Apolipoprotein H

Apolipoprotein H (Apo-H), previously known as (β₂-glycoprotein I, beta-2 glycoprotein I), is a multifunctional apolipoprotein. One of its functions is to bind cardiolipin. When bound the structure of cardiolipin and Apo-H both undergo large changes in structure.cite journal | author = Borchman D, Harris EN, Pierangeli SS, Lamba OP | title = Interactions and molecular structure of cardiolipin and beta 2-glycoprotein 1 (beta 2-GP1) | journal = Clin. Exp. Immunol. | volume = 102 | issue = 2 | pages = 373–8 | year = 1995 | pmid = 7586693 | doi = ] Within the structure of Apo-H is a stretch of positively charged amino acids, (protein sequence positions 282-287) Lys-Asn-Lys-Glu-Lys-Lys, are involved in phospholipid binding (See image on right).cite journal | author = Sheng Y, Sali A, Herzog H, Lahnstein J, Krilis SA | title = Site-directed mutagenesis of recombinant human beta 2-glycoprotein I identifies a cluster of lysine residues that are critical for phospholipid binding and anti-cardiolipin antibody activity | journal = J. Immunol. | volume = 157 | issue = 8 | pages = 3744–51 | year = 1996 | pmid = 8871678 | doi = ]

Apo-H has a complex involvement in agglutination, it appears to alter ADP mediated agglutenation of platlets.cite journal | author = Nimpf J, Wurm H, Kostner GM | title = Interaction of beta 2-glycoprotein-I with human blood platelets: influence upon the ADP-induced aggregation | journal = Thromb. Haemost. | volume = 54 | issue = 2 | pages = 397–401 | year = 1985 | pmid = 4082080 | doi = ] Normally Apo-H assumes an anti-coagulation activity in serum (by inhibiting coagulation factors), however changes in blood factors can result of a reversal of that activity.

Inhibitory activities

Apo-H appears to completely inhibit serotonin release by the plateletscite journal | author = Nimpf J, Wurm H, Kostner GM | title = Beta 2-glycoprotein-I (apo-H) inhibits the release reaction of human platelets during ADP-induced aggregation | journal = Atherosclerosis | volume = 63 | issue = 2-3 | pages = 109–14 | year = 1987 | pmid = 3827975 | doi = ] and prevents subsequent waves of the ADP-induced aggregation. The activity of Apo-H appears to involve the binding of agglutenating, negatively charged compounds, and inhibits agglutenation by the contact activation of the intrinsic blood coagulation pathway. cite journal | author = Schousboe I | title = beta 2-Glycoprotein I: a plasma inhibitor of the contact activation of the intrinsic blood coagulation pathway | journal = Blood | volume = 66 | issue = 5 | pages = 1086–91 | year = 1985 | pmid = 4052628 | doi = ] Apo-H causes a reduction of the prothrombinase binding sites on platelets and reduces the activation caused by collagen when thrombin is present at physiological serum concentrations of Apo-H suggesting a regulatory role of Apo-H in coagulation.cite journal | author = Nimpf J, Bevers EM, Bomans PH, "et al" | title = Prothrombinase activity of human platelets is inhibited by beta 2-glycoprotein-I | journal = Biochim. Biophys. Acta | volume = 884 | issue = 1 | pages = 142–9 | year = 1986 | pmid = 3768409 | doi = ]

Apo-H also inhibits the generation of factor Xa in the presence of platelets.cite journal | author = Shi W, Chong BH, Hogg PJ, Chesterman CN | title = Anticardiolipin antibodies block the inhibition by beta 2-glycoprotein I of the factor Xa generating activity of platelets | journal = Thromb. Haemost. | volume = 70 | issue = 2 | pages = 342–5 | year = 1993 | pmid = 8236146 | doi = ] Apo-H also inhibits that activation of factor XIIa.cite journal | author = Schousboe I, Rasmussen MS | title = Synchronized inhibition of the phospholipid mediated autoactivation of factor XII in plasma by beta 2-glycoprotein I and anti-beta 2-glycoprotein I | journal = Thromb. Haemost. | volume = 73 | issue = 5 | pages = 798–804 | year = 1995 | pmid = 7482406 | doi = ]

In addition, Apo-H inhibits the activation of protein C blocking its activity on phosphatidylserine:phosphatidylcholine vesiclescite journal | author = Keeling DM, Wilson AJ, Mackie IJ, Isenberg DA, Machin SJ | title = Role of beta 2-glycoprotein I and anti-phospholipid antibodies in activation of protein C "in vitro" | journal = J. Clin. Pathol. | volume = 46 | issue = 10 | pages = 908–11 | year = 1993 | pmid = 8227406 | doi = ] however once protein C is activated, Apo-H fails to inhibit activity. Since protein C is involved in factor Va degradation Apo-H indirectly inhibits the degradation of factor Va. cite journal | author = Matsuda J, Gohchi K, Kawasugi K, Gotoh M, Saitoh N, Tsukamoto M | title = Inhibitory activity of anti-beta 2-glycoprotein I antibody on factor Va degradation by activated-protein C and its cofactor protein S | journal = Am. J. Hematol. | volume = 49 | issue = 1 | pages = 89–91 | year = 1995 | pmid = 7741146 | doi = ] This inhibitory activity was diminished by adding phospholipids suggesting the Apo-H inhibition of protein C is phospholipid competitive.cite journal | author = Mori T, Takeya H, Nishioka J, Gabazza EC, Suzuki K | title = beta 2-Glycoprotein I modulates the anticoagulant activity of activated protein C on the phospholipid surface | journal = Thromb. Haemost. | volume = 75 | issue = 1 | pages = 49–55 | year = 1996 | pmid = 8713779 | doi = ] This indicates that under certain conditions Apo-H takes on a procoagulation properties.

Pathology

Anti-cardiolipin antibodies are found in both infectious (syphilis) and autoimmune disease(sclerosis, lupus).cite journal | author = Kumar KS, Jyothy A, Prakash MS, Rani HS, Reddy PP | title = Beta2-glycoprotein I dependent anticardiolipin antibodies and lupus anticoagulant in patients with recurrent pregnancy loss | journal = Journal of postgraduate medicine | volume = 48 | issue = 1 | pages = 5–10 | year = 2002 | pmid = 12082318 | doi = ] The activity of anti-cardiolipin antibodies in autoimmune antiphospholipid syndrome requires apolipoprotein H.cite journal | author = McNeil HP, Simpson RJ, Chesterman CN, Krilis SA | title = Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein I (apolipoprotein H) | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 87 | issue = 11 | pages = 4120–4 | year = 1990 | pmid = 2349221 | doi = ] cite journal | author = Hunt JE, McNeil HP, Morgan GJ, Crameri RM, Krilis SA | title = A phospholipid-beta 2-glycoprotein I complex is an antigen for anticardiolipin antibodies occurring in autoimmune disease but not with infection | journal = Lupus | volume = 1 | issue = 2 | pages = 75–81 | year = 1992 | pmid = 1301967 | doi = ] The subset of antibodies that bind Apo-H and alter its activity are condsidered different fromantibodies that bind thrombin, serum phospholipids and are called anti-apolipoprotein antibodies. In autoimmune disease, anti-apolipoprotein antibodies (Anti β₂ glycoprotein I antibodies) strongly associate with thrombitic forms of lupus and sclerosis.

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