Skip to main content

Advertisement

SpringerLink
Log in

Natural Antibodies: from First-Line Defense Against Pathogens to Perpetual Immune Homeostasis

  • Published:
Clinical Reviews in Allergy & Immunology Aims and scope Submit manuscript

Abstract

Natural antibodies (nAbs) are most commonly defined as immunoglobulins present in the absence of pathological conditions or deliberate immunizations. Occurrence of nAbs in germ- and antigen-free mice suggest that their production is driven, at least in part, by self-antigens. Accordingly, nAbs are constituted of natural autoantibodies (nAAbs), and can belong to the IgM, IgG, or IgA subclasses. These nAbs provide immediate protection against infection while the adaptive arm of the immune system mounts a specific and long-term response. Beyond immediate protection from infection, nAbs have been shown to play various functional roles in the immune system, which include clearance of apoptotic debris, suppression of autoimmune and inflammatory responses, regulation of B cell responses, selection of the B cell repertoires, and regulation of B cell development. These various functions of nAbs are afforded by their reactivity, which is broad, cross-reactive, and shown to recognize evolutionarily fixed epitopes shared between foreign and self-antigens. Furthermore, nAbs have unique characteristics that also contribute to their functional roles and set them apart from antigen-specific antibodies. In further support for the role of nAbs in the protection against infections and in the maintenance of immune homeostasis, the therapeutic preparation of polyclonal immunoglobulins, intravenous immunoglobulin (IVIG), rich in nAbs is commonly used in the replacement therapy of primary and secondary immunodeficiencies and in the immunotherapy of a large number of autoimmune and inflammatory diseases. Here, we review several topics on nAbs features and functions, and therapeutic applications in human diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Macnalty AS (1954) Emil von Behring, born March 15, 1854. Br Med J 1:668–670

    Article  CAS  Google Scholar 

  2. Marrack JR (1933) The chemistry of antigens and antibodies. J Phys Chem 38:989–989. https://doi.org/10.1021/j150358a015

    Article  Google Scholar 

  3. João C, Negi VS, Kazatchkine MD, Bayry J, Kaveri SV (2018) Passive serum therapy to immunomodulation by IVIG: a fascinating journey of antibodies. J Immunol 200:1957–1963. https://doi.org/10.4049/jimmunol.1701271

    Article  CAS  PubMed  Google Scholar 

  4. Black CA (1997) A brief history of the discovery of the immunoglobulins and the origin of the modern immunoglobulin nomenclature. Immunol Cell Biol 75:65–68. https://doi.org/10.1038/icb.1997.10

    Article  CAS  PubMed  Google Scholar 

  5. Dunkelberger JR, Song W-C (2010) Complement and its role in innate and adaptive immune responses. Cell Res 20:34–50. https://doi.org/10.1038/cr.2009.139

    Article  CAS  PubMed  Google Scholar 

  6. Boyden SV (1966) Natural antibodies and the immune response. Adv Immunol 5:1–28. https://doi.org/10.1016/S0065-2776(08)60271-0

    Article  CAS  PubMed  Google Scholar 

  7. Baumgarth N (2011) The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat Rev Immunol 11:34–46. https://doi.org/10.1038/nri2901

    Article  CAS  PubMed  Google Scholar 

  8. Holodick NE, Rodríguez-Zhurbenko N, Hernández AM (2017) Defining natural antibodies. Front Immunol 8:872. https://doi.org/10.3389/fimmu.2017.00872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kawahara T, Ohdan H, Zhao G, Yang YG, Sykes M (2003) Peritoneal cavity B cells are precursors of splenic IgM natural antibody-producing cells. J Immunol 171:5406–5414. https://doi.org/10.4049/JIMMUNOL.171.10.5406

    Article  CAS  PubMed  Google Scholar 

  10. Baumgarth N, Waffarn EE, Nguyen TTT (2015) Natural and induced B-1 cell immunity to infections raises questions of nature versus nurture. Ann N Y Acad Sci 1362:188–199. https://doi.org/10.1111/nyas.12804

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Montecino-Rodriguez E, Dorshkind K (2012) B-1 B cell development in the fetus and adult. Immunity 36:13–21. https://doi.org/10.1016/j.immuni.2011.11.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Casali P, Notkins AL (1989) CD5+ B lymphocytes, polyreactive antibodies and the human B-cell repertoire. Immunol Today 10:364–368. https://doi.org/10.1016/0167-5699(89)90268-5

    Article  CAS  PubMed  Google Scholar 

  13. Kasaian MT, Ikematsu H, Casali P (1992) Identification and analysis of a novel human surface CD5- B lymphocyte subset producing natural antibodies. J Immunol 148:2690–2702

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Griffin DO, Holodick NE, Rothstein TL (2011) Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+CD27+CD43+CD70−. J Exp Med 208:67–80. https://doi.org/10.1084/jem.20101499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Quách TD, Rodríguez-Zhurbenko N, Hopkins TJ, Guo X, Hernández AM, Li W, Rothstein TL (2016) Distinctions among circulating antibody-secreting cell populations, including B-1 cells, in human adult peripheral blood. J Immunol 196:1060–1069. https://doi.org/10.4049/jimmunol.1501843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Capolunghi F, Cascioli S, Giorda E, Rosado MM, Plebani A, Auriti C, Seganti G, Zuntini R, Ferrari S, Cagliuso M, Quinti I, Carsetti R (2008) CpG drives human transitional B cells to terminal differentiation and production of natural antibodies. J Immunol 180:800–808. https://doi.org/10.4049/JIMMUNOL.180.2.800

    Article  CAS  PubMed  Google Scholar 

  17. Desiderio SV, Yancopoulos GD, Paskind M et al (1984) Insertion of N regions into heavy-chain genes is correlated with expression of terminal deoxytransferase in B cells. Nature 311:752–755

    Article  CAS  Google Scholar 

  18. Yang Y, Wang C, Yang Q, Kantor AB, Chu H, Ghosn EEB, Qin G, Mazmanian SK, Han J, Herzenberg LA (2015) Distinct mechanisms define murine B cell lineage immunoglobulin heavy chain (IgH) repertoires. Elife 4:e09083. https://doi.org/10.7554/eLife.09083

    Article  PubMed  PubMed Central  Google Scholar 

  19. Rechavi E, Lev A, Lee YN, Simon AJ, Yinon Y, Lipitz S, Amariglio N, Weisz B, Notarangelo LD, Somech R (2015) Timely and spatially regulated maturation of B and T cell repertoire during human fetal development. Sci Transl Med 7:276ra25–276ra25. https://doi.org/10.1126/scitranslmed.aaa0072

    Article  CAS  PubMed  Google Scholar 

  20. Coutinho A, Kazatchkine MD, Avrameas S (1995) Natural autoantibodies. Curr Opin Immunol 7:812–818. https://doi.org/10.1016/0952-7915(95)80053-0

    Article  CAS  PubMed  Google Scholar 

  21. Lacroix-Desmazes S, Kaveri SV, Mouthon L, Ayouba A, Malanchère E, Coutinho A, Kazatchkine MD (1998) Self-reactive antibodies (natural autoantibodies) in healthy individuals. J Immunol Methods 216:117–137. https://doi.org/10.1016/S0022-1759(98)00074-X

    Article  CAS  PubMed  Google Scholar 

  22. Hayakawa K, Asano M, Shinton SA et al (1999) Positive selection of natural autoreactive B cells. Science 285:113–116. https://doi.org/10.1126/science.285.5424.113

    Article  CAS  PubMed  Google Scholar 

  23. Kearney JF, Patel P, Stefanov EK, King RG (2015) Natural antibody repertoires: development and functional role in inhibiting allergic airway disease. Annu Rev Immunol 33:475–504. https://doi.org/10.1146/annurev-immunol-032713-120140

    Article  CAS  PubMed  Google Scholar 

  24. Wardemann H, Yurasov S, Schaefer A et al (2003) Predominant autoantibody production by early human B cell precursors. Science 301:1374–1377. https://doi.org/10.1126/science.1086907

    Article  CAS  PubMed  Google Scholar 

  25. Feeney AJ (1991) Predominance of the prototypic T15 anti-phosphorylcholine junctional sequence in neonatal pre-B cells. J Immunol 147:4343–4350

    CAS  PubMed  Google Scholar 

  26. Binder CJ, Hörkkö S, Dewan A, Chang MK, Kieu EP, Goodyear CS, Shaw PX, Palinski W, Witztum JL, Silverman GJ (2003) Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 9:736–743. https://doi.org/10.1038/nm876

    Article  CAS  PubMed  Google Scholar 

  27. New JS, King RG, Kearney JF (2016) Manipulation of the glycan-specific natural antibody repertoire for immunotherapy. Immunol Rev 270:32–50

    Article  CAS  Google Scholar 

  28. Bayry J, Misra N, Dasgupta S, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV (2005) Natural autoantibodies: immune homeostasis and therapeutic intervention. Expert Rev Clin Immunol 1:213–222. https://doi.org/10.1586/1744666X.1.2.213

    Article  CAS  PubMed  Google Scholar 

  29. Kaveri SV (2012) Intravenous immunoglobulin: exploiting the potential of natural antibodies. Autoimmun Rev 11:792–794. https://doi.org/10.1016/j.autrev.2012.02.006

    Article  CAS  PubMed  Google Scholar 

  30. Briles DE, Nahm M, Schroer K et al (1981) Antiphosphocholine antibodies found in normal mouse serum are protective against intravenous infection with type 3 streptococcus pneumoniae. J Exp Med 153:694–705. https://doi.org/10.1084/JEM.153.3.694

    Article  CAS  PubMed  Google Scholar 

  31. Zhou Z-H, Zhang Y, Hu Y-F, Wahl LM, Cisar JO, Notkins AL (2007) The broad antibacterial activity of the natural antibody repertoire is due to polyreactive antibodies. Cell Host Microbe 1:51–61. https://doi.org/10.1016/j.chom.2007.01.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ochsenbein AF, Fehr T, Lutz C et al (1999) Control of early viral and bacterial distribution and disease by natural antibodies. Science 286:2156–2159. https://doi.org/10.1126/science.286.5447.2156

    Article  CAS  PubMed  Google Scholar 

  33. Heyman B (2000) Regulation of antibody responses via antibodies, complement, and Fc receptors. Annu Rev Immunol 18:709–737. https://doi.org/10.1146/annurev.immunol.18.1.709

    Article  CAS  PubMed  Google Scholar 

  34. Boes M, Prodeus AP, Schmidt T, Carroll MC, Chen J (1998) A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection. J Exp Med 188:2381–2386. https://doi.org/10.1084/JEM.188.12.2381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ehrenstein MR, O’Keefe TL, Davies SL, Neuberger MS (1998) Targeted gene disruption reveals a role for natural secretory IgM in the maturation of the primary immune response. Proc Natl Acad Sci U S A 95:10089–10093. https://doi.org/10.1073/PNAS.95.17.10089

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Baumgarth N, Herman OC, Jager GC, Brown LE, Herzenberg LA, Chen J (2000) B-1 and B-2 cell-derived immunoglobulin M antibodies are nonredundant components of the protective response to influenza virus infection. J Exp Med 192:271–280. https://doi.org/10.1084/JEM.192.2.271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Boes M (2000) Role of natural and immune IgM antibodies in immune responses. Mol Immunol 37:1141–1149. https://doi.org/10.1016/S0161-5890(01)00025-6

    Article  CAS  PubMed  Google Scholar 

  38. Panda S, Zhang J, Tan NS, Ho B, Ding JL (2013) Natural IgG antibodies provide innate protection against ficolin-opsonized bacteria. EMBO J 32:2905–2919. https://doi.org/10.1038/emboj.2013.199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Panda S, Zhang J, Yang L, Anand GS, Ding JL (2015) Molecular interaction between natural IgG and ficolin – mechanistic insights on adaptive-innate immune crosstalk. Sci Rep 4:3675. https://doi.org/10.1038/srep03675

    Article  CAS  Google Scholar 

  40. Kaveri SV, Maddur MS, Hegde P, Lacroix-Desmazes S, Bayry J (2011) Intravenous immunoglobulins in immunodeficiencies: more than mere replacement therapy. Clin Exp Immunol 164:2–5. https://doi.org/10.1111/j.1365-2249.2011.04387.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Roifman CM, Schroeder H, Berger M, Sorensen R, Ballow M, Buckley RH, Gewurz A, Korenblat P, Sussman G, Lemm G (2003) Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in primary immune deficiency: a randomized double-blind trial. Int Immunopharmacol 3:1325–1333. https://doi.org/10.1016/S1567-5769(03)00134-6

    Article  CAS  PubMed  Google Scholar 

  42. Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, el-Gamal Y, Harville TO, Hossny E, Mazer B, Nelson R, Secord E, Jordan SC, Stiehm ER, Vo AA, Ballow M (2017) Update on the use of immunoglobulin in human disease: a review of evidence. J Allergy Clin Immunol 139:S1–S46. https://doi.org/10.1016/J.JACI.2016.09.023

    Article  CAS  PubMed  Google Scholar 

  43. Bayry J, Lacroix-Desmazes S, Donkova-Petrini V, Carbonneil C, Misra N, Lepelletier Y, Delignat S, Varambally S, Oksenhendler E, Levy Y, Debre M, Kazatchkine MD, Hermine O, Kaveri SV (2004) Natural antibodies sustain differentiation and maturation of human dendritic cells. Proc Natl Acad Sci U S A 101:14210–14215. https://doi.org/10.1073/pnas.0402183101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV (2004) Intravenous immunoglobulin for infectious diseases: back to the pre-antibiotic and passive prophylaxis era? Trends Pharmacol Sci 25:306–310. https://doi.org/10.1016/j.tips.2004.04.002

    Article  CAS  PubMed  Google Scholar 

  45. Bayry J, Fournier EM, Maddur MS, Vani J, Wootla B, Sibéril S, Dimitrov JD, Lacroix-Desmazes S, Berdah M, Crabol Y, Oksenhendler E, Lévy Y, Mouthon L, Sautès-Fridman C, Hermine O, Kaveri SV (2011) Intravenous immunoglobulin induces proliferation and immunoglobulin synthesis from B cells of patients with common variable immunodeficiency: a mechanism underlying the beneficial effect of IVIg in primary immunodeficiencies. J Autoimmun 36:9–15. https://doi.org/10.1016/j.jaut.2010.09.006

    Article  CAS  PubMed  Google Scholar 

  46. Maddur MS, Kaveri SV, Bayry J (2017) Circulating normal IgG as stimulator of regulatory T cells: lessons from intravenous immunoglobulin. Trends Immunol 38:789–792. https://doi.org/10.1016/j.it.2017.08.008

    Article  CAS  PubMed  Google Scholar 

  47. Elliott MR, Ravichandran KS (2010) Clearance of apoptotic cells: implications in health and disease. J Cell Biol 189:1059–1070. https://doi.org/10.1083/jcb.201004096

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Manderson AP, Botto M, Walport MJ (2004) The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol 22:431–456. https://doi.org/10.1146/annurev.immunol.22.012703.104549

    Article  CAS  PubMed  Google Scholar 

  49. Chen Y, Khanna S, Goodyear CS, Park YB, Raz E, Thiel S, Gronwall C, Vas J, Boyle DL, Corr M, Kono DH, Silverman GJ (2009) Regulation of dendritic cells and macrophages by an anti-apoptotic cell natural antibody that suppresses TLR responses and inhibits inflammatory arthritis. J Immunol 183:1346–1359. https://doi.org/10.4049/jimmunol.0900948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Chen Y, Park Y-B, Patel E, Silverman GJ (2009) IgM antibodies to apoptosis-associated determinants recruit C1q and enhance dendritic cell phagocytosis of apoptotic cells. J Immunol 182:6031–6043. https://doi.org/10.4049/JIMMUNOL.0804191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Notley CA, Brown MA, Wright GP, Ehrenstein MR (2011) Natural IgM is required for suppression of inflammatory arthritis by apoptotic cells. J Immunol 186:4967–4972. https://doi.org/10.4049/jimmunol.1003021

    Article  CAS  PubMed  Google Scholar 

  52. Anania C, Gustafsson T, Hua X, Su J, Vikstroem M, de Faire U, Heimbuerger M, Jogestrand T, Frostegard J (2010) Increased prevalence of vulnerable atherosclerotic plaques and low levels of natural IgM antibodies against phosphorylcholine in patients with systemic lupus erythematosus. Arthritis Res Ther 12:R214. https://doi.org/10.1186/ar3193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kaveri SV, Silverman GJ, Bayry J (2012) Natural IgM in immune equilibrium and harnessing their therapeutic potential. J Immunol 188:939–945. https://doi.org/10.4049/JIMMUNOL.1102107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Ehrenstein MR, Cook HT, Neuberger MS (2000) Deficiency in serum immunoglobulin (Ig)M predisposes to development of IgG autoantibodies. J Exp Med 191:1253–1258. https://doi.org/10.1084/JEM.191.7.1253

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Schwartz-Albiez R, Laban S, Eichmüller S, Kirschfink M (2008) Cytotoxic natural antibodies against human tumours: an option for anti-cancer immunotherapy? Autoimmun Rev 7:491–495. https://doi.org/10.1016/J.AUTREV.2008.03.012

    Article  CAS  PubMed  Google Scholar 

  56. Norrby-Teglund A, Haque KN, Hammarström L (2006) Intravenous polyclonal IgM-enriched immunoglobulin therapy in sepsis: a review of clinical efficacy in relation to microbiological aetiology and severity of sepsis. J Intern Med 260:509–516. https://doi.org/10.1111/j.1365-2796.2006.01726.x

    Article  CAS  PubMed  Google Scholar 

  57. Maddur MS, Vani J, Lacroix-Desmazes S, Kaveri S, Bayry J (2010) Autoimmunity as a predisposition for infectious diseases. PLoS Pathog 6:e1001077. https://doi.org/10.1371/journal.ppat.1001077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gilardin L, Bayry J, Kaveri SV (2015) Intravenous immunoglobulin as clinical immune-modulating therapy. CMAJ 187:257–264. https://doi.org/10.1503/cmaj.130375

    Article  PubMed  PubMed Central  Google Scholar 

  59. Kazatchkine MD, Kaveri SV (2001) Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med 345:747–755. https://doi.org/10.1056/NEJMra993360

    Article  CAS  PubMed  Google Scholar 

  60. Seite J-F, Shoenfeld Y, Youinou P, Hillion S (2008) What is the contents of the magic draft IVIg? Autoimmun Rev 7:435–439. https://doi.org/10.1016/J.AUTREV.2008.04.012

    Article  PubMed  Google Scholar 

  61. Imbach P, d’Apuzzo V, Hirt A et al (1981) High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 317:1228–1231. https://doi.org/10.1016/S0140-6736(81)92400-4

    Article  Google Scholar 

  62. Lünemann JD, Nimmerjahn F, Dalakas MC (2015) Intravenous immunoglobulin in neurology—mode of action and clinical efficacy. Nat Rev Neurol 11:80–89. https://doi.org/10.1038/nrneurol.2014.253

    Article  CAS  PubMed  Google Scholar 

  63. Gelfand EW (2012) Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med 367:2015–2025. https://doi.org/10.1056/NEJMra1009433

    Article  CAS  PubMed  Google Scholar 

  64. Sewell WAC, Kerr J, Behr-Gross M-E, Peter H-H (2014) European consensus proposal for immunoglobulin therapies. Eur J Immunol 44:2207–2214. https://doi.org/10.1002/eji.201444700

    Article  CAS  PubMed  Google Scholar 

  65. Galeotti C, Kaveri SV, Bayry J (2017) IVIG-mediated effector functions in autoimmune and inflammatory diseases. Int Immunol 29:491–498. https://doi.org/10.1093/intimm/dxx039

    Article  CAS  PubMed  Google Scholar 

  66. Nimmerjahn F, Ravetch JV (2007) The antiinflammatory activity of IgG: the intravenous IgG paradox. J Exp Med 204:11–15. https://doi.org/10.1084/JEM.20061788

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Akilesh S, Petkova S, Sproule TJ, Shaffer DJ, Christianson GJ, Roopenian D (2004) The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease. J Clin Invest 113:1328–1333. https://doi.org/10.1172/JCI18838

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Rossi F, Dietrich G, Kazatchkine MD (1989) Anti-idiotypes against autoantibodies in normal immunoglobulins: evidence for network regulation of human autoimmune responses. Immunol Rev 110:135–149. https://doi.org/10.1111/j.1600-065X.1989.tb00031.x

    Article  CAS  PubMed  Google Scholar 

  69. Basta M, Dalakas MC (1994) High-dose intravenous immunoglobulin exerts its beneficial effect in patients with dermatomyositis by blocking endomysial deposition of activated complement fragments. J Clin Invest 94:1729–1735. https://doi.org/10.1172/JCI117520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Le pottier L, Bendaoud B, Dueymes M et al (2007) BAFF, a new target for Iintravenous immunoglobulin in autoimmunity and cancer. J Clin Immunol 27:257–265. https://doi.org/10.1007/s10875-007-9082-2

    Article  CAS  PubMed  Google Scholar 

  71. Watanabe M, Uchida K, Nakagaki K, Kanazawa H, Trapnell BC, Hoshino Y, Kagamu H, Yoshizawa H, Keicho N, Goto H, Nakata K (2007) Anti-cytokine autoantibodies are ubiquitous in healthy individuals. FEBS Lett 581:2017–2021. https://doi.org/10.1016/J.FEBSLET.2007.04.029

    Article  CAS  PubMed  Google Scholar 

  72. Séïté J-F, Goutsmedt C, Youinou P, Pers JO, Hillion S (2014) Intravenous immunoglobulin induces a functional silencing program similar to anergy in human B cells. J Allergy Clin Immunol 133:181–188.e1-9. https://doi.org/10.1016/j.jaci.2013.08.042

    Article  CAS  PubMed  Google Scholar 

  73. Séïté J-F, Cornec D, Renaudineau Y et al (2010) IVIg modulates BCR signaling through CD22 and promotes apoptosis in mature human B lymphocytes. Blood 116:1698–1704. https://doi.org/10.1182/blood-2009-12-261461

    Article  CAS  PubMed  Google Scholar 

  74. Prasad NK, Papoff G, Zeuner A et al (1998) Therapeutic preparations of normal polyspecific IgG (IVIg) induce apoptosis in human lymphocytes and monocytes: a novel mechanism of action of IVIg involving the Fas apoptotic pathway. J Immunol 161:3781–3790

    CAS  PubMed  Google Scholar 

  75. von Gunten S, Simon H-U (2008) Natural anti-Siglec autoantibodies mediate potential immunoregulatory mechanisms: implications for the clinical use of intravenous immunoglobulins (IVIg). Autoimmun Rev 7:453–456. https://doi.org/10.1016/J.AUTREV.2008.03.015

    Article  Google Scholar 

  76. Viard I, Wehrli P, Bullani R et al (1998) Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282:490–493

    Article  CAS  Google Scholar 

  77. Bayry J, Lacroix-Desmazes S, Carbonneil C et al (2003) Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin. Blood 101:758–765. https://doi.org/10.1182/blood-2002-05-14472002-05-1447

    Article  CAS  PubMed  Google Scholar 

  78. Bayry J, Lacroix-Desmazes S, Delignat S et al (2003) Intravenous immunoglobulin abrogates dendritic cell differentiation induced by interferon-α present in serum from patients with systemic lupus erythematosus. Arthritis Rheum 48:3497–3502. https://doi.org/10.1002/art.11346

    Article  CAS  PubMed  Google Scholar 

  79. Maddur MS, Othy S, Hegde P, Vani J, Lacroix-Desmazes S, Bayry J, Kaveri SV (2010) Immunomodulation by intravenous immunoglobulin: role of regulatory T cells. J Clin Immunol 30(Suppl 1):S4–S8. https://doi.org/10.1007/s10875-010-9394-5

    Article  CAS  PubMed  Google Scholar 

  80. Kessel A, Ammuri H, Peri R, Pavlotzky ER, Blank M, Shoenfeld Y, Toubi E (2007) Intravenous immunoglobulin therapy affects T regulatory cells by increasing their suppressive function. J Immunol 179:5571–5575. https://doi.org/10.4049/jimmunol.179.8.5571

    Article  CAS  PubMed  Google Scholar 

  81. Maddur MS, Rabin M, Hegde P, Bolgert F, Guy M, Vallat JM, Magy L, Bayry J, Kaveri SV (2014) Intravenous immunoglobulin exerts reciprocal regulation of Th1/Th17 cells and regulatory T cells in Guillain-Barre syndrome patients. Immunol Res 60:320–329. https://doi.org/10.1007/s12026-014-8580-6

    Article  CAS  PubMed  Google Scholar 

  82. Maddur MS, Trinath J, Rabin M, Bolgert F, Guy M, Vallat JM, Magy L, Balaji KN, Kaveri SV, Bayry J (2015) Intravenous immunoglobulin-mediated expansion of regulatory T cells in autoimmune patients is associated with increased prostaglandin E2 levels in the circulation. Cell Mol Immunol 12:650–652. https://doi.org/10.1038/cmi.2014.117

    Article  CAS  PubMed  Google Scholar 

  83. Maddur MS, Vani J, Hegde P, Lacroix-Desmazes S, Kaveri SV, Bayry J (2011) Inhibition of differentiation, amplification, and function of human TH17 cells by intravenous immunoglobulin. J Allergy Clin Immunol 127:823–830.e1–7. https://doi.org/10.1016/j.jaci.2010.12.1102

    Article  CAS  PubMed  Google Scholar 

  84. Maddur MS, Kaveri SV, Bayry J (2011) Comparison of different IVIg preparations on IL-17 production by human Th17 cells. Autoimmun Rev 10:809–810. https://doi.org/10.1016/j.autrev.2011.02.007

    Article  CAS  PubMed  Google Scholar 

  85. Trinath J, Hegde P, Sharma M, Maddur MS, Rabin M, Vallat JM, Magy L, Balaji KN, Kaveri SV, Bayry J (2013) Intravenous immunoglobulin expands regulatory T cells via induction of cyclooxygenase-2-dependent prostaglandin E2 in human dendritic cells. Blood 122:1419–1427. https://doi.org/10.1182/blood-2012-11-468264

    Article  CAS  PubMed  Google Scholar 

  86. Othy S, Hegde P, Topçu S et al (2013) Intravenous gammaglobulin inhibits encephalitogenic potential of pathogenic T cells and interferes with their trafficking to the central nervous system, implicating sphingosine-1 phosphate receptor 1-mammalian target of rapamycin axis. J Immunol 190:4535–4541. https://doi.org/10.4049/jimmunol.1201965

    Article  CAS  PubMed  Google Scholar 

  87. Maddur MS, Sharma M, Hegde P, Lacroix-Desmazes S, Kaveri SV, Bayry J (2013) Inhibitory effect of IVIG on IL-17 production by Th17 cells is independent of anti-IL-17 antibodies in the immunoglobulin preparations. J Clin Immunol 33(Suppl 1):S62–S66. https://doi.org/10.1007/s10875-012-9752-6

    Article  CAS  PubMed  Google Scholar 

  88. Massoud AH, Yona M, Xue D, Chouiali F, Alturaihi H, Ablona A, Mourad W, Piccirillo CA, Mazer BD (2014) Dendritic cell immunoreceptor: a novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells. J Allergy Clin Immunol 133:853–863. https://doi.org/10.1016/j.jaci.2013.09.029

    Article  CAS  PubMed  Google Scholar 

  89. Bozza S, Käsermann F, Kaveri SV, Romani L, Bayry J (2019) Intravenous immunoglobulin protects from experimental allergic bronchopulmonary aspergillosis via a sialylation-dependent mechanism. Eur J Immunol 49:195–198. https://doi.org/10.1002/eji.201847774

    Article  CAS  PubMed  Google Scholar 

  90. Kaneko Y, Nimmerjahn F, Ravetch JV (2006) Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science 313:670–673. https://doi.org/10.1126/science.1129594

    Article  CAS  PubMed  Google Scholar 

  91. Fiebiger BM, Maamary J, Pincetic A, Ravetch JV (2015) Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs. Proc Natl Acad Sci U S A 112:E2385–E2394

    Article  CAS  Google Scholar 

  92. Schwab I, Mihai S, Seeling M, Kasperkiewicz M, Ludwig RJ, Nimmerjahn F (2014) Broad requirement for terminal sialic acid residues and FcγRIIB for the preventive and therapeutic activity of intravenous immunoglobulins in vivo. Eur J Immunol 44:1444–1453. https://doi.org/10.1002/eji.201344230

    Article  CAS  PubMed  Google Scholar 

  93. Galeotti C, Stephen-Victor E, Karnam A, Das M, Gilardin L, Maddur MS, Wymann S, Vonarburg C, Chevailler A, Dimitrov JD, Benveniste O, Bruhns P, Kaveri SV, Bayry J (2019) Intravenous immunoglobulin induces IL-4 in human basophils by signaling through surface-bound IgE. J Allergy Clin Immunol https://doi.org/10.1016/J.JACI.2018.10.064

    Article  Google Scholar 

  94. Maddur MS, Stephen-Victor E, Das M, Prakhar P, Sharma VK, Singh V, Rabin M, Trinath J, Balaji KN, Bolgert F, Vallat JM, Magy L, Kaveri SV, Bayry J (2017) Regulatory T cell frequency, but not plasma IL-33 levels, represents potential immunological biomarker to predict clinical response to intravenous immunoglobulin therapy. J Neuroinflammation 14:58. https://doi.org/10.1186/s12974-017-0818-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Sharma M, Schoindre Y, Hegde P, Saha C, Maddur MS, Stephen-Victor E, Gilardin L, Lecerf M, Bruneval P, Mouthon L, Benveniste O, Kaveri SV, Bayry J (2014) Intravenous immunoglobulin-induced IL-33 is insufficient to mediate basophil. Sci Rep 4:5672. https://doi.org/10.1038/srep05672

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Sharma M, Das M, Stephen-Victor E, Galeotti C, Karnam A, Maddur MS, Bruneval P, Kaveri SV, Bayry J (2018) Regulatory T cells induce activation rather than suppression of human basophils. Sci Immunol 3:eaan0829. https://doi.org/10.1126/sciimmunol.aan0829

    Article  PubMed  Google Scholar 

  97. Chan AC, Carter PJ (2010) Therapeutic antibodies for autoimmunity and inflammation. Nat Rev Immunol 10:301–316. https://doi.org/10.1038/nri2761

    Article  CAS  PubMed  Google Scholar 

  98. Spirig R, Campbell IK, Koernig S, Chen CG, Lewis BJB, Butcher R, Muir I, Taylor S, Chia J, Leong D, Simmonds J, Scotney P, Schmidt P, Fabri L, Hofmann A, Jordi M, Spycher MO, Cattepoel S, Brasseit J, Panousis C, Rowe T, Branch DR, Baz Morelli A, Käsermann F, Zuercher AW (2018) rIgG1 Fc hexamer inhibits antibody-mediated autoimmune disease via effects on complement and FcγRs. J Immunol 200:2542–2553. https://doi.org/10.4049/jimmunol.1701171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Stephen-Victor E, Bayry J (2018) Multimerized IgG1 Fc molecule as an anti-inflammatory agent. Nat Rev Rheumatol 14:390–392. https://doi.org/10.1038/s41584-018-0013-9

    Article  CAS  PubMed  Google Scholar 

  100. Kiessling P, Lledo-Garcia R, Watanabe S et al (2017) The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: a randomized phase 1 study. Sci Transl Med 9:eaan1208. https://doi.org/10.1126/scitranslmed.aan1208

    Article  CAS  PubMed  Google Scholar 

  101. Ulrichts P, Guglietta A, Dreier T, van Bragt T, Hanssens V, Hofman E, Vankerckhoven B, Verheesen P, Ongenae N, Lykhopiy V, Enriquez FJ, Cho JH, Ober RJ, Ward ES, de Haard H, Leupin N (2018) Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J Clin Invest 128:4372–4386. https://doi.org/10.1172/JCI97911

    Article  PubMed  PubMed Central  Google Scholar 

  102. Bayry J, Kaveri SV (2018) Kill ‘em all: efgartigimod immunotherapy for autoimmune diseases. Trends Pharmacol Sci 39:919–922. https://doi.org/10.1016/j.tips.2018.08.004

    Article  CAS  PubMed  Google Scholar 

  103. von Gunten S, Shoenfeld Y, Blank M, Branch DR, Vassilev T, Käsermann F, Bayry J, Kaveri S, Simon HU (2014) IVIG pluripotency and the concept of Fc-sialylation: challenges to the scientist. Nat Rev Immunol 14:349–349. https://doi.org/10.1038/nri3401-c1

    Article  CAS  Google Scholar 

  104. Saha C, Das M, Patil V, Stephen-Victor E, Sharma M, Wymann S, Jordi M, Vonarburg C, Kaveri SV, Bayry J (2017) Monomeric immunoglobulin A from plasma inhibits human Th17 responses in vitro independent of FcαRI and DC-SIGN. Front Immunol 8:275. https://doi.org/10.3389/fimmu.2017.00275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Rossato E, Ben Mkaddem S, Kanamaru Y, Hurtado-Nedelec M, Hayem G, Descatoire V, Vonarburg C, Miescher S, Zuercher AW, Monteiro RC (2015) Reversal of arthritis by human monomeric IgA through the receptor-mediated SH2 domain-containing phosphatase 1 inhibitory pathway. Arthritis Rheum 67:1766–1777. https://doi.org/10.1002/art.39142

    Article  CAS  Google Scholar 

  106. Morva A, Lemoine S, Achour A, Pers JO, Youinou P, Jamin C (2012) Maturation and function of human dendritic cells are regulated by B lymphocytes. Blood 119:106–114. https://doi.org/10.1182/blood-2011-06-360768

    Article  CAS  PubMed  Google Scholar 

  107. Maddur MS, Kaveri SV, Bayry J (2012) Regulation of human dendritic cells by B cells depends on the signals they receive. Blood 119:3863–3864. https://doi.org/10.1182/blood-2012-02-408948

    Article  CAS  PubMed  Google Scholar 

  108. Maddur MS, Kaveri SV, Bayry J (2018) Induction of human dendritic cell maturation by naïve and memory B-cell subsets requires different activation stimuli. Cell Mol Immunol 15:1074–1076. https://doi.org/10.1038/s41423-018-0017-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Hermine O, Tough DF, Kaveri SV (2005) Modulation of dendritic cell maturation and function by B lymphocytes. J Immunol 175:15–20. https://doi.org/10.4049/JIMMUNOL.175.1.15

    Article  CAS  PubMed  Google Scholar 

  110. Maddur MS, Sharma M, Hegde P, Stephen-Victor E, Pulendran B, Kaveri SV, Bayry J (2014) Human B cells induce dendritic cell maturation and favour Th2 polarization by inducing OX-40 ligand. Nat Commun 5:4092. https://doi.org/10.1038/ncomms5092

  111. Tiller T, Tsuiji M, Yurasov S, Velinzon K, Nussenzweig MC, Wardemann H (2007) Autoreactivity in human IgG+ memory B cells. Immunity 26:205–213. https://doi.org/10.1016/j.immuni.2007.01.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sabouri Z, Schofield P, Horikawa K, Spierings E, Kipling D, Randall KL, Langley D, Roome B, Vazquez-Lombardi R, Rouet R, Hermes J, Chan TD, Brink R, Dunn-Walters DK, Christ D, Goodnow CC (2014) Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity. Proc Natl Acad Sci U S A 111:E2567–E2575. https://doi.org/10.1073/pnas.1406974111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Shopsin B, Kaveri SV, Bayry J (2016) Tackling difficult Staphylococcus aureus infections: antibodies show the way. Cell Host Microbe 20:555–557. https://doi.org/10.1016/J.CHOM.2016.10.018

    Article  CAS  PubMed  Google Scholar 

  114. Diep BA, Le VTM, Badiou C et al (2016) IVIG-mediated protection against necrotizing pneumonia caused by MRSA. Sci Transl Med 8:357ra124. https://doi.org/10.1126/scitranslmed.aag1153

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

Supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne Université, Université Paris Descartes France and the Indo-French Center for Promotion of Advanced Research (CEFIPRA) Project 5203-3. The research on intravenous immunoglobulin is supported in part by grants from CSL Behring (France and Switzerland) and Laboratoire Français du Fractionnement et des Biotechnologies, France.

Author information

Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Sorbonne Université, Université Paris Descartes, Sorbonne Paris Cité, 15 rue de l’Ecole de Médicine, F-75006, Paris, France

    Mohan S. Maddur, Sébastien Lacroix-Desmazes, Jordan D. Dimitrov, Jagadeesh Bayry & Srini V. Kaveri

  2. United Nations Special Envoy for AIDS in Eastern Europe and Central Asia, Geneva, Switzerland

    Michel D. Kazatchkine

Authors
  1. Mohan S. Maddur
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sébastien Lacroix-Desmazes
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jordan D. Dimitrov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michel D. Kazatchkine
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jagadeesh Bayry
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Srini V. Kaveri
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Srini V. Kaveri.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval and Informed Consent

Not applicable.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Maddur, M.S., Lacroix-Desmazes, S., Dimitrov, J.D. et al. Natural Antibodies: from First-Line Defense Against Pathogens to Perpetual Immune Homeostasis. Clinic Rev Allerg Immunol 58, 213–228 (2020). https://doi.org/10.1007/s12016-019-08746-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12016-019-08746-9

Keywords

Search

Navigation