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Antibodies as defensive enzymes

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Abstract

Antibodies (Abs) and enzymes are structural and functional relatives. Abs with promiscuous peptidase activity are ubiquitous in healthy humans, evidently derived from germline variable domain immunoglobulin genes encoding the serine protease-like nucleophilic function. Exogenous and endogenous electrophilic antigens can bind the nucleophilic sites covalently, and recent evidence suggests that immunization with such antigens can induce proteolytic antibodies. Previously, Ab catalytic activities have been linked to pathogenic autoimmune reactions, but recent studies indicate that proteolytic Abs may also serve beneficial functions. An example is the rapid and selective cleavage of the HIV-1 coat protein gp120 by IgMs found in uninfected humans. The selectivity of this reaction appears to derive from recognition of gp120 as a superantigen. A second example is the cleavage of amyloid β-peptide by IgM and IgG from aged humans, a phenomenon that may represent a specific proteolytic response to a neurotoxic endogenous peptide implicated in the pathogenesis of Alzheimer’s disease.

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References

  1. Abderhalden E (1912) Die Schutzfermente. Springer, Berlin

  2. Ames PR, Alves J, Murat I, et al (1999) Oxidative stress in systemic lupus erythematosus and allied conditions with vascular involvement. Rheumatology 38:529

    Google Scholar 

  3. Bangale Y, Cavill D, Gordon T, et al (2002) Vasoactive intestinal peptide binding autoantibodies in autoimmune humans and mice. Peptides 23:2251

    Google Scholar 

  4. Bangale Y, Karle S, Zhou Y-X, et al (2003) VIPase autoantibodies in Fas-defective mice and patients with autoimmune disease. FASEB J 17:628

    Google Scholar 

  5. Berberian L, Goodglick L, Kipps TJ, et al (1993) Immunoglobulin VH3 gene products: natural ligands for HIV gp120. Science 261:1588

    Google Scholar 

  6. Bernoud-Hubac N, Roberts J (2002) Identification of oxidized derivatives of neuroketals. Biochemistry 41:11466

    Google Scholar 

  7. Biro A, Sarmay G, Rozsnyay Z, et al (1992) A trypsin-like serine protease activity on activated human B cells and various B cell lines. Eur J Immunol 22:2547

    Google Scholar 

  8. Brorson JR, Bindokas VP, Iwama T, et al (1995) The Ca2+ influx induced by beta-amyloid peptide 25–35 in cultured hippocampal neurons results from network excitation. J Neurobiol 26:325

    Google Scholar 

  9. Casali P, Notkins AL (1989) CD5+ B lymphocytes, polyreactive antibodies and the human B-cell repertoire. Immunol Today 10:364

    Google Scholar 

  10. Chavin SI, Franklin EC (1969) Studies on antigen-binding activity of macroglobulin antibody subunits and their enzymatic fragments. J Biol Chem 244:1345

    Google Scholar 

  11. Chen TY, Huang CC, Tsao CJ (1993) Hemostatic molecular markers in nephrotic syndrome. Am J Hematol 44:276

    Google Scholar 

  12. Crabb JW, O’Neil J, Miyagi M, et al (2002) Hydroxynonenal inactivates cathepsin B by forming Michael adducts with active site residues. Protein Sci 11:831

    Google Scholar 

  13. Deichmann U, Muller-Hill B (1998) The fraud of Abderhalden’s enzymes. Nature 393:109

    Google Scholar 

  14. DeMattos RB, Bales KR, Cummins DJ, et al (2001) Peripheral anti-A beta antibody alters CNS and plasma A beta clearance and decreases brain A beta burden in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 98:885

    Google Scholar 

  15. Dodel RC, Du Y, Depboylu C, et al (2004) Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer’s disease. J Neurol Neurosurg Psychiatry 75:1472

    Google Scholar 

  16. Erhan S, Greller LD (1974) Do immunoglobulins have proteolytic activity? Nature 251:353

  17. Fersht A (1985) Enzyme structure and mechanism. Freeman, New York

  18. Gao Q-S, Sun M, Rees A, et al (1995) Site-directed mutagenesis of proteolytic antibody light chain. J Mol Biol 253:658

    Google Scholar 

  19. Gaskin F, Finley J, Fang Q, et al (1993) Human antibodies reactive with beta-amyloid protein in Alzheimer’s disease. J Exp Med 177:1181

    Google Scholar 

  20. Gololobov G, Sun M, Paul S (1999) Innate antibody catalysis. Mol Immunol 36:1215

    Google Scholar 

  21. Goodglick L, Zevit N, Neshat MS, et al (1995) Mapping the Ig superantigen-binding site of HIV-1 gp120. J Immunol 155:5151

    Google Scholar 

  22. Grabar P (1975) Hypothesis. Auto-antibodies and immunological theories: an analytical review. Clin Immunol Immunopathol 4:453

    Google Scholar 

  23. Hasegawa M, Fujimoto M, Poe JC, et al (2001) A CD19-dependent signaling pathway regulates autoimmunity in lyn-deficient mice. J Immunol 167:2469

    Google Scholar 

  24. Hasegawa M, Fujimoto M, Poe JC, et al (2001) CD19 can regulate B lymphocyte signal transduction independent of complement activation. J Immunol 167:3190

    Google Scholar 

  25. Hyman BT, Smith C, Buldyrev I, et al (2001) Autoantibodies to amyloid-beta and Alzheimer’s disease. Ann Neurol 49:808

    Google Scholar 

  26. Inoue M, Hiratake J, Suzuki H, et al (2000) Identification of catalytic nucleophile of Escherichia coli gamma-glutamyltranspeptidase by gamma-monofluorophosphono derivative of glutamic acid: N-terminal thr-391 in small subunit is the nucleophile. Biochemistry 39:7764

    Google Scholar 

  27. Jeannin P, Lecoanet-Henchoz S, Delneste Y, et al (1998) Alpha-1 antitrypsin up-regulates human B cell differentiation selectively into IgE- and IgG4- secreting cells. Eur J Immunol 28:1815

    Google Scholar 

  28. Jia Y, Kappock TJ, Frick T, et al (2000) Lipases provide a new mechanistic model for polyhydroxybutyrate (PHB) synthases: characterization of the functional residues in Chromatium vinosum PHB synthase. Biochemistry 39:3927

    Google Scholar 

  29. Kalaga R, Li L, O’Dell J, et al (1995) Unexpected presence of polyreactive catalytic antibodies in IgG from unimmunized donors and decreased levels in rheumatoid arthritis. J Immunol 155:2695

    Google Scholar 

  30. Karray S, Zouali M (1997) Identification of the B cell superantigen-binding site of HIV-1 gp120. Proc Natl Acad Sci USA 94:1356

    Google Scholar 

  31. Kaul M, Lipton SA (1999) Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis. Proc Natl Acad Sci USA 96:8212

    Google Scholar 

  32. Kohen F, Kim JB, Linder HR, et al (1980) Monoclonal immunoglobulin G augments hydrolysis of an ester of the homologous hapten: An esterase-like activity of the antibody-containing site. FEBS Lett 111:427

    Google Scholar 

  33. Ku GS, Quigley JP, Sultzer BM (1981) Time-dependent inhibition of tuberculin-induced lymphocyte DNA synthesis by a serine protease inhibitor. J Immunol 126:2209

    Google Scholar 

  34. Ku GS, Quigley JP, Sultzer BM (1983) The inhibition of the mitogenic stimulation of B lymphocytes by a serine protease inhibitor: commitment to proliferation correlates with an enhanced expression of a cell-associated arginine-specific serine enzyme. J Immunol 131:2494

    Google Scholar 

  35. Kwong PD, Wyatt R, Robinson J, et al (1998) Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 393:648

    Google Scholar 

  36. Lacroix-Desmazes S, Moreau A, Sooryanarayana, et al (1999) Catalytic activity of antibodies against factor VIII in patients with hemophilia A. Nat Med 5:1044

  37. Lefevre S, Debat H, Thomas D, et al (2001) A suicide-substrate mechanism for hydrolysis of beta-lactams by an anti-idiotypic catalytic antibody. FEBS Lett 489:25

    Google Scholar 

  38. Li L, Kaveri S, Tyutyulkova S, et al (1995) Catalytic activity of anti-thyroglobulin antibodies. J Immunol 154:3328

    Google Scholar 

  39. Liu R, McAllister C, Lyubchenko Y, et al (2004) Proteolytic antibody light chains alter beta-amyloid aggregation and prevent cytotoxicity. Biochemistry 43:9999

    Google Scholar 

  40. Lucey MD, Newkirk MM, Neville C, et al (2000) Association between IgM response to IgG damaged by glyoxidation and disease activity in rheumatoid arthritis. J Rheumatol 27:319

    Google Scholar 

  41. Lue LF, Walker DG (2002) Modeling Alzheimer’s disease immune therapy mechanisms: interactions of human postmortem microglia with antibody-opsonized amyloid beta peptide. J Neurosci Res 70:599

    Google Scholar 

  42. Matsuura K, Sinohara H (1996) Catalytic cleavage of vasopressin by human Bence Jones proteins at the arginylglycinamide bond. Biol Chem 377:587

    Google Scholar 

  43. Matsuura K, Yamamoto K, Sinohara H (1994) Amidase activity of human Bence Jones proteins. Biochem Biophys Res Commun 204:57

    Google Scholar 

  44. Mitsuda Y, Hifumi E, Tsuruhata K, et al (2004) Catalytic antibody light chain capable of cleaving a chemokine receptor CCR-5 peptide with a high reaction rate constant. Biotechnol Bioeng 86:217

    Google Scholar 

  45. Mizuguchi J, Utsunomiya N, Nakanishi M, et al (1989) Differential sensitivity of anti-IgM-induced and NaF-induced inositol phospholipid metabolism to serine protease inhibitors in BAL17 B lymphoma cells. Biochem J 263:641

    Google Scholar 

  46. Morelock MM, Rothlein R, Bright SM, et al (1994) Isotype choice for chimeric antibodies affects binding properties. J Biol Chem 269:13048

    Google Scholar 

  47. Nath A, Hall E, Tuzova M, et al (2003) Autoantibodies to amyloid beta-peptide (Abeta) are increased in Alzheimer’s disease patients and Abeta antibodies can enhance Abeta neurotoxicity: implications for disease pathogenesis and vaccine development. Neuromolecular Med 3:29

    Google Scholar 

  48. Nevinsky GA, Buneva VN (2003) Catalytic antibodies in healthy humans and patients with autoimmune and viral diseases. J Cell Mol Med 7:265

    Google Scholar 

  49. Nevinsky GA, Kit YYa, Semenov DV, et al (1998) Secretory immunoglobulin A from human milk catalyzes milk protein phosphorylation. Appl Biochem Biotechnol 75:77

  50. Nishiyama Y, Bhatia G, Bangale Y, et al (2004) Towards selective covalent inactivation of pathogenic antibodies: a phosphonate diester analog of vasoactive intestinal peptide that inactivates catalytic autoantibodies. J Biol Chem 279:7877

    Google Scholar 

  51. O’Keefe TL, Williams GT, Batista FD, et al (1999) Deficiency in CD22, a B cell-specific inhibitory receptor, is sufficient to predispose to development of high affinity autoantibodies. J Exp Med 189:1307

    Google Scholar 

  52. Oleksyszyn J, Powers JC (1994) Amino acid and peptide phosphonate derivatives as specific inhibitors of serine peptidases. Methods Enzymol 244:423

    Google Scholar 

  53. Olshevsky U, Helseth E, Furman C, et al (1990) Identification of individual human immunodeficiency virus type 1 gp120 amino acids important for CD4 receptor binding. J Virol 64:5701

    Google Scholar 

  54. Paul S (1996) Natural catalytic antibodies. Mol Biotechnol 5:197

    Google Scholar 

  55. Paul S, Karle S, Planque S, et al (2004) Naturally occurring proteolytic antibodies: selective IgM-catalyzed hydrolysis of HIV gp120. J Biol Chem 279:39611

    Google Scholar 

  56. Paul S, Li L, Kalaga R, et al (1995) Natural catalytic antibodies: peptide hydrolyzing activities of Bence Jones proteins and VL fragment. J Biol Chem 270:15257

    Google Scholar 

  57. Paul S, Planque S, Zhou Y-X, et al (2003) Specific HIV gp120 cleaving antibodies induced by covalently reactive analog of gp120. J Biol Chem 278:20429

    Google Scholar 

  58. Paul S, Tramontano A, Gololobov G, et al (2001) Phosphonate ester probes for proteolytic antibodies. J Biol Chem 276:28314

    Google Scholar 

  59. Paul S, Volle DJ, Beach CM, et al (1989) Catalytic hydrolysis of vasoactive intestinal peptide by human autoantibody. Science 244:1158

    Google Scholar 

  60. Planque S, Bangale Y, Song X-T, et al (2004) Ontogeny of proteolytic immunity: IgM serine proteases. J Biol Chem 279:14024

    Google Scholar 

  61. Planque S, Taguchi H, Burr G, et al (2003) Broadly distributed chemical reactivity of natural antibodies expressed in coordination with specific antigen binding activity. J Biol Chem 278:20436

    Google Scholar 

  62. Pollard S, Meier W, Chow P, et al (1991) CD4-binding regions of human immunodeficiency virus envelope glycoprotein gp120 defined by proteolytic digestion. Proc Natl Acad Sci USA 88:11320

    Google Scholar 

  63. Rangan SK, Liu R, Brune D, et al (2003) Degradation of β-amyloid by proteolytic antibody light chains. Biochemistry 42:14328

    Google Scholar 

  64. Rao G, Philipp M (1991) Irreversible inhibition of a monoclonal antibody by a nitrophenyl ester. J Protein Chem 10:117

    Google Scholar 

  65. Raso V, Stollar BD (1975) The antibody-enzyme analogy. Comparison of enzymes and antibodies specific for phosphopyridoxyltyrosine. Biochemistry 14:591

    Google Scholar 

  66. Richieri SP, Bartholomew R, Aloia RC, et al (1998) Characterization of highly purified, inactivated HIV-1 particles isolated by anion exchange chromatography. Vaccine 16:119

    Google Scholar 

  67. Saveliev AN, Ivanen DR, Kulminskaya AA, et al (2003) Amylolytic activity of IgM and IgG antibodies from patients with multiple sclerosis. Immunol Lett 86:291

    Google Scholar 

  68. Shuster AM, Gololobov GV, Kvashuk OA, et al (1992) DNA hydrolyzing autoantibodies. Science 256:665

    Google Scholar 

  69. Sigurdsson EM, Knudsen E, Asuni A, et al (2004) An attenuated immune response is sufficient to enhance cognition in an Alzheimer’s disease mouse model immunized with amyloid-beta derivatives. J Neurosci 24:6277

    Google Scholar 

  70. Siliciano RF (1996) The role of CD4 in HIV envelope-mediated pathogenesis. Curr Top Microbiol Immunol 205:159

    Google Scholar 

  71. Sun M, Gao QS, Kirnarskiy L, et al (1997) Cleavage specificity of a proteolytic antibody light chain and effects of the heavy chain variable domain. J Mol Biol 271:374

    Google Scholar 

  72. Taguchi H, Burr G, Karle S, et al (2002) A mechanism-based probe for gp120-hydrolyzing antibodies. Bioorg Med Chem Lett 12:3167

    Google Scholar 

  73. Taguchi H, Planque S, Nishiyama Y, et al (2004) Catalytic hydrolysis of amyloid β-peptide (Aβ) by human antibodies. 9th International Conference on Alzheimer’s Disease and Related Disorders, July 2004, Philadelphia, PA. Abstract P4-331

  74. Taguchi H, Planque S, Nishiyama Y, et al (2004) IgM defense enzymes directed to amyloid β peptide. 9th International Conference on Alzheimer’s Disease and Related Disorders. July 2004, Philadelphia, PA. Abstract P3-418

  75. Townsley-Fuchs J, Kam L, Fairhurst R, et al (1996) Human immunodeficiency virus-1 (HIV-1) gp120 superantigen-binding serum antibodies. A host factor in homosexual HIV-1 transmission. J Clin Invest 98:1794

    Google Scholar 

  76. Tramontano A, Gololobov G, Paul S (2000) Proteolytic antibodies: origins, selection and induction. In: Paul S (ed) Chemical Immunology: catalytic antibodies, vol 77. Karger, Basel, pp 1–17

  77. Tramontano A, Janda KD, Lerner RA (1986) Catalytic antibodies. Science 234:1566

  78. Tyutyulkova S, Gao Q-S, Thompson A, et al (1996) Efficient vasoactive intestinal polypeptide hydrolyzing antibody light chains selected from an asthma patient by phage display. Biochim Biophys Acta 1316:217

    Google Scholar 

  79. Van Erp R, Gribnau TC, Sommeren AP van, et al (1991) Affinity of monoclonal antibodies. Interpretation of the positive cooperative nature of anti-hCG/hCG interactions. J Immunol Methods 140:235

    Google Scholar 

  80. Vocadlo DJ, Davies GJ, Laine R, et al (2001) Catalysis by hen egg-white lysozyme proceeds via a covalent intermediate. Nature 412:835

    Google Scholar 

  81. Wagner J, Lerner RA, Barbas CF 3rd (1995) Efficient aldolase catalytic antibodies that use the enamine mechanism of natural enzymes. Science 270:1797

    Google Scholar 

  82. Walter J, Bode W (1983) The X-ray crystal structure analysis of the refined complex formed by bovine trypsin and p-amidinophenylpyruvate at 1.4 A resolution. Hoppe-Seyler’s Z Physiol Chem 364:S949

  83. Watson JN, Dookhun V, Borgford TJ, et al (2003) Mutagenesis of the conserved active-site tyrosine changes a retaining sialidase into an inverting sialidase. Biochemistry 42:12682

    Google Scholar 

  84. Weksler ME, Relkin N, Turkenich R, et al (2002) Patients with Alzheimer disease have lower levels of serum anti-amyloid peptide antibodies than healthy elderly individuals. Exp Gerontol 37:943

    Google Scholar 

  85. Wentworth P, Jones LH, Wentworth AD, et al (2001) Antibody catalysis of the oxidation of water. Science 293:1806

    Google Scholar 

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Acknowledgements

Supported by NIH grants AI31268 and AI058865, and grants from Dana Foundation and Alzheimer’s Association. We thank Laura Nixon for administering our research.

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Authors and Affiliations

  1. Chemical Immunology and Therapeutics Research Center, Department of Pathology and Laboratory Medicine, University of Texas-Houston Medical School, MSB 2.250, 6431 Fannin, Houston, TX 77030, USA

    Sudhir Paul, Yasuhiro Nishiyama, Stephanie Planque, Sangeeta Karle & Hiroaki Taguchi

  2. Rickettsial Disease Lab, California Department of Health Services, Richmond, CA 94804, USA

    Carl Hanson

  3. Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA

    Marc E. Weksler

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  1. Sudhir Paul
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  2. Yasuhiro Nishiyama
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Correspondence to Sudhir Paul.

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Paul, S., Nishiyama, Y., Planque, S. et al. Antibodies as defensive enzymes. Springer Semin Immun 26, 485–503 (2005). https://doi.org/10.1007/s00281-004-0191-1

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