Schematic representation of the hypothesis that anti–β₂-GPI Abs in complex with β₂-GPI may be able to amplify the production of autoantibodies via their ability to bind and crosslink TLR4. (A) The steps that have been delineated in in vitro experiments to be important in the generation of autoantibodies directed against β₂-GPI. Step 1: the uptake and intracellular processing of the autoantigen β₂-GPI (complexed to phospholipid or in the oxidized form) via as yet poorly delineated mechanisms. Step 2: the presentation (by activated DCs) of the β₂-GPI cryptic epitope to autoreactive CD4⁺ HLA class II–restricted T cells. DCs have been shown to release an array of cytokines that lead to Th1 polarization. Step 3: activated autoreactive CD4⁺ T cells providing help to autoreactive B cells, which have also received a signal via the B-cell receptor (BCR) (see step 4). Step 4: the ligation by β₂-GPI of the B-cell receptor on autoreactive B cells. Step 5: anti–β₂-GPI autoantibody production. (B) It is hypothesized that oxidized β₂-GPI or the anti–β₂-GPI Ab/β₂-GPI complex may function as an immunologic adjuvant by providing a costimulatory signal via TLR4 on DCs (circled A) and B cells (circled B), leading to the amplification of the signals delineated in panel A. The thick blue line denotes the amplification of steps 1 to 5.