Anti-apolipoprotein antibodies

Autoantibody
Anti-Apolipoprotein,
β-2 Glycoprotein 1
Autoantigen
Isoform 		Apolipoprotein H
Autoantigen gene APOH
Affected organ(s) Cardiovascular
Affected
tissue(s) 		serum
Affected cell(s) blood platelets
Also Affected serum proteins
Associated
Disease(s) 		Idiopathic Thrombosis,
Sclerosis,
Systemic lupus erythematosus
DR4-DQ3
HLA associations DR53
DRB1*0402 (DR4)

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.

structure of Apolipoprotein H

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 hapolotype 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 disequilbrium 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.

References

  1. ↑ Viard JP, Amoura Z, Bach JF (1991). "[Anti-beta 2 glycoprotein I antibodies in systemic lupus erythematosus: a marker of thrombosis associated with a circulating anticoagulant]". C. R. Acad. Sci. III, Sci. Vie (in French) 313 (13): 607–12. PMID 1782567.
  2. ↑ Sammaritano LR, Gharavi AE, Soberano C, Levy RA, Lockshin MD (1992). "Phospholipid binding of antiphospholipid antibodies and placental anticoagulant protein". J. Clin. Immunol. 12 (1): 27–35. doi:10.1007/BF00918270. PMID 1372614.
  3. ↑ Galli M, Bevers EM, Comfurius P, Barbui T, Zwaal RF (1993). "Effect of antiphospholipid antibodies on procoagulant activity of activated platelets and platelet-derived microvesicles". Br. J. Haematol. 83 (3): 466–72. doi:10.1111/j.1365-2141.1993.tb04672.x. PMID 8485053.
  4. ↑ Tsutsumi A, Matsuura E, Ichikawa K; et al. (1996). "Antibodies to beta 2-glycoprotein I and clinical manifestations in patients with systemic lupus erythematosus". Arthritis Rheum. 39 (9): 1466–74. doi:10.1002/art.1780390905. PMID 8814057.
  5. ↑ Takeya H, Mori T, Gabazza EC; et al. (1997). "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. doi:10.1172/JCI119401. PMC 508058. PMID 9151800.
  6. ↑ Shi W, Chong BH, Hogg PJ, Chesterman CN (1993). "Anticardiolipin antibodies block the inhibition by beta 2-glycoprotein I of the factor Xa generating activity of platelets". Thromb. Haemost. 70 (2): 342–5. PMID 8236146.
  7. ↑ Schousboe I, Rasmussen MS (1995). "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. PMID 7482406.
  8. ↑ Hattori N, Kuwana M, Kaburaki J, Mimori T, Ikeda Y, Kawakami Y (2000). "T cells that are autoreactive to beta2-glycoprotein I in patients with antiphospholipid syndrome and healthy individuals". Arthritis Rheum. 43 (1): 65–75. doi:10.1002/1529-0131(200001)43:1<65::AID-ANR9>3.0.CO;2-I. PMID 10643701.
  9. ↑ Galeazzi M, Sebastiani GD, Tincani A; et al. (2000). "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. doi:10.1177/096120330000900109. PMID 10715100.
  10. ↑ Ioannidis JP, Tektonidou MG, Vlachoyiannopoulos PG; et al. (1999). "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. doi:10.1016/S0198-8859(99)00122-6. PMID 10626742.
  11. ↑ Klitz W, Maiers M, Spellman S; et al. (2003). "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. doi:10.1034/j.1399-0039.2003.00103.x. PMID 12974796.
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