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  • Review Article
  • Published:

Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes

Nature Reviews Immunology volume 13, pages 118–132 (2013)Cite this article

Subjects

Key Points

  • Marginal zone (MZ) B cells are strategically located at the interface between the circulation and the white pulp of the spleen, where they provide a first line of defence by rapidly producing IgM and class-switched IgG antibodies in response to infections by blood-borne viruses and encapsulated bacteria. Mouse MZ B cells primarily express a non-mutated B cell receptor (BCR) and enter the circulation only to shuttle antigens to the follicle, whereas human MZ B cells express a mutated BCR and extensively recirculate.

  • MZ B cells may also produce IgM and class-switched IgG and IgA antibodies in response to commensal antigens that physiologically translocate from the intestinal mucosa to the general circulation in the absence of infection. This innate-like humoral response may generate a ready-to-use pre-immune antibody repertoire that provides a rapid systemic line of defence not only against pathogens, but also against commensal bacteria that breach the mucosal barrier.

  • In mice, MZ B cells originate from splenic transitional stage 2 B cells via a pathway involving the BCR, the B cell-activating factor (BAFF) receptor and the receptor NOTCH2. In humans, some MZ B cells may arise from immature or transitional B cells located in the liver and mesenteric lymph nodes via a fetal pathway involving NOTCH2, whereas other MZ B cells may emerge from transitional or germinal centre B cells located in the spleen through a postnatal pathway involving the BCR, Toll-like receptors (TLRs) and CD40.

  • MZ B cells have a lower activation threshold than follicular B cells, which permits the rapid initiation of IgM production and of IgG- and IgA-inducing class-switch recombination (CSR) in the absence of CD40-dependent help from T follicular helper (TFH) cells. This T cell-independent pathway requires dual BCR and TLR engagement by conserved microbial antigens together with co-stimulatory signals from dendritic cells, macrophages and neutrophils via various cytokines, including BAFF, a proliferation-inducing ligand (APRIL), interleukin-6 (IL-6), IL-10, IL-21, interferon-α (IFNα), IFNβ and CXC-chemokine ligand 10 (CXCL10).

  • MZ B cells can also undergo T cell-dependent antibody production by following either a follicular pathway involving CD40-dependent help from germinal centre TFH cells or an extrafollicular pathway involving CD40-dependent help from extrafollicular TFH cells or invariant natural killer T (iNKT) cells. In addition to expressing CD40 ligand, TFH and iNKT cells secrete various CSR- and antibody-inducing cytokines, including IL-4, IL-21 and IFNγ.

  • In humans, MZ B cells probably have a heterogeneous ontogeny and can undergo somatic hypermutation both before and after birth through either an extrafollicular T cell-independent or a follicular T cell-dependent pathway. The extrafollicular T cell-independent pathway diversifies MZ B cells mainly during fetal life or after postnatal exposure to conserved commensal antigens or native polysaccharides, whereas the follicular T cell-dependent pathway may diversify MZ B cells predominantly after postnatal exposure to proteins or protein-conjugated polysaccharides.

Abstract

Protective responses to microorganisms involve the nonspecific but rapid defence mechanisms of the innate immune system, followed by the specific but slow defence mechanisms of the adaptive immune system. Located as sentinels at the interface between the circulation and lymphoid tissue, splenic marginal zone B cells rapidly respond to blood-borne antigens by adopting 'crossover' defensive strategies that blur the conventional boundaries of innate and adaptive immunity. This Review discusses how marginal zone B cells function as innate-like lymphocytes that mount rapid antibody responses to both T cell-dependent and T cell-independent antigens. These responses require the integration of activation signals from germline-encoded and somatically recombined receptors for microorganisms with helper signals from effector cells of the innate and adaptive immune systems.

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Figure 1: T cell-independent responses by mouse MZ B cells.
Figure 2: T cell-independent responses by human MZ B cells.
Figure 3: T cell-dependent responses by mouse MZ B cells.

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References

  1. Janeway, C. A. Jr & Medzhitov, R. Innate immune recognition. Annu. Rev. Immunol. 20, 197–216 (2002).

    CAS  PubMed  Google Scholar 

  2. Cooper, M. D. & Alder, M. N. The evolution of adaptive immune systems. Cell 124, 815–822 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Bendelac, A., Bonneville, M. & Kearney, J. F. Autoreactivity by design: innate B and T lymphocytes. Nature Rev. Immunol. 1, 177–186 (2001).

    Article  CAS  Google Scholar 

  4. Martin, F., Oliver, A. M. & Kearney, J. F. Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 14, 617–629 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Martin, F. & Kearney, J. F. Marginal-zone B cells. Nature Rev. Immunol. 2, 323–335 (2002). References 3 and 5 describe the function, ontogeny and reactivity of MZ B cells.

    CAS  Google Scholar 

  6. Treml, L. S. et al. TLR stimulation modifies BLyS receptor expression in follicular and marginal zone B cells. J. Immunol. 178, 7531–7539 (2007).

    Article  CAS  PubMed  Google Scholar 

  7. He, B. et al. The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88. Nature Immunol. 11, 836–845 (2010). This was the first demonstration that BAFF and APRIL activate B cells through a signalling pathway involving the TLR-associated protein MYD88.

    Article  CAS  Google Scholar 

  8. Pone, E. J. et al. BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-κB pathway. Nature Commun. 3, 767 (2012). This was the first demonstration that TI antigens trigger B cell activation and class switching by co-engaging BCRs and TLRs.

    Article  CAS  Google Scholar 

  9. Mebius, R. E. & Kraal, G. Structure and function of the spleen. Nature Rev. Immunol. 5, 606–616 (2005). This article provides an overview of the structure, vascularization, cell composition and function of the spleen in mice and humans.

    CAS  Google Scholar 

  10. Chen, Y. et al. Defective microarchitecture of the spleen marginal zone and impaired response to a thymus-independent type 2 antigen in mice lacking scavenger receptors MARCO and SR-A. J. Immunol. 175, 8173–8180 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Kang, Y. S. et al. A dominant complement fixation pathway for pneumococcal polysaccharides initiated by SIGN-R1 interacting with C1q. Cell 125, 47–58 (2006). This work shows that MZ macrophages generate innate immune responses against encapsulated bacteria via an antibody-independent mechanism involving the uptake receptor SIGNR1 and an unusual complement activation pathway.

    Article  CAS  PubMed  Google Scholar 

  12. Bergtold, A., Desai, D. D., Gavhane, A. & Clynes, R. Cell surface recycling of internalized antigen permits dendritic cell priming of B cells. Immunity 23, 503–514 (2005).

    Article  CAS  PubMed  Google Scholar 

  13. Batista, F. D. & Harwood, N. E. The who, how and where of antigen presentation to B cells. Nature Rev. Immunol. 9, 15–27 (2009). This article provides an overview of the localization and mechanisms of antigen recognition by B cells.

    Article  CAS  Google Scholar 

  14. Balázs, M., Martin, F., Zhou, T. & Kearney, J. F. Blood dendritic cells interact with splenic marginal zone B cells to initiate T-independent immune responses. Immunity 17, 341–352 (2002).

    Article  PubMed  Google Scholar 

  15. Colino, J., Shen, Y. & Snapper, C. M. Dendritic cells pulsed with intact Streptococcus pneumoniae elicit both protein- and polysaccharide-specific immunoglobulin isotype responses in vivo through distinct mechanisms. J. Exp. Med. 195, 1–13 (2002). References 14 and 15 demonstrate that DCs interact with MZ B cells to induce antibody responses against blood-borne microorganisms.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Steiniger, B., Barth, P. & Hellinger, A. The perifollicular and marginal zones of the human splenic white pulp: do fibroblasts guide lymphocyte immigration? Am. J. Pathol. 159, 501–512 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Steiniger, B., Timphus, E. & Barth, P. The splenic marginal zone in humans and rodents: an enigmatic compartment and its inhabitants. Histochem. Cell Biol. 126, 641–648 (2006).

    Article  CAS  PubMed  Google Scholar 

  18. Puga, I. et al. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nature Immunol. 13, 170–180 (2012). This paper indicates that neutrophils provide unconventional help to human MZ B cells to generate antibodies specific for conserved microbial structures.

    Article  CAS  Google Scholar 

  19. Spencer, J., Finn, T., Pulford, K. A., Mason, D. Y. & Isaacson, P. G. The human gut contains a novel population of B lymphocytes which resemble marginal zone cells. Clin. Exp. Immunol. 62, 607–612 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Tierens, A., Delabie, J., Michiels, L., Vandenberghe, P. & De Wolf-Peeters, C. Marginal-zone B cells in the human lymph node and spleen show somatic hypermutations and display clonal expansion. Blood 93, 226–234 (1999).

    CAS  PubMed  Google Scholar 

  21. Dono, M. et al. Heterogeneity of tonsillar subepithelial B lymphocytes, the splenic marginal zone equivalents. J. Immunol. 164, 5596–5604 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Weill, J. C., Weller, S. & Reynaud, C. A. Human marginal zone B cells. Annu. Rev. Immunol. 27, 267–285 (2009). This article provides an updated overview of the differences between human and mouse MZ B cells.

    Article  CAS  PubMed  Google Scholar 

  23. Weller, S. et al. Human blood IgM “memory” B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire. Blood 104, 3647–3654 (2004). This was the first demonstration that MZ B cells recirculate in humans.

    Article  CAS  PubMed  Google Scholar 

  24. Berkowska, M. A. et al. Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways. Blood 118, 2150–2158 (2011). This work provides molecular evidence that human MZ B cells are distinct from canonical memory B cells and may originate outside the germinal centre.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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). This work demonstrates the essential role of MZ B cells in early antibody responses to TI antigens in mice.

    Article  CAS  Google Scholar 

  26. MacLennan, I. C. et al. Extrafollicular antibody responses. Immunol. Rev. 194, 8–18 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Amlot, P. L. & Hayes, A. E. Impaired human antibody response to the thymus-independent antigen, DNP-Ficoll, after splenectomy. Implications for post-splenectomy infections. Lancet 1, 1008–1011 (1985).

    Article  CAS  PubMed  Google Scholar 

  28. Kruetzmann, S. et al. Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J. Exp. Med. 197, 939–945 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Castagnola, E. & Fioredda, F. Prevention of life-threatening infections due to encapsulated bacteria in children with hyposplenia or asplenia: a brief review of current recommendations for practical purposes. Eur. J. Haematol. 71, 319–326 (2003).

    Article  PubMed  Google Scholar 

  30. Wasserstrom, H., Bussel, J., Lim, L. C. & Cunningham-Rundles, C. Memory B cells and pneumococcal antibody after splenectomy. J. Immunol. 181, 3684–3689 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Di Sabatino, A. et al. Depletion of immunoglobulin M memory B cells is associated with splenic hypofunction in inflammatory bowel disease. Am. J. Gastroenterol. 100, 1788–1795 (2005). References 27–31 indicate that human MZ B cells mediate protective antibody responses to encapsulated bacteria.

    Article  CAS  PubMed  Google Scholar 

  32. Traggiai, E. et al. Selective preservation of bone marrow mature recirculating but not marginal zone B cells in murine models of chronic inflammation. PLoS ONE 5, e11262 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Carsetti, R. et al. The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency. J. Allergy Clin. Immunol. 115, 412–417 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Hart, M. et al. Loss of discrete memory B cell subsets is associated with impaired immunization responses in HIV-1 infection and may be a risk factor for invasive pneumococcal disease. J. Immunol. 178, 8212–8220 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Weller, S. et al. IgM+IgD+CD27+ B cells are markedly reduced in IRAK-4-, MyD88- and TIRAP- but not UNC-93B-deficient patients. Blood 120, 4992–5001 (2012). This was the first demonstration that the maintenance of human MZ B cells is highly dependent on signals from TLRs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pillai, S. & Cariappa, A. The follicular versus marginal zone B lymphocyte cell fate decision. Nature Rev. Immunol. 9, 767–777 (2009). This article provides an overview of the ontogeny of MZ B cells.

    Article  CAS  Google Scholar 

  37. Szomolanyi-Tsuda, E. & Welsh, R. M. T-cell-independent antiviral antibody responses. Curr. Opin. Immunol. 10, 431–435 (1998).

    Article  CAS  PubMed  Google Scholar 

  38. Gatto, D., Ruedl, C., Odermatt, B. & Bachmann, M. F. Rapid response of marginal zone B cells to viral particles. J. Immunol. 173, 4308–4316 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Galili, U., Rachmilewitz, E. A., Peleg, A. & Flechner, I. A unique natural human IgG antibody with anti-α-galactosyl specificity. J. Exp. Med. 160, 1519–1531 (1984).

    Article  CAS  PubMed  Google Scholar 

  40. Ochsenbein, A. F. et al. Control of early viral and bacterial distribution and disease by natural antibodies. Science 286, 2156–2159 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. Macpherson, A. J. & Harris, N. L. Interactions between commensal intestinal bacteria and the immune system. Nature Rev. Immunol. 4, 478–485 (2004).

    Article  CAS  Google Scholar 

  42. Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Wei, B. et al. Resident enteric microbiota and CD8+ T cells shape the abundance of marginal zone B cells. Eur. J. Immunol. 38, 3411–3425 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Clarke, T. B. et al. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nature Med. 16, 228–231 (2010). This was the first demonstration that molecules from the commensal microbiota enhance innate immunity after translocating from the intestine to the general circulation.

    Article  CAS  PubMed  Google Scholar 

  45. Lamouse-Smith, E. S., Tzeng, A. & Starnbach, M. N. The intestinal flora is required to support antibody responses to systemic immunization in infant and germ free mice. PLoS ONE 6, e27662 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bos, N. A. 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. 19, 2335–2339 (1989).

    Article  CAS  PubMed  Google Scholar 

  47. Butler, J. E. et al. Antibody repertoire development in fetal and neonatal piglets. II. Characterization of heavy chain complementarity-determining region 3 diversity in the developing fetus. J. Immunol. 165, 6999–7010 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Kool, J. et al. Detection of intestinal flora-derived bacterial antigen complexes in splenic macrophages of rats. J. Histochem. Cytochem. 42, 1435–1441 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Krueger, J. M. et al. Peptidoglycans as promoters of slow-wave sleep. II. Somnogenic and pyrogenic activities of some naturally occurring muramyl peptides; correlations with mass spectrometric structure determination. J. Biol. Chem. 259, 12659–12662 (1984).

    CAS  PubMed  Google Scholar 

  50. Brenchley, J. M. et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nature Med. 12, 1365–1371 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Haas, A. et al. Systemic antibody responses to gut commensal bacteria during chronic HIV-1 infection. Gut 60, 1506–1519 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Chung, J. B., Silverman, M. & Monroe, J. G. Transitional B cells: step by step towards immune competence. Trends Immunol. 24, 343–349 (2003).

    Article  CAS  PubMed  Google Scholar 

  53. Mackay, F. & Schneider, P. Cracking the BAFF code. Nature Rev. Immunol. 9, 491–502 (2009).

    Article  CAS  Google Scholar 

  54. Martin, F. & Kearney, J. F. Positive selection from newly formed to marginal zone B cells depends on the rate of clonal production, CD19, and btk. Immunity 12, 39–49 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Cariappa, A. et al. The follicular versus marginal zone B lymphocyte cell fate decision is regulated by Aiolos, Btk, and CD21. Immunity 14, 603–615 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Wen, L. et al. Evidence of marginal-zone B cell- positive selection in spleen. Immunity 23, 297–308 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Tanigaki, K. et al. Notch–RBP-J signaling is involved in cell fate determination of marginal zone B cells. Nature Immunol. 3, 443–450 (2002).

    Article  CAS  Google Scholar 

  58. Hampel, F. et al. CD19-independent instruction of murine marginal zone B-cell development by constitutive Notch2 signaling. Blood 118, 6321–6331 (2011). References 54–58 show that signals from the BCR and NOTCH2 are important for the development of MZ B cells.

    Article  CAS  PubMed  Google Scholar 

  59. Scheeren, F. A. et al. T cell-independent development and induction of somatic hypermutation in human IgM+ IgD+ CD27+ B cells. J. Exp. Med. 205, 2033–2042 (2008). This works show that human MZ B cells develop during fetal life and undergo SHM through an antigen-independent process that does not require T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Capolunghi, F. et al. CpG drives human transitional B cells to terminal differentiation and production of natural antibodies. J. Immunol. 180, 800–808 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Tsuiji, M. et al. A checkpoint for autoreactivity in human IgM+ memory B cell development. J. Exp. Med. 203, 393–400 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Isnardi, I. et al. IRAK-4- and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans. Immunity 29, 746–757 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  64. Cinamon, G., Zachariah, M. A., Lam, O. M., Foss, F. W. Jr & Cyster, J. G. Follicular shuttling of marginal zone B cells facilitates antigen transport. Nature Immunol. 9, 54–62 (2008).

    Article  CAS  Google Scholar 

  65. Lu, T. T. & Cyster, J. G. Integrin-mediated long-term B cell retention in the splenic marginal zone. Science 297, 409–412 (2002). References 63–65 elucidate the mechanisms by which MZ B cells localize in the splenic MZ and transport antigens to the follicle.

    Article  CAS  PubMed  Google Scholar 

  66. Fukui, Y. et al. Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration. Nature 412, 826–831 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Croker, B. A. et al. The Rac2 guanosine triphosphatase regulates B lymphocyte antigen receptor responses and chemotaxis and is required for establishment of B-1a and marginal zone B lymphocytes. J. Immunol. 168, 3376–3386 (2002).

    Article  CAS  PubMed  Google Scholar 

  68. Rubtsov, A. et al. Lsc regulates marginal-zone B cell migration and adhesion and is required for the IgM T-dependent antibody response. Immunity 23, 527–538 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Karlsson, M. C. et al. Macrophages control the retention and trafficking of B lymphocytes in the splenic marginal zone. J. Exp. Med. 198, 333–340 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Dempsey, P. W., Allison, M. E., Akkaraju, S., Goodnow, C. C. & Fearon, D. T. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science 271, 348–350 (1996).

    Article  CAS  PubMed  Google Scholar 

  71. Test, S. T., Mitsuyoshi, J., Connolly, C. C. & Lucas, A. H. Increased immunogenicity and induction of class switching by conjugation of complement C3d to pneumococcal serotype 14 capsular polysaccharide. Infect. Immun. 69, 3031–3040 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 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. 198, 1923–1935 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chappell, C. P., Draves, K. E., Giltiay, N. V. & Clark, E. A. Extrafollicular B cell activation by marginal zone dendritic cells drives T cell-dependent antibody responses. J. Exp. Med. 209, 1825–1840 (2012). References 72 and 73 demonstrate that MZ B cells respond to protein antigens by following follicular or extrafollicular TD pathways.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Weller, S. et al. CD40–CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans. Proc. Natl Acad. Sci. USA 98, 1166–1170 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Weller, S. et al. Somatic diversification in the absence of antigen-driven responses is the hallmark of the IgM+ IgD+ CD27+ B cell repertoire in infants. J. Exp. Med. 205, 1331–1342 (2008). References 74 and 75 provide evidence that human MZ B cells undergo somatic diversification via a CD40-independent pathway that may not require antigens.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Genestier, L. et al. TLR agonists selectively promote terminal plasma cell differentiation of B cell subsets specialized in thymus-independent responses. J. Immunol. 178, 7779–7786 (2007).

    Article  CAS  PubMed  Google Scholar 

  77. Rubtsov, A. V. et al. TLR agonists promote marginal zone B cell activation and facilitate T-dependent IgM responses. J. Immunol. 180, 3882–3888 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Rawlings, D. J., Schwartz, M. A., Jackson, S. W. & Meyer-Bahlburg, A. Integration of B cell responses through Toll-like receptors and antigen receptors. Nature Rev. Immunol. 12, 282–294 (2012).

    Article  CAS  Google Scholar 

  79. Belperron, A. A., Dailey, C. M. & Bockenstedt, L. K. Infection-induced marginal zone B cell production of Borrelia hermsii-specific antibody is impaired in the absence of CD1d. J. Immunol. 174, 5681–5686 (2005).

    Article  CAS  PubMed  Google Scholar 

  80. Haas, K. M., Poe, J. C. & Tedder, T. F. CD21/35 promotes protective immunity to Streptococcus pneumoniae through a complement-independent but CD19-dependent pathway that regulates PD-1 expression. J. Immunol. 183, 3661–3671 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Garcia de Vinuesa, C., O'Leary, P., Sze, D. M., Toellner, K. M. & MacLennan, I. C. T-independent type 2 antigens induce B cell proliferation in multiple splenic sites, but exponential growth is confined to extrafollicular foci. Eur. J. Immunol. 29, 1314–1323 (1999).

    Article  CAS  PubMed  Google Scholar 

  82. Timens, W., Boes, A. & Poppema, S. Human marginal zone B cells are not an activated B cell subset: strong expression of CD21 as a putative mediator for rapid B cell activation. Eur. J. Immunol. 19, 2163–2166 (1989).

    Article  CAS  PubMed  Google Scholar 

  83. 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, 1691–1703 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Dunn-Walters, D. K., Isaacson, P. G. & Spencer, J. Analysis of mutations in immunoglobulin heavy chain variable region genes of microdissected marginal zone (MGZ) B cells suggests that the MGZ of human spleen is a reservoir of memory B cells. J. Exp. Med. 182, 559–566 (1995).

    Article  CAS  PubMed  Google Scholar 

  85. 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, 1679–1689 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Seifert, M. & Kuppers, R. Molecular footprints of a germinal center derivation of human IgM+(IgD+)CD27+ B cells and the dynamics of memory B cell generation. J. Exp. Med. 206, 2659–2669 (2009). This work provides molecular evidence that human MZ B cells originate in a germinal centre reaction and may therefore be considered to be bona fide IgM+ memory B cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Tangye, S. G. & Good, K. L. Human IgM+CD27+ B cells: memory B cells or “memory” B cells? J. Immunol. 179, 13–19 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Kuraoka, M. et al. Activation-induced cytidine deaminase expression and activity in the absence of germinal centers: insights into hyper-IgM syndrome. J. Immunol. 183, 3237–3248 (2009).

    Article  CAS  PubMed  Google Scholar 

  89. Roll, P., Palanichamy, A., Kneitz, C., Dorner, T. & Tony, H. P. Regeneration of B cell subsets after transient B cell depletion using anti-CD20 antibodies in rheumatoid arthritis. Arthritis Rheum. 54, 2377–2386 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Carey, J. B., Moffatt-Blue, C. S., Watson, L. C., Gavin, A. L. & Feeney, A. J. Repertoire-based selection into the marginal zone compartment during B cell development. J. Exp.Med. 205, 2043–2052 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Swanson, C. L. et al. Type I IFN enhances follicular B cell contribution to the T cell-independent antibody response. J. Exp. Med. 207, 1485–1500 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Do, R. K. et al. Attenuation of apoptosis underlies B lymphocyte stimulator enhancement of humoral immune response. J. Exp. Med. 192, 953–964 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 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).

    Article  CAS  PubMed  Google Scholar 

  94. Mond, J. J., Lees, A. & Snapper, C. M. T cell-independent antigens type 2. Annu. Rev. Immunol. 13, 655–692 (1995).

    Article  CAS  PubMed  Google Scholar 

  95. Garcia De Vinuesa, C. et al. Dendritic cells associated with plasmablast survival. Eur. J. Immunol. 29, 3712–3721 (1999). Together with references 14 and 81, this work demonstrates that DCs enhance antibody responses to TI antigens by supporting the survival of extrafollicular plasmablasts derived from MZ B cells.

    Article  CAS  PubMed  Google Scholar 

  96. Litinskiy, M. B. et al. Antigen presenting cells induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nature Immunol. 3, 822–829 (2002).

    Article  CAS  Google Scholar 

  97. Pack, M. et al. DEC-205/CD205+ dendritic cells are abundant in the white pulp of the human spleen, including the border region between the red and white pulp. Immunology 123, 438–446 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ogembo, J. G. et al. SIRPα/CD172a and FHOD1 are unique markers of littoral cells, a recently evolved major cell population of red pulp of human spleen. J. Immunol. 188, 4496–4505 (2012).

    Article  CAS  PubMed  Google Scholar 

  99. Cols, M. et al. Stromal endothelial cells establish a bidirectional crosstalk with chronic lymphocytic leukemia cells through the TNF-related factors BAFF, APRIL, and CD40L. J. Immunol. 188, 6071–6083 (2012).

    Article  CAS  PubMed  Google Scholar 

  100. Xu, W. et al. Epithelial cells trigger frontline immunoglobulin class switching through a pathway regulated by the inhibitor SLPI. Nature Immunol. 8, 294–303 (2007).

    Article  CAS  Google Scholar 

  101. He, B., Qiao, X. & Cerutti, A. CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J. Immunol. 173, 4479–4491 (2004). References 96 and 99–101 show that BAFF and APRIL are produced by several innate cell types and induce CD40-independent class switching.

    Article  CAS  PubMed  Google Scholar 

  102. Groom, J. R. et al. BAFF and MyD88 signals promote a lupuslike disease independent of T cells. J. Exp. Med. 204, 1959–1971 (2007). This study provides an elegant demonstration that BAFF promotes antibody production through a mechanism involving the TLR-associated protein MYD88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Castigli, E. et al. Transmembrane activator and calcium modulator and cyclophilin ligand interactor enhances CD40-driven plasma cell differentiation. J. Allergy Clin. Immunol. 120, 885–891 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Brodeur, S. R. et al. C4b-binding protein (C4BP) activates B cells through the CD40 receptor. Immunity 18, 837–848 (2003).

    Article  CAS  PubMed  Google Scholar 

  105. Li, S. et al. Rapidly induced, T-cell independent xenoantibody production is mediated by marginal zone B cells and requires help from NK cells. Blood 110, 3926–3935 (2007).

    Article  CAS  PubMed  Google Scholar 

  106. Leadbetter, E. A. et al. NK T cells provide lipid antigen-specific cognate help for B cells. Proc. Natl Acad. Sci. USA 105, 8339–8344 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Snapper, C. M. Mechanisms underlying in vivo polysaccharide-specific immunoglobulin responses to intact extracellular bacteria. Ann. NY Acad. Sci. 1253, 92–101 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Cunningham, A. F. et al. Salmonella induces a switched antibody response without germinal centers that impedes the extracellular spread of infection. J. Immunol. 178, 6200–6207 (2007).

    Article  CAS  PubMed  Google Scholar 

  109. Cobb, B. A., Wang, Q., Tzianabos, A. O. & Kasper, D. L. Polysaccharide processing and presentation by the MHCII pathway. Cell 117, 677–687 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Oliver, A. M., Martin, F. & Kearney, J. F. IgMhighCD21high lymphocytes enriched in the splenic marginal zone generate effector cells more rapidly than the bulk of follicular B cells. J. Immunol. 162, 7198–7207 (1999).

    CAS  PubMed  Google Scholar 

  111. Attanavanich, K. & Kearney, J. F. Marginal zone, but not follicular B cells, are potent activators of naive CD4 T cells. J. Immunol. 172, 803–811 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Crotty, S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 29, 621–663 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Idoyaga, J., Suda, N., Suda, K., Park, C. G. & Steinman, R. M. Antibody to Langerin/CD207 localizes large numbers of CD8α+ dendritic cells to the marginal zone of mouse spleen. Proc. Natl Acad. Sci. USA 106, 1524–1529 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Schmitt, N. et al. Human dendritic cells induce the differentiation of interleukin-21-producing T follicular helper-like cells through interleukin-12. Immunity 31, 158–169 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Bentebibel, S. E., Schmitt, N., Banchereau, J. & Ueno, H. Human tonsil B-cell lymphoma 6 (BCL6)-expressing CD4+ T-cell subset specialized for B-cell help outside germinal centers. Proc. Natl Acad. Sci. USA 108, E488–E497 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Barral, P. et al. B cell receptor-mediated uptake of CD1d-restricted antigen augments antibody responses by recruiting invariant NKT cell help in vivo. Proc. Natl Acad. Sci. USA 105, 8345–8350 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Bialecki, E. et al. Role of marginal zone B lymphocytes in invariant NKT cell activation. J. Immunol. 182, 6105–6113 (2009). Together with reference 106, references 116 and 117 indicate that MZ B cells undergo antibody production after interacting with iNKT cells.

    Article  CAS  PubMed  Google Scholar 

  118. De Santo, C. et al. Invariant NKT cells modulate the suppressive activity of IL-10-secreting neutrophils differentiated with serum amyloid A. Nature Immunol. 11, 1039–1046 (2010).

    Article  CAS  Google Scholar 

  119. Hargreaves, D. C. et al. A coordinated change in chemokine responsiveness guides plasma cell movements. J. Exp. Med. 194, 45–56 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Ellyard, J. I., Avery, D. T., Mackay, C. R. & Tangye, S. G. Contribution of stromal cells to the migration, function and retention of plasma cells in human spleen: potential roles of CXCL12, IL-6 and CD54. Eur. J. Immunol. 35, 699–708 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Avery, D. T. et al. BAFF selectively enhances the survival of plasmablasts generated from human memory B cells. J. Clin. Invest. 112, 286–297 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. He, B. et al. Intestinal bacteria trigger T cell-independent immunoglobulin A2 class switching by inducing epithelial-cell secretion of the cytokine APRIL. Immunity 26, 812–826 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Lindh, E. et al. AIRE regulates T-cell-independent B-cell responses through BAFF. Proc. Natl Acad. Sci. USA 105, 18466–18471 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Jego, G. et al. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity 19, 225–234 (2003).

    Article  CAS  PubMed  Google Scholar 

  125. Xu, W. et al. Macrophages induce differentiation of plasma cells through CXCL10/IP-10. J. Exp. Med. 209, 1813–1823 (2012). References 124 and 125 describe novel plasma cell differentiation pathways that involve an interplay between IL-6, type I IFNs and CXCL10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Hendricks, J. et al. Class-switched marginal zone B cells in spleen have relatively low numbers of somatic mutations. Mol. Immunol. 48, 874–882 (2011).

    Article  CAS  PubMed  Google Scholar 

  127. Scapini, P. et al. G-CSF-stimulated neutrophils are a prominent source of functional BLyS. J. Exp. Med. 197, 297–302 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Crepaldi, L. et al. Up-regulation of IL-10R1 expression is required to render human neutrophils fully responsive to IL-10. J. Immunol. 167, 2312–2322 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Rauch, P. J. et al. Innate response activator B cells protect against microbial sepsis. Science 335, 597–601 (2012). This work demonstrates that a unique subset of innate B cells generates protection against sepsis by producing the pleiotropic cytokine GM-CSF.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Chu, V. T. et al. Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nature Immunol. 12, 151–159 (2011).

    Article  CAS  Google Scholar 

  131. Bernasconi, N. L., Traggiai, E. & Lanzavecchia, A. Maintenance of serological memory by polyclonal activation of human memory B cells. Science 298, 2199–2202 (2002). This work suggests that the long-lived survival of antibody-producing MZ and memory B cells is highly dependent on innate microbial signals.

    Article  CAS  PubMed  Google Scholar 

  132. Lande, R. et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA–peptide complexes in systemic lupus erythematosus. Sci. Transl. Med. 3, 73ra19 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  133. He, B. et al. HIV-1 envelope triggers polyclonal Ig class switch recombination through a CD40-independent mechanism involving BAFF and C-type lectin receptors. J. Immunol. 176, 3931–3941 (2006).

    Article  CAS  PubMed  Google Scholar 

  134. Castigli, E. et al. TACI and BAFF-R mediate isotype switching in B cells. J. Exp. Med. 201, 35–39 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Kaminski, D. A. & Stavnezer, J. Enhanced IgA class switching in marginal zone and B1 B cells relative to follicular/B2 B cells. J. Immunol. 177, 6025–6029 (2006).

    Article  CAS  PubMed  Google Scholar 

  136. Le Bon, A. et al. Type I interferons potently enhance humoral immunity and can promote isotype switching by stimulating dendritic cells in vivo. Immunity 14, 461–470 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Barral, P. et al. CD169+ macrophages present lipid antigens to mediate early activation of iNKT cells in lymph nodes. Nature Immunol. 11, 303–312 (2010).

    Article  CAS  Google Scholar 

  138. Tarkowski, A. et al. Immunization of humans with polysaccharide vaccines induces systemic, predominantly polymeric IgA2-subclass antibody responses. J. Immunol. 144, 3770–3778 (1990).

    CAS  PubMed  Google Scholar 

  139. Carson, P. J., Schut, R. L., Simpson, M. L., O'Brien, J. & Janoff, E. N. Antibody class and subclass responses to pneumococcal polysaccharides following immunization of human immunodeficiency virus-infected patients. J. Infect. Dis. 172, 340–345 (1995). References 122, 138 and 139 suggest that human IgG2 and IgA2 antibodies can be produced through TI pathways.

    Article  CAS  PubMed  Google Scholar 

  140. Dammers, P. M., de Boer, N. K., Deenen, G. J., Nieuwenhuis, P. & Kroese, F. G. The origin of marginal zone B cells in the rat. Eur. J. Immunol. 29, 1522–1531 (1999).

    Article  CAS  PubMed  Google Scholar 

  141. Toellner, K. M. et al. Low-level hypermutation in T cell-independent germinal centers compared with high mutation rates associated with T cell-dependent germinal centers. J. Exp. Med. 195, 383–389 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Herlands, R. A., Christensen, S. R., Sweet, R. A., Hershberg, U. & Shlomchik, M. J. T cell-independent and Toll-like receptor-dependent antigen-driven activation of autoreactive B cells. Immunity 29, 249–260 (2008). References 141 and 142 show that B cells can undergo SHM in a TI manner.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Lanning, D. K., Rhee, K. J. & Knight, K. L. Intestinal bacteria and development of the B-lymphocyte repertoire. Trends Immunol. 26, 419–425 (2005).

    Article  CAS  PubMed  Google Scholar 

  144. Mao, C. et al. T cell-independent somatic hypermutation in murine B cells with an immature phenotype. Immunity 20, 133–144 (2004).

    Article  CAS  PubMed  Google Scholar 

  145. Aranburu, A. et al. TLR ligation triggers somatic hypermutation in transitional B cells inducing the generation of IgM memory B cells. J. Immunol. 185, 7293–7301 (2010). References 144 and 145 provide additional evidence that some B cells activate the SHM machinery in response to innate signals without requiring T cells.

    Article  CAS  PubMed  Google Scholar 

  146. van de Pavert, S. A. & Mebius, R. E. New insights into the development of lymphoid tissues. Nature Rev. Immunol. 10, 664–674 (2010).

    Article  CAS  Google Scholar 

  147. Zindl, C. L. et al. The lymphotoxin LTα1β2 controls postnatal and adult spleen marginal sinus vascular structure and function. Immunity 30, 408–420 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Mueller, S. N. & Germain, R. N. Stromal cell contributions to the homeostasis and functionality of the immune system. Nature Rev. Immunol. 9, 618–629 (2009).

    Article  CAS  Google Scholar 

  149. Schneider, K. et al. Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus. Cell Host Microbe 3, 67–76 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors are supported by European Research Council 2011 Advanced Grant 20110310 (A.C.); US National Institutes of Health research grants AI074378, AI61093, AI95613 and AI96187 (A.C.); Ministerio de Ciencia e Innovación grant SAF 2008–02725 (A.C.); and the Juan de la Cierva programme (I.P.).

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Authors and Affiliations

  1. Catalan Institute for Research and Advanced Studies (ICREA), Barcelona Biomedical Research Park, Av. Dr. Aiguader 88, 08003, Barcelona, Spain

    Andrea Cerutti

  2. Department of Medicine, The Immunology Institute, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, 10029, New York, USA

    Andrea Cerutti & Montserrat Cols

  3. Institut Hospital del Mar d'Investigacions Mèdiques (IMIM), Barcelona Biomedical Research Park, Av. Dr. Aiguader 88, 08003, Barcelona, Spain

    Andrea Cerutti & Irene Puga

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Glossary

Toll-like receptors

(TLRs). A large family of germline-encoded pattern-recognition receptors that initiate innate and adaptive immune responses after recognizing conserved molecular signatures associated with microorganisms.

B cell receptors

(BCRs). A term that refers to transmembrane immunoglobulin molecules irrespective of their heavy-chain constant region.

B-1 cells

IgMhiIgDlowMAC1+B220lowCD23− cells that are dominant in the peritoneal and pleural cavities. Their precursors develop in the fetal liver and omentum, and in adult mice the size of the B-1 cell population is kept constant owing to the self-renewing capacity of these cells. B-1 cells recognize self components, as well as common bacterial antigens, and they secrete antibodies that tend to have a low affinity and broad specificity.

Metallophilic macrophages

A subset of macrophages that is located at the border of the white pulp and the marginal zone of the spleen. These cells are stained by silver impregnation, which explains the name.

C-type lectin receptors

(CLRs). A large family of germline-encoded pattern-recognition receptors that initiate innate and adaptive immune responses after recognizing specific conserved molecular signatures associated with microorganisms.

Peyer's patches

Groups of lymphoid nodules present in the small intestine that are massed together on the intestinal wall, opposite the line of attachment of the mesentery. Peyer's patches consist of a subepithelial dome area, B cell follicles and interfollicular T cell zones.

Class-switch recombination

(CSR). A switch in the DNA that encodes the constant region of the immunoglobulin heavy chain, from Cμ (which encodes the constant region of IgM) to Cγ, Cα or Cε, which encode the constant regions of IgG, IgA and IgE, respectively. This is accomplished through an intrachromosomal deletional rearrangement.

Somatic hypermutation

(SHM). A unique mutation mechanism that is targeted to the variable regions of rearranged immunoglobulin gene segments. Combined with selection for B cells that produce high-affinity antibodies, SHM leads to the affinity maturation of B cells in germinal centres.

Congenital asplenia

A genetic deficiency of unknown origin in humans that results in the absence of splenic development and is frequently associated with cardiovascular malformations.

Natural antibodies

Antibodies spontaneously released by B-1 cells and marginal zone B cells in the absence of immunization or infection. These antibodies have a low affinity and broad specificity for conserved self and microbial antigens and mostly belong to the IgM class, but also include IgG and IgA, particularly in humans.

Transitional B cells

Refers to transitional stage 1 (T1) and transitional stage 2 (T2) B cells, which are immature, newly formed B cells that are present in the bone marrow, blood and spleen and give rise to marginal zone and follicular B cells.

Follicular dendritic cells

(FDCs). Cells with a dendritic morphology that are present in lymph nodes. These cells display on their surface intact antigens that are held in immune complexes, and B cells in the lymph node can interact with these antigens. FDCs are of non-haematopoietic origin and are not related to dendritic cells.

T cell-independent pathway

(TI pathway). A pathway followed by B cells to produce antibodies specific for TI antigens such as microbial LPS and capsular polysaccharides. The pathway usually involves extrafollicular marginal zone B cells and B-1 cells and does not require help from T cells.

T cell-dependent pathway

(TD pathway). A pathway followed by B cells to produce antibodies specific for TD antigens such as microbial proteins. The pathway usually involves follicular B cells and requires help from T cells expressing CD40 ligand. However, extrafollicular marginal zone B cells can also respond to TD antigens.

AID

(Activation-induced cytidine deaminase). A DNA cytidine deaminase that mediates somatic hypermutation and class-switch recombination.

T follicular helper cells

(TFH cells). CD4+ T helper cells that are essential for the induction of class switching in the germinal centres of secondary follicles during antibody responses to T cell-dependent antigens.

Hyper-IgM syndrome

(HIGM syndrome). A congenital immunodeficiency characterized by defective immunoglobulin heavy-chain class switching and increased IgM production. The underlying molecular defect involves CD40 ligand (in HIGM1), activation-induced cytidine deaminase (in HIGM2), CD40 (in HIGM3), uracil DNA glycosylase (in HIGM4) or other unknown B cell proteins (in HIGM5).

Germinal centre

A lymphoid structure that arises in follicles after exposure to T cell-dependent protein antigens. This structure fosters the induction of B cell clonal expansion, class-switch recombination and somatic hypermutation, followed by the development of memory B cells and long-lived plasma cells that express high-affinity antibodies.

Invariant natural killer T cells

(iNKT cells). A subset of innate-like lymphocytes expressing an invariant Vα14+ T cell receptor that recognizes soluble glycolipids loaded on the non-polymorphic MHC class I-like molecule CD1d. In humans, CD1c might serve the same function that CD1d has in mice.

Innate response activator B cells

B-1 cell-derived plasmablasts that populate perifollicular areas of both mouse and human spleens and secrete the cytokine GM-CSF.

Neutrophil extracellular trap

(NET). A set of extracellular fibres produced by an activated neutrophil to ensnare invading microorganisms. NETs enhance neutrophil-mediated killing of extracellular pathogens while minimizing damage to host cells.

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Cerutti, A., Cols, M. & Puga, I. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol 13, 118–132 (2013). https://doi.org/10.1038/nri3383

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