Binding of beta 2-glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells.
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). 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. 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. Here we show that presentation of a disease-relevant cryptic T-cell determinant in beta(2)GPI is induced as a direct consequence of antigen processing from beta(2)GPI bound to anionic PL. 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. 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. Our finding is the first demonstration of an in vitro mechanism eliciting pathogenic autoreactive T-cell responses to beta(2)GPI and should be useful in clarifying the pathogenesis of APS.
Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan. kuwanam@sc.itc.keio.ac.jp
Masataka
M
Kuwana
Eiji
E
Matsuura
Kazuko
K
Kobayashi
Yuka
Y
Okazaki
Junichi
J
Kaburaki
Yasuo
Y
Ikeda
Yutaka
Y
Kawakami
D000818:Animals; D000838:Anions / Q000378:metabolism; D017951:Antigen Presentation / Q000276:immunology*; D016736:Antiphospholipid Syndrome / Q000276:immunology / Q000473:pathology; D001324:Autoantigens / Q000276:immunology / Q000378:metabolism*; D002417:Cattle; D002460:Cell Line; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D053482:beta 2-Glycoprotein I
D000838:Anions; D001324:Autoantigens; D018984:Epitopes, T-Lymphocyte; D006023:Glycoproteins; D010446:Peptide Fragments; D010743:Phospholipids; D053482:beta 2-Glycoprotein I