title: Beta2-glycoprotein I: antiphospholipid syndrome and T-cell reactivity.
abstract: There is increasing evidence showing that recurrent thrombosis and intrauterine fetal loss in antiphospholipid syndrome (APS) are attributable to antiphospholipid (aPL) antibodies. We have recently identified autoreactive CD4+ T cells to beta2-glycoprotein I (beta2GPI) that promote production of pathogenic antiphospholipid antibodies. beta2GPI-specific CD4+ T cells preferentially recognize the antigenic peptide containing the major phospholipid (PL)-binding site in the context of DR53. T-cell helper activity that stimulates B cells to produce IgG anti-beta2GPI antibodies is mediated through IL-6 and CD40-CD154 interaction. beta2GPI-specific T cells respond to reduced beta2GPI and recombinant beta2GPI fragments produced in a bacterial expression system but not to native beta2GPI, indicating that the epitopes recognized by beta2GPI-specific T cells are 'cryptic' determinants, which are generated at a subthreshold level by the processing of native beta2GPI under normal circumstances. Although beta2GPI-specific T cells are detected in both APS patients and healthy individuals, these autoreactive T cells are activated in vivo in APS patients but not in healthy individuals. These findings indicate activation of beta2GPI-specific T cells and subsequent production of pathogenic anti-beta2GPI antibodies can be induced by the exposure of such T cells to cryptic peptides of beta2GPI efficiently presented by functional antigen-presenting cells (APC). Delineating the mechanisms that induce the efficient processing and presentation of cryptic determinants of beta2GPI as a consequence of antigen processing would clarify the etiology that initiates the autoantibody response in APS.
authors.affiliation: Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. kuwanam@sc.itc.keio.ac.jp
authors.forename: Masataka
authors.initials: M
authors.lastname: Kuwana
mesh_terms: D020816:Amino Acid Motifs; D017152:Antibodies, Antiphospholipid / Q000737:chemistry; D017951:Antigen Presentation; D016736:Antiphospholipid Syndrome / Q000378:metabolism* / Q000473:pathology; D001323:Autoantibodies / Q000737:chemistry; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D019013:CD40 Antigens / Q000096:biosynthesis; D023201:CD40 Ligand / Q000096:biosynthesis; D006023:Glycoproteins / Q000378:metabolism / Q000502:physiology*; D006684:HLA-DR Antigens / Q000737:chemistry; D059845:HLA-DRB4 Chains; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism; D008954:Models, Biological; D010455:Peptides / Q000737:chemistry; D053482:beta 2-Glycoprotein I
chemical_list: D017152:Antibodies, Antiphospholipid; D001323:Autoantibodies; D019013:CD40 Antigens; D006023:Glycoproteins; D006684:HLA-DR Antigens; C050610:HLA-DR53; D059845:HLA-DRB4 Chains; D015850:Interleukin-6; D010455:Peptides; D053482:beta 2-Glycoprotein I; D023201:CD40 Ligand