Excessive exposure to anionic surfaces maintains autoantibody response to β₂-glycoprotein I in patients with antiphospholipid syndrome

Antiphospholipid syndrome (APS) is an autoimmune prothrombotic disorder associated with autoantibodies to phospholipid (PL)-binding proteins, such as β₂-glycoprotein I (β₂GPI). We have recently reported that binding of β₂GPI to anionic PL facilitates processing and presentation of the cryptic β₂GPI epitope that activates pathogenic autoreactive T cells. To clarify mechanisms that induce sustained presentation of the dominant antigenic β₂GPI determinant in patients with APS, T-cell proliferation induced by β₂GPI-treated phosphatidylserine liposome (β ₂GPI/PS) was evaluated in bulk peripheral blood mononuclear cell cultures. T cells from patients with APS responded to β₂GPI/PS in the presence of immunoglobulin G (IgG) anti-β₂GPI antibodies derived from APS plasma, and this response was completely inhibited either by the depletion of monocytes or by the addition of anti-FcγRI antibody. These findings indicate that efficient presentation of the cryptic determinants can be achieved by monocytes undergoing FcγRI-mediated uptake of β₂GPI-bound anionic surfaces in the presence of IgG anti-β₂GPI antibodies. Finally, β₂GPI-bound oxidized LDL or activated platelets also induced the specific T-cell response. Continuous exposure to these anionic surfaces may play a critical role in maintaining the pathogenic anti-β₂GPI antibody response in patients with APS.