Innate-Like B Cells and Their Rules of Engagement

  • Nicole BaumgarthEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 785)


Antibodies are an integral part of the immune system. They are produced in response to an infection or insult but are also present prior to any encounter with antigen as so-called natural antibodies. This review focuses on the tissues and cellular origins of natural antibodies. It summarizes recent data showing that B-1 cells, an innate-like B cell population distinct in development, repertoire, and tissue location from the majority conventional or B-2 cells, are the main contributors of natural antibodies in mice in steady state. Furthermore, they show that natural IgM production appears largely confined to B-1 cell populations in the spleen and bone marrow. In contrast, B-1 cells in the body cavities, sites of predominance of this population, harbor B-1 cells that do not constitutively produce antibodies. Instead, these cells act as rapid immune responders that relocate to secondary lymphoid tissues and differentiate to cytokine and antibody-secreting cells shortly after an infection. Thus, the process of B-1 cell response participation is distinct from that of B-2 cell activation as the accumulation of effector B-1 cells does not rely on extensive clonal expansion, but instead on their rapid migration and redistribution, a process that appears under the control of infection-induced innate signals.


Antibody secretion B-1 cells Body cavities Natural IgM Innate-like responses 



The work by the author’s laboratory described in this review was supported by NIH/NAID AI051354 and AI085568 and the University of California, Davis.


  1. 1.
    Shapiro-Shelef M, Calame K. Regulation of plasma-cell development. Nature Rev Immunol. 2005;5:230–42.CrossRefGoogle Scholar
  2. 2.
    Qi H. From SAP-less T cells to helpless B cells and back: dynamic T-B cell interactions underlie germinal center development and function. Immunol Rev. 2012 May;247(1):24–35.PubMedCrossRefGoogle Scholar
  3. 3.
    Hooijkaas H, Benner R, Pleasants J, Wostmann B. Isotypes and specificities of immunoglobulins produced by germ-free mice fed chemically defined ultrafiltered “antigen-free” diet. Eur J Immunol. 1984;14:1127–30.PubMedCrossRefGoogle Scholar
  4. 4.
    Bos N, Kimura H, Meeuwsen C, De Visser H, Hazenberg M, Wostmann B, et al. Serum immunoglobulin levels and naturally occurring antibodies against carbohydrate antigens in germ-free BALB/c mice fed chemically defined ultrafiltered diet. Eur J Immunol. 1989;19:2335–9.PubMedCrossRefGoogle Scholar
  5. 5.
    Haury M, Sundblad A, Grandien A, Barreau C, Coutinho A, Nobrega A. The repertoire of serum IgM in normal mice is largely independent of external antigenic contact. Eur J Immunol. 1997;27:1557–63.PubMedCrossRefGoogle Scholar
  6. 6.
    Briles DE, Nahm M, Schroer K, Davie J, Baker P, Kearney J, et al. Antiphosphocholine antibodies found in normal mouse serum are protective against intravenous infection with type 3 Streptococcus pneumoniae. J Exp Med. 1981;153:694–705.PubMedCrossRefGoogle Scholar
  7. 7.
    Masmoudi H, Mota-Santos T, Huetz F, Coutinho A, Cazenave PA. All T15 Id-positive antibodies (but not the majority of VHT15+ antibodies) are produced by peritoneal CD5+ B lymphocytes. Int Immunol. 1990;2:515–20.PubMedCrossRefGoogle Scholar
  8. 8.
    Baumgarth N, Herman OC, Jager GC, Herzenberg LA, Herzenberg LA. Innate and acquired humoral immunities to influenza virus are provided by distinct arms of the immune system. Proc Natl Acad Sci USA. 1999;96:2250–5.PubMedCrossRefGoogle Scholar
  9. 9.
    Ochsenbein AF, Fehr T, Lutz C, Suter M, Brombacher F, Hengartner H, et al. Control of early viral and bacterial distribution and disease by natural antibodies. Science. 1999;286:2156–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Montecino-Rodriguez E, Dorshkind K. B-1 B cell development in the fetus and adult. Immunity. 2012 Jan 27;36(1):13–21.PubMedCrossRefGoogle Scholar
  11. 11.
    Montecino-Rodriguez E, Dorshkind K. Formation of B-1 B cells from neonatal B-1 transitional cells exhibits NF-kappaB redundancy. J Immunol. 2011 Dec 1;187(11):5712–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Montecino-Rodriguez E, Lethers H, Dorshkind K. Identification of a B-1 B cell-specified progenitor. Nature Immunol. 2006;3:293–301.CrossRefGoogle Scholar
  13. 13.
    Song H, Cerny J. Functional heterogeneity of marginal zone B cells revealed by their ability to generate both early antibody-forming cells and germinal centers with hypermutation and memory in response to a T-dependent antigen. J Exp Med. 2003 Dec 15;198(12):1923–35.PubMedCrossRefGoogle Scholar
  14. 14.
    Haas KM, Poe JC, Steeber DA, Tedder TF. B-1a and B-1b cells exhibit distinct developmental requirements and have unique functional roles in innate and adaptive immunity to S. pneumoniae. Immunity. 2005 Jul;23(1):7–18.PubMedCrossRefGoogle Scholar
  15. 15.
    Alugupalli KR, Leong JM, Woodland RT, Muramatsu M, Honjo T, Gerstein RM. B1b lymphocytes confer T cell-independent long-lasting immunity. Immunity. 2004;21:379–90.PubMedCrossRefGoogle Scholar
  16. 16.
    Choi YS, Baumgarth N. Dual role for B-1a cells in immunity to influenza virus infection. J Exp Med. 2008 Dec 22;205(13):3053–64.PubMedCrossRefGoogle Scholar
  17. 17.
    Baumgarth N. The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat Rev Immunol. 2011 Jan;11(1):34–46.PubMedCrossRefGoogle Scholar
  18. 18.
    Stall AM, Wells SM, Lam KP. B-1 cells: unique origins and functions. Sem Immunol. 1996;8:45–59.CrossRefGoogle Scholar
  19. 19.
    Kroese FGM, Butcher EC, Stall AM, Lalor PA, Adams S, Herzenberg LA. Many of the IgA producing plasma cells in murine gut are derived from self-replenishing precursors in the peritoneal cavity. Int Immunol. 1989;1:75–84.PubMedCrossRefGoogle Scholar
  20. 20.
    Baumgarth N, Herman OC, Jager GC, Brown LE, Herzenberg LA, Chen J. 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 Jul 17;192(2):271–80.PubMedCrossRefGoogle Scholar
  21. 21.
    Boes M, Prodeus AP, Schmidt T, Carroll MC, Chen J. A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection. J Exp Med. 1998 Dec 21;188(12):2381–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Jayasekera JP, Moseman EA, Carroll MC. Natural antibody and complement mediate neutralization of influenza virus in the absence of prior immunity. J Virol. 2007 Apr;81(7):3487–94.PubMedCrossRefGoogle Scholar
  23. 23.
    Zhou ZH, Zhang Y, Hu YF, Wahl LM, Cisar JO, Notkins AL. The broad antibacterial activity of the natural antibody repertoire is due to polyreactive antibodies. Cell Host Microbe. 2007 Mar 15;1(1):51–61.PubMedCrossRefGoogle Scholar
  24. 24.
    Baumgarth N, Chen J, Herman OC, Jager GC, Herzenberg LA. The role of B-1 and B-2 cells in immune protection from influenza virus infection. Curr Top Microbiol Immunol. 2000;252:163–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Baumgarth N. A two-phase model of B-cell activation. Immunol Rev. 2000 Aug;176:171–80.PubMedCrossRefGoogle Scholar
  26. 26.
    Macpherson AJ, Gatto D, Sainsbury E, Harriman GR, Hengartner H, Zinkernagel RM. A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria. Science. 2000 Jun 23;288(5474):2222–6.PubMedCrossRefGoogle Scholar
  27. 27.
    Notkins A. Polyreactivity of antibody molecules. Trends Immunol. 2004;25:174–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Kulik L, Fleming SD, Moratz C, Reuter JW, Novikov A, Chen K, et al. Pathogenic natural antibodies ­recognizing annexin IV are required to develop intestinal ischemia-reperfusion injury. J Immunol. 2009 May 1;182(9):5363–73.PubMedCrossRefGoogle Scholar
  29. 29.
    Shaw PX, Horkko S, Chang MK, Curtiss LK, Palinski W, Silverman GJ, et al. Natural antibodies with the T15 idiotype may act in atherosclerosis, apoptotic clearance, and protective immunity. J Clin Invest. 2000 Jun;105(12):1731–40.PubMedCrossRefGoogle Scholar
  30. 30.
    Binder CJ, Silverman GJ. Natural antibodies and the autoimmunity of atherosclerosis. Springer Semin Immunopathol. 2005 Mar;26(4):385–404.PubMedCrossRefGoogle Scholar
  31. 31.
    Chen GY, Tang J, Zheng P, Liu Y. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science. 2009 Mar 27;323(5922):1722–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Chou MY, Fogelstrand L, Hartvigsen K, Hansen LF, Woelkers D, Shaw PX, et al. Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans. J Clin Invest. 2009 May;119(5):1335–49.PubMedCrossRefGoogle Scholar
  33. 33.
    Parker W, Lundberg-Swanson K, Holzknecht ZE, Lateef J, Washburn SA, Braedehoeft SJ, et al. Isohemagglutinins and xenoreactive antibodies: members of a distinct family of natural antibodies. Hum Immunol. 1996 Feb;45(2):94–104.PubMedCrossRefGoogle Scholar
  34. 34.
    Boes M, Schmidt T, Linkemann K, Beaudette BC, Marshak-Rothstein A, Chen J. Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM. Proc Natl Acad Sci USA. 2000 Feb 1;97(3):1184–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Zhang M, Alicot EM, Chiu I, Li J, Verna N, Vorup-Jensen T, et al. Identification of the target self-antigens in reperfusion injury. J Exp Med. 2006 Jan 23;203(1):141–52.PubMedCrossRefGoogle Scholar
  36. 36.
    Hooijkaas H, van der Linde-Preesman AA, Benne S, Benner R. Frequency analysis of the antibody specificity repertoire of mitogen-reactive B cells and “spontaneously” occurring “background” plaque-forming cells in nude mice. Cell Immunol. 1985 Apr 15;92(1):154–62.PubMedCrossRefGoogle Scholar
  37. 37.
    Van Oudenaren A, Haaijman JJ, Benner R. Frequencies of background cytoplasmic Ig-containing cells in various lymphoid organs of athymic and euthymic mice as a function of age and immune status. Immunology. 1984 Apr;51(4):735–42.PubMedGoogle Scholar
  38. 38.
    Ohdan H, Swenson KG, Kruger Gray HS, Yang Y-G, Xu Y, Thall AD, et al. Mac-1-negative B-1b phenotype of natural antibody-producing cells, including those responding to Galα1,3Gal epitopes in α1,3-galactosyltransferase-deficient mice. J Immunol. 2000;165:5518–29.PubMedGoogle Scholar
  39. 39.
    Kawahara T, Ohdan H, Zhao G, Yang Y-G, Sykes M. Peritoneal cavity B cells are precursors of splenic IgM natural antibody-producing cells. J Immunol. 2003;171:5406–14.PubMedGoogle Scholar
  40. 40.
    Murakami M, Tsubata T, Shinkura R, Nisitani S, Okamoto M, Yoshioka H, et al. Oral administration of lipopolysaccharides activates B-1 cells in the peritoneal cavity and lamina propria of the gut and induces autoimmune symptoms in an autoantibody transgenic mouse. J Exp Med. 1994 Jul 1;180(1):111–21.PubMedCrossRefGoogle Scholar
  41. 41.
    Nisitani S, Tsubata T, Murakami M, Honjo T. Administration of interleukin-5 or -10 activates peritoneal B-1 cells and induces autoimmune hemolytic anemia in anti-erythrocyte autoantibody-transgenic mice. Eur J Immunol. 1995;25:3047–52.PubMedCrossRefGoogle Scholar
  42. 42.
    Berland R, Wortis HH. Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol. 2002;20:253–300.PubMedCrossRefGoogle Scholar
  43. 43.
    Tumang JR, Frances R, Yeo SG, Rothstein TL. Cutting edge: Spontaneously Ig-secreting B-1 cells violate the accepted paradigm for expression of differentiation-associated transcription factors. J Immunol. 2005;174:3173–7.PubMedGoogle Scholar
  44. 44.
    Fairfax KA, Corcoran LM, Pridans C, Huntington ND, Kallies A, Nutt SL, et al. Different kinetics of Blimp-1 induction in B cell subsets revealed by reporter gene. J Immunol. 2007;178:4104–11.PubMedGoogle Scholar
  45. 45.
    Ha S, Tsuji M, Suzuki K, Meek B, Yasuda N, Kaisho T, et al. Regulation of B1 cell migration by signals through toll-like receptors. J Exp Med. 2006;203:2541–50.PubMedCrossRefGoogle Scholar
  46. 46.
    Yang Y, Tung JW, Ghosn EEB, Herzenberg LA, Herzenberg LA. Division and differentiation of natural antibody-producing cells in mouse spleen. Proc Natl Acad Sci USA. 2007;104:4542–6.PubMedCrossRefGoogle Scholar
  47. 47.
    Slifka MK, Antia R, Whitmire JK, Ahmed R. Humoral immunity due to long-lived plasma cells. Immunity. 1998;8:363–72.PubMedCrossRefGoogle Scholar
  48. 48.
    Crotty S, Kersh EN, Cannons J, Schwartzberg PL, Ahmed R. SAP is required for generating long-term humoral immunity. Nature. 2002;421:282–7.CrossRefGoogle Scholar
  49. 49.
    Choi YS, Dieter JA, Rothaeusler K, Luo Z, Baumgarth N. B-1 cells in the bone marrow are a significant source of natural IgM. European journal of immunology. 2012 Jan;42(1):120–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Shaffer AL, Lin K-I, Kuo TC, Yu X, Hurt EM, Rosenwald A, et al. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity. 2002;17:51–62.PubMedCrossRefGoogle Scholar
  51. 51.
    Kallies A, Hasbold J, Fairfax K, Pridans C, Emsllie D, McKenzie BS, et al. Initiation of plasma-cell differentiation is independent of the transcription factor Blimp-1. Immunity. 2007;26:555–66.PubMedCrossRefGoogle Scholar
  52. 52.
    Sciammas R, Davis MM. Blimp-1; immunoglobulin secretion and the switch to plasma cells. Curr Top Microbiol Immunol. 2005;290:201–24.PubMedCrossRefGoogle Scholar
  53. 53.
    Lin K-I, Angelin-Duclos C, Kuo TC, Calame K. Blimp-1 dependent repression of Pax-5 is required for differentiation of B cells to immunoglobulin M-secreting plasma cells. Mol Cell Immunol. 2002;22:4771–80.Google Scholar
  54. 54.
    Delogu A, Schebesta A, Sun Q, Aschenbrenner K, Perlot T, Busslinger M. Gene repression by Pax5 in B cells is essential for blood cell homeostasis and is reversed in plasma cells. Immunity. 2006;24:269–81.PubMedCrossRefGoogle Scholar
  55. 55.
    Nera K-P, Kohonen P, Narvi E, Peippo A, Mustonen L, Terho P, et al. Loss of Pax5 promotes plasma cell differentiation. Immunity. 2006;24:283–93.PubMedCrossRefGoogle Scholar
  56. 56.
    Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM, et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature. 2001;412:300–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Iwakoshi NN, Lee A-H, Vallabhajosyula P, Otipoby K, Rajewsky K, Glimcher LH. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nature Immunol. 2003;4:321–9.CrossRefGoogle Scholar
  58. 58.
    Sciammas R, Davis MM. Modular nature of Blimp-1 in the regulation of gene expression during B cell maturation. J Immunol. 2004;172:5427–40.PubMedGoogle Scholar
  59. 59.
    Savitsky D, Calame K. B-1 B lymphocytes require Blimp-1 for immunoglobulin secretion. J Exp Med. 2006;203:2305–14.PubMedCrossRefGoogle Scholar
  60. 60.
    Chace JH, Fleming AL, Gordon JA, Perandones CE, Cowdery JS. Regulation of differentiation of peritoneal B-1a (CD5+) B cells: Activated peritoneal macrophages release prostaglandin E2, which inhibits IgM secretion by peritoneal B-1a cells. J Immunol. 1995;154:5630–6.PubMedGoogle Scholar
  61. 61.
    Ansel KM, Harris RB, Cyster JG. CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. Immunity. 2002 Jan;16(1):67–76.PubMedCrossRefGoogle Scholar
  62. 62.
    Sangster MY, Riberdy JM, Gonzalez M, Topham DJ, Baumgarth N, Doherty PC. An early CD4+ T cell-dependent immunoglobulin A response to influenza infection in the absence of key cognate T-B interactions. J Exp Med. 2003 Oct 6;198(7):1011–21.PubMedCrossRefGoogle Scholar
  63. 63.
    Sealy R, Surman S, Hurwitz JL, Coleclough C. Antibody response to influenza infection of mice: different patterns for glycoprotein and nucleocapsid antigens. Immunology. 2003 Apr;108(4):431–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Coro ES, Chang WL, Baumgarth N. Type I IFN receptor signals directly stimulate local B cells early following influenza virus infection. J Immunol. 2006 Apr 1;176(7):4343–51.PubMedGoogle Scholar
  65. 65.
    McLaren C, Butchko GM. Regional T- and B-cell responses in influenza-infected ferrets. Infect Immun. 1978 Oct;22(1):189–94.PubMedGoogle Scholar
  66. 66.
    Savitsky D, Calame K. B-1 B lymphocytes require Blimp-1 for immunoglobulin secretion. J Exp Med. 2006 Oct 2;203(10):2305–14.PubMedCrossRefGoogle Scholar
  67. 67.
    Hermesh T, Moltedo B, Moran TM, Lopez CB. Antiviral instruction of bone marrow leukocytes during respiratory viral infections. Cell host & microbe. 2010 May 20;7(5):343–53.CrossRefGoogle Scholar
  68. 68.
    O’Garra A, Howard M. IL-10 production by CD5 B cells. Annals of the New York Academy of Sciences. 1992 May 4;651:182–99.PubMedCrossRefGoogle Scholar
  69. 69.
    Rauch PJ, Chudnovskiy A, Robbins CS, Weber GF, Etzrodt M, Hilgendorf I, et al. Innate response activator B cells protect against microbial sepsis. Science. 2012 Feb 3;335(6068):597–601.PubMedCrossRefGoogle Scholar
  70. 70.
    Bouaziz JD, Yanaba K, Tedder TF. Regulatory B cells as inhibitors of immune responses and inflammation. Immunological reviews. 2008 Aug;224:201–14.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Center for Comparative MedicineUniversity of California, DavisDavisUSA
  2. 2.Department of Pathology, Microbiology and ImmunologyUniversity of CaliforniaDavisUSA

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