Thromb Haemost 2001; 85(01): 36-41
DOI: 10.1055/s-0037-1612660
Review Article
Schattauer GmbH

Anti-αvβ3 Antibodies in Chronic Immune Thrombocytopenic Purpura

Satoru Kosugi
1   Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, and Department of Blood Transfusion, Osaka University Hospital, Osaka, Japan
,
Yoshiaki Tomiyama
1   Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, and Department of Blood Transfusion, Osaka University Hospital, Osaka, Japan
,
Shigenori Honda
1   Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, and Department of Blood Transfusion, Osaka University Hospital, Osaka, Japan
,
Hirokazu Kashiwagi
1   Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, and Department of Blood Transfusion, Osaka University Hospital, Osaka, Japan
,
Masamichi Shiraga
1   Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, and Department of Blood Transfusion, Osaka University Hospital, Osaka, Japan
,
Seiji Tadokoro
1   Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, and Department of Blood Transfusion, Osaka University Hospital, Osaka, Japan
,
Teruo Kiyoi
1   Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, and Department of Blood Transfusion, Osaka University Hospital, Osaka, Japan
,
Yoshiyuki Kurata
1   Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, and Department of Blood Transfusion, Osaka University Hospital, Osaka, Japan
,
Yuji Matsuzawa
1   Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, and Department of Blood Transfusion, Osaka University Hospital, Osaka, Japan
› Author Affiliations
Further Information

Publication History

Received 15 March 2000

Accepted after resubmission 03 August 2000

Publication Date:
08 December 2017 (online)

Summary

In chronic immune thrombocytopenic purpura (ITP), anti-GPIIb-IIIa (αIIbβ3) autoantibodies have been detected in serum and/or platelet-associated IgG (PAIgG) and considered as one of the major causes. We examined whether anti-αvβ3 antibodies might be present in ITP cases because of the similarity between αvβ3 and GPIIb-IIIa (αIIbβ3). Modified antigen capture ELISA (MACE) using human umbilical vein endothelial cells (HUVEC) showed the presence of serum anti-αvβ3 antibodies in 23 of 80 ITP patients (29%). Cross-adsorption studies between platelets and HUVEC demonstrated that most of anti-αvβ3 and anti-GPIIb-IIIa antibodies exclusively reacted with αvβ3 and GPIIb-IIIa, respectively. Platelet-associated anti-GPIIb-IIIa antibodies did not react with αvβ3, either. Interestingly, patients having anti-αvβ3 antibodies showed significantly lower platelet counts than negative patients. These results indicate the serum anti-αvβ3 antibodies are different ones from the classical anti-GPIIb-IIIa (αIIbβ3) antibodies and would provide a new insight into the pathophysiology of ITP as well as the autoantigenic epitopes on β3 integrins.

 
  • References

  • 1 George JN, El-Harase MA, Raskob GE. Chronic idiopathic thrombocytopenic purpura. N Engl J Med 1994; 331: 1207-11.
  • 2 McMillan R, Tani P, Millard F, Berchtold P, Renshow L, Woods Jr VL. Platelet-associated and plasma anti-glycoprotein autoantibodies in chronic ITP. Blood 1987; 70: 1040-5.
  • 3 Kiefel V, Santoso S, Kaufmann E, Mueller-Eckhardt C. Autoantibodies against platelet glycoprotein Ib/IX: a frequent finding in autoimmune thrombocytopenic purpura. Br J Haematol 1991; 79: 256-62.
  • 4 Beardsley DS, Spiegel JE, Jacobs MM, Handin RI, Lux SE. Platelet membrane glycoprotein IIIa contains target antigens that bind anti-platelet antibodies in immune thrombocytopenias. J Clin Invest 1984; 74: 1701-7.
  • 5 Tomiyama Y, Kurata Y, Shibata Y, Honda S, Furubayashi T, Mizutani H, Tsubakio T, Yonezawa Y, Tarui S. Immunochemical characterization of an autoantigen on platelet glycoprotein IIb in chronic ITP: comparison with the Baka alloantigen. Br J Haematol 1989; 71: 77-83.
  • 6 Kekomaki R, Dawson B, McFarland J, Kunicki TJ. Localization of human platelet autoantigens to the cysteine-rich region of glycoprotein IIIa. J Clin invest 1991; 88: 847-54.
  • 7 Fujisawa K, O’Tool TE, Tani P, Loftus JC, Plow EF, Ginsberg MH, McMillan R. Autoantibodies to the presumptive cytoplasmic domain of platelet glycoprotein Ilia in patients with chronic immune thrombocytopenic purpura. Blood 1991; 77: 2207-13.
  • 8 Fujisawa K, Tani P, O’Tool TE, Ginsberg MH, McMillan R. Different specificities of platelet-associated and plasma autoantibodies to platelet GPIIb-IIIa in patients with chronic ITP. Blood 1992; 79: 1441-6.
  • 9 Fujisawa K, McMillan R. Platelet-associated antibody to glycoprotein IIb/IIIa from chronic immune thrombocytopenic purpura patients often binds to divalent cation-dependent antigens. Blood 1993; 81: 1284-9.
  • 10 Kosugi S, Tomiyama Y, Shiraga M, Kashiwagi H, Mizutani H, Kanakura Y, Kurata Y, Matsuzawa Y. Platelet-associated anti-glycoprotein (GP) IIb-IIIa autoantibodies in chronic immune thrombocytopenic purpura mainly recognize cation-dependent conformations: comparison with the epitopes of serum autoantibodies. Thromb Haemost 1996; 75: 339-45.
  • 11 Bowditch RD, Tani P, McMillan R. Reactivity of autoantibodies from chronic ITP patients with recombinant glycoprotein IIIa peptides. Br J Haematol 1995; 91: 178-84.
  • 12 Bowditch RD, Tani P, Fong KC, McMillan R. Characterization of autoantigenic epitopes on platelet glycoprotein IIb/IIIa using random peptide libraries. Blood 1996; 88: 4579-84.
  • 13 Smyth S, Joneckis C, Parise L. Regulation of vascular integrins. Blood 1993; 81: 2827-43.
  • 14 Shattil SJ. Function and regulation of the β3 integrins in hemostasis and vascular biology. Thromb Haemost 1995; 74: 149-55.
  • 15 Fitzgerald LA, Poncz M, Steiner B, Rall SC, Bennet JS, Phillips DR. Comparison of cDNA-derived protein sequences of the human fibronectin and vitronectin receptor a-subunits and platelet glycoprotein IIb. Biochemistry 1987; 26: 8158-65.
  • 16 Brooks PC, Montgomery AM, Rosenfeld M, Reisfeld RA, Hu T, Klier G, Cheresh DA. Integrin αvβ3 antagonists promote tumor regression by inducing apoptosis of antigenic blood vessels. Cell 1994; 79: 1157-64.
  • 17 Liaw L, Skinner MP, Raines EW, Ross R, Cheresh DA, Schwartz SM, Giachelli CM. The adhesive and migratory effects of osteopontin are mediated via distinct cell surface integrins. Role of αvβ3 on smooth muscle cell migration to osteopontin in vitro. J Clin Invest 1995; 95: 713-24.
  • 18 George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, Blanchette VS, Bussel JB, Cines DB, Kelton JG, Lichtin AE, McMillan R, Okerbloom JA, Regan DH, Warrier I. Idiopathic thrombocytopenic purpura. a practice guideline developed by explicit methods for the american society of hematology. Blood 1996; 88: 3-40.
  • 19 Newman PJ, Allen RW, Kahn RA, Kunicki TJ. Quantitation of membrane glycoprotein IIIa on intact human platelets using the monoclonal antibody, AP3. Blood 1985; 65: 227-32.
  • 20 Cheresh DA, Harper JR. Arg-Gly-Asp recognition by a cell adhesion receptor requires its 130-kDa alpha subunit. J Biol Chem 1987; 262: 1434-7.
  • 21 Tomiyama Y, Tsubakio T, Piotrowicz RS, Kurata Y, Loftus JC, Kunicki TJ. The Arg-Gly-Asp (RGD) recognition site of platelet glycoprotein IIb-IIIa on nonactivated platelets is accessible to high-affinity macromolecules. Blood 1992; 79: 2303-12.
  • 22 Kosugi S, Tomiyama Y, Shiraga M, Kashiwagi H, Nakao H, Kanayama Y, Kurata Y, Matsuzawa Y. Cyclic thrombocytopenia associated with IgM anti-GPIIb-IIIa autoantibodies. Br J Haematol 1994; 88: 809-15.
  • 23 Kosugi S, Imai Y, Kurata Y, Tomiyama Y, Shiraga M, Honda S, Nishikawa M, Yonezawa T, Kanakura Y, Matsuzawa Y. Platelet-associated IgM elevated in patients with chronic hepatitis C contains no anti-platelet autoantibodies. Liver 1997; 17: 230-7.
  • 24 Suzuki K, Tatsumi H, Satoh S, Senda T, Nakata T, Jujii J, Taniguchi N. Manganese-superoxide dismutase in endothelial cells: localization and mechanism of induction. Am J Physiol 1993; 265: H1173-8.
  • 25 Jaffe EA, Nachman RL, Becher CG, Minick CR. Culture of human endothelial cells derived from umbilical vein: Identification by morphologic and immunologic criteria. J Clin Invest 1973; 52: 2745-56.
  • 26 Schett G, Xu Q, Amberger A, van der Zee R, Recheis H, Willeit J, Wick G. Autoantibodies against heat shock protein 60 mediate endothelial cytotoxicity. J Clin Invest 1995; 96: 2569-77.
  • 27 Coller BS, Cheresh DA, Asch E, Seligsohn U. Platelet vitronectin receptor expression differentiates Iraqi-Jewish from Arab patients with Glanzmann thrombasthenia in Israel. Blood 1991; 77: 75-83.
  • 28 Meroni PL, D’Cruz D, Khamashta M, Youinou P, Hughes GRV. Anti-endothelial cell antibodies: only for scientists or for clinicians too?. Clin Exp Immunol 1996; 104: 199-202.
  • 29 Belizna C, Tervaert JW. Specificity, pathogenecity, and clinical value of antiendothelial cell antibodies. Semin Arthritis Rheum 1997; 27: 98-109.
  • 30 Semple JW, Freedman J. Increased antiplatelet T helper lymphocyte reactivity in patients with autoimmune thrombocytopenia. Blood 1991; 78: 2619-25.
  • 31 Semple JW, Milev Y, Cosgrave D, Mody M, Hornstein A, Blanchette V, Freedman J. Differences in serum cytokine levels in acute and chronic autoimmune thrombocytopenic purpura: relationship to platelet phenotype and antiplatelet T-cell reactivity. Blood 1996; 87: 4245-54.
  • 32 Kuwana M, Kaburaki J, Ikeda Y. Autoreactive T cells to platelet GPIIb-IIIa in immune thrombocytopenic purpura: Role in production of anti-platelet autoantibody. J Clin Invest 1998; 102: 1393-402.
  • 33 Roberts K, Yokoyama WM, Kehn PJ, Shevach EM. The vitronectin receptor serves as an accessory molecule for the activation of a subset of gamma/delta T cells. J Exp Med 1991; 173: 231-40.
  • 34 Rabinowich H, Lin W, Amoscato A, Herberman RB, Whiteside TL. Expression of vitronectin receptor on human NK cells and its role in protein phosphorylation, cytokine production, and cell proliferation. J Immunol 1995; 154: 1124-35.
  • 35 Wang R, Furihata K, McFarland JG, Friedman K, Aster RH, Newman PJ. An amino acid polymorphism within the RGD binding domain of platelet membrane glycoprotein IIIa is responsible for the formation of the Pena/Penb alloantigen system. J Clin Invest 1992; 90: 2038-43.
  • 36 Honda S, Honda Y, Bauer B, Ruan C, Kunicki TJ. The impact of three dimensional structure on the expression of PIA alloantigens on human integrin beta 3. Blood 1995; 86: 234-42.
  • 37 Loftus JC, Halloran CE, Ginsberg MH, Feigen LP, Zablocki JA, Smith JW. The amino-terminal one-third of αIIb defines the ligand recognition specificity of Integrin αIIbβ3 . J Biol Chem 1996; 271: 2033-9.