Disease relevance of APOH

• The discovery of a full range of sequence variation and identification of race-specific informative SNPs in the APOH gene may facilitate the rapid evaluation of this variation in relation to autoimmune diseases [1].
• Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder in association with autoantibodies to phospholipid (PL)-binding plasma proteins, such as beta(2)-glycoprotein I (beta(2)GPI) [2].
• Anti-beta(2)GPI-negative patients without arterial thrombosis did not express the VV genotype [3].
• Hepatitis B virus surface antigen binds to apolipoprotein H [4].
• We have cloned and sequenced ApoH cDNAs both from human liver and from a human hepatoma cell line (HepG2) [5].

High impact information on APOH

• Bacterial induction of autoantibodies to beta2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome [6].
• A calcium-dependent megalin-mediated beta2-glycoprotein-I endocytosis was subsequently demonstrated by ligand blotting of rabbit renal cortex and uptake analysis in megalin-expressing cells [7].
• In addition to explaining the high urinary excretion of beta2-glycoprotein-I in patients with renal tubule failure, the data provide molecular evidence for the suggested function of beta2-glycoprotein-I as a linking molecule mediating cellular recognition of phosphatidylserine-exposing particles [7].
• The activity of the platelet APC inhibitor was immediate and was not enhanced by heparin, distinguishing it from the circulating protein C inhibitor [8].
• Action of anticardiolipin and antibodies to beta2-glycoprotein-I on trophoblast proliferation as a mechanism for fetal death [9].

Chemical compound and disease context of APOH

• OBJECTIVE: To clarify the consequences of the valine/leucine polymorphism at position 247 of the beta(2)-glycoprotein I (beta(2)GPI) gene in patients with antiphospholipid syndrome (APS), by investigating the correlation between genotypes and the presence of anti-beta(2)GPI antibody [10].
• An Endogenous Inhibitor of Angiogenesis derived from a Transitional Cell Carcinoma: Clipped beta2-Glycoprotein-I [11].
• We therefore sought to determine the prevalence and levels of antibodies to beta2-glycoprotein-I and to cardiolipin before, during, and after thrombosis in patients with SLE, and to compare them with patients who did not have thrombosis [12].
• beta 2 glycoprotein-I inhibits factor XII activation on triglyceride rich lipoproteins: the effect of antibodies from plasma of patients with antiphospholipid syndrome [13].
• Antibodies to beta 2-glycoprotein-I: urea resistance, binding specificity, and association with thrombosis [14].

Biological context of APOH

• By direct DNA sequencing of PCR amplified fragments corresponding to the eight APOH exons, we identified two missense mutations that correspond to the APOH*1 and APOH*3w alleles [15].
• In this study, we describe a two-allelic RsaI restriction fragment length polymorphism identified by Southern blot analysis and by allele-specific polymerase chain reaction amplification for the human beta 2-glycoprotein I (beta 2-I; apolipoprotein H = APOH) gene [16].
• No significant effects of the APOH genotypes on any of the plasma lipid levels were observed [17].
• By hybridizing a cDNA probe for APOH to a panel of somatic cell hybrids, we show that the structural locus for this protein maps to 17q23----qter and is therefore not part of the RCA cluster on chromosome 1 [18].
• APOH allele frequencies were: APOH*2 = 0.877, APOH*3 = 0.098, APOH*1 = 0.025, with the majority of the sample being homozygous [19].

Anatomical context of APOH

• To confirm whether these are functional mutations, we mutagenized APOH cDNAs and transiently expressed them in COS-1 cells [20].
• We have recently found that CD4(+) T cells autoreactive to beta(2)GPI in patients with APS preferentially recognize a cryptic peptide encompassing amino acid residues 276-290 (p276-290), which contains the major PL-binding site, in the context of DR53 [2].
• In addition, the p276-290-reactive T-cell response was primed by stimulating peripheral blood T cells from DR53-carrying healthy individuals with dendritic cells bearing PL-bound beta(2)GPI in vitro [2].
• However, it is not clear how previously cryptic p276-290 becomes visible to the immune system and elicits a pathogenics autoimmune response to beta(2)GPI [2].
• Dendritic cells or macrophages pulsed with PL-bound beta(2)GPI induced a response of p276-290-specific CD4(+) T-cell lines generated from the patients in an HLA-DR-restricted and antigen-processing-dependent manner but those with beta(2)GPI or PL alone did not [2].

Associations of APOH with chemical compounds

• We also observed an interaction between staff and the APOH polymorphism in affecting cholesterol levels [21].
• A significant increase in functional affinity for purified megalin was observed when beta2-glycoprotein-I was bound to the acidic phospholipids, phosphatidylserine and cardiolipin [7].
• Apolipoprotein H (apoH, protein; APOH, gene) is a single chain glycoprotein that exists in plasma both in a free form and in combination with lipoprotein particles [22].
• The sample included 872 Chinese, 179 Asiatic Indians (Dravidian), 91 Filipinos, and 17 Malays. APOH polymorphism was determined by isoelectric focusing of sera in thin-layer polyacrylamide gels containing 3 M urea followed by immunoblotting [23].
• Due to an additional glycosylation site located on the CCP2 domain of bovine beta(2)GPI a small change in the characteristic SAXS parameters was observed, which coincided with results obtained from SDS-PAGE [24].

Physical interactions of APOH

• The binding of beta2-glycoprotein-I and beta2-glycoprotein-I- phospholipid complexes to megalin was completely blocked by receptor-associated protein [7].
• It has been shown that APOH has structural similarities with the regulation of complement activation (RCA) protein superfamily and is involved in phospholipid binding interactions on platelets and as an autoantigen in complex with anionic phospholipids [18].
• DeltaV did not associate with apoER2'. We conclude that domain V is involved in both binding beta(2)GPI to anionic PL and in interaction with apoER2' and subsequent activation of platelets [25].
• These results demonstrate that annexin II mediates the binding of beta(2)GPI to endothelial cells [26].
• It is the main target antigen for antiphospholipid antibodies in patients with antiphospholipid syndrome (APS). beta(2)GPI binds with high affinity to the atherogenic lipoprotein Lp(a) which shares structural homology with plasminogen, a key molecule in the fibrinolytic system [27].

Regulatory relationships of APOH

• Moreover, a specific p38 MAPK inihibitor SB203580 decreased aCL/beta(2)GPI-induced TF mRNA expression [28].
• IgG anti-beta(2)GPI antibodies recognized the beta(2)GPI at the endothelial surface inducing its activation with an increase of ICAM-I and a decrease in the expression of thrombomodulin favoring a pro-thrombotic state in the vascular endothelium [27].
• METHODS: Sixty-five Japanese patients with APS and/or systemic lupus erythematosus who were positive for antiphospholipid antibodies and 61 controls were analyzed for the presence of the Val/Leu(247) polymorphism of beta(2)GPI [10].
• Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFbetaTrCP-dependent destruction of the APC Inhibitor Emi1 [29].

Other interactions of APOH

• In addition to APOE the gene products of five other apolipoprotein loci were screened and low frequency variation, possibly due to European admixture, was observed in two systems (APOH and APOA-IV) [30].
• The binding site in beta(2)GPI for interaction with apoER2' does not overlap with the hydrophobic insertion loop in domain V [25].
• Finally, surface plasmon resonance studies revealed high affinity binding between annexin II and beta(2)GPI [26].
• We hypothesize that LBA/CHS1/BG proteins function in polarized vesicle trafficking by guiding intracellular vesicles to activated receptor complexes and thus facilitate polarized secretion and/or membrane deposition of immune effector molecules [31].
• Thus, aCL/beta(2)GPI plays dual roles in the pathogenesis of APS, firstly by deranging the fibrinolytic system and secondly by activating monocytes, endothelial cells and thrombocytes to produce TF or thromboxane [28].

Analytical, diagnostic and therapeutic context of APOH

• APOH exhibits a genetically determined structural polymorphism due to the presence of three common alleles (APOH*1, APOH*2 and APOH*3) detectable by isoelectric focusing (IEF) and immunoblotting [15].
• A South Korean population from Kongju (n = 350) was screened by isoelectric focusing and immunoblotting procedures to determine the distribution of genetic variations in 3 apolipoprotein genes including APOA-IV, APOE and APOH [32].
• The site of biosynthesis for APOH was established by Northern blot analysis [18].
• Screening of serum by using a surface plasmon resonance analysis assay identified beta2-glycoprotein-I/apolipoprotein H as a plasma component binding to the renal epithelial endocytic receptor megalin [7].
• N-terminal region sequence analysis of the molecule has identified the cofactor as beta 2-glycoprotein I (beta 2GPI) (apolipoprotein H), a plasma protein known to bind to anionic phospholipids [33].

References