Binding of beta 2-glycoprotein I to anionic phospholipids facilitates processing and presentation of a cryptic epitope that activates pathogenic autoreactive T cells.

Abstract:

: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.

journal_name

Blood

journal_title

Blood

authors

Kuwana M,Matsuura E,Kobayashi K,Okazaki Y,Kaburaki J,Ikeda Y,Kawakami Y

doi

10.1182/blood-2004-08-3145

subject

Has Abstract

pub_date

2005-02-15 00:00:00

pages

1552-7

issue

4

eissn

0006-4971

issn

1528-0020

pii

2004-08-3145

journal_volume

105

pub_type

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