Beta2-glycoprotein I: antiphospholipid syndrome and T-cell reactivity.

There is increasing evidence showing that recurrent thrombosis and intrauterine fetal loss in antiphospholipid syndrome (APS) are attributable to antiphospholipid (aPL) antibodies. We have recently identified autoreactive CD4+ T cells to beta2-glycoprotein I (beta2GPI) that promote production of pathogenic antiphospholipid antibodies. beta2GPI-specific CD4+ T cells preferentially recognize the antigenic peptide containing the major phospholipid (PL)-binding site in the context of DR53. T-cell helper activity that stimulates B cells to produce IgG anti-beta2GPI antibodies is mediated through IL-6 and CD40-CD154 interaction. beta2GPI-specific T cells respond to reduced beta2GPI and recombinant beta2GPI fragments produced in a bacterial expression system but not to native beta2GPI, indicating that the epitopes recognized by beta2GPI-specific T cells are 'cryptic' determinants, which are generated at a subthreshold level by the processing of native beta2GPI under normal circumstances. Although beta2GPI-specific T cells are detected in both APS patients and healthy individuals, these autoreactive T cells are activated in vivo in APS patients but not in healthy individuals. These findings indicate activation of beta2GPI-specific T cells and subsequent production of pathogenic anti-beta2GPI antibodies can be induced by the exposure of such T cells to cryptic peptides of beta2GPI efficiently presented by functional antigen-presenting cells (APC). Delineating the mechanisms that induce the efficient processing and presentation of cryptic determinants of beta2GPI as a consequence of antigen processing would clarify the etiology that initiates the autoantibody response in APS.