| Antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the presence of autoantibodies to phospholipid (PL)-binding proteins, such as beta2-glycoprotein I (beta2GPI), and clinical manifestations including thrombosis and/or recurrent pregnancy loss. beta2GPI-reactive T cells have been shown to be activated in patients with APS, but the mechanism responsible for this activation remains unclear. Recent studies have proposed that exposure of a cryptic epitope on beta2GPI, as a consequence of binding to PL, leads to the activation of beta2GPI-autoreactive T cells in APS patients. To test this hypothesis, we evaluated the development of beta2GPI-reactive T cells in a murine model of aPL production. C57BL/6 mice were immunized repeatedly with human beta2GPI in the presence of lipopolysaccharide (LPS) to induce aPL production. High levels of circulating aPL were observed as early as the second immunization, but splenic T cell reactivity to beta2GPI was not detectable in vitro until after the fourth immunization. Splenic T cells from mice producing high levels of aPL proliferated in response to native human beta2GPI, alone or bound to anionic PL, but PL-bound beta2GPI appeared to be a more potent antigen. beta2GPI-reactive T cells produced IL-2 and IFN-gamma, but not IL-4 or IL-10, suggesting a TH1 bias of this T cell response. These results demonstrate that T cell reactivity to beta2GPI can develop in nonautoimmune individuals repeatedly exposed to this antigen in a proinflammatory context (e.g., LPS). Our data further suggest that the beta2GPI-reactive T cells induced in this model have a TH1 bias and may be more reactive to a PL-dependent epitope on beta2GPI than to native beta2GPI. |
