Advertisement

The Multifaceted B Cell Response in Allergen Immunotherapy

  • Rodrigo Jiménez-Saiz
  • Sarita U. Patil
Immunotherapy and Immunomodulators (B Vickery, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Immunotherapy and Immunomodulators

Abstract

While allergen immunotherapy (AIT) for IgE-mediated diseases holds curative potential, the considerable heterogeneity in clinical outcomes may relate to the complex mechanisms of tolerance. The regulation of humoral immunity by AIT contributes to the suppression of allergic responses. Recent findings have revealed novel roles for IgA and IgG antibodies in the induction of tolerance. These mechanisms synergize with their ability to block allergen-IgE binding and mediate inhibitory signaling of effector cells of the allergic response. In addition, the regulatory activity of B cells in AIT extends beyond IL-10 secretion and induction of IgG4. Here, we review the evolution of the B cell response during AIT with special emphasis on the novel protective mechanisms entailing humoral immunity.

Keywords

B cell immunity Allergen immunotherapy Blocking IgG antibodies IgA response B regulatory cells Allergy 

Notes

Acknowledgements

We thank Dr. Bert Ruiter, Dr. Oscar Palomares, and Mr. Yosef Ellenbogen for critical review of the manuscript. Dr. Jiménez-Saiz is a Juan de La cierva – Incorporación scholar granted by the Spanish Ministry of Economy and Competitivity. Dr. Patil is a Principal Investigator at the Center for Inflammatory and Immunological Diseases at Massachusetts General Hospital and Harvard Medical School and is supported by the National Institutes of Health K23AI121491 grant from National Institutes of Allergy and Infectious Diseases.

Compliance with Ethical Standards

Conflict of Interest

Drs. Jiménez-Saiz and Patil declare no conflict of interest. Dr. Patil reports grants from National Institutes of Health, National Institutes of Allergy and Infectious Diseases.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Pawankar R. Allergic diseases and asthma: a global public health concern and a call to action. World Allergy Organ J. 2014;7(1):12.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Akdis CA, Akdis M. Advances in allergen immunotherapy: aiming for complete tolerance to allergens. Sci Transl Med. 2015;7(280):280ps6.PubMedGoogle Scholar
  3. 3.
    Galli SJ, Tsai M. IgE and mast cells in allergic disease. Nat Med. 2012;18(5):693–704.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Soria I, Lopez-Relano J, Vinuela M, Tudela JI, Angelina A, Benito-Villalvilla C, et al. Oral myeloid cells uptake allergoids coupled to mannan driving Th1/Treg responses upon sublingual delivery in mice. Allergy. 2018;73(4):875–84.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Tordesillas L, Mondoulet L, Blazquez AB, Benhamou PH, Sampson HA, Berin MC. Epicutaneous immunotherapy induces gastrointestinal LAP(+) regulatory T cells and prevents food-induced anaphylaxis. J Allergy Clin Immunol. 2017;139(1):189–201 e4.PubMedGoogle Scholar
  6. 6.
    Vonk MM, Wagenaar L, Pieters RHH, Knippels LMJ, Willemsen LEM, Smit JJ, et al. The efficacy of oral and subcutaneous antigen-specific immunotherapy in murine cow’s milk- and peanut allergy models. Clin Transl Allergy. 2017;7:13.Google Scholar
  7. 7.
    Hesse L, van Ieperen N, Habraken C, Petersen AH, Korn S, Smilda T, et al. Subcutaneous immunotherapy with purified Der p1 and 2 suppresses type 2 immunity in a murine asthma model. Allergy. 2018;73(4):862–74.PubMedPubMedCentralGoogle Scholar
  8. 8.
    Globinska A, Boonpiyathad T, Satitsuksanoa P, Kleuskens M, van de Veen W, Sokolowska M, et al. Mechanisms of allergen-specific immunotherapy: diverse mechanisms of immune tolerance to allergens. Ann Allergy Asthma Immunol 2018.Google Scholar
  9. 9.
    Jiménez-Saiz R, Chu DK, Waserman S, Jordana M. Initiation, Persistence and exacerbation of food allergy. In: Schmidt-Weber CB, editor. Allergy prevention and exacerbation. Birkhäuser Advances in Infectious Diseases. Cham: Springer International Publishing; 2017. p. 121–44.Google Scholar
  10. 10.
    Kulis MD, Patil SU, Wambre E, Vickery BP. Immune mechanisms of oral immunotherapy. J Allergy Clin Immunol. 2018;141(2):491–8.PubMedGoogle Scholar
  11. 11.
    Narisety SD, Frischmeyer-Guerrerio PA, Keet CA, Gorelik M, Schroeder J, Hamilton RG, et al. A randomized, double-blind, placebo-controlled pilot study of sublingual versus oral immunotherapy for the treatment of peanut allergy. J Allergy Clin Immunol. 2015;135(5):1275–82 e1–6.PubMedGoogle Scholar
  12. 12.
    Vickery BP, Scurlock AM, Kulis M, Steele PH, Kamilaris J, Berglund JP, et al. Sustained unresponsiveness to peanut in subjects who have completed peanut oral immunotherapy. J Allergy Clin Immunol. 2014;133(2):468–75.PubMedGoogle Scholar
  13. 13.
    Varshney P, Jones SM, Scurlock AM, Perry TT, Kemper A, Steele P, et al. A randomized controlled study of peanut oral immunotherapy: clinical desensitization and modulation of the allergic response. J Allergy Clin Immunol. 2011;127(3):654–60.PubMedPubMedCentralGoogle Scholar
  14. 14.
    Jones SM, Pons L, Roberts JL, Scurlock AM, Perry TT, Kulis M, et al. Clinical efficacy and immune regulation with peanut oral immunotherapy. J Allergy Clin Immunol. 2009;124(2):292–300 e1-97.PubMedPubMedCentralGoogle Scholar
  15. 15.
    Mousallem T, Burks AW. Immunology in the clinic review series; focus on allergies: immunotherapy for food allergy. Clin Exp Immunol. 2012;167(1):26–31.PubMedPubMedCentralGoogle Scholar
  16. 16.
    •• Jimenez-Saiz R, Chu DK, Mandur TS, Walker TD, Gordon ME, Chaudhary R, et al. Lifelong memory responses perpetuate humoral TH2 immunity and anaphylaxis in food allergy. J Allergy Clin Immunol. 2017;140(6):1604–15 e5 Murine study that identified mechanisms underlying persistent IgE-food allergy and challenged the notion that long-lived IgE+ PCs maintain humoral IgE, which identified memory B cells as a therapeutic target with disease-transforming potential.PubMedGoogle Scholar
  17. 17.
    • Wisniewski JA, Commins SP, Agrawal R, Hulse KE, Yu MD, Cronin J, et al. Analysis of cytokine production by peanut-reactive T cells identifies residual Th2 effectors in highly allergic children who received peanut oral immunotherapy. Clin Exp Allergy. 2015;45(7):1201–13 Clinical study in peanut allergic patients undergoing oral AIT that reported the presence of peanut-reactive T H 2 cells after 12–24 months of therapy, which could be the cause of unsuccesful AIT. PubMedPubMedCentralGoogle Scholar
  18. 18.
    Yang Z, Robinson MJ, Allen CD. Regulatory constraints in the generation and differentiation of IgE-expressing B cells. Curr Opin Immunol. 2014;28:64–70.PubMedGoogle Scholar
  19. 19.
    Erazo A, Kutchukhidze N, Leung M, Christ AP, Urban JF Jr, Curotto de Lafaille MA, et al. Unique maturation program of the IgE response in vivo. Immunity. 2007;26(2):191–203.PubMedPubMedCentralGoogle Scholar
  20. 20.
    Jimenez-Saiz R, Ellenbogen Y, Koenig J, Gordon ME, Walker TD, Rosace D, et al. IgG1(+) B cell immunity predates IgE responses in epicutaneous sensitization to foods. Allergy 2018.Google Scholar
  21. 21.
    •• He JS, Subramaniam S, Narang V, Srinivasan K, Saunders SP, Carbajo D, et al. IgG1 memory B cells keep the memory of IgE responses. Nat commun. 2017;8(1):641 This murine study identified a phentoypicically distinct population of IgG 1 + memory B cells that gives rise to high affinity IgE. PubMedPubMedCentralGoogle Scholar
  22. 22.
    • Looney TJ, Lee JY, Roskin KM, Hoh RA, King J, Glanville J, et al. Human B-cell isotype switching origins of IgE. J Allergy Clin Immunol. 2016;137(2):579–86 e7 The analysis of blood from healthy and allergic donors provided indirect evidence that IgE cells originated primarily via sequential class-switching from IgG 1 . PubMedGoogle Scholar
  23. 23.
    Ramadani F, Bowen H, Upton N, Hobson PS, Chan YC, Chen JB, et al. Ontogeny of human IgE-expressing B cells and plasma cells. Allergy. 2017;72(1):66–76.PubMedGoogle Scholar
  24. 24.
    Vercelli D, Geha RS. Regulation of IgE synthesis in humans: a tale of two signals. J Allergy Clin Immunol. 1991;88(3 Pt 1):285–95.PubMedGoogle Scholar
  25. 25.
    Turqueti-Neves A, Otte M, Schwartz C, Schmitt ME, Lindner C, Pabst O, et al. The extracellular domains of IgG1 and T cell-derived IL-4/IL-13 are critical for the polyclonal memory IgE response in vivo. PLoS Biol. 2015;13(11):e1002290.PubMedPubMedCentralGoogle Scholar
  26. 26.
    Clay CD, Strait RT, Mahler A, Khodoun MV, Finkelman FD. Anti-FcgammaRIIB mAb suppresses murine IgG-dependent anaphylaxis by Fc domain targeting of FcgammaRIII. J Allergy Clin Immunol. 2018;141(4):1373–81 e5.PubMedGoogle Scholar
  27. 27.
    Beutier H, Gillis CM, Iannascoli B, Godon O, England P, Sibilano R, et al. IgG subclasses determine pathways of anaphylaxis in mice. J Allergy Clin Immunol. 2017;139(1):269–80 e7.PubMedGoogle Scholar
  28. 28.
    Hofmaier S, Hatzler L, Rohrbach A, Panetta V, Hakimeh D, Bauer CP, et al. “Default” versus “pre-atopic” IgG responses to foodborne and airborne pathogenesis-related group 10 protein molecules in birch-sensitized and nonatopic children. J Allergy Clin Immunol. 2015;135(5):1367–74 e1–8.PubMedGoogle Scholar
  29. 29.
    Huang X, Tsilochristou O, Perna S, Hofmaier S, Cappella A, Bauer CP, et al. Evolution of the IgE and IgG repertoire to a comprehensive array of allergen molecules in the first decade of life. Allergy. 2018;73(2):421–30.PubMedGoogle Scholar
  30. 30.
    Strait RT, Morris SC, Finkelman FD. IgG-blocking antibodies inhibit IgE-mediated anaphylaxis in vivo through both antigen interception and Fc gamma RIIb cross-linking. J Clin Invest. 2006;116(3):833–41.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Burton OT, Logsdon SL, Zhou JS, Medina-Tamayo J, Abdel-Gadir A, Noval Rivas M, et al. Oral immunotherapy induces IgG antibodies that act through FcgammaRIIb to suppress IgE-mediated hypersensitivity. J Allergy Clin Immunol. 2014;134(6):1310–7 e6.PubMedPubMedCentralGoogle Scholar
  32. 32.
    • Vizzardelli C, Gindl M, Roos S, Mobs C, Nagl B, Zimmann F, et al. Blocking antibodies induced by allergen-specific immunotherapy ameliorate allergic airway disease in a human/mouse chimeric model. Allergy. 2018;73(4):851–61 This study reported that post-IT sera with IgE-blocking activity ameliorate allergic airway inflammation in a human/mouse chimeric model of respiratory allergy independently of AIT-induced cellular changes.PubMedGoogle Scholar
  33. 33.
    Reithofer M, Boll SL, Kitzmuller C, Horak F, Sotoudeh M, Bohle B, et al. Alum-adjuvanted allergoids induce functional IgE-blocking antibodies. Clin Exp Allergy. 2018;48(6):741–4.PubMedPubMedCentralGoogle Scholar
  34. 34.
    • Zha L, Leoratti FMS, He L, Mohsen MO, Cragg M, Storni F, et al. An unexpected protective role of low-affinity allergen-specific IgG through the inhibitory receptor FcgammaRIIb. J Allergy Clin Immunol. 2018. This murine study demonstrated that the affinity of the IgG antibodies dictates the mechanism of mast cell inhibition. Google Scholar
  35. 35.
    •• Burton OT, Tamayo JM, Stranks AJ, Koleoglou KJ, Oettgen HC. Allergen-specific IgG antibody signaling through FcgammaRIIb promotes food tolerance. J Allergy Clin Immunol. 2018;141(1):189–201 e3 This study in mice provided mechanistic data indicating that allergen-specific IgG antibodies can act to induce and sustain immunologic tolerance to foods.PubMedGoogle Scholar
  36. 36.
    • Ohsaki A, Venturelli N, Buccigrosso TM, Osganian SK, Lee J, Blumberg RS, et al. Maternal IgG immune complexes induce food allergen-specific tolerance in offspring. J Exp Med. 2018;215(1):91–113 This murine study found that interactions of maternal IgG-IC and offspring FcRn are critical for induction of T reg cell responses and control of food-specific tolerance in neonates.PubMedPubMedCentralGoogle Scholar
  37. 37.
    Tiller T, Kofer J, Kreschel C, Busse CE, Riebel S, Wickert S, et al. Development of self-reactive germinal center B cells and plasma cells in autoimmune FcγRIIB-deficient mice. J Exp Med. 2010;207(12):2767–78.PubMedPubMedCentralGoogle Scholar
  38. 38.
    Palomares O, Akdis M, Martin-Fontecha M, Akdis CA. Mechanisms of immune regulation in allergic diseases: the role of regulatory T and B cells. Immunol Rev. 2017;278(1):219–36.PubMedGoogle Scholar
  39. 39.
    •• Orengo JM, Radin AR, Kamat V, Badithe A, Ben LH, Bennett BL, et al. Treating cat allergy with monoclonal IgG antibodies that bind allergen and prevent IgE engagement. Nat Commun. 2018;9:15 A proof of concept randomized trial showing that a single dose of two monoclonal, high affinity IgG 4 antibodies specific to Fel d 1 were sufficient to prevent clinical reactivity. Google Scholar
  40. 40.
    James LK, Shamji MH, Walker SM, Wilson DR, Wachholz PA, Francis JN, et al. Long-term tolerance after allergen immunotherapy is accompanied by selective persistence of blocking antibodies. J Allergy Clin Immunol. 2011;127(2):509–16 e1–5.PubMedGoogle Scholar
  41. 41.
    Boyman O, Kaegi C, Akdis M, Bavbek S, Bossios A, Chatzipetrou A, et al. EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders. Allergy. 2015;70(7):727–54.PubMedGoogle Scholar
  42. 42.
    •• Patil SU, Ogunniyi AO, Calatroni A, Tadigotla VR, Ruiter B, Ma A, et al. Peanut oral immunotherapy transiently expands circulating Ara h 2-specific B cells with a homologous repertoire in unrelated subjects. J Allergy Clin Immunol. 2015;136(1):125–34 e12 Analysis of peanut-specific B cells demonstrated that the induced allergen-specific B cell repertoire is oligoclinal and somatically hypermutated in patients during AIT.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Vickery BP, Lin J, Kulis M, Fu Z, Steele PH, Jones SM, et al. Peanut oral immunotherapy modifies IgE and IgG4 responses to major peanut allergens. J Allergy Clin Immunol. 2013;131(1):128 34 e1–3.PubMedGoogle Scholar
  44. 44.
    • Hoh RA, Joshi SA, Liu Y, Wang C, Roskin KM, Lee JY, et al. Single B-cell deconvolution of peanut-specific antibody responses in allergic patients. J Allergy Clin Immunol. 2016;137(1):157–67 Analysis of peanut-specific B cells found that AIT increases their frequency in the blood, and can stimulate somatic mutation of allergen-specific IgG4. PubMedGoogle Scholar
  45. 45.
    Dodev TS, Bowen H, Shamji MH, Bax HJ, Beavil AJ, McDonnell JM, et al. Inhibition of allergen-dependent IgE activity by antibodies of the same specificity but different class. Allergy. 2015;70(6):720–4.PubMedPubMedCentralGoogle Scholar
  46. 46.
    Steele L, Mayer L, Berin MC. Mucosal immunology of tolerance and allergy in the gastrointestinal tract. Immunol Res. 2012;54(1–3):75–82.PubMedGoogle Scholar
  47. 47.
    • Shade KT, Platzer B, Washburn N, Mani V, Bartsch YC, Conroy M, et al. A single glycan on IgE is indispensable for initiation of anaphylaxis. J Exp Med. 2015;212(4):457–67 Using murine models, this study discovered that IgE glycosylation is critical in allergic reactions. PubMedPubMedCentralGoogle Scholar
  48. 48.
    Fagarasan S, Kawamoto S, Kanagawa O, Suzuki K. Adaptive immune regulation in the gut: T cell-dependent and T cell-independent IgA synthesis. Annu Rev Immunol. 2010;28:243–73.PubMedGoogle Scholar
  49. 49.
    Carlier FM, Sibille Y, Pilette C. The epithelial barrier and immunoglobulin A system in allergy. Clin Exp Allergy. 2016;46(11):1372–88.PubMedGoogle Scholar
  50. 50.
    Stokes CR, Soothill JF, Turner MW. Immune exclusion is a function of IgA. Nature. 1975;255(5511):745–6.PubMedGoogle Scholar
  51. 51.
    Pabst O. New concepts in the generation and functions of IgA. Nat Rev Immunol. 2012;12(12):821–32.PubMedGoogle Scholar
  52. 52.
    Leong KW, Ding JL. The unexplored roles of human serum IgA. DNA Cell Biol. 2014;33(12):823–9.PubMedPubMedCentralGoogle Scholar
  53. 53.
    Cunningham-Rundles C. Physiology of IgA and IgA deficiency. J Clin Immunol. 2001;21(5):303–9.PubMedGoogle Scholar
  54. 54.
    Tuano KS, Orange JS, Sullivan K, Cunningham-Rundles C, Bonilla FA, Davis CM. Food allergy in patients with primary immunodeficiency diseases: prevalence within the US Immunodeficiency Network (USIDNET). J Allergy Clin Immunol. 2015;135(1):273–5.PubMedGoogle Scholar
  55. 55.
    Kukkonen K, Kuitunen M, Haahtela T, Korpela R, Poussa T, Savilahti E. High intestinal IgA associates with reduced risk of IgE-associated allergic diseases. Ped Allergy Immunol. 2010;21(1):67–73.Google Scholar
  56. 56.
    Dzidic M, Abrahamsson TR, Artacho A, Björkstén B, Collado MC, Mira A, et al. Aberrant IgA responses to the gut microbiota during infancy precede asthma and allergy development. J Allergy Clin Immunol. 2017;139(3):1017–25.e14.PubMedGoogle Scholar
  57. 57.
    Taudorf E, Moller C, Russell MW. Secretory IgA response in oral immunotherapy. Investigation in birch pollinosis. Allergy. 1994;49(9):760–5.PubMedGoogle Scholar
  58. 58.
    Jimenez-Saiz R, Rupa P, Mine Y. Immunomodulatory effects of heated ovomucoid-depleted egg white in a BALB/c mouse model of egg allergy. J Agric Food Chem. 2011;59(24):13195–202.PubMedGoogle Scholar
  59. 59.
    Leonard SA, Martos G, Wang W, Nowak-Wegrzyn A, Berin MC. Oral immunotherapy induces local protective mechanisms in the gastrointestinal mucosa. J Allergy Clin Immunol. 2012;129(6):1579–87 e1.PubMedPubMedCentralGoogle Scholar
  60. 60.
    Shima K, Koya T, Tsukioka K, Sakagami T, Hasegawa T, Fukano C, et al. Effects of sublingual immunotherapy in a murine asthma model sensitized by intranasal administration of house dust mite extracts. Allergol Int. 2017;66(1):89–96.PubMedGoogle Scholar
  61. 61.
    Kulis M, Saba K, Kim EH, Bird JA, Kamilaris N, Vickery BP, et al. Increased peanut-specific IgA levels in saliva correlate with food challenge outcomes after peanut sublingual immunotherapy. J Allergy Clin Immunol. 2012;129(4):1159–62.PubMedPubMedCentralGoogle Scholar
  62. 62.
    Pilette C, Nouri-Aria K, Durham S. Serum IgA response to grass pollen during allergen-injection immunotherapy for seasonal rhinitis. J Allergy Clin Immunol. 2004;113(2):S105.Google Scholar
  63. 63.
    Kim W-J, Choi IS, Kim CS, Lee J-H, Kang H-W. Relationship between serum IgA level and allergy/asthma. Korean J Int Med. 2017;32(1):137–45.Google Scholar
  64. 64.
    Schwarze J, Cieslewicz G, Joetham A, Sun LK, Sun WN, Chang TW, et al. Antigen-specific immunoglobulin-a prevents increased airway responsiveness and lung eosinophilia after airway challenge in sensitized mice. Am J Respir Crit Care Med. 1998;158(2):519–25.PubMedGoogle Scholar
  65. 65.
    Strait RT, Mahler A, Hogan S, Khodoun M, Shibuya A, Finkelman FD. Ingested allergens must be absorbed systemically to induce systemic anaphylaxis. J Allergy Clin Immunol. 2011;127(4):982–9 e1.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Yamaki K, Nakashima T, Miyatake K, Ishibashi Y, Ito A, Kuranishi A, et al. IgA attenuates anaphylaxis and subsequent immune responses in mice: possible application of IgA to vaccines. Immunol Res. 2014;58(1):106–17.PubMedGoogle Scholar
  67. 67.
    Yamaki K, Miyatake K, Nakashima T, Morioka A, Yamamoto M, Ishibashi Y, et al. Intravenous IgA complexed with antigen reduces primary antibody response to the antigen and anaphylaxis upon antigen re-exposure by inhibiting Th1 and Th2 activation in mice. Immunopharmacol Immunotoxicol. 2014;36(5):316–28.PubMedGoogle Scholar
  68. 68.
    • Patel PS, King RG, Kearney JF. Pulmonary alpha-1,3-glucan-specific IgA-secreting B cells suppress the development of cockroach allergy. J Immunol. 2016;197(8):3175–87 This murine study reported that neonatal generation of pulmonary alpha-1,3-Glucan-Specific IgA-PCs prevented the development of cockroach allergy, and identified it as a prophylactic strategy.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Mkaddem SB, Christou I, Rossato E, Berthelot L, Lehuen A, Monteiro RC. IgA, IgA receptors, and their anti-inflammatory properties. Fc Receptors: Springer; 2014. p. 221–35.Google Scholar
  70. 70.
    Monteiro RC. Immunoglobulin A as an anti-inflammatory agent. Clin Exp Immunol. 2014;178(Suppl 1):108–10.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Pasquier B, Launay P, Kanamaru Y, Moura IC, Pfirsch S, Ruffie C, et al. Identification of FcalphaRI as an inhibitory receptor that controls inflammation: dual role of FcRgamma ITAM. Immunity. 2005;22(1):31–42.PubMedGoogle Scholar
  72. 72.
    Shen C, Detry B, Lecocq M, Pilette C. A novel IgA/Delta-like 4/Notch axis induces immunosuppressive activity in human dendritic cells. Clin Immunol. 2016;168:37–46.PubMedGoogle Scholar
  73. 73.
    Monteiro RC, Hostoffer RW, Cooper MD, Bonner JR, Gartland GL, Kubagawa H. Definition of immunoglobulin A receptors on eosinophils and their enhanced expression in allergic individuals. J Clin Invest. 1993;92(4):1681–5.PubMedPubMedCentralGoogle Scholar
  74. 74.
    Muraki M, Gleich GJ, Kita H. Antigen-specific IgG and IgA, but not IgE, activate the effector functions of eosinophils in the presence of antigen. Int Arch Allergy Immunol. 2011;154(2):119–27.PubMedGoogle Scholar
  75. 75.
    Diana J, Moura IC, Vaugier C, Gestin A, Tissandie E, Beaudoin L, et al. Secretory IgA induces tolerogenic dendritic cells through SIGNR1 dampening autoimmunity in mice. J Immunol. 2013;191(5):2335–43.PubMedGoogle Scholar
  76. 76.
    Matsumoto M, Baba A, Yokota T, Nishikawa H, Ohkawa Y, Kayama H, et al. Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity. 2014;41(6):1040–51.PubMedGoogle Scholar
  77. 77.
    • Lino AC, Dang VD, Lampropoulou V, Welle A, Joedicke J, Pohar J, et al. LAG-3 inhibitory receptor expression identifies immunosuppressive natural regulatory plasma cells. Immunity. 2018;49(1):120–33.e9 Identication of a novel subset of natural regulatory PCs characterized by the expression of LAG-3 in mice.PubMedPubMedCentralGoogle Scholar
  78. 78.
    van de Veen W. The role of regulatory B cells in allergen immunotherapy. Curr Opin Allergy Clin Immunol. 2017;17(6):447–52.PubMedGoogle Scholar
  79. 79.
    Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity. 2015;42(4):607–12.PubMedGoogle Scholar
  80. 80.
    Mauri C, Menon M. Human regulatory B cells in health and disease: therapeutic potential. J Clin Invest. 2017;127(3):772–9.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Akdis CA, Blesken T, Akdis M, Wuthrich B, Blaser K. Role of interleukin 10 in specific immunotherapy. J Clin Invest. 1998;102(1):98–106.PubMedPubMedCentralGoogle Scholar
  82. 82.
    van de Veen W, Stanic B, Yaman G, Wawrzyniak M, Sollner S, Akdis DG, et al. IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J Allergy Clin Immunol. 2013;131(4):1204–12.PubMedGoogle Scholar
  83. 83.
    • Boonpiyathad T, Meyer N, Moniuszko M, Sokolowska M, Eljaszewicz A, Wirz OF, et al. High-dose bee venom exposure induces similar tolerogenic B-cell responses in allergic patients and healthy beekeepers. Allergy. 2017;72(3):407–15 Detailed characterization of allergen-specific B cells before and after bee venom tolerance induction in humans.PubMedGoogle Scholar
  84. 84.
    Mota I, Martins C, Borrego LM. Regulatory B cells and allergy: uncovering the link. J Investig Allergol Clin Immunol. 2017;27(4):204–12.Google Scholar
  85. 85.
    van de Veen W, Stanic B, Wirz OF, Jansen K, Globinska A, Akdis M. Role of regulatory B cells in immune tolerance to allergens and beyond. J Allergy Clin Immunol. 2016;138(3):654–65.PubMedGoogle Scholar
  86. 86.
    Ray A, Wang L, Dittel BN. IL-10-independent regulatory B-cell subsets and mechanisms of action. Int Immunol. 2015;27(10):531–6.PubMedGoogle Scholar
  87. 87.
    • Oleinika K, Rosser EC, Matei DE, Nistala K, Bosma A, Drozdov I, et al. CD1d-dependent immune suppression mediated by regulatory B cells through modulations of iNKT cells. Nat Commun. 2018;9(1):684 Discovery of a novel mechanism by which Bregs restrain excessive inflammation via lipid presentation in mice.PubMedPubMedCentralGoogle Scholar
  88. 88.
    • Sun J, Wang J, Pefanis E, Chao J, Rothschild G, Tachibana I, et al. Transcriptomics identify CD9 as a marker of murine IL-10-competent regulatory B cells. Cell Rep. 2015;13(6):1110–7 Identification of CD9 as a functional marker of most IL-10 competent murine Breg cells.PubMedPubMedCentralGoogle Scholar
  89. 89.
    •• Braza F, Chesne J, Durand M, Dirou S, Brosseau C, Mahay G, et al. A regulatory CD9(+) B-cell subset inhibits HDM-induced allergic airway inflammation. Allergy. 2015;70(11):1421–31 Murine study reporting that injection of CD9+ Bregs controls the expansion of lung effector T cells allowing the establishment of a favorable regulatory T cells/effector T cells ratio in lungs, which strengthens the potential for Breg-targeted therapies in allergic asthma. PubMedGoogle Scholar
  90. 90.
    Natarajan P, Singh A, McNamara JT, Secor ER Jr, Guernsey LA, Thrall RS, et al. Regulatory B cells from hilar lymph nodes of tolerant mice in a murine model of allergic airway disease are CD5+, express TGF-beta, and co-localize with CD4+Foxp3+ T cells. Mucosal Immunol. 2012;5(6):691–701.PubMedPubMedCentralGoogle Scholar
  91. 91.
    Liu ZQ, Wu Y, Song JP, Liu X, Liu Z, Zheng PY, et al. Tolerogenic CX3CR1+ B cells suppress food allergy-induced intestinal inflammation in mice. Allergy. 2013;68(10):1241–8.PubMedGoogle Scholar
  92. 92.
    Muehlhoefer A, Saubermann LJ, Gu X, Luedtke-Heckenkamp K, Xavier R, Blumberg RS, et al. Fractalkine is an epithelial and endothelial cell-derived chemoattractant for intraepithelial lymphocytes in the small intestinal mucosa. J Immunol. 2000;164(6):3368–76.PubMedGoogle Scholar
  93. 93.
    Zhang HP, Wu Y, Liu J, Jiang J, Geng XR, Yang G, et al. TSP1-producing B cells show immune regulatory property and suppress allergy-related mucosal inflammation. Sci Rep. 2013;3:3345.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Murphy-Ullrich JE, Poczatek M. Activation of latent TGF-beta by thrombospondin-1: mechanisms and physiology. Cytokine Growth Factor Rev. 2000;11(1–2):59–69.PubMedGoogle Scholar
  95. 95.
    Cerutti A. The regulation of IgA class switching. Nat Rev Immunol. 2008;8(6):421–34.PubMedPubMedCentralGoogle Scholar
  96. 96.
    Cooke RA, Menzel AE, Kessler WR, Myers PA. The antibody mechanisms of ragweed allergy; electrophoretic and chemical studies. I. The blocking antibody. J Exp Med. 1955;101(2):177–96.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular Biology, Chemistry SchoolComplutense UniversityMadridSpain
  2. 2.Department of Medicine Division of Rheumatology, Allergy, and Immunology, Department of Pediatrics, Division of Allergy and Immunology, Food Allergy CenterMassachusetts General Hospital and Harvard Medical SchoolBostonUSA

Personalised recommendations