Molecular Studies on Phospholipid-Binding Sites and Cryptic Epitopes Appearing on β<sub>2</sub>-Glycoprotein I Structure Recognized by Anticardiolipin Antibodies

Matsuura, Eiji; Igarashi, Makoto; Igarashi, Yoshiko; Katahira, T.; Nagae, Hisato; Ichikawa, Kenji; Triplett, Douglas A.; Koike, Takao

doi:10.1177/096120339400400104

Cited by 47 publications

(33 citation statements)

References 40 publications

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“…aCL antibodies also have been reported to bind to ␤2GPI adsorbed to microtiter plates under certain conditions. Matsuura et al (15) demonstrated that aCL antibodies could bind ␤2GPI adsorbed to irradiated plates but not to nonirradiated plates. They suggested that a cryptic epitope was expressed by a conformational change occurring when ␤2GPI interacted with some surfaces, such as irradiated plates or cardiolipin, but not when it interacted with other surfaces, such as nonirradiated plates.…”

Section: Discussionmentioning

confidence: 99%

“…Some groups concluded that these antibodies recognize a complex antigen that includes both ␤2GPI and anionic phospholipid (6) whereas others have observed aCL binding to ␤2GPI in the absence of phospholipid (7)(8)(9)(10)(11)(12)(13)(14). Others argue that a cryptic epitope, recognized by these antibodies, is generated when ␤2GPI binds to either cardiolipin-coated or ␥-irradiated plastic microplate wells (15). Others have demonstrated that these autoantibodies bind ␤2GPI in solution in the absence of phospholipid (16)(17)(18)(19)(20).…”

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confidence: 99%

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Anti-β2 glycoprotein I (β2GPI) autoantibodies recognize an epitope on the first domain of β2GPI

Iverson

Victoria

Marquis

1998

Proc. Natl. Acad. Sci. U.S.A.

231

212

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Anticardiolipin (aCL) autoantibodies are associated with thrombosis, recurrent fetal loss, and thrombocytopenia. Only aCL found in autoimmune disease require the participation of the phospholipid binding plasma protein ␤2 glycoprotein I (␤2GPI) for antibody binding and now are called anti-␤2GPI. The antigenic specificity of aCL affinity purified from 11 patients with high titers was evaluated in an effort to better understand the pathophysiology associated with aCL. Seven different recombinant domain-deleted mutants of human ␤2GPI, and full length human ␤2GPI (wildtype), were used in competition assays to inhibit the autoantibodies from binding to immobilized wild-type ␤2GPI. Only those domain-deleted mutants that contained domain 1 inhibited the binding to immobilized wild-type ␤2GPI from all of the patients. The domain-deleted mutants that contained domain 1 inhibited all aCL in a similar but not identical pattern, suggesting that these aCL recognize a similar, but distinguishable, epitope(s) present on domain 1.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Anti-β2 glycoprotein I (β2GPI) autoantibodies recognize an epitope on the first domain of β2GPI

Iverson

Victoria

Marquis

1998

Proc. Natl. Acad. Sci. U.S.A.

231

212

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“…DNA and apoptotic membranes [15,161. Recently, a particular region namely Cys281-Cys288 located on the fifth domain of P2GPI was identified as the PL bin ding site by using synthesized peptide analogues (17], This was also confirmed by molecu lar studies using human (32GPI-deleted mutants [18]. However, there are some contradictory results about the requirement of the tertiary conformation of P2GPI in the PL binding (18,19], The finding that P2GPI is required for aCL binding to cardiolipin has generated considerable controversy regarding the true antigenic target of aCL.…”

Section: Introductionmentioning

confidence: 69%

Pathogenic Role Of Antiprotein-Phospholipid Antibodies

Carreras¹,

Forastiero²

1996

Pathophysiol Haemos Thromb

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Antiphospholipid antibodies (aPL) are a heterogeneous family of antibodies, including those specific for a variety of phospholipid (PL)-binding proteins and also those reacting with PL molecules. The former seem to be associated with the antiphospholipid syndrome (APS). At present, the main proteins proposed as antigens are β2 glycoprotein I, prothrombin, protein C, protein S, kininogens and annexin V. Anionic PL might play a key role “in vivo” in the binding of aPL to PL-bound proteins. Different mechanisms may be involved in the pathogenesis of the APS, including effects of aPL on the protein C system and antithrombin III and also on platelets, endothelial cells and monocytes. Recent data on experimental animal models have provided support for a causative role of aPL in the clinical complications of the APS.

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“…7 These domains have a homologous 60-amino acid repeating sequence with both inter-and intraregional disulfide bridges, and domain V has a 6-residue insertion and a 19-residue C-terminal extension. The major PL-binding site on ␤ 2 GPI has been identified as a highly positively charged amino acid sequence located at positions 281 to 288 in domain V. [8][9][10] Recent crystal structure analysis has revealed that ␤ 2 GPI adheres to anionic PLs via a large positively charged area formed by 14 basic amino acid residues in domain V, including the major PL-binding site. 11 Autoantibodies to ␤ 2 GPI were shown to be pathogenic, based on the following observations in patients with APS and experimental animal models.…”

Section: Introductionmentioning

confidence: 99%

Autoreactive CD4+ T-cell clones to β2-glycoprotein I in patients with antiphospholipid syndrome: preferential recognition of the major phospholipid-binding site

Arai

Yoshida

Kaburaki

et al. 2001

Blood

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Autoreactive CD4 ؉ T cells to ␤ 2 -glycoprotein I (␤ 2 GPI) that promote antiphospholipid antibody production were recently identified in patients with antiphospholipid syndrome (APS). To further examine antigen recognition profiles and T-cell helper activity in ␤ 2 GPI-reactive T cells, 14 CD4 ؉ T-cell clones specific to ␤ 2 GPI were generated from 3 patients with APS by repeated stimulation of peripheral blood T cells with recombinant ␤ 2 GPI. At least 4 distinct T-cell epitopes were identified, but the majority of the ␤ 2 GPI-specific T-cell clones responded to a peptide encompassing amino acid residues 276 to 290 of ␤ 2 GPI (KVSFFCKNKEKKCSY; single-letter amino acid codes) that contains the major phospholipid-binding site in the context of the DRB4*0103 allele. Ten of 12 ␤ 2 GPI-specific T-cell clones were able to stimulate autologous peripheral blood B cells to promote anti-␤ 2 GPI antibody production in the presence of recombinant ␤ 2 GPI. T-cell helper activity was exclusively found in T-cell clones capable of producing interleukin 6 (IL-6). In vitro anti-␤ 2 GPI antibody production induced by T-cell clones was inhibited by anti-IL-6 or anti-CD40 ligand monoclonal antibody. In addition, exogenous IL-6 augmented anti-␤ 2 GPI antibody production in cultures of the T-cell clone lacking IL-6 expression. These results indicate that ␤ 2 GPI-specific CD4 ؉ T cells in patients with APS preferentially recognize the antigenic peptide containing the major phospholipid-binding site and have the capacity to stimulate B cells to produce anti-␤ 2 GPI antibodies through IL-6 expression and CD40-CD40 ligand engagement. These findings are potentially useful for clarifying the pathogenesis of APS and for developing therapeutic strategies that suppress pathogenic antiphospholipid antibody production in these patients.

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Molecular Studies on Phospholipid-Binding Sites and Cryptic Epitopes Appearing on β₂-Glycoprotein I Structure Recognized by Anticardiolipin Antibodies

Cited by 47 publications

References 40 publications

Anti-β2 glycoprotein I (β2GPI) autoantibodies recognize an epitope on the first domain of β2GPI

Anti-β2 glycoprotein I (β2GPI) autoantibodies recognize an epitope on the first domain of β2GPI

Pathogenic Role Of Antiprotein-Phospholipid Antibodies

Autoreactive CD4+ T-cell clones to β2-glycoprotein I in patients with antiphospholipid syndrome: preferential recognition of the major phospholipid-binding site

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Molecular Studies on Phospholipid-Binding Sites and Cryptic Epitopes Appearing on β2-Glycoprotein I Structure Recognized by Anticardiolipin Antibodies

Cited by 47 publications

References 40 publications

Anti-β2 glycoprotein I (β2GPI) autoantibodies recognize an epitope on the first domain of β2GPI

Anti-β2 glycoprotein I (β2GPI) autoantibodies recognize an epitope on the first domain of β2GPI

Pathogenic Role Of Antiprotein-Phospholipid Antibodies

Autoreactive CD4+ T-cell clones to β2-glycoprotein I in patients with antiphospholipid syndrome: preferential recognition of the major phospholipid-binding site

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Molecular Studies on Phospholipid-Binding Sites and Cryptic Epitopes Appearing on β₂-Glycoprotein I Structure Recognized by Anticardiolipin Antibodies