Skip to main content
SpringerLink
Log in
Book cover

Human Monoclonal Antibodies pp 53–81Cite as

IgM Natural Autoantibodies in Physiology and the Treatment of Disease

  • Protocol
  • First Online:

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1904))

Abstract

Antibodies are vital components of the adaptive immune system for the recognition and response to foreign antigens. However, some antibodies recognize self-antigens in healthy individuals. These autoreactive antibodies may modulate innate immune functions. IgM natural autoantibodies (IgM-NAAs) are a class of primarily polyreactive immunoglobulins encoded by germline V-gene segments which exhibit low affinity but broad specificity to both foreign and self-antigens. Historically, these autoantibodies were closely associated with autoimmune disease. Nevertheless, not all human autoantibodies are pathogenic and compelling evidence indicates that IgM-NAAs may exert a spectrum of effects from injurious to protective depending upon cellular and molecular context. In this chapter, we review the current state of knowledge regarding the potential physiological and therapeutic roles of IgM-NAAs in different disease conditions such as atherosclerosis, cancer, and autoimmune disease. We also describe the discovery of two reparative IgM-NAAs by our laboratory and delineate their proposed mechanisms of action in central nervous system (CNS) disease.

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

Protocol
USD   49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Springer Nature is developing a new tool to find and evaluate Protocols. Learn more

References

  1. Walport MJ (2001) Complement. First of two parts. N Engl J Med 344(14):1058–1066

    Article  CAS  PubMed  Google Scholar 

  2. Toapanta FR, Ross TM (2006) Complement-mediated activation of the adaptive immune responses: role of C3d in linking the innate and adaptive immunity. Immunol Res 36(1–3):197–210

    Article  CAS  PubMed  Google Scholar 

  3. Aggarwal A (2014) Role of autoantibody testing. Best Pract Res Clin Rheumatol 28(6):907–920

    Article  PubMed  Google Scholar 

  4. Zaichik A, Churilov LP, Utekhin VJ (2008) Autoimmune regulation of genetically determined cell functions in health and disease. Pathophysiology 15(3):191–207

    Article  CAS  PubMed  Google Scholar 

  5. Piro A, Tagarelli A, Tagarelli G et al (2008) Paul Ehrlich: the Nobel Prize in physiology or medicine 1908. Int Rev Immunol 27(1–2):1–17

    Article  CAS  PubMed  Google Scholar 

  6. Haury M, Sundblad A, Grandien A et al (1997) The repertoire of serum IgM in normal mice is largely independent of external antigenic contact. Eur J Immunol 27(6):1557–1563

    Article  CAS  PubMed  Google Scholar 

  7. Boes M (2000) Role of natural and immune IgM antibodies in immune responses. Mol Immunol 37(18):1141–1149

    Article  CAS  PubMed  Google Scholar 

  8. Meffre E, Salmon JE (2007) Autoantibody selection and production in early human life. J Clin Invest 117(3):598–601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Merbl Y, Zucker-Toledano M, Quintana FJ, Cohen IR (2007) Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics. J Clin Invest 117(3):712–718

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Elkon K, Casali P (2008) Nature and functions of autoantibodies. Nat Clin Pract Rheumatol 4(9):491–498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kaveri SV, Silverman GJ, Bayry J (2012) Natural IgM in immune equilibrium and harnessing their therapeutic potential. J Immunol 188(3):939–945

    Article  CAS  PubMed  Google Scholar 

  12. Carroll MC (1998) The role of complement and complement receptors in induction and regulation of immunity. Annu Rev Immunol 16:545–568

    Article  CAS  PubMed  Google Scholar 

  13. Sakamoto N, Shibuya K, Shimizu Y et al (2001) A novel Fc receptor for IgA and IgM is expressed on both hematopoietic and non-hematopoietic tissues. Eur J Immunol 31(5):1310–1316

    Article  CAS  PubMed  Google Scholar 

  14. Shibuya A, Sakamoto N, Shimizu Y et al (2000) Fc alpha/mu receptor mediates endocytosis of IgM-coated microbes. Nat Immunol 1(5):441–446

    Article  CAS  PubMed  Google Scholar 

  15. Kaetzel CS (2005) The polymeric immunoglobulin receptor: bridging innate and adaptive immune responses at mucosal surfaces. Immunol Rev 206:83–99

    Article  CAS  PubMed  Google Scholar 

  16. Johansen FE, Pekna M, Norderhaug IN et al (1999) Absence of epithelial immunoglobulin A transport, with increased mucosal leakiness, in polymeric immunoglobulin receptor/secretory component-deficient mice. J Exp Med 190(7):915–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kubagawa H, Carroll MC, Jacob CO et al (2015) Nomenclature of Toso, Fas apoptosis inhibitory molecule 3, and IgM FcR. J Immunol 194(9):4055–4057

    Article  CAS  PubMed  Google Scholar 

  18. Kubagawa H, Kubagawa Y, Jones D et al (2014) The old but new IgM Fc receptor (FcmuR). Curr Top Microbiol Immunol 382:3–28

    CAS  PubMed  Google Scholar 

  19. Kubagawa H, Oka S, Kubagawa Y et al (2009) Identity of the elusive IgM Fc receptor (FcmuR) in humans. J Exp Med 206(12):2779–2793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Shima H, Takatsu H, Fukuda S et al (2010) Identification of TOSO/FAIM3 as an Fc receptor for IgM. Int Immunol 22(3):149–156

    Article  CAS  PubMed  Google Scholar 

  21. Berland R, Wortis HH (2002) Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol 20:253–300

    Article  CAS  PubMed  Google Scholar 

  22. Peaker CJ, Neuberger MS (1993) Association of CD22 with the B cell antigen receptor. Eur J Immunol 23(6):1358–1363

    Article  CAS  PubMed  Google Scholar 

  23. Muller J, Nitschke L (2014) The role of CD22 and Siglec-G in B-cell tolerance and autoimmune disease. Nat Rev Rheumatol 10(7):422–428

    Article  PubMed  CAS  Google Scholar 

  24. O'Keefe TL, Williams GT, Davies SL et al (1996) Hyperresponsive B cells in CD22-deficient mice. Science 274(5288):798–801

    Article  CAS  PubMed  Google Scholar 

  25. Jellusova J, Nitschke L (2011) Regulation of B cell functions by the sialic acid-binding receptors siglec-G and CD22. Front Immunol 2:96

    PubMed  Google Scholar 

  26. Hardy RR, Hayakawa K (2001) B cell development pathways. Annu Rev Immunol 19:595–621

    Article  CAS  PubMed  Google Scholar 

  27. LeBien TW, Tedder TF (2008) B lymphocytes: how they develop and function. Blood 112(5):1570–1580

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Herzenberg LA, Herzenberg LA (1989) Toward a layered immune system. Cell 59(6):953–954

    Article  CAS  PubMed  Google Scholar 

  29. Chung JB, Silverman M, Monroe JG (2003) Transitional B cells: step by step towards immune competence. Trends Immunol 24(6):343–349

    Article  CAS  PubMed  Google Scholar 

  30. Deenen GJ, Kroese FG (1993) Kinetics of peritoneal B-1a cells (CD5 B cells) in young adult mice. Eur J Immunol 23(1):12–16

    Article  CAS  PubMed  Google Scholar 

  31. Kantor AB, Stall AM, Adams S et al (1992) Adoptive transfer of murine B-cell lineages. Ann N Y Acad Sci 651:168–169

    Article  CAS  PubMed  Google Scholar 

  32. Kantor AB, Stall AM, Adams S et al (1992) Differential development of progenitor activity for three B-cell lineages. Proc Natl Acad Sci U S A 89(8):3320–3324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tung JW, Mrazek MD, Yang Y et al (2006) Phenotypically distinct B cell development pathways map to the three B cell lineages in the mouse. Proc Natl Acad Sci U S A 103(16):6293–6298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Herzenberg LA, Stall AM, Lalor PA et al (1986) The Ly-1 B cell lineage. Immunol Rev 93:81–102

    Article  CAS  PubMed  Google Scholar 

  35. Hayakawa K, Hardy RR, Parks DR et al (1983) The “Ly-1 B” cell subpopulation in normal immunodefective, and autoimmune mice. J Exp Med 157(1):202–218

    Article  CAS  PubMed  Google Scholar 

  36. Ghosn EE, Yamamoto R, Hamanaka S et al (2012) Distinct B-cell lineage commitment distinguishes adult bone marrow hematopoietic stem cells. Proc Natl Acad Sci U S A 109(14):5394–5398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Martin F, Oliver AM, Kearney JF (2001) Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity 14(5):617–629

    Article  CAS  PubMed  Google Scholar 

  38. Choi YS, Baumgarth N (2008) Dual role for B-1a cells in immunity to influenza virus infection. J Exp Med 205(13):3053–3064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 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(1):67–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Wong SC, Chew WK, Tan JE et al (2002) Peritoneal CD5+ B-1 cells have signaling properties similar to tolerant B cells. J Biol Chem 277(34):30707–30715

    Article  CAS  PubMed  Google Scholar 

  41. Hayakawa K, Hardy RR, Stall AM et al (1986) Immunoglobulin-bearing B cells reconstitute and maintain the murine Ly-1 B cell lineage. Eur J Immunol 16(10):1313–1316

    Article  CAS  PubMed  Google Scholar 

  42. Boes M, Esau C, Fischer MB et al (1998) Enhanced B-1 cell development, but impaired IgG antibody responses in mice deficient in secreted IgM. J Immunol 160(10):4776–4787

    CAS  PubMed  Google Scholar 

  43. Nguyen TT, Elsner RA, Baumgarth N (2015) Natural IgM prevents autoimmunity by enforcing B cell central tolerance induction. J Immunol 194(4):1489–1502

    Article  CAS  PubMed  Google Scholar 

  44. Freitas AA, Viale AC, Sundblad A et al (1991) Normal serum immunoglobulins participate in the selection of peripheral B-cell repertoires. Proc Natl Acad Sci U S A 88(13):5640–5644

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kearney JF, Patel P, Stefanov EK et al (2015) Natural antibody repertoires: development and functional role in inhibiting allergic airway disease. Annu Rev Immunol 33:475–504

    Article  CAS  PubMed  Google Scholar 

  46. Patel PS, Kearney JF (2015) Neonatal exposure to pneumococcal phosphorylcholine modulates the development of house dust mite allergy during adult life. J Immunol 194(12):5838–5850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Vollmers HP, Brandlein S (2009) Natural antibodies and cancer. New Biotechnol 25(5):294–298

    Article  CAS  Google Scholar 

  48. Madi A, Bransburg-Zabary S, Maayan-Metzger A, Dar G, Ben-Jacob E, Cohen IR (2015) Tumor-associated and disease-associated autoantibody repertoires in healthy colostrum and maternal and newborn cord sera. J Immunol 194(11):5272–5281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Heyman B (2000) Regulation of antibody responses via antibodies, complement, and Fc receptors. Annu Rev Immunol 18:709–737

    Article  CAS  PubMed  Google Scholar 

  50. Heyman B, Pilstrom L, Shulman MJ (1988) Complement activation is required for IgM-mediated enhancement of the antibody response. J Exp Med 167(6):1999–2004

    Article  CAS  PubMed  Google Scholar 

  51. Ochsenbein AF, Fehr T, Lutz C et al (1999) Control of early viral and bacterial distribution and disease by natural antibodies. Science 286(5447):2156–2159

    Article  CAS  PubMed  Google Scholar 

  52. Zhou ZH, Zhang Y, Hu YF et al (2007) The broad antibacterial activity of the natural antibody repertoire is due to polyreactive antibodies. Cell Host Microbe 1(1):51–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Stager S, Alexander J, Kirby AC, Botto M, Rooijen NV, Smith DF et al (2003) Natural antibodies and complement are endogenous adjuvants for vaccine-induced CD8+ T-cell responses. Nat Med 9(10):1287–1292

    Article  PubMed  CAS  Google Scholar 

  54. Kohler H, Bayry J, Nicoletti A et al (2003) Natural autoantibodies as tools to predict the outcome of immune response? Scand J Immunol 58(3):285–289

    Article  CAS  PubMed  Google Scholar 

  55. Jayasekera JP, Moseman EA, Carroll MC (2007) Natural antibody and complement mediate neutralization of influenza virus in the absence of prior immunity. J Virol 81(7):3487–3494

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rapaka RR, Ricks DM, Alcorn JF et al (2010) Conserved natural IgM antibodies mediate innate and adaptive immunity against the opportunistic fungus Pneumocystis murina. J Exp Med 207(13):2907–2919

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Fernandez Gonzalez S, Jayasekera JP, Carroll MC (2008) Complement and natural antibody are required in the long-term memory response to influenza virus. Vaccine 26(Suppl 8):I86–I93

    Article  PubMed  CAS  Google Scholar 

  58. Henson PM (2017) Cell removal: efferocytosis. Annu Rev Cell Dev Biol 33:127–144

    Article  CAS  PubMed  Google Scholar 

  59. Manderson AP, Botto M, Walport MJ (2004) The role of complement in the development of systemic lupus erythematosus. Annu Rev Immunol 22:431–456

    Article  CAS  PubMed  Google Scholar 

  60. Ansel KM, Harris RB, Cyster JG (2002) CXCL13 is required for B1 cell homing, natural antibody production, and body cavity immunity. Immunity 16(1):67–76

    Article  CAS  PubMed  Google Scholar 

  61. Tanabe S, Yamashita T (2018) B-1a lymphocytes promote oligodendrogenesis during brain development. Nat Neurosci 21(4):506–516

    Article  CAS  PubMed  Google Scholar 

  62. Hosseini H, Li Y, Kanellakis P et al (2015) Phosphatidylserine liposomes mimic apoptotic cells to attenuate atherosclerosis by expanding polyreactive IgM producing B1a lymphocytes. Cardiovasc Res 106(3):443–452

    Article  CAS  PubMed  Google Scholar 

  63. Binder CJ, Horkko S, Dewan A et al (2003) Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 9(6):736–743

    Article  CAS  PubMed  Google Scholar 

  64. Hörkkö S, Bird DA, Miller E et al (1999) Monoclonal autoantibodies specific for oxidized phospholipids or oxidized phospholipid–protein adducts inhibit macrophage uptake of oxidized low-density lipoproteins. J Clin Invest 103(1):117–128

    Article  PubMed  PubMed Central  Google Scholar 

  65. Binder CJ, Hörkkö S, Dewan A et al (2003) Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL. Nat Med 9:736

    Article  CAS  PubMed  Google Scholar 

  66. Thorp E, Cui D, Schrijvers DM et al (2008) Mertk receptor mutation reduces efferocytosis efficiency and promotes apoptotic cell accumulation and plaque necrosis in atherosclerotic lesions of Apoe−/− mice. Arterioscler Thromb Vasc Biol 28(8):1421–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Chang MK, Bergmark C, Laurila A et al (1999) Monoclonal antibodies against oxidized low-density lipoprotein bind to apoptotic cells and inhibit their phagocytosis by elicited macrophages: evidence that oxidation-specific epitopes mediate macrophage recognition. Proc Natl Acad Sci U S A 96(11):6353–6358

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Suthers B, Hansbro P, Thambar S et al (2012) Pneumococcal vaccination may induce anti-oxidized low-density lipoprotein antibodies that have potentially protective effects against cardiovascular disease. Vaccine 30(27):3983–3985

    Article  CAS  PubMed  Google Scholar 

  69. Grönwall C, Vas J, Silverman G (2012) Protective roles of natural IgM antibodies. Front Immunol 3:66

    Article  PubMed  PubMed Central  Google Scholar 

  70. Tsiantoulas D, Perkmann T, Afonyushkin T et al (2015) Circulating microparticles carry oxidation-specific epitopes and are recognized by natural IgM antibodies. J Lipid Res 56(2):440–448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Brändlein S, Pohle T, Ruoff N et al (2003) Natural IgM antibodies and immunosurveillance mechanisms against epithelial cancer cells in humans. Cancer Res 63(22):7995–8005

    PubMed  Google Scholar 

  72. Brandlein S, Pohle T, Vollmers C et al (2004) CFR-1 receptor as target for tumor-specific apoptosis induced by the natural human monoclonal antibody PAM-1. Oncol Rep 11(4):777–784

    PubMed  Google Scholar 

  73. Brandlein S, Rauschert N, Rasche L et al (2007) The human IgM antibody SAM-6 induces tumor-specific apoptosis with oxidized low-density lipoprotein. Mol Cancer Ther 6(1):326–333

    Article  PubMed  Google Scholar 

  74. Hensel F, Hermann R, Schubert C et al (1999) Characterization of glycosylphosphatidylinositol-linked molecule CD55/decay-accelerating factor as the receptor for antibody SC-1-induced apoptosis. Cancer Res 59(20):5299–5306

    CAS  PubMed  Google Scholar 

  75. Hermann R, Hensel F, Muller EC et al (2001) Deactivation of regulatory proteins hnRNP A1 and A2 during SC-1 induced apoptosis. Hum Antibodies 10(2):83–90

    Article  CAS  PubMed  Google Scholar 

  76. Varambally S, Bar-Dayan Y, Bayry J et al (2004) Natural human polyreactive IgM induce apoptosis of lymphoid cell lines and human peripheral blood mononuclear cells. Int Immunol 16(3):517–524

    Article  CAS  PubMed  Google Scholar 

  77. Brandlein S, Lorenz J, Ruoff N et al (2002) Human monoclonal IgM antibodies with apoptotic activity isolated from cancer patients. Hum Antibodies 11(4):107–119

    Article  PubMed  Google Scholar 

  78. Daeron M (1997) Fc receptor biology. Annu Rev Immunol 15:203–234

    Article  CAS  PubMed  Google Scholar 

  79. Ravetch JV, Clynes RA (1998) Divergent roles for Fc receptors and complement in vivo. Annu Rev Immunol 16:421–432

    Article  CAS  PubMed  Google Scholar 

  80. Schwartz-Albiez R (2012) Naturally occurring antibodies directed against carbohydrate tumor antigens. In: Lutz HU (ed) Naturally occurring antibodies (NAbs). Springer, New York, NY, pp 27–43

    Chapter  Google Scholar 

  81. Erttmann R (2008) Treatment of neuroblastoma with human natural antibodies. Autoimmun Rev 7(6):496–500

    Article  PubMed  Google Scholar 

  82. Ollert MW, David K, Schmitt C, Hauenschild A et al (1996) Normal human serum contains a natural IgM antibody cytotoxic for human neuroblastoma cells. Proc Natl Acad Sci U S A 93(9):4498–4503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. David K, Heiligtag S, Ollert MW et al (2001) Initial characterization of the apoptosis-inducing receptor for natural human anti-neuroblastoma IgM. Med Pediatr Oncol 36(1):251–257

    Article  CAS  PubMed  Google Scholar 

  84. Larkin JMG, Norsworthy PJ, A'Hern RP et al (2006) Anti-αGal-dependent complement-mediated cytotoxicity in metastatic melanoma. Melanoma Res 16(2):157–163

    Article  CAS  PubMed  Google Scholar 

  85. Poynton CH, Jackson S, Fegan C et al (1992) Use of IgM enriched intravenous immunoglobulin (pentaglobin) in bone marrow transplantation. Bone Marrow Transplant 9(6):451–457

    CAS  PubMed  Google Scholar 

  86. Kreymann KG, de Heer G, Nierhaus A et al (2007) Use of polyclonal immunoglobulins as adjunctive therapy for sepsis or septic shock. Crit Care Med 35(12):2677–2685

    CAS  PubMed  Google Scholar 

  87. Norrby-Teglund A, Haque KN, Hammarstrom 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(6):509–516

    Article  CAS  PubMed  Google Scholar 

  88. Haque KN, Zaidi MH, Bahakim H (1988) IgM-enriched intravenous immunoglobulin therapy in neonatal sepsis. Am J Dis Child (1960) 142(12):1293–1296

    CAS  Google Scholar 

  89. Stehr SN, Knels L, Weissflog C et al (2008) Effects of IGM-enriched solution on polymorphonuclear neutrophil function, bacterial clearance, and lung histology in endotoxemia. Shock (Augusta, GA) 29(2):167–172

    Google Scholar 

  90. Rieben R, Roos A, Muizert YT et al (1999) Immunoglobulin M-enriched human intravenous immunoglobulin prevents complement activation in vitro and in vivo in a rat model of acute inflammation. Blood 93(3):942–951

    CAS  PubMed  Google Scholar 

  91. Maddur MS, Vani J, Lacroix-Desmazes S et al (2010) Autoimmunity as a predisposition for infectious diseases. PLoS Pathog 6(11):e1001077

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Marcia MB, Neelima MB, Nelson NHT (1995) Anti-endotoxin human monoclonal antibody A6H4C5 (HA-1A) utilizes the VH4.21 gene. Clin Infect Dis 21:S186–S1S9

    Article  Google Scholar 

  93. Hurez V, Kazatchkine MD, Vassilev T et al (1997) Pooled normal human polyspecific IgM contains neutralizing anti-idiotypes to IgG autoantibodies of autoimmune patients and protects from experimental autoimmune disease. Blood 90(10):4004–4013

    CAS  PubMed  Google Scholar 

  94. Vassilev T, Yamamoto M, Aissaoui A et al (1999) Normal human immunoglobulin suppresses experimental myasthenia gravis in SCID mice. Eur J Immunol 29(8):2436–2442

    Article  CAS  PubMed  Google Scholar 

  95. Vassilev T, Mihaylova N, Voynova E et al (2006) IgM-enriched human intravenous immunoglobulin suppresses T lymphocyte functions in vitro and delays the activation of T lymphocytes in hu-SCID mice. Clin Exp Immunol 145(1):108–115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Jayne DR, Esnault VL, Lockwood CM (1993) ANCA anti-idiotype antibodies and the treatment of systemic vasculitis with intravenous immunoglobulin. J Autoimmun 6(2):207–219

    Article  CAS  PubMed  Google Scholar 

  97. Rossi F, Jayne DR, Lockwood CM et al (1991) Anti-idiotypes against anti-neutrophil cytoplasmic antigen autoantibodies in normal human polyspecific IgG for therapeutic use and in the remission sera of patients with systemic vasculitis. Clin Exp Immunol 83(2):298–303

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Yehuda S, Elias T (2005) Protective autoantibodies: role in homeostasis, clinical importance, and therapeutic potential. Arthritis Rheum 52(9):2599–2606

    Article  CAS  Google Scholar 

  99. Bolton WK, Schrock JH, Davis JS IV (1982) Rheumatoid factor inhibition of in vitro binding of IgG complexes in the human glomerulus. Arthritis Rheum 25(3):297–303

    Article  CAS  PubMed  Google Scholar 

  100. Andersson A, Forsgren S, Soderstrom A et al (1991) Monoclonal, natural antibodies prevent development of diabetes in the non-obese diabetic (NOD) mouse. J Autoimmun 4(5):733–742

    Article  CAS  PubMed  Google Scholar 

  101. Walpen AJ, Laumonier T, Aebi C et al (2004) Immunoglobulin M-enriched intravenous immunoglobulin inhibits classical pathway complement activation, but not bactericidal activity of human serum. Xenotransplantation 11(2):141–148

    Article  PubMed  Google Scholar 

  102. Lobo PI, Schlegel KH, Bajwa A et al (2015) Natural IgM switches the function of lipopolysaccharide-activated murine bone marrow-derived dendritic cells to a regulatory dendritic cell that suppresses innate inflammation. J Immunol 195(11):5215–5226

    Article  CAS  PubMed  Google Scholar 

  103. Lobo PI, Bajwa A, Schlegel KH et al (2012) Natural IgM anti-leukocyte autoantibodies attenuate excess inflammation mediated by innate and adaptive immune mechanisms involving Th-17. J Immunol 188(4):1675–1685

    Article  CAS  PubMed  Google Scholar 

  104. Ehrenstein MR, Notley CA (2010) The importance of natural IgM: scavenger, protector and regulator. Nat Rev Immunol 10(11):778–786

    Article  CAS  PubMed  Google Scholar 

  105. Bibl M, Esselmann H, Otto M et al (2004) Cerebrospinal fluid amyloid beta peptide patterns in Alzheimer’s disease patients and nondemented controls depend on sample pretreatment: indication of carrier-mediated epitope masking of amyloid beta peptides. Electrophoresis 25(17):2912–2918

    Article  CAS  PubMed  Google Scholar 

  106. Giacobini E, Becker RE (2007) One hundred years after the discovery of Alzheimer’s disease. A turning point for therapy? J Alzheimers Dis 12(1):37–52

    Article  CAS  PubMed  Google Scholar 

  107. Bard F, Cannon C, Barbour R et al (2000) Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6(8):916–919

    Article  CAS  PubMed  Google Scholar 

  108. Lambracht-Washington D, Rosenberg RN (2013) Advances in the development of vaccines for Alzheimer’s disease. Discov Med 15(84):319–326

    PubMed  PubMed Central  Google Scholar 

  109. Banks WA, Farr SA, Morley JE et al (2007) Anti-amyloid beta protein antibody passage across the blood-brain barrier in the SAMP8 mouse model of Alzheimer’s disease: an age-related selective uptake with reversal of learning impairment. Exp Neurol 206(2):248–256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Marcello A, Wirths O, Schneider-Axmann T, Degerman-Gunnarsson M, Lannfelt L, Bayer TA (2011) Reduced levels of IgM autoantibodies against N-truncated pyroglutamate Abeta in plasma of patients with Alzheimer’s disease. Neurobiol Aging 32(8):1379–1387

    Article  CAS  PubMed  Google Scholar 

  111. Taguchi H, Planque S, Nishiyama Y et al (2008) Autoantibody-catalyzed hydrolysis of amyloid beta peptide. J Biol Chem 283(8):4714–4722

    Article  CAS  PubMed  Google Scholar 

  112. Lang W, Rodriguez M, Lennon VA et al (1984) Demyelination and remyelination in murine viral encephalomyelitis. Ann N Y Acad Sci 436:98–102

    Article  CAS  PubMed  Google Scholar 

  113. Traugott U, Stone SH, Raine CS (1982) Chronic relapsing experimental autoimmune encephalomyelitis. treatment with combinations of myelin components promotes clinical and structural recovery. J Neurol Sci 56(1):65–73

    Article  CAS  PubMed  Google Scholar 

  114. Rodriguez M, Kenny JJ, Thiemann RL et al (1990) Theiler’s virus-induced demyelination in mice immunosuppressed with anti-IgM and in mice expressing the xid gene. Microb Pathog 8(1):23–35

    Article  CAS  PubMed  Google Scholar 

  115. Rodriguez M, Lennon VA (1990) Immunoglobulins promote remyelination in the central nervous system. Ann Neurol 27(1):12–17

    Article  CAS  PubMed  Google Scholar 

  116. Rodriguez M (1991) Immunoglobulins stimulate central nervous system remyelination: electron microscopic and morphometric analysis of proliferating cells. Lab Investig 64(3):358–370

    CAS  PubMed  Google Scholar 

  117. Rodriguez M, Lennon VA, Benveniste EN et al (1987) Remyelination by oligodendrocytes stimulated by antiserum to spinal cord. J Neuropathol Exp Neurol 46(1):84–95

    Article  CAS  PubMed  Google Scholar 

  118. Miller DJ, Sanborn KS, Katzmann JA et al (1994) Monoclonal autoantibodies promote central nervous system repair in an animal model of multiple sclerosis. J Neurosci 14(10):6230–6238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Miller DJ, Bright JJ, Sriram S et al (1997) Successful treatment of established relapsing experimental autoimmune encephalomyelitis in mice with a monoclonal natural autoantibody. J Neuroimmunol 75(1–2):204–209

    Article  CAS  PubMed  Google Scholar 

  120. Asakura K, Miller DJ, Pease LR et al (1998) Targeting of IgMkappa antibodies to oligodendrocytes promotes CNS remyelination. J Neurosci 18(19):7700–7708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Warrington AE, Asakura K, Bieber AJ et al (2000) Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc Natl Acad Sci U S A 97(12):6820–6825

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Bieber AJ, Warrington A, Asakura K et al (2002) Human antibodies accelerate the rate of remyelination following lysolecithin-induced demyelination in mice. Glia 37(3):241–249

    Article  PubMed  Google Scholar 

  123. Mitsunaga Y, Ciric B, Van Keulen V et al (2002) Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic-progressive demyelinating disease. FASEB J 16(10):1325–1327

    Article  CAS  PubMed  Google Scholar 

  124. Wootla B, Denic A, Watzlawik JO et al (2016) Antibody-mediated oligodendrocyte remyelination promotes axon health in progressive demyelinating disease. Mol Neurobiol 53(8):5217–5228

    Article  CAS  PubMed  Google Scholar 

  125. Ciric B, Van Keulen V, Paz Soldan M, Rodriguez M, Pease LR (2004) Antibody-mediated remyelination operates through mechanism independent of immunomodulation. J Neuroimmunol 146(1–2):153–161

    Article  CAS  PubMed  Google Scholar 

  126. Mullin AP, Cui C, Wang Y et al (2017) rHIgM22 enhances remyelination in the brain of the cuprizone mouse model of demyelination. Neurobiol Dis 105:142–155

    Article  CAS  PubMed  Google Scholar 

  127. Wright BR, Warrington AE, Edberg DD et al (2009) Cellular mechanisms of central nervous system repair by natural autoreactive monoclonal antibodies. Arch Neurol 66(12):1456–1459

    Article  PubMed  PubMed Central  Google Scholar 

  128. Cui C, Wang J, Mullin AP et al (2018) The antibody rHIgM22 facilitates hippocampal remyelination and ameliorates memory deficits in the cuprizone mouse model of demyelination. Brain Res 1694:73–86

    Article  CAS  PubMed  Google Scholar 

  129. Banks WA, Terrell B, Farr SA et al (2002) Passage of amyloid beta protein antibody across the blood-brain barrier in a mouse model of Alzheimer’s disease. Peptides 23(12):2223–2226

    Article  CAS  PubMed  Google Scholar 

  130. Pirko I, Ciric B, Gamez J et al (2004) A human antibody that promotes remyelination enters the CNS and decreases lesion load as detected by T2-weighted spinal cord MRI in a virus-induced murine model of MS. FASEB J 18(13):1577–1579

    Article  CAS  PubMed  Google Scholar 

  131. Warrington AE, Bieber AJ, Ciric B et al (2007) A recombinant human IgM promotes myelin repair after a single, very low dose. J Neurosci Res 85(5):967–976

    Article  CAS  PubMed  Google Scholar 

  132. Asakura K, Miller DJ, Murray K et al (1996) Monoclonal autoantibody SCH94.03, which promotes central nervous system remyelination, recognizes an antigen on the surface of oligodendrocytes. J Neurosci Res 43(3):273–281

    Article  CAS  PubMed  Google Scholar 

  133. Howe CL, Bieber AJ, Warrington AE et al (2004) Antiapoptotic signaling by a remyelination-promoting human antimyelin antibody. Neurobiol Dis 15(1):120–131

    Article  CAS  PubMed  Google Scholar 

  134. Watzlawik J, Holicky E, Edberg DD et al (2010) Human remyelination promoting antibody inhibits apoptotic signaling and differentiation through Lyn kinase in primary rat oligodendrocytes. Glia 58(15):1782–1793

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wittenberg NJ, Im H, Xu X et al (2012) High-affinity binding of remyelinating natural autoantibodies to myelin-mimicking lipid bilayers revealed by nanohole surface plasmon resonance. Anal Chem 84(14):6031–6039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Paz Soldan MM, Warrington AE, Bieber AJ et al (2003) Remyelination-promoting antibodies activate distinct Ca2+ influx pathways in astrocytes and oligodendrocytes: relationship to the mechanism of myelin repair. Mol Cell Neurosci 22(1):14–24

    Article  PubMed  CAS  Google Scholar 

  137. Watzlawik JO, Warrington AE, Rodriguez M (2013) PDGF is required for remyelination-promoting IgM stimulation of oligodendrocyte progenitor cell proliferation. PLoS One 8(2):e55149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Vana AC, Flint NC, Harwood NE et al (2007) Platelet-derived growth factor promotes repair of chronically demyelinated white matter. J Neuropathol Exp Neurol 66(11):975–988

    Article  CAS  PubMed  Google Scholar 

  139. Colognato H, Baron W, Avellana-Adalid V et al (2002) CNS integrins switch growth factor signalling to promote target-dependent survival. Nat Cell Biol 4(11):833–841

    Article  CAS  PubMed  Google Scholar 

  140. Frost EE, Buttery PC, Milner R et al (1999) Integrins mediate a neuronal survival signal for oligodendrocytes. Curr Biol 9(21):1251–1254

    Article  CAS  PubMed  Google Scholar 

  141. Baron W, Shattil SJ, Ffrench-Constant C (2002) The oligodendrocyte precursor mitogen PDGF stimulates proliferation by activation of alpha(v)beta3 integrins. EMBO J 21(8):1957–1966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Howe CL, Mayoral S, Rodriguez M (2006) Activated microglia stimulate transcriptional changes in primary oligodendrocytes via IL-1beta. Neurobiol Dis 23(3):731–739

    Article  CAS  PubMed  Google Scholar 

  143. Zorina Y, Stricker J, Caggiano AO et al (2018) Human IgM antibody rHIgM22 promotes phagocytic clearance of myelin debris by microglia. Sci Rep 8(1):9392

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  144. Xu X, Warrington AE, Wright BR et al (2011) A human IgM signals axon outgrowth: coupling lipid raft to microtubules. J Neurochem 119(1):100–112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Xu X, Wittenberg NJ, Jordan LR et al (2013) A patterned recombinant human IgM guides neurite outgrowth of CNS neurons. Sci Rep 3:2267

    Article  PubMed  PubMed Central  Google Scholar 

  146. Denic A, Bieber A, Warrington A et al (2009) Brainstem 1H nuclear magnetic resonance (NMR) spectroscopy: marker of demyelination and repair in spinal cord. Ann Neurol 66(4):559–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Wootla B, Denic A, Watzlawik JO et al (2015) A single dose of a neuron-binding human monoclonal antibody improves brainstem NAA concentrations, a biomarker for density of spinal cord axons, in a model of progressive multiple sclerosis. J Neuroinflammation 12:83

    Article  PubMed  PubMed Central  Google Scholar 

  148. Xu X, Denic A, Jordan LR et al (2015) A natural human IgM that binds to gangliosides is therapeutic in murine models of amyotrophic lateral sclerosis. Dis Model Mech 8(8):831–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Ripps ME, Huntley GW, Hof PR et al (1995) Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 92(3):689–693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Pollerberg EG, Sadoul R, Goridis C et al (1985) Selective expression of the 180-kD component of the neural cell adhesion molecule N-CAM during development. J Cell Biol 101(5 Pt 1):1921–1929

    Article  CAS  PubMed  Google Scholar 

  151. Kleene R, Mzoughi M, Joshi G et al (2010) NCAM-induced neurite outgrowth depends on binding of calmodulin to NCAM and on nuclear import of NCAM and fak fragments. J Neurosci 30(32):10784–10798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Giza J, Biederer T (2010) Polysialic acid: a veteran sugar with a new site of action in the brain. Proc Natl Acad Sci U S A 107(23):10335–10336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Czepiel M, Leicher L, Becker K et al (2014) Overexpression of polysialylated neural cell adhesion molecule improves the migration capacity of induced pluripotent stem cell-derived oligodendrocyte precursors. Stem Cells Transl Med 3(9):1100–1109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Watzlawik JO, Kahoud RJ, Ng S et al (2015) Polysialic acid as an antigen for monoclonal antibody HIgM12 to treat multiple sclerosis and other neurodegenerative disorders. J Neurochem 134(5):865–878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Warrington AE, Bieber AJ, Van Keulen V et al (2004) Neuron-binding human monoclonal antibodies support central nervous system neurite extension. J Neuropathol Exp Neurol 63(5):461–473

    Article  CAS  PubMed  Google Scholar 

  156. Xu X, Denic A, Warrington AE et al (2013) Therapeutics to promote CNS repair: a natural human neuron-binding IgM regulates membrane-raft dynamics and improves motility in a mouse model of multiple sclerosis. J Clin Immunol 33(Suppl 1):S50–S56

    Article  PubMed  CAS  Google Scholar 

  157. Lopez PH, Schnaar RL (2009) Gangliosides in cell recognition and membrane protein regulation. Curr Opin Struct Biol 19(5):549–557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Vyas AA, Patel HV, Fromholt SE et al (2002) Gangliosides are functional nerve cell ligands for myelin-associated glycoprotein (MAG), an inhibitor of nerve regeneration. Proc Natl Acad Sci U S A 99(12):8412–8417

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Sheikh KA, Sun J, Liu Y et al (1999) Mice lacking complex gangliosides develop Wallerian degeneration and myelination defects. Proc Natl Acad Sci U S A 96(13):7532–7537

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Nguyen T, Mehta NR, Conant K et al (2009) Axonal protective effects of the myelin-associated glycoprotein. J Neurosci 29(3):630–637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Montecino-Rodriguez E, Dorshkind K (2012) B-1 B cell development in the fetus and adult. Immunity 36(1):13–21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Nakahara J, Tan-Takeuchi K, Seiwa C et al (2003) Signaling via immunoglobulin Fc receptors induces oligodendrocyte precursor cell differentiation. Dev Cell 4(6):841–852

    Article  CAS  PubMed  Google Scholar 

  163. Nielsen JA, Maric D, Lau P et al (2006) Identification of a novel oligodendrocyte cell adhesion protein using gene expression profiling. J Neurosci 26(39):9881–9891

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgment

M.F.S. is supported by grant from the National MS Society (NMSS).

Author information

Authors and Affiliations

  1. Department of Neurology, Mayo Clinic, Rochester, MN, USA

    Mahboobeh Fereidan-Esfahani, Tarek Nayfeh, Arthur Warrington, Charles L. Howe & Moses Rodriguez

Authors
  1. Mahboobeh Fereidan-Esfahani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tarek Nayfeh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arthur Warrington
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Charles L. Howe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Moses Rodriguez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Arthur Warrington or Charles L. Howe .

Editor information

Editors and Affiliations

  1. Department of Pathology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel

    Michael Steinitz

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Fereidan-Esfahani, M., Nayfeh, T., Warrington, A., Howe, C.L., Rodriguez, M. (2019). IgM Natural Autoantibodies in Physiology and the Treatment of Disease. In: Steinitz, M. (eds) Human Monoclonal Antibodies. Methods in Molecular Biology, vol 1904. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-8958-4_3

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-8958-4_3

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-8957-7

  • Online ISBN: 978-1-4939-8958-4

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation