Covalent Binding Antibodies Suppress Advanced glycation: On the Innate Tier of Adaptive Immunity

Cover Page

Cite item

Full Text

Abstract

Non-enzymatic protein glycation is a source of metabolic stress that contributes to cytotoxicity and tissue damage. Hyperglycemia has been linked to elevation of advanced glycation endproducts, which mediate much of the vascular pathology leading to diabetic complications. Enhanced glycation of immunoglobulins and their accelerated vascular clearance is proposed as a natural mechanism to intercept alternative advanced glycation endproducts, thereby mitigating microvascular disease. We reported that antibodies against the glycoprotein KLH have elevated reactivity for glycopeptides from diabetic serum. These reactions are mediated by covalent binding between antibody light chains and carbonyl groups of glycated peptides. Diabetic animals that were immunized to induce reactive antibodies had attenuated diabetic nephropathy, which correlated with reduced levels of circulating and kidney-bound glycation products. Molecular analysis of antibody glycation revealed the preferential modification of light chains bearing germline-encoded lambda V regions. We previously noted that antibody fragments carrying V regions in the germline configuration are selected from a human Fv library by covalent binding to a reactive organophosphorus ester. These Fv fragments were specifically modified at light chain V region residues, which map to the combining site at the interface between light and heavy chains. These findings suggest that covalent binding is an innate property of antibodies, which may be encoded in the genome for specific physiological purposes. This hypothesis is discussed in context with current knowledge of the natural antibodies that recognize altered self molecules and the catalytic autoantibodies found in autoimmune disease.

Full Text

The generation of an enormous diversity of antibodies in response to the multitude of possible antigens is a signature of instructive or adaptive immunity. The structural basis for adaptive immunity is expressed in the variability of the antigen binding sites displayed on antibodies and B cell receptors. Thus, antibodies are conventionally associated with the genetic recombination and accumulated mutations in their variable (V) regions that incrementally improve the complementarity between the antibody combining site and groups on the antigen. In contrast to affinity that matures gradually over time through multiple weak interactions, binding through strong forces such as a covalent bond could enable a more rapid and efficient way to capture certain antigens. Is there any case where antibodies use this form of binding and what purpose could such a binding mechanism serveAntibodies that bind ligands covalently have been sought in approaches to generate enzyme-like catalytic antibodies (1). Covalent binding is used by enzymes to stabilize reactive intermediates in catalysis of many types of reactions. Reactive immunization was conceived as a strategy to elicit antibodies that bind their ligands through a covalent complex (2). Such antibody complexes might mimic enzyme intermediates to catalyze the transformation of the bound substrate. The premise assumes that this form of binding could be evoked through the conventional affinity maturation process for antibody induction. Implicitly, such antibodies would have experimentally conferred, and therefore artificial, activity. In the prototypical example, immunization against synthetic antigens containing a reactive dicarbonyl group provided antibodies that bind through Schiff base - enamine adducts. The covalently reactive clones were shown to possess remarkable aldolase activity (2). As predicted, the covalent binding function arises from the somatically mutated V region genes, positioning one or more nucleophilic lysine residues in the combining site (3).
×

About the authors

T Shcheglova

Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences

Lavrentiev Av. 10, Novosibirsk 630090, Russia

S P Makker

Department of Pediatrics, University of California, Davis – School of Medicine Davis

California USA

A Tramontano

Department of Pediatrics, University of California, Davis – School of Medicine Davis

Email: tramontano@ucdavis.edu
California USA

References

  1. Lerner R.A., Benkovic S.J., Schultz P.G. // At the crossroads of chemistry and immunology: catalytic antibodies. Science. 1991. 252. 659–667.
  2. Wagner J., Lerner R.A., Barbas C.F., 3rd. Efficient aldolase catalytic antibodies that use the enamine mechanism of natural enzymes.// Science. 1995. 270. 1797–1800.
  3. Zhu X., Tanaka F., Hu Y., Heine A., Fuller R., Zhong G., Olson A.J., Lerner R.A., Barbas C.F., 3rd, Wilson I.A.// The origin of enantioselectivity in aldolase antibodies: crystal structure, site-directed mutagenesis, and computational analysis. J Mol Biol. 2004. 343. 1269–1280.
  4. Chou M.Y., Fogelstrand L., Hartvigsen K., Hansen L.F., Woelkers D., Shaw P.X., Choi J., Perkmann T., Backhed F., Miller Y.I., et al.// Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans. J Clin Invest. 2009. 119. 1335–1349.
  5. Kearney J.F.// Innate-like B cells. Springer Semin Immunopathol. 2005. 26. 377–383.
  6. Lutz H.U., Binder C.J., Kaveri S.// Naturally occurring auto-antibodies in homeostasis and disease. Trends Immunol. 2009. 30.43–51.
  7. Briles D.E., Forman C., Hudak S., Claflin J.L.// Anti-phosphorylcholine antibodies of the T15 idiotype are optimally protective against Streptococcus pneumoniae. J Exp Med. 1982. 156.1177–1185.
  8. Vlassara H., Palace M.R.// Diabetes and advanced glycation endproducts. J Intern Med. 2002. 251.87–101.
  9. Brownlee M.// Glycation products and the pathogenesis of diabetic complications. Diabetes Care. 1992. 15. 1835–1843.
  10. Cerami A., Vlassara H., Brownlee M.// Role of advanced glycosylation products in complications of diabetes. Diabetes Care. 1988. 11 Suppl 1. 73–79.
  11. Saito A., Nagai R., Tanuma A., Hama H., Cho K., Takeda T., Yoshida Y., Toda T., Shimizu F., Horiuchi S., et al.// Role of megalin in endocytosis of advanced glycation end products: implications for a novel protein binding to both megalin and advanced glycation end products. J Am Soc Nephrol. 2003. 14. 1123–1131.
  12. Zhu W., Sano H., Nagai R., Fukuhara K., Miyazaki A., Horiuchi S.// The role of galectin-3 in endocytosis of advanced glycation end products and modified low density lipoproteins. Biochem Biophys Res Commun. 2001. 280. 1183–1188.
  13. Vlassara H.// The AGE-receptor in the pathogenesis of diabetic complications. Diabetes Metab Res Rev. 2001. 17. 436–443.
  14. Pricci F., Leto G., Amadio L., Iacobini C., Romeo G., Cordone S., Gradini R., Barsotti P., Liu F.T., Di Mario U., et al.// Role of galectin-3 as a receptor for advanced glycosylation end products. Kidney Int Suppl. 2000. 77. S31–39.
  15. Smedsrod B., Melkko J., Araki N., Sano H., Horiuchi S.// Advanced glycation end products are eliminated by scavenger-receptor-mediated endocytosis in hepatic sinusoidal Kupffer and endothelial cells. Biochem J. 1997. 322 ( Pt 2). 567–573.
  16. Vasan S., Foiles P.G., Founds H.W.// Therapeutic potential of AGE inhibitors and breakers of AGE protein cross-links. Expert Opin Investig Drugs. 2001. 10. 1977–1987.
  17. Bucciarelli L.G., Wendt T., Qu W., Lu Y., Lalla E., Rong L.L., Goova M.T., Moser B., Kislinger T., Lee D.C., et al.// RAGE blockade stabilizes established atherosclerosis in diabetic apolipoprotein E-null mice. Circulation. 202. 106. 2827–2835.
  18. Liggins J., Furth A.J.// Role of protein-bound carbonyl groups in the formation of advanced glycation endproducts. Biochim Biophys. 1997. Acta. 1361. 123–130.
  19. Soulis-Liparota T., Cooper M., Papazoglou D., Clarke B., Jerums G.// Retardation by aminoguanidine of development of albuminuria, mesangial expansion, and tissue fluorescence in streptozocin-induced diabetic rat. Diabetes. 1991. 40. 1328–1334.
  20. Cohen M.P., Sharma K., Jin Y., Hud E., Wu V.Y., Tomaszewski J., Ziyadeh F.N.// Prevention of diabetic nephropathy in db/db mice with glycated albumin antagonists. A novel treatment strategy. J Clin Invest. 1995. 95. 2338–2345.
  21. Cohen M.P., Hud E., Wu V.Y.// Amelioration of diabetic nephropathy by treatment with monoclonal antibodies against glycated albumin. Kidney Int. 1994. 45. 1673–1679.
  22. Lapolla A., Tonani R., Fedele D., Garbeglio M., Senesi A., Seraglia R., Favretto D., Traldi, P.// Non-enzymatic glycation of IgG: an in vivo study. Horm Metab Res. 2002.34. 260–264.
  23. Kennedy D.M., Skillen A.W., Self, C.H.// Glycation of monoclonal antibodies impairs their ability to bind antigen. Clin Exp Immunol. 1994. 98. 245–251.
  24. Danze P.M., Tarjoman A., Rousseaux J., Fossati P., Dautrevaux M.// Evidence for an increased glycation of IgG in diabetic patients. Clin Chim Acta. 1987. 166. 143–153.
  25. Gugliucci A., Menini T.// Circulating advanced glycation peptides in streptozotocininduced diabetic rats: evidence for preferential modification of IgG light chains. Life Sci. 1998. 62. 2141–2150.
  26. Mitsuhashi T., Li Y.M., Fishbane S., Vlassara H.// Depletion of reactive advanced glycation endproducts from diabetic uremic sera using a lysozyme-linked matrix. J Clin Invest. 1997. 100. 847–854.
  27. Armentano F., Knight T., Makker S., Tramontano A.// Induction of covalent binding antibodies. Immunol Lett. 2006. 103. 51–57.
  28. Shcheglova T., Makker S., Tramontano A.// Reactive immunization suppresses advanced glycation and mitigates diabetic nephropathy. J Am Soc Nephrol. 2009. 20. 1012–1019.
  29. Kennedy D.M., Skillen A.W., Self C.H.// Glycation increases the vascular clearance rate of IgG in mice. Clin Exp Immunol. 1993. 94. 447–451.
  30. Kowluru A., Kowluru R.A.// Preferential excretion of glycated albumin in C57BL-KsJ mice: effects of diabetes. Experientia. 1992. 48. 486–488.
  31. Groop L., Makipernaa A., Stenman S., DeFronzo R.A., Teppo A.M.// Urinary excretion of κ light chains in patients with diabetes mellitus. Kidney Int. 1990. 37. 1120–1125.
  32. Hutchison C.A., Harding S., Hewins P., Mead G.P., Townsend J., Bradwell A.R., Cockwell P.// Quantitative assessment of serum and urinary polyclonal free light chains in patients with chronic kidney disease. Clin J Am Soc Nephrol. 2008. 3. 1684–1690.
  33. May R.J., Beenhouwer D.O., Scharff M.D.// Antibodies to keyhole limpet hemocyanin cross-react with an epitope on the polysaccharide capsule of Cryptococcus neoformans and other carbohydrates: implications for vaccine development. J Immunol. 2003. 171. 4905–4912.
  34. Harris J.R., Markl J.// Keyhole limpet hemocyanin (KLH): a biomedical review. Micron. 1999. 30. 597–623.
  35. Reshetnyak A.V., Armentano M.F., Ponomarenko N.A., Vizzuso D., Durova O.M., Ziganshin R., Serebryakova M., Govorun V., Gololobov G., Morse H.C., 3rd, et al. // Routes to covalent catalysis by reactive selection for nascent protein nucleophiles. J Am Chem Soc. 2007. 129. 16175–16182.
  36. Griffiths A.D., Williams S.C., Hartley O., Tomlinson I.M., Waterhouse P., Crosby W.L., Kontermann R.E., Jones P.T., Low N.M., Allison T.J., et al.// Isolation of high affinity human antibodies directly from large synthetic repertoires. Embo J. 1994. 13. 3245–3260.
  37. Shaw P.X., Goodyear C.S., Chang M.K., Witztum J.L., Silverman G.J.// The autoreactivity of anti-phosphorylcholine antibodies for atherosclerosis-associated neo-antigens and apoptotic cells. J Immunol. 2003. 170. 6151–6157.
  38. Quartier P., Potter P.K., Ehrenstein M.R., Walport M.J., Botto M.// Predominant role of IgM-dependent activation of the classical pathway in the clearance of dying cells by murine bone marrow-derived macrophages in vitro. Eur J Immunol. 2005. 35. 252–260.
  39. Pasare C., Medzhitov R.// Toll-like receptors: linking innate and adaptive immunity. Adv Exp Med Biol. 2005. 560. 11–18.
  40. Binder C.J., Shaw P.X., Chang M.K., Boullier A., Hartvigsen K., Horkko S., Miller Y.I., Woelkers D.A., Corr M., Witztum J.L.// The role of natural antibodies in atherogenesis. J Lipid Res. 2005. 46. 1353–1363.
  41. Toyoda K., Nagae R., Akagawa M., Ishino K., Shibata T., Ito S., Shibata N., Yamamoto T., Kobayashi M., Takasaki Y., et al.// Protein-bound 4-hydroxy-2-nonenal: an endogenous triggering antigen of antI-DNA response. J Biol Chem. 2007. 282. 25769–25778.
  42. Younis N., Sharma R., Soran H., Charlton-Menys V., Elseweidy M., Durrington P.N. // Glycation as an atherogenic modification of LDL. Curr Opin Lipidol. 2008. 19. 378–384.
  43. Akagawa M., Ito S., Toyoda K., Ishii Y., Tatsuda E., Shibata T., Yamaguchi S., Kawai Y., Ishino K., Kishi Y., et al.// Bispecific abs against modified protein and DNA with oxidized lipids. Proc Natl Acad Sci U S A. 2006. 103. 6160–6165.
  44. Horiuchi S., Murakami M., Takata K., Morino Y.// Scavenger receptor for aldehydemodified proteins. J. Biol. Chem. 1986. 261. 4962–4966.
  45. Zhou Z.H., Tzioufas A.G., Notkins A.L.// Properties and function of polyreactive antibodies and polyreactive antigen-binding B cells. J Autoimmun. 2007. 29. 219–228.
  46. Kawarada Y., Miura N., Sugiyama T.// Antibody against single-stranded DNA useful for detecting apoptotic cells recognizes hexadeoxynucleotides with various base sequences. J Biochem. 1998. 123. 492–498.
  47. Frankfurt O.S., Robb J.A., Sugarbaker E.V., Villa L.// Monoclonal antibody to singlestranded DNA is a specific and sensitive cellular marker of apoptosis. Exp Cell Res. 1996. 226. 387–397.
  48. Shuster A.M., Gololobov G.V., Kvashuk O.A., Bogomolova A.E., Smirnov I.V., Gabibov A.G.// DNA hydrolyzing autoantibodies. Science. 1992. 256. 665–667.
  49. Kim Y.R., Kim J.S., Lee S.H., Lee W.R., Sohn J.N., Chung Y.C., Shim H.K., Lee,S.C., Kwon M.H., Kim Y.S.// Heavy and light chain variable single domains of an anti-DNA binding antibody hydrolyze both double- and single-stranded DNAs without sequence specificity. J Biol Chem. 2006. 281. 15287–15295.
  50. Gololobov G.V., Chernova E.A., Schourov D.V., Smirnov I.V., Kudelina I.A., Gabibov A.G.// Cleavage of supercoiled plasmid DNA by autoantibody Fab fragment: application of the flow linear dichroism technique. Proc Natl Acad Sci U S A. 1995. 92. 254–257.
  51. Gololobov G.V., Rumbley C.A., Rumbley J.N., Schourov D.V., Makarevich O.I., Gabibov A.G., Voss E.W., Jr., Rodkey L.S.// DNA hydrolysis by monoclonal anti-ssDNA autoantibody BV 04-01: origins of catalytic activity. Mol Immunol. 1997. 34. 1083–1093.
  52. Wellmann U., Letz M., Herrmann M., Angermuller S., Kalden J.R., Winkler T.H. //The evolution of human anti-double-stranded DNA autoantibodies. Proc Natl Acad Sci U S A. 2005. 102. 9258–9263.
  53. Demaison C., Chastagner P., Theze J., Zouali M.// Somatic diversification in the heavy chain variable region genes expressed by human autoantibodies bearing a lupus-associated nephritogenic anti-DNA idiotype. Proc Natl Acad Sci U S A. 1994. 91. 514–518.
  54. Harada T., Suzuki N., Mizushima Y., Sakane T.// Usage of a novel class of germ-line Ig variable region gene for cationic anti-DNA autoantibodies in human lupus nephritis and its role for the development of the disease. J Immunol. 1994. 153. 4806–4815.
  55. O’Keefe T.L., Datta S.K., Imanishi-Kari T.// Cationic residues in pathogenic anti-DNA autoantibodies arise by mutations of a germ-line gene that belongs to a large VH gene subfamily. Eur J Immunol. 1992. 22. 619–624.
  56. Tanner J.J., Komissarov A.A., Deutscher S.L.// Crystal structure of an antigen-binding fragment bound to single-stranded DNA. J Mol Biol. 2001. 314. 807–822.
  57. Herron J.N., He X.M., Ballard D.W., Blier P.R., Pace P.E., Bothwell A.L., Voss E.W., Jr., Edmundson A.B.// An autoantibody to single-stranded DNA: comparison of the threedimensional structures of the unliganded Fab and a deoxynucleotide-Fab complex. Proteins. 1991. 11. 159–175.
  58. Giusti A.M., Chien N.C., Zack D.J., Shin S.U., Scharff M.D.// Somatic diversification of S107 from an antiphosphocholine to an anti-DNA autoantibody is due to a single base change in its heavy chain variable region. Proc Natl Acad Sci U S A. 1987. 84. 2926–2930.
  59. Kieber-Emmons T., von Feldt J.M., Godillot A.P., McCallus D., Srikantan V., Weiner D.B., Williams W.V.// Isolated VH4 heavy chain variable regions bind DNA characterization of a recombinant antibody heavy chain library derived from patient(s) with active SLE. Lupus. 1994. 3. 379–392.
  60. Siminovitch K.A., Chen P.P.// The biologic significance of human natural autoimmune responses: relationship to the germline, early immune and malignant B cell variable gene repertoire. Int Rev Immunol. 1990. 5. 265–277.
  61. Siminovitch K.A., Misener V., Kwong P.C., Song Q.L., Chen P.P.// A natural autoantibody is encoded by germline heavy and lambda light chain variable region genes without somatic mutation. J Clin Invest. 1989. 84. 1675–1678.
  62. Sanz I., Dang H., Takei M., Talal N., Capra J.D.// VH sequence of a human anti-Sm autoantibody. Evidence that autoantibodies can be unmutated copies of germline genes. J Immunol. 1989. 142. 883–887.
  63. Planque S., Bangale Y., Song X.T., Karle S., Taguchi H., Poindexter B., Bick R., Edmundson A., Nishiyama Y., Paul S.// Ontogeny of proteolytic immunity: IgM serine proteases. J Biol Chem. 2004. 279. 14024–14032.
  64. Matejuk A., Beardall M., Xu Y., Tian Q., Phillips D., Alabyev B., Mannoor K., Chen C./Exclusion of natural autoantibody-producing B cells from IgG memory B cell compartment during T cell-dependent immune responses. J Immunol. 2009. 182. 7634–7643.
  65. Brown M., Schumacher M.A., Wiens G.D., Brennan R.G., Rittenberg M.B.// The structural basis of repertoire shift in an immune response to phosphocholine. J Exp Med. 2000. 191. 2101–2112.
  66. Tawfik D.S., Chap R., Green B.S., Sela M., Eshhar Z.// Unexpectedly high occurrence of catalytic antibodies in MRL/lpr and SJL mice immunized with a transition-state analog: is there a linkage to autoimmunity- Proc Natl Acad Sci U S A. 1995. 92. 2145–2149.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2009 Shcheglova T., Makker S.P., Tramontano A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies