Anti-apolipoprotein antibodies explained

In autoimmune disease, anti-apolipoprotein H (AAHA) antibodies, also called anti-β2 glycoprotein I antibodies, comprise a subset of anti-cardiolipin antibodies and lupus anticoagulant. These antibodies are involved in sclerosis and are strongly associated with thrombotic forms of lupus.[1] As a result, AAHA are strongly implicated in autoimmune deep vein thrombosis.

Also, it was proposed that AAHA is responsible for lupus anticoagulant. However, antiphospholipid antibodies bind phospholipids at sites similar to sites bound by anti-coagulants such as PAP1 sites and augment anti-coagulation activity.[2] This contrasts with the major, specific, activity of AAHA, defining a subset of anti-cardiolipin antibodies that specifically interacts with Apo-H.[3] AHAA only inhibits the anti-coagulation activity in the presence of Apo-H and the AAHA component of ACLA correlates with a history of frequent thrombosis.[4] This can be contrasted with lupus anticoagulant which inhibits agglutination in the presence of thrombin. A subset of AHAA appear to mimic the activity of lupus anticoagulant and increase Apo-H binding to phospholipids.[5] These two activities can be differentiated by the binding to Apo-H domains, whereas binding to the 5th domain promotes that anti-coagulant activity binding to the more N-terminal domains promotes lupus anticoagulant-like activities.

AAHA interferes with factor Xa inhibition by Apo-H increasing factor Xa generation. However, like Apo-H the Lupus anticoagulant inhibits factor Xa generation.[6]

AAHA also inhibited the autoactivation of factor XII [7] while at high AAHA concentrations, factor XIIa activation increases at levels comparable to Apo-H that cause inhibition of factor XIIa activation. A synchronized inhibition of factor XII autoactivation by Apo-H and AHAA has been suggested.

Genetics

The haplotype HLA-DR4-DQ3 appears to play a role in the pathogenic AAHA production. The alleles primarily recognized are HLA-DR53[8] (DRB4*01), DRB1*0402,[9] DQA1*03,[10] and possibly DQB1*0302. All of these alleles are in linkage disequilibrium in the DRB4*01:DRB1*0402:DQA1*0301:DQB1*0302 haplotype, also called DR4-DQ8 and also the DQA1:0303:DQB1*0301 haplotype, DR4-DQ7.3. However, in European Americans which reflects a broad area of Europe in which the original studies were conducted only DR4(0402)-DQ8 was found, indicating that the entire haplotype is involved.[11]

HLA-DR7 may also be associated with these antibodies and the common haplotype association is the HLA-DR53 serotype.

Notes and References

  1. Viard JP, Amoura Z, Bach JF . [Anti-beta 2 glycoprotein I antibodies in systemic lupus erythematosus: a marker of thrombosis associated with a circulating anticoagulant] . fr . Comptes Rendus de l'Académie des Sciences, Série III . 313 . 13 . 607–12 . 1991 . 1782567 .
  2. Sammaritano LR, Gharavi AE, Soberano C, Levy RA, Lockshin MD . Phospholipid binding of antiphospholipid antibodies and placental anticoagulant protein . J. Clin. Immunol. . 12 . 1 . 27–35 . 1992 . 1372614 . 10.1007/BF00918270 .
  3. Galli M, Bevers EM, Comfurius P, Barbui T, Zwaal RF . Effect of antiphospholipid antibodies on procoagulant activity of activated platelets and platelet-derived microvesicles . Br. J. Haematol. . 83 . 3 . 466–72 . 1993 . 8485053 . 10.1111/j.1365-2141.1993.tb04672.x .
  4. Tsutsumi A, Matsuura E, Ichikawa K . Antibodies to beta 2-glycoprotein I and clinical manifestations in patients with systemic lupus erythematosus . Arthritis Rheum. . 39 . 9 . 1466–74 . 1996 . 8814057 . 10.1002/art.1780390905 . etal.
  5. Takeya H, Mori T, Gabazza EC . Anti-beta2-glycoprotein I (beta2GPI) monoclonal antibodies with lupus anticoagulant-like activity enhance the beta2GPI binding to phospholipids . J. Clin. Invest. . 99 . 9 . 2260–8 . 1997 . 9151800 . 10.1172/JCI119401 . 508058 . etal.
  6. Shi W, Chong BH, Hogg PJ, Chesterman CN . Anticardiolipin antibodies block the inhibition by beta 2-glycoprotein I of the factor Xa generating activity of platelets . Thromb. Haemost. . 70 . 2 . 342–5 . 1993 . 8236146 . 10.1055/s-0038-1649577.
  7. Schousboe I, Rasmussen MS . Synchronized inhibition of the phospholipid mediated autoactivation of factor XII in plasma by beta 2-glycoprotein I and anti-beta 2-glycoprotein I . Thromb. Haemost. . 73 . 5 . 798–804 . 1995 . 7482406 . 10.1055/s-0038-1653871.
  8. Hattori N, Kuwana M, Kaburaki J, Mimori T, Ikeda Y, Kawakami Y . T cells that are autoreactive to beta2-glycoprotein I in patients with antiphospholipid syndrome and healthy individuals . Arthritis Rheum. . 43 . 1 . 65–75 . 2000 . 10643701 . 10.1002/1529-0131(200001)43:1<65::AID-ANR9>3.0.CO;2-I.
  9. Galeazzi M, Sebastiani GD, Tincani A . HLA class II alleles associations of anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus . Lupus . 9 . 1 . 47–55 . 2000 . 10715100 . 10.1177/096120330000900109 . etal.
  10. Ioannidis JP, Tektonidou MG, Vlachoyiannopoulos PG . HLA associations of anti-beta2 glycoprotein I response in a Greek cohort with antiphospholipid syndrome and meta-analysis of four ethnic groups . Hum. Immunol. . 60 . 12 . 1274–80 . 1999 . 10626742 . 10.1016/S0198-8859(99)00122-6 . etal.
  11. Klitz W, Maiers M, Spellman S . New HLA haplotype frequency reference standards: high-resolution and large sample typing of HLA DR-DQ haplotypes in a sample of European Americans . Tissue Antigens . 62 . 4 . 296–307 . 2003 . 12974796 . 10.1034/j.1399-0039.2003.00103.x . etal.

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