T cells that are autoreactive to beta(2)-glycoprotein I in patients with antiphospholipid syndrome and healthy individuals

Objective. To identify the T cells responsive to beta(2)-glycoprotein I (be ta(2)GPI) that mediate antiphospholipid antibody production in patients wit h antiphospholipid syndrome (APS). Methods. In vitro proliferative responses and ;anti-beta(2)GPI antibody pro duction induced by beta(2)GPI 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 be ta(2)GPI in its native form. In contrast, reduced beta(2)GPI was able to st imulate T cells not only from all 12 patients with anti-beta(2)GPI antibodi es, but also from 10 of 25 individuals without anti-beta(2)GPI antibodies. The specificity of the responses to beta(2)GPI was confirmed by activation of the reduced beta(2)GPI-primed T cells by recombinant beta(2)GPI in secon dary cultures. Characterization of the T cell response induced by beta(2)GP I revealed that the response was associated with the presence of the DR53-a ssociated alleles, the responding T cells were CD4+ and restricted by HLA c lass II, and antigenic peptides were located in domains IV and/or V, Anti-b eta(2)GPI antibody production was induced specifically in anti-beta(2)GPI a ntibody-positive patients, in PBMC cultures with reduced beta(2)GPI. Anti-b eta(2)GPI antibodies produced in vitro recognized beta(2)GPI immobilized wi th cardiolipin or beta(2)GPI coated on "high-binding" polystyrene plates. Conclusion. These results strongly suggest that CD4+ and HLA class II-restr icted T cells responsive to beta(2)GPI are involved in the production of an tiphospholipid antibodies in APS patients.