google Scholar 

  17. Berberian, L., Goodglick, L., Kipps, T. J. & Braun, J. Immunoglobulin VH3 gene products: natural ligands for HIV gp120. Science 261, 1588–1591 (1993). Prescient insights into the supraclonal-targeted properties of a B-cell superantigen expressed during systemic infection with HIV.

    CAS  PubMed  Google Scholar 

  18. Goodglick, L., Zevit, N., Neshat, M. S. & Braun, J. Mapping the Ig superantigen-binding site of HIV-1 gp120. J. Immunol. 155, 5151–5159 (1995).

    CAS  PubMed  Google Scholar 

  19. Neshat, M. N., Goodglick, L., Lim, K. & Braun, J. Mapping the B cell superantigen binding site for HIV-1 gp120 on a VH3 Ig. Int. Immunol. 12, 305–312 (2000).

    CAS  PubMed  Google Scholar 

  20. Karray, S. et al. Structural basis of the gp120 superantigen binding site on human immunoglobulins. J. Immunol. 161, 6681–6688 (1998).

    CAS  PubMed  Google Scholar 

  21. Silverman, G. J., Roben, P., Bouvet, J.-P. & Sasano, M. Superantigen properties of a human sialoprotein involved in gut-associated immunity. J. Clin. Invest. 96, 417–426 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Domiati-Saad, R. et al. Staphylococcal enterotoxin D functions as a human B cell superantigen by rescuing VH4-expressing B cells from apoptosis. J. Immunol. 156, 3608–3620 (1996).

    CAS  PubMed  Google Scholar 

  23. Donati, D. et al. Identification of a polyclonal B-cell activator in Plasmodium falciparum. Infect. Immun. 72, 5412–5418 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Woof, J. M. The human IgA-Fc α receptor interaction and its blockade by streptococcal IgA-binding proteins. Biochem. Soc. Trans. 30, 491–494 (2002).

    CAS  PubMed  Google Scholar 

  25. Sanders, J. D., Bastida-Corcuera, F. D., Arnold, K. F., Wunderlich, A. C. & Corbeil, L. B. Genetic manipulation of immunoglobulin binding proteins of Haemophilus somnus. Microb. Pathog. 34, 131–139 (2003).

    CAS  PubMed  Google Scholar 

  26. Guo, M., Han, Y. W., Sharma, A. & De Nardin, E. Identification and characterization of human immunoglobulin G Fc receptors of Fusobacterium nucleatum. Oral Microbiol. Immunol. 15, 119–123 (2000).

    CAS  PubMed  Google Scholar 

  27. Medina, E., Schulze, K., Chhatwal, G. S. & Guzman, C. A. Nonimmune interaction of the SfbI protein of Streptococcus pyogenes with the immunoglobulin G F(ab')2 fragment. Infect. Immun. 68, 4786–4788 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Olsson, A. et al. Structure and evolution of the repetitive gene encoding streptococcal protein G. Eur. J. Biochem. 168, 319–324 (1987).

    CAS  PubMed  Google Scholar 

  29. Ait-Azzouzene, D. et al. An immunoglobulin C κ-reactive single chain antibody fusion protein induces tolerance through receptor editing in a normal polyclonal immune system. J. Exp. Med. 201, 817–828 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Romagnani, S. et al. Demonstration on protein A of two distinct immunoglobulin-binding sites and their role in the mitogenic activity of Staphylococcus aureus Cowan I on human B cells. J. Immunol. 129, 596–602 (1982). Classic in vitro studies demonstrating the essential requirement for the B-cell superantigen-associated specificity of SpA for mitogenic properties.

    CAS  PubMed  Google Scholar 

  31. Das, C. & Langone, J. J. Dissociation between murine spleen cell mitogenic activity of enterotoxin contaminants and anti-tumor activity of staphylococcal protein A. J. Immunol. 142, 2943–2948 (1989).

    CAS  PubMed  Google Scholar 

  32. Kozlowski, L. M., Kunning, S. R., Zheng, Y., Wheatley, L. M. & Levinson, A. I. Staphylococcus aureus Cowan I-induced human immunoglobin responses: preferential IgM rheumatoid factor production and V H 3 mRNA expression by protein A-binding B cells. J. Clin. Immunol. 15, 145–151 (1995).

    CAS  PubMed  Google Scholar 

  33. Kristiansen, S. V., Pascual, V. & Lipsky, P. E. Staphylococcal protein A induces biased production of Ig by VH3-expressing B lymphocytes. J. Immunol. 153, 2974–2984 (1994).

    CAS  PubMed  Google Scholar 

  34. Goodyear, C. S. & Silverman, G. J. Death by a B cell superantigen: in vivo VH-targeted apoptotic supraclonal B cell deletion by a Staphylococcal toxin. J. Exp. Med. 197, 1125–1139 (2003). Elucidation of primary pathways for activation-induced cell death that is induced by a B-cell superantigen.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Goodyear, C. S. & Silverman, G. J. Staphylococcal toxin induced preferential and prolonged in vivo deletion of innate-like B lymphocytes. Proc. Natl Acad. Sci. USA 101, 11392–11397 (2004). Demonstration of preferential deletion of MZ B cells by SpA, which yields long-lasting functional immune defects.

    CAS  PubMed  Google Scholar 

  36. Gray, D., Kumararatne, D. S., Lortan, J., Khan, M. & MacLennan, I. C. Relation of intra-splenic migration of marginal zone B cells to antigen localization on follicular dendritic cells. Immunology 52, 659–669 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Groeneveld, P. H., Erich, T. & Kraal, G. In vivo effects of LPS on B lymphocyte subpopulations. Migration of marginal zone-lymphocytes and IgD-blast formation in the mouse spleen. Immunobiology 170, 402–411 (1985).

    CAS  PubMed  Google Scholar 

  38. Liu, Y. J., Oldfield, S. & MacLennan, I. C. Memory B cells in T cell-dependent antibody responses colonize the splenic marginal zones. Eur. J. Immunol. 18, 355–362 (1988).

    CAS  PubMed  Google Scholar 

  39. Vinuesa, C. G. et al. Tracking the response of Xid B cells in vivo: TI-2 antigen induces migration and proliferation but Btk is essential for terminal differentiation. Eur. J. Immunol. 31, 1340–1350 (2001).

    CAS  PubMed  Google Scholar 

  40. Cinamon, G. et al. Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nature Immunol. 5, 713–720 (2004).

    CAS  Google Scholar 

  41. Oliver, A. M., Martin, F., Gartland, G. L., Carter, R. H. & Kearney, J. F. Marginal zone B cells exhibit unique activation, proliferative and immunoglobulin secretory responses. Eur. J. Immunol. 27, 2366–2374 (1997).

    CAS  PubMed  Google Scholar 

  42. Li, X., Martin, F., Oliver, A. M., Kearney, J. F. & Carter, R. H. Antigen receptor proximal signaling in splenic B-2 cell subsets. J. Immunol. 166, 3122–3129 (2001).

    CAS  PubMed  Google Scholar 

  43. Lopes-Carvalho, T. & Kearney, J. F. Development and selection of marginal zone B cells. Immunol. Rev. 197, 192–205 (2004).

    PubMed  Google Scholar 

  44. Verkoczy, L. K., Martensson, A. S. & Nemazee, D. The scope of receptor editing and its association with autoimmunity. Curr. Opin. Immunol. 16, 808–814 (2004).

    CAS  PubMed  Google Scholar 

  45. Silverman, G. J. et al. A B cell superantigen-induced persistent 'hole' in the B-1 repertoire. J. Exp. Med. 192, 87–98 (2000). First demonstration of the special relationship between a superantigen and innate-like B cells.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Hao, Z. & Rajewsky, K. Homeostasis of peripheral B cells in the absence of B cell influx from the bone marrow. J. Exp. Med. 194, 1151–1164 (2001). Elegant demonstration of the different rates of turnover of mature B-cell subsets.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Pepys, M. B. Role of complement in the induction of immunological responses. Transplant Rev. 32, 93–120 (1976).

    CAS  PubMed  Google Scholar 

  48. Heyman, B. The immune complex: possible ways of regulating the antibody response. Immunol. Today 11, 310–313 (1990).

    CAS  PubMed  Google Scholar 

  49. Guinamard, R., Okigaki, M., Schlessinger, J. & Ravetch, J. V. Absence of marginal zone B cells in Pyk-2-deficient mice defines their role in the humoral response. Nature Immunol. 1, 31–36 (2000).

    CAS  Google Scholar 

  50. Pozdnyakova, O., Guttormsen, H. K., Lalani, F. N., Carroll, M. C. & Kasper, D. L. Impaired antibody response to group B streptococcal type III capsular polysaccharide in C3- and complement receptor 2-deficient mice. J. Immunol. 170, 84–90 (2003).

    CAS  PubMed  Google Scholar 

  51. Silverman, G. J. Adoptive transfer of a superantigen-induced 'hole' in the repertoire of natural IgM-secreting cells. Cell. Immunol. 209, 76–80 (2001).

    CAS  PubMed  Google Scholar 

  52. Forster, I. & Rajewsky, K. Expansion and functional activity of Ly-1+ B cells upon transfer of peritoneal cells into allotype-congenic, newborn mice. Eur. J. Immunol. 17, 521–528 (1987).

    CAS  PubMed  Google Scholar 

  53. Lalor, P. A., Herzenberg, L. A., Adams, S. & Stall, A. M. Feedback regulation of murine Ly-1 B cell development. Eur. J. Immunol. 19, 507–513 (1989).

    CAS  PubMed  Google Scholar 

  54. Hayakawa, K., Hardy, R. R., Stall, A. M., Herzenberg, L. A. & Herzenberg, L. A. Immunoglobulin-bearing B cells reconstitute and maintain the murine Ly-1 B cell lineage. Eur. J. Immunol. 16, 1313–1316 (1986).

    CAS  PubMed  Google Scholar 

  55. Hayakawa, K., Hardy, R. R., Herzenberg, L. A. & Herzenberg, L. A. Progenitors for Ly-1 B cells are distinct from progenitors for other B cells. J. Exp. Med. 161, 1554–1568 (1985).

    CAS  PubMed  Google Scholar 

  56. Kantor, A. B., Stall, A. M., Adams, S., Watanabe, K. & Herzenberg, L. A. De novo development and self-replenishment of B cells. Int. Immunol. 7, 55–68 (1995).

    CAS  PubMed  Google Scholar 

  57. Goodyear, C. S. & Silverman, G. J. B cell superantigens: a microbe's answer to innate-like B cells and natural antibodies. Springer Semin. Immunopathol. 26, 463–484 (2005).

    CAS  PubMed  Google Scholar 

  58. Viau, M., Cholley, B., Bjorck, L. & Zouali, M. Down-modulation of the antigen receptor by a superantigen for human B cells. Immunol. Lett. 92, 91–96 (2004).

    CAS  PubMed  Google Scholar 

  59. Fruman, D. A., Satterthwaite, A. B. & Witte, O. N. Xid-like phenotypes: a B cell signalosome takes shape. Immunity 13, 1–3 (2000).

    CAS  PubMed  Google Scholar 

  60. Chung, J. B., Sater, R. A., Fields, M. L., Erikson, J. & Monroe, J. G. CD23 defines two distinct subsets of immature B cells which differ in their responses to T cell help signals. Int. Immunol. 14, 157–166 (2002).

    CAS  PubMed  Google Scholar 

  61. Niiro, H. & Clark, E. A. Regulation of B-cell fate by antigen-receptor signals. Nature Rev. Immunol. 2, 945–956 (2002). Classic review of BCR-signalling pathways.

    CAS  Google Scholar 

  62. Shi, Y. F., Sahai, B. M. & Green, D. R. Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature 339, 625–626 (1989).

    CAS  PubMed  Google Scholar 

  63. Lenardo, M. et al. Mature T lymphocyte apoptosis — immune regulation in a dynamic and unpredictable antigenic environment. Annu. Rev. Immunol. 17, 221–253 (1999).

    CAS  Google Scholar 

  64. Hildeman, D. A., Zhu, Y., Mitchell, T. C., Kappler, J. & Marrack, P. Molecular mechanisms of activated T cell death in vivo. Curr. Opin. Immunol. 14, 354–359 (2002).

    CAS  PubMed  Google Scholar 

  65. Strasser, A. The role of BH3-only proteins in the immune system. Nature Rev. Immunol. 5, 189–200 (2005).

    CAS  Google Scholar 

  66. Goodyear, C. S., Sugiyama, F. & Silverman, G. J. Temporal and dose-dependent relationships between in vivo B cell receptor-targeted proliferation and deletion-induced by a microbial B cell toxin. J. Immunol. 176, 2262–2271 (2006).

    CAS  PubMed  Google Scholar 

  67. Silverman, G. J. et al. The dual phases of the response to neonatal exposure to a VH family-restricted staphylococcal B-cell superantigen. J. Immunol. 161, 5720–5732 (1998).

    CAS  PubMed  Google Scholar 

  68. Baumgarth, N., Herman, O. C., Jager, G. C., Brown, L. & Herzenberg, L. A. Innate and acquired humoral immunities to influenza virus are mediated by distinct arms of the immune system. Proc. Natl Acad. Sci. USA 96, 2250–2255 (1999).

    CAS  PubMed  Google Scholar 

  69. Herzenberg, L. A. et al. The Ly-1 B cell lineage. Immunol Rev. 93, 81–102 (1986).

    CAS  PubMed  Google Scholar 

  70. Viau, M., Longo, N. S., Lipsky, P. E. & Zouali, M. Staphylococcal protein a deletes B-1a and marginal zone B lymphocytes expressing human immunoglobulins: an immune evasion mechanism. J. Immunol. 175, 7719–7727 (2005).

    CAS  PubMed  Google Scholar 

  71. Berberian, L., Shukla, J., Jefferis, R. & Braun, J. Effects of HIV infection on VH3 (D12 idiotope) B cells in vivo. J. Acquir. Immune. Defic. Syndr. 7, 641–646 (1994).

    CAS  PubMed  Google Scholar 

  72. Scamurra, R. W. et al. Impact of HIV-1 infection on V H 3 gene repertoire of naive human B cells. J. Immunol. 164, 5482–5491 (2000).

    CAS  PubMed  Google Scholar 

  73. Muller, S. et al. B-cell abnormalities in AIDS: stable and clonally-restricted antibody response in HIV-1 infection. Scand. J. Immunol. 38, 327–334 (1993).

    CAS  PubMed  Google Scholar 

  74. Chang, Q., Abadi, J., Alpert, P. & Pirofski, L. A pneumococcal capsular polysaccharide vaccine induces a repertoire shift with increased VH3 expression in peripheral B cells from human immunodeficiency virus (HIV)-uninfected but not HIV-infected persons. J. Infect. Dis. 181, 1313–1321 (2000).

    CAS  PubMed  Google Scholar 

  75. Simberkoff, M. S., El Sadr, W., Schiffman, G. & Rahal, J. J. Jr. Streptococcus pneumoniae infections and bacteremia in patients with acquired immune deficiency syndrome, with report of a pneumococcal vaccine failure. Am. Rev. Respir. Dis. 130, 1174–1176 (1984).

    CAS  PubMed  Google Scholar 

  76. Grau, I. et al. Epidemiologic changes in bacteremic pneumococcal disease in patients with human immunodeficiency virus in the era of highly active antiretroviral therapy. Arch. Intern. Med. 165, 1533–1540 (2005).

    PubMed  Google Scholar 

  77. Badr, G. et al. HIV type 1 glycoprotein 120 inhibits human B cell chemotaxis to CXC chemokine ligand (CXCL) 12, CC chemokine ligand (CCL)20, and CCL21. J. Immunol. 175, 302–310 (2005).

    CAS  PubMed  Google Scholar 

  78. Foster, T. J. The Staphylococcus aureus 'superbug'. J. Clin. Invest. 114, 1693–1696 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Palmqvist, N., Foster, T., Tarkowski, A. & Josefsson, E. Protein A is a virulence factor in Staphylococcus aureus arthritis and septic death. Microb. Pathog. 33, 239–249 (2002).

    CAS  PubMed  Google Scholar 

  80. Patel, A. H., Nowlan, P., Weavers, E. D. & Foster, T. Virulence of protein A-deficient and α-toxin-deficient mutants of Staphylococcus aureus isolated by allele replacement. Infect. Immun. 55, 3103–3110 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Patella, V., Casolaro, V., Bjorck, L. & Marone, G. Protein L. A bacterial Ig-binding protein that activates human basophils and mast cells. J. Immunol. 145, 3054–3061 (1990).

    CAS  PubMed  Google Scholar 

  82. Patella, V., Giuliano, A., Florio, G., Bouvet, J. P. & Marone, G. Endogenous superallergen protein Fv interacts with the VH3 region of IgE to induce cytokine secretion from human basophils. Int. Arch. Allergy. Immunol. 118, 197–199 (1999).

    CAS  PubMed  Google Scholar 

  83. Patella, V., Florio, G., Petraroli, A. & Marone, G. HIV-1 gp120 induces IL-4 and IL-13 release from human FcεRI+ cells through interaction with the VH3 region of IgE. J. Immunol. 164, 589–595 (2000).

    CAS  PubMed  Google Scholar 

  84. Kozlowski, L., Lambris, J. D., Silverman, G. J. & Levinson, A. Complement activation by a B cell superantigen. J. Immunol. 157, 1200–1206 (1996).

    CAS  PubMed  Google Scholar 

  85. Kozlowski, L. M., Li, W., Goldschmidt, M. & Levinson, A. I. In vivo inflammatory response to a prototypic B cell superantigen: elicitation of an Arthus reaction by staphylococcal protein A. J. Immunol. 160, 5246–5252 (1998).

    CAS  PubMed  Google Scholar 

  86. Palmqvist, N., Silverman, G. J., Josefsson, E. & Tarkowski, A. Bacterial cell wall-expressed protein A triggers supraclonal B-cell responses upon in vivo infection with Staphylococcus aureus. Microbes Infect. 7, 1501–1511 (2005). First demonstration that SpA mediates B-cell superantigen effects during in vivo infection.

    CAS  PubMed  Google Scholar 

  87. Silverman, G. J. & Lucas, A. H. Variable region diversity in human circulating antibodies specific for the capsular polysaccharide of Haemophilus influenzae type b. Preferential usage of two types of VH3 heavy chains. J. Clin. Invest. 88, 911–920 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Silverman, G. J. & Rapaport, E. Variable region restriction in circulating human antibodies specific for pneumococcal capsular polysaccharides. FASEB J. 6, A1223 (1992).

    Google Scholar 

  89. Shaw, D. R., Kirkham, P., Schroeder, H. W. J., Roben, P. & Silverman, G. J. Structure-function studies of human monoclonal antibodies to pneumococcus type 3 polysaccharide. Ann. NY Acad. Sci. 764, 370–373 (1995).

    CAS  PubMed  Google Scholar 

  90. McKenney, D. et al. Broadly protective vaccine for Staphylococcus aureus based on an in vivo-expressed antigen. Science 284, 1523–1527 (1999).

    CAS  PubMed  Google Scholar 

  91. Grimaldi, C. M., Michael, D. J. & Diamond, B. Cutting edge: expansion and activation of a population of autoreactive marginal zone B cells in a model of estrogen-induced lupus. J. Immunol. 167, 1886–1890 (2001).

    CAS  PubMed  Google Scholar 

  92. Silverman, G. J., Goodyear, C. S. & Siegel, D. L. On the mechanism of staphylococcal protein A immunomodulation. Transfusion 45, 274–280 (2005).

    CAS  PubMed  Google Scholar 

  93. Sasso, E. H. Immunoglobulin V genes in rheumatoid arthritis. Rheum. Dis. Clin. North Am. 18, 809–836 (1992).

    CAS  PubMed  Google Scholar 

  94. Jacobin, M. J. et al. Human IgG monoclonal anti-αIIbβ3-binding fragments derived from immunized donors using phage display. J. Immunol. 168, 2035–2045 (2002).

    CAS  PubMed  Google Scholar 

  95. Roark, J. H., Bussel, J. B., Cines, D. B. & Siegel, D. L. Genetic analysis of autoantibodies in idiopathic thrombocytopenic purpura reveals evidence of clonal expansion and somatic mutation. Blood 100, 1388–1398 (2002).

    CAS  PubMed  Google Scholar 

  96. Newkirk, M. M. et al. Restricted immunoglobulin variable region gene usage by hybridoma rheumatoid factors from patients with systemic lupus erythematosus and rheumatoid arthritis. Mol. Immunol. 30, 255–263 (1993).

    CAS  PubMed  Google Scholar 

  97. Festenstein, H. Immunogenetic and biologic aspects of in vitro lymphocyte allo-transformation (MLR) in the mouse. Transplant Rev. 15, 62 (1973).

    CAS  PubMed  Google Scholar 

  98. Marrack, P., Kushnir, E. & Kappler, J. A maternally inherited superantigen encoded by a mammary tumour virus. Nature 349, 524–526 (1991).

    CAS  PubMed  Google Scholar 

  99. Cary, S. P., Lee, J., Wagenknecht, R. & Silverman, G. J. Characterization of superantigen-induced clonal deletion with a novel clan III-restricted avian monoclonal antibody: exploiting evolutionary distance to create antibodies specific for a conserved VH region surface. J. Immunol. 164, 4730–4741 (2000).

    CAS  PubMed  Google Scholar 

  100. Enever, C., Tomlinson, I. M., Lund, J., Levens, M. & Holliger, P. Engineering high affinity superantigens by phage display. J. Mol. Biol. 347, 107–120 (2005).

    CAS  PubMed  Google Scholar 

  101. Goodyear, C. S. & Silverman, G. J. in Protein-Protein Interactions: a molecular cloning manual (ed. Golemis, E.) 143–166 (Cold Spring Harbor Laboratory Press, 2002).

    Google Scholar 

  102. Smith, D. et al. Whole-body autoradiography reveals that the Peptostreptococcus magnus immunoglobulin-binding domains of protein L preferentially target B lymphocytes in the spleen and lymph nodes in vivo. Cell Microbiol. 6, 609–623 (2004).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Our work on B-cell superantigens is supported by National Institutes of Health, USA and the Alliance for Lupus Research. We appreciate the central contributions of E. Stura, and the images used to generate Figure 1.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gregg J. Silverman.

Ethics declarations

Competing interests

G.J.S. has received limited research support from Repligen Corporation, Waltham, Massachusetts, USA.

Related links

Related links

DATABASES

Entrez Genome

HIV-1

FURTHER INFORMATION

Gregg Silverman's homepage

Glossary

Mitogen

A factor that induces lymphocyte proliferation by any mechanism.

Fab

Fragment of an antibody that includes the variable regions of the heavy and light chains that directly interact for binding of an antigen, as well as the light-chain constant region and the first constant-region domain of the heavy chain.

Fc region

Crystallizable fragment of an antibody that includes the heavy-chain constant region domains responsible for effector functions.

B2 cell

The main population of mature recirculating B cells, which are the predominant population in the primary follicle. These cells do not express CD5, respond more slowly to antigen than B1 cells, produce antibodies of narrow specificity and depend on MHC-class-II-mediated T-cell help.

Marginal-zone B cell

Mature B cells resident in the extra-follicular region outside the marginal sinuses of the spleen.

T-cell-independent responses

An antibody response to polymeric antigens, such as polysaccharides and lipids, that does not require antigen-specific T-cell help.

FTY720

A sphingosine-like drug that is phosphorylated intracellularly by sphingosine kinase and has immunosuppressive activity through functioning as an antagonist and downregulator of the sphingosine-1-phosphate (S1P) receptor S1P1 and other S1P receptors.

Receptor editing

A molecular process that involves secondary rearrangements of the light chains or heavy chains that replace existing immunoglobulin molecules to generate a new antigen receptor with altered specificity.

B1 cells (B1a and B1b)

The minority population of mature B cells that are a major source of constitutively expressed IgM. The B1a cells express CD5, whereas the B1b cells do not, and together these B1 cells generally respond quickly to antigen to produce antibodies of broad specificity and do not require MHC-class-II-mediated T-cell help.

BCR signalosome

The complex of the antigen receptor and associated co-receptors that is responsible for antigen-mediated signalling.

Mitochondrial membrane potential

A membrane potential change that shows the integrity of the mitochondrial membrane is disturbed, and this can progress to overt disruption. If this occurs, the release of mitochondrial factors that include cytochrome c and activated caspases rapidly activates the executioner phase of apoptosis.

Intrinsic pathway of cell death

Pathways of apoptosis that are not initiated through membrane-associated death receptors, but are dependent on mitochondrial release of oxidatively active and proteolytic factors.

Hapten

Minimal molecular determinant that can be bound by an antibody but cannot by itself elicit an immune response. Antibodies that are specific for a hapten can be generated when the hapten is chemically linked to a protein carrier that is able to elicit a T-cell response.

Arthus reaction

An erythematous and oedematous reaction discovered by Maurice Arthus when he injected hyperimmunized rabbits with the same soluble antigen intradermally. In the reverse passive Arthus reaction, Fc-receptor-mediated inflammation is more dominant than complement-mediated inflammation.

Idiopathic thrombocytopenic purpura

An autoimmune disease that is associated with autoantibody-mediated destruction of platelets.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Silverman, G., Goodyear, C. Confounding B-cell defences: lessons from a staphylococcal superantigen. Nat Rev Immunol 6, 465–475 (2006). https://doi.org/10.1038/nri1853

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri1853

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing