T cells that are autoreactive to β2-glycoprotein I in patients with antiphospholipid syndrome and healthy individuals

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Abstract
Objective To identify the T cells responsive to β2-glycoprotein I (β2GPI) that mediate antiphospholipid antibody production in patients with antiphospholipid syndrome (APS). Methods In vitro proliferative responses and anti-β2GPI antibody production induced by β2GPI were examined in peripheral blood mononuclear cell (PBMC) cultures from 12 APS patients, 13 systemic lupus erythematosus patients without APS, and 12 healthy donors. Results Peripheral blood T cells from all subjects failed to respond to β2GPI in its native form. In contrast, reduced β2GPI was able to stimulate T cells not only from all 12 patients with anti-β2GPI antibodies, but also from 10 of 25 individuals without anti-β2GPI antibodies. The specificity of the responses to β2GPI was confirmed by activation of the reduced β2GPI-primed T cells by recombinant β2GPI in secondary cultures. Characterization of the T cell response induced by β2GPI revealed that the response was associated with the presence of the DR53-associated alleles, the responding T cells were CD4+ and restricted by HLA class II, and antigenic peptides were located in domains IV and/or V. Anti-β2GPI antibody production was induced specifically in anti-β2GPI antibody–positive patients, in PBMC cultures with reduced β2GPI. Anti-β2GPI antibodies produced in vitro recognized β2GPI immobilized with cardiolipin or β2GPI coated on “high-binding” polystyrene plates. Conclusion These results strongly suggest that CD4+ and HLA class II–restricted T cells responsive to β2GPI are involved in the production of antiphospholipid antibodies in APS patients.