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.
Similar content being viewed by others
References
Macnalty AS (1954) Emil von Behring, born March 15, 1854. Br Med J 1:668–670
Marrack JR (1933) The chemistry of antigens and antibodies. J Phys Chem 38:989–989. https://doi.org/10.1021/j150358a015
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
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
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
Boyden SV (1966) Natural antibodies and the immune response. Adv Immunol 5:1–28. https://doi.org/10.1016/S0065-2776(08)60271-0
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
Holodick NE, Rodríguez-Zhurbenko N, Hernández AM (2017) Defining natural antibodies. Front Immunol 8:872. https://doi.org/10.3389/fimmu.2017.00872
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Feeney AJ (1991) Predominance of the prototypic T15 anti-phosphorylcholine junctional sequence in neonatal pre-B cells. J Immunol 147:4343–4350
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
New JS, King RG, Kearney JF (2016) Manipulation of the glycan-specific natural antibody repertoire for immunotherapy. Immunol Rev 270:32–50
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Gelfand EW (2012) Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med 367:2015–2025. https://doi.org/10.1056/NEJMra1009433
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Chan AC, Carter PJ (2010) Therapeutic antibodies for autoimmunity and inflammation. Nat Rev Immunol 10:301–316. https://doi.org/10.1038/nri2761
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Corresponding author
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
About this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12016-019-08746-9