Advertisement

Springer Seminars in Immunopathology

, Volume 15, Issue 2–3, pp 155–171 | Cite as

Evolution and pathophysiology of the human natural anti-α-galactosyl IgG (anti-Gal) antibody

  • Uri Galili
Article

Summary

Anti-Gal is a human natural antibody which interacts specifically with the mammalian carbohydrate structure Galα1-3Galβ1-4GlcNAc-R, termed, the α-galactosyl epitope. This antibody constitutes approximately 1% of circulating IgG in human serum and is produced, upon stimulation, by 1% of circulating B lymphocytes. Anti-Gal is also present as IgA antibodies in body secretions such as saliva, milk and colostrum. The antigenic source for the constant production of anti-Gal seems to be the α-galactosyl-like epitopes found on many bacteria of the gastrointestinal flora. Whereas anti-Gal is abundant in humans, apes and Old World monkeys, it is absent from New World monkeys, prosimians and nonprimate mammals. The latter group of species produces, however, large amounts of α-galactosyl epitopes (> 106 epitopes per cell). It is estimated that anti-Gal appeared in ancestral Old World primates less than 28 million years ago, possibly as a result of an evolutionary event which exerted a selective pressure for the suppression of α-galactosyl epitopes expression by inactivation of the gene for the enzyme α1,3 galactosyltransferase. This also resulted in the loss of immune tolerance to the α-galactosyl epitope and the production of anti-Gal. The physiologic role of this antibody is not clear as yet. It may participate in the protection against gastrointestinal bacteria. In addition it seems to contribute to the removal of normal and pathologically senescent red cells by interacting with the few hundred cryptic α-galactosyl epitopes which are exposed de novo in the course of red cell aging, thereby opsonizing these cells for phagocytosis by reticuloendothelial macrophages. The α-galactosyl epitope has been found to be aberrantly expressed on human cells and the interaction of anti-Gal with such epitopes may result in autoimmune disease. Preliminary data suggest such a mechanism in Graves' disease. Anti-Gal has been found to interact with therapeutic recombinant proteins expressing α-galactosyl epitopes, but so far there is no indication that it affects the half-life in the circulation and the biologic activity. Detection of anti-Gal in the seminal fluid and in the cerebrospinal fluid may serve as a simple means for assessment of damage to the blood-genital tract barrier or the blood-brain barrier. Studies on the interaction of anti-Gal with aberrantly expressed α-galactosyl epitopes on human cells may elucidate the possible role of anti-Gal in human autoimmune diseases.

Keywords

World Monkey Seminal Fluid World Primate Human Autoimmune Disease Body Secretion 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Almeida IC, Milani SR, Gorin AJ, Travoassos LR (1991) Complement mediated lysis of Trypanosoma cruzi tryptomastigotes by human anti α-galactosyl antibodies. J Immunol 146:2394Google Scholar
  2. 2.
    Arumugham RG, Hsieh TCY, Tanzer ML, Laine RA (1986) Structures of the asparagine-linked sugar chains of laminin. Biochem Biophys Acta 883:112Google Scholar
  3. 3.
    Avila JL, Rojas M, Galili U (1989) Immunogenic Galα1→Gal carbohydrate epitopes are present on pathogenic American Trypanosoma and Leishmania. J Immunol 142:2828Google Scholar
  4. 4.
    Baenziger JU, Fiete D (1979) Structure of complex oligosaccharides of fetuin. J Biol Chem 254:789Google Scholar
  5. 5.
    Basu M, Basu S (1973) Enzymatic synthesis of a blood group-related pentaglycosyl ceramide by an α-galactosyltransferase from rabbit bone marrow. J Biol Chem 248:12700Google Scholar
  6. 6.
    Betteridge A, Watkins WM (1983) Two α-2-d-galactosyltransferases in rabbit stomach mucosa with different acceptor substrate specificities. Eur J Biochem 132:29Google Scholar
  7. 7.
    Blake DD, Goldstein IJ (1981) An α-D-galactosyltransferase in Ehrlich ascites tumor cells. Biosynthesis and characterization of a trisaccharide [α-d-galactose (1–3)-N-acetyllatosamine]. J Biol Chem 256:5387Google Scholar
  8. 8.
    Blanken WM, Van den Eijnden DH (1985) Biosynthesis of terminal Galα→3Galβ1–4GlcNAc-R oligosaccharide sequence on glycoconjugates: purification and acceptor specificity of a UDP-Gal: N-acetyllactosaminide α1–3 galactosyltransferase. J Biol Chem 260:12927Google Scholar
  9. 9.
    Björndal H, Lindberg B, Nimmich W (1971) Structural studies on Klebsiella O group 1 and 6 lipopolysaccharides. Acta Chem Scand 25:750Google Scholar
  10. 10.
    Castronovo V, Foidart J, LiVecchi M, Foidart JB, Bracke M, Marcell M, Mahieu P (1987) Human anti-alpha-galactosyl IgG reduces the lung colonization by murine MO4 cells. Invasion Metastasis 7:325Google Scholar
  11. 11.
    Castronovo V, Parent B, Steeg PS, Colin C, Foidart JM, Lambotte R, Mahieu P (1989) Human natural anti-Gal antibodies may play a role in the natural anti-tumor defense system. J Natl Cancer Inst 81:212Google Scholar
  12. 12.
    Clark GF, Krivan HC, Wilkins TD, Smith DF (1986) Toxin A from Clostridium difficile binds to rabbit erythrocyte glycolipids with terminal Galα1–3Galβ1–4GlcNAc sequences. Arch Biochem Biophys 257:217Google Scholar
  13. 13.
    Couto AS, Goncalves MF, Colli W, de Lederkremer RM (1990) The N-linked carbohydrate chain of the 85-kilodalton glycoprotein from Trypanosoma cruzi trypomastigotes contains sialyl, fucosyl and galactosyl (α1–3) galactose units. Mol Biochem Parasitol 39:101Google Scholar
  14. 14.
    Cummings RD, Mattox SA (1988) Retinoic acid-induced differentiation of the mouse teratocarcinoma cell line F9 is accompanied by an increase in the activity of UDP-galactose: β-d-galactosyl-α1,3-galactosyltransferase. J Biol Chem 263:511Google Scholar
  15. 15.
    Curval M, Linberg B, Longren J, Rüden U, Nimmich W (1973) Structural studies on the Klebsiella O group 8 lipopolsyaccharides. Acta Chem Scand 27:4019Google Scholar
  16. 16.
    Davin JC, Malaise M, Foidart JM, Mahieu P (1987) Anti-α-galactosyl antibodies and immune complexes in children with Henoch-Schönlein purpura or IgA nephropathy. Kidney Int 31:1132Google Scholar
  17. 17.
    de Waard P, Koorevaar A, Kamerling JP, Vliegenthart JFG (1991) Structure determination by 1H-NMR spectroscopy of (sulfated) sialylated N-linked carbohydrate chains released from porcine thyroglobulin by peptide-N 4-(N-acetyl-β-glucosaminyl) asparagine amidase-F. J Biol Chem 266:4237Google Scholar
  18. 18.
    Dorland L, van Halbeek H, Vliegenthart JFG (1984) TThe identification of terminal α(1–3)- linked galactose in N-acetyllactosamine type of glycopeptides by means of 500-MHz 1H-NMR spectroscopy. Biochem Biophys Res Commun 122:859Google Scholar
  19. 19.
    Eckhardt AE, Goldstein IJ (1983) Isolation and characterization of a family of α-d-galactosyl-containing glycoproteins from Ehrlich ascites tumor cells. Biochemistry 22:5290Google Scholar
  20. 20.
    Edge ASB, Spiro RG (1985) Thyroid cell surface glycoproteins. Nature and disposition of carbohydrate units and evaluation of their blood group I activity. J Biol Chem 260:15332Google Scholar
  21. 21.
    Egge H, Kordowicz M, Peter-Katalinic J, Hanfland P (1985) Immunochemistry of I/i-active oligo- and polyglycosylceramides from rabbit erythrocyte membranes. J Biol Chem 260:4927Google Scholar
  22. 22.
    Elices MJ, Blake DD, Goldstein IJ (1986) Purification and characterization of a UDP-Gal: β-d-Gal(1,4)-d-GlcNAc α(1–3) galactosyltransferase from Ehrlich ascites tumor cells. J Biol Chem 261:6064Google Scholar
  23. 23.
    Endo A, Rothfield L (1969) Studies on phospholipid requiring bacteria enzymes. I. Purification and properties of uridine diphosphate galatose: lipolysaccharide α-3 galactosyltransferase. Biochemsitry 8:3500Google Scholar
  24. 24.
    Etienne-Decerf J, Malaise M, Mahieu P, Winand R (1987) Elevated anti-α-galactosyl antibody titers. A marker of progression in autoimmune thyroid disorders and in endocrine ophthalmopathy. Acta Endocrinol (Copenh) 115:67Google Scholar
  25. 25.
    Eto T, Iichikawa Y, Nishimura K, Ando S, Yamakawa T (1968) Chemistry of lipids of the posthemolytic residue or stroma of erythrocytes. XVI. Occurrence of ceramide pentasaccharide in the membrane of erythrocytes and reticulocytes in rabbit. J Biochem (Tokyo) 64:205Google Scholar
  26. 26.
    Gabrielli A, Leoni P, Danielli G, Herrmann K, Krieg T, Wieslander J (1991) Antibodies against galactosyl α(1–3) galactose in connective tissue disease. Arthritis Rheum 34:375Google Scholar
  27. 27.
    Galili U (1989) Abnormal expression of α-galactosyl epitopes in man: a trigger for autoimmune processes? Lancet II:358Google Scholar
  28. 28.
    Galili U (1992) The natural anti-Gal antibody: evolution and autoimmunity in man. In: Bona CA, Kaushik AK (eds) Molecular immunobiology of self-reactivity, Dekker, New York, p 355Google Scholar
  29. 29.
    Galili U, Swanson K (1991) Gene sequences suggest inactivation of α1–3 galactosyltransferase in catarrhines after the divergence of apes from monkeys. Proc Natl Acad Sci USA 88:7401Google Scholar
  30. 30.
    Galili U, Manny N, Izak G (1980) EA rosette formation: a simple means to increase sensitivity of antiglobulin test in patients with anti red cell antibodies. Br J Haematol 47:227Google Scholar
  31. 31.
    Galili U, Korkesh A, Kahane I, Rachmilewitz EA (1983) Demonstration of a natural anti-galactosyl IgG antibody on thalassemic red blood cells. Blood 61:1258Google Scholar
  32. 32.
    Galili U, Rachmilewitz EA, Peleg A, Flechner I (1984) A unique natural human IgG antibody with anti-α-galactosyl specificity. J Exp Med 160:1519Google Scholar
  33. 33.
    Galili U, Macher BA, Buehler J, Shohet SB (1985) Human natural anti-α-galactosyl IgG. II. The specific recognition of α(1→3)-linked galactose residues. J Exp Med 162:573Google Scholar
  34. 34.
    Galili U, Flechner I, Kniszinski A, Danon D, Rachmilewitz EA (1986) The natural anti-α-galactosyl IgG on human normal senescent red blood cells. Br J Haematol 62:317Google Scholar
  35. 35.
    Galili U, Clark MR, Shohet SB (1986) Excessive binding of the natural anti-α-galactosyl IgG to sickle red cells may contribute to extravascular cell destruction. J Clin Invest 77:27Google Scholar
  36. 36.
    Galili U, Clark MR, Shohet SB, Buehler J, Macher BA (1987) Evolutionary relationship between the anti-Gal antibody and the Galα1→3Gal epitope in primates. Proc Natl Acad Sci USA 84:1369Google Scholar
  37. 37.
    Galili U, Buehler J, Shohet SB, Macher BA (1987) The human natural anti-Gal IgG. III. The subtlety of immune tolerance in man as demonstrated by cross-reactivity between natural anti-Gal and anti-B antibodies. J Exp Med 165:693Google Scholar
  38. 38.
    Galili U, Basbaum C, Shohet SB, Buehler J, Macher BA (1987) Identification of erythrocyte Galα1→3Gal glycosphingolipids with a mouse monoclonal antibody Gal-13. J Biol Chem 262:4683Google Scholar
  39. 39.
    Galili U, Mandrell RE, Hamadeh RM, Shohet SB, Griffis JM (1988) Interaction between human natural anti-α-galactosyl immunoglobulin G and bacteria of the human flora. Infect Immun 56:1730Google Scholar
  40. 40.
    Galili U, Kobrin E, Shohet SB, Stults CLM, Macher BA (1988) Man, apes, and Old World monkeys differ from other mammals in the expression of α-galactosyl epitopes on nucleated cells. J Biol Chem 263:17755Google Scholar
  41. 41.
    Galili U, Thall A, Marcher BA (1990) Evolution of the Galα1–3Galβ1–4GlcNAc-R epitope in mammals. Trends Glycosci Glycotechnol 2:303Google Scholar
  42. 42.
    Galili U, Ron M, Sharon R (1992) The natural anti α-galactosyl IgG in seminal fluid. A simple means to determine damage to the blood-genital tract barrier in infertile males. J Immunol Methods 151:117Google Scholar
  43. 43.
    Gerwig GS, de Waard P, Kamerling JP, Vliegenthart JFG, Morgenstern E, Lamed R, Bayer EA (1989) Novel O-linked carbohydrate chains in the cellulase complex (Cellulosome) of Clostridium thermocellum. J Biol Chem 264:1027Google Scholar
  44. 44.
    Geyer R, Geyer H, Strim S, Hunsmann G, Schneider J, Dabrowski U, Darbrowski J (1984) Major oligosaccharides in the glycoprotein of Friend murine leukemia virus: structure elucidation by one- and two-dimensional proton nuclear magnetic resonance and methylation analysis. Biochemistry 23:5628Google Scholar
  45. 45.
    Hamadeh RM, Jarvis GA, Galili U, Mandrell RE, Zhou P, Griffiss JM (1992) Human natural anti-Gal IgG regulates alternative complement pathway activation on bacterial surfaces. J Clin Invest 89:1223Google Scholar
  46. 46.
    Hendricks SP, He P, Stults CLM, Macher BA (1990) Regulation of the expression of Galα1–3Galβ1–4GlcNAc glycosphingolipids in kidney. J Biol Chem 265:17621Google Scholar
  47. 47.
    Hironaka T, Furukawa K, Esmon PC, Fournel MA, Sawada S, Kato M, Minaga T, Kobata A (1992) Comparative study of the sugar chains of factor VIII purified from human plasma and from culture media of recombinant baby hamster kidney cells. J Biol Chem 267:8012Google Scholar
  48. 48.
    Honma K, Manabe H, Tomita M, Hamada A (1981) Isolation and partial structure characterization of macroglycolipids from rabbit red cell membrane. J Biochem (Tokyo) 90:1187Google Scholar
  49. 49.
    Jann K, Jann B (1984) Structure and biosynthesis of O-antigens. In: Riestcel ET (ed) Handbook of endotoxins, vol I. Chemistry of endotoxins. Elsevier, Amsterdam, p 138Google Scholar
  50. 50.
    Jansson PE, Lindberg AA, Lindberg B, Wollin R (1981) Structural studies on the hexose region of the core lipopolysaccharides from Enterobacteriaceae. Eur J Biochem 115:571Google Scholar
  51. 51.
    Joziasse DH, Shaper JH, Van den Eijnden DH, Van Tunen AH, Shaper NL (1989) Bovine α1–3 galactosyltransferase: isolation and characterization of a cDNA clone. Identification of homologous sequences in human genomic DNA. J Biol Chem 264:14290Google Scholar
  52. 52.
    Kagawa Y, Takasaki S, Utsumi J, Hosoi K, Shimizu H, Kochibe N, Kobata A (1988) Comparative study of the asparagine-linked sugar chains of natural human interferone-β1 and recombinant human interferon-β1 produced by three different mammalian cells. J Biol Chem 263:17508Google Scholar
  53. 53.
    Kahane I, Ben Chetrit E, Shifter A, Rachmilewitz EA (1980) The erythrocyte membranes in β-thalassemia. Lower sialic acid levels in glycophorin. Biochim Biophys Acta 596:10Google Scholar
  54. 54.
    Kay MMB (1975) Mechanism of removal of red cells by macrophages in situ. Proc Natl Acad Sci USA 72:3521Google Scholar
  55. 55.
    Kress BC, Spiro RG (1986) Studies on the glycoprotein nature of the thyrotropin receptor: interaction with lectins and purification of the bovine protein with the use of Bandeiraea (Griffonia) simplicifolia I affinity chromatography. Endocrinology 118:974Google Scholar
  56. 56.
    Krivan HC, Clark GF, Smith DF, Wilkins DT (1986) Cell surface binding site for Clostridium difficile enterotoxin: evidence of a glycoconjugate containing the sequence Galα→ 3Galβ1→4GlcNAc. Infect Immun 53:573Google Scholar
  57. 57.
    Larsen RD, Rajan VP, Ruff M, Kukowska-Latallo J, Cummings RD, Lowe JB (1989) Isolation of a cDNA encoding murine UDP galactose: β d-galactosyl-1,4-N-acetyl-d-glucosamine α1,3-galactosyltransferase: expression cloning by gene transfer. Proc Natl Acad Sci USA 86:8227Google Scholar
  58. 58.
    Larsen RD, Rivera-Marrero CA, Ernst LK, Cummings RD, Lowe JD (1990) Frameshift and nonsense mutations in a human genomic sequence homologous to a murine UDP-Galβ-d-Gal(1,4)-d-GlcNAcα(1,3) galactosyltransferase cDNA. J Biol Chem 265:7055Google Scholar
  59. 59.
    Lüderitz O, Simmons DAR, Westphal O (1965) The immunochemistry of Salmonella chemotype VI O-antigen. The structure of oligosaccharides from Salmonella group U 043 lipopolysaccharides. Biochem J 97:820Google Scholar
  60. 60.
    Magnani JL, Brockhaus M, Smith DF, Ginsburg V, Blaszczyk M, Mitchell KF, Steplewski Z, Koprowski H (1981) A monosialoganglioside is a monoclonal antibody-defined antigen of colon carcinoma. Science 212:55Google Scholar
  61. 61.
    Menke AC, Behrman SJ (1979) Immunological infertility. Clin Obstet Gynecol 22:231Google Scholar
  62. 62.
    Mohan PS, Spiro RG (1985) Macromolecular organization of basement membranes. Characterization and comparison of glomerular basement membrane and lens capsule components by immunochemical and lectin affinity procedures. J Biol Chem 261:4328Google Scholar
  63. 63.
    Nayak BR, Spiro RG (1991) Localization and structure of the asparagine-linked oligosac-charides of type IV collagen from glomerular basement membrane and lens capsule. J Biol Chem 266:13978Google Scholar
  64. 64.
    Nilsson B, Nordén NE, Svenson S (1979) Structural studies on the carbohydrate portion of fetuin. J Biol Chem 254:4545Google Scholar
  65. 65.
    Parekh RB, Dwek RA, Edge CJ, Rademacher TW (1989) N-Glycosylation and the production of recombinant glycoproteins. Trends Biotechnol 7:117Google Scholar
  66. 66.
    Pilbeam D (1984) The descent of hominoids. Sci Am 250:60Google Scholar
  67. 67.
    Rademacher TW, Rarekh RB, Dwek RA (1988) Glycobiology. Annu Rev Biochem 57:785Google Scholar
  68. 68.
    Ravindran S, Satapathy AK, Das MK (1988) Naturally occurring anti-α-galactosyl antibodies in human Plasmodium falciparum infections: a possible role for autoantibodies in malaria. Immunol Lett 19:137Google Scholar
  69. 69.
    Rumke P, Hekman A (1979) Sterility: an immunologic disorder? Clin Obest Gynecol 20:691Google Scholar
  70. 70.
    Santer UV, DeSantis R, Hard KJ, van Kuik JA, Vliegenthart JFG, Won B, Glick MC (1979) N-linked oligosaccharide changes with oncogenic transformation require sialylation of multiantennae. Eur J Biochem 181:249Google Scholar
  71. 71.
    Shibata S, Peters BP, Roberts DD, Goldstein TJ, Liotta LA (1982) Isolation of laminin by affinity chromatography on immobilized Griffonia simplificifolia I lectin. FEBS Lett 142:194Google Scholar
  72. 72.
    Smith DF, Larsen RD, Mattox S, Lowe JB, Cummings RD (1990) Transfer and expression of murine UDP-Gal:β-d-Galα-1,3galactosyltransferase gene in transfected Chinese hamster ovary cells. J Biol Chem 265:6225Google Scholar
  73. 73.
    Sorette MP, Galili U, Clark MR (1991) Comparison of serum anti-band 3 and anti-Gal antibody binding to density separated human red blood cells. Blood 77:628Google Scholar
  74. 74.
    Spiro RG, Bhoyroo VD (1984) Occurrence of α-d-galactosyl residues in the thyroglobulin from several species. Localization in the saccharide chains of the complex carbohydrate units. J Biol Chem 259:9858Google Scholar
  75. 75.
    Springer GF, Horton RF (1969) Blood group isoantibody stimulation in man by feeding blood group-active bacteria. J Clin Invest 48:1280Google Scholar
  76. 76.
    Stellner K, Saito H, Hakomori S (1973) Determination of amino sugar linkage in glycolipids by methylation. Amino sugar linkage of ceramide pentasaccharides of rabbit erythrocytes and of Forssman antigen. Arch Biochem Biophys 133:464Google Scholar
  77. 77.
    Suzuki E, Naiki M (1984) Heterophile antibodies to rabbit erythrocytes in human sera and identification of the antigen as a glycolipid. J Biochem (Tokyo) 83:103Google Scholar
  78. 78.
    Tanigawara Y, Hori R, Okumura K, Tsuji J, Shimizu N, Noma S, Suzuki J, Livingston DJ, Richards SM, Keyes LD, Couch RC, Erickson MK (1990) Pharmacokinetics in chimpanzee of recombinant human tissue plasminogen activator produced in mouse C127 and Chinese hamster ovary cells. Chem Pharm Bull (Tokyo) 38:517Google Scholar
  79. 79.
    Ten Brinke M, De Regt J (1970) 51Cr-half life time of heavy and light human erythrocytes. Scand J Haematol 7:336Google Scholar
  80. 80.
    Thall A, Galili U (1990) The differential expression of Galα1→3Galβ1→4GlcNAc-R residues on mammalian secreted N-glycosylated glycoproteins. Biochemistry 29:3959Google Scholar
  81. 81.
    Thall A, Galili U (1991) Almost one percent of human B cells secrete the anti-Gal antibody (abstract). FASEB J 5:A988Google Scholar
  82. 82.
    Thall A, Etienne-Decerf J, Winand R, Galili U (1991) The α-Galactosyl epitopes on human normal and autoimmune thyroid cells. Autoimmunity 10:81Google Scholar
  83. 83.
    Thall A, Etienne-Decerf J, Winand R, Galili U (1991) The α-galactosyl epitope on mammalian thyroid cells. Acta Endocrinol (Copenh) 124:692Google Scholar
  84. 84.
    Towbin H, Rosenfelder G, Weislander J, Avila JL, Rojas M, Szarfman A, Esser K, Nowack H, Timple R (1987) Circulating antibodies to mouse laminin in Chagas disease, American cutaneous leishmaniasis and normal individuals recognize terminal galactosyl (α1–3) galactose epitopes. J Exp Med 166:419Google Scholar
  85. 85.
    Tsuji J, Noma S, Suzuki J, Okumura K, Shimizu N (1990) Specificity of human natural antibody to recombinant tissue-type plasminogen activator (t-PA) expressed on mouse C127 cells. Chem Pharm Bull (Tokyo) 38:765Google Scholar
  86. 86.
    Uemura K, Yuzawa M, Taketomi T (1978) Characterization of major glycolipids in bovine erythrocyte membrane. J Biochem (Tokyo) 83:463Google Scholar
  87. 87.
    Weislander J, Mannson O, Kallin E, Gabrielli A, Nowack H, Timpl R (1990) Specificity of human antibodies against Galα1–3Gal carbohydrate epitope and distinction from natural antibodies reacting with Galα1–2Gal or Galα1–4Gal. Glycoconjugate J 7:85Google Scholar
  88. 88.
    Winand R, Galili U (1992) The natural anti-Gal antibody induces iodine uptake in thyrocytes of patients with Graves' disease. FASEB J 6:A1048Google Scholar

Copyright information

© Springer-Verlag New York, Inc. 1993

Authors and Affiliations

  • Uri Galili
    • 1
  1. 1.Department of Microbiology and ImmunologyMedical College of PennsylvaniaPhiladelphiaUSA

Personalised recommendations