TY - JOUR
T1 - Binding of β2-glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells
AU - Kuwana, Masataka
AU - Matsuura, Eiji
AU - Kobayashi, Kazuko
AU - Okazaki, Yuka
AU - Kaburaki, Junichi
AU - Ikeda, Yasuo
AU - Kawakami, Yutaka
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2005/2/15
Y1 - 2005/2/15
N2 - Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder in association with autoantibodies to phospholipid (PL)-binding plasms proteins, such as β2-glycoprotein I (β2GPI). We have recently found that CD4+ T cells autoreactive to β 2GPI 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 β2GPI. Here we show that presentation of a disease-relevant cryptic T-cell determinant in β2GPI is induced as a direct consequence of antigen processing from β2GPI bound to anionic PL. Dendritic cells or macrophages pulsed with PL-bound β2GPI 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 β2GPI 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 β2GPI in vitro. Our finding is the first demonstration of an in vitro mechanism eliciting pathogenic autoreactive T-cell responses to β2GPI and should be useful in clarifying the pathogenesis of APS.
AB - Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder in association with autoantibodies to phospholipid (PL)-binding plasms proteins, such as β2-glycoprotein I (β2GPI). We have recently found that CD4+ T cells autoreactive to β 2GPI 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 β2GPI. Here we show that presentation of a disease-relevant cryptic T-cell determinant in β2GPI is induced as a direct consequence of antigen processing from β2GPI bound to anionic PL. Dendritic cells or macrophages pulsed with PL-bound β2GPI 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 β2GPI 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 β2GPI in vitro. Our finding is the first demonstration of an in vitro mechanism eliciting pathogenic autoreactive T-cell responses to β2GPI and should be useful in clarifying the pathogenesis of APS.
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U2 - 10.1182/blood-2004-08-3145
DO - 10.1182/blood-2004-08-3145
M3 - Article
C2 - 15486070
AN - SCOPUS:13544259567
VL - 105
SP - 1552
EP - 1557
JO - Blood
JF - Blood
SN - 0006-4971
IS - 4
ER -