The Role of TLR4 on B Cell Activation and Anti- β2GPI Antibody Production in the Antiphospholipid Syndrome

Abstract

High titer of anti-β₂-glycoprotein I antibodies (anti-β₂GPI Ab) plays a pathogenic role in antiphospholipid syndrome (APS). Numerous studies have focused on the pathological mechanism in APS; however, little attention is paid to the immune mechanism of production of anti-β₂GPI antibodies in APS. Our previous study demonstrated that Toll-like receptor 4 (TLR4) plays a vital role in the maturation of bone marrow-derived dendritic cells (BMDCs) from the mice immunized with human β₂-glycoprotein I (β₂GPI). TLR4 is required for the activation of B cells and the production of autoantibody in mice treated with β₂GPI. However, TLR4 provides a third signal for B cell activation and then promotes B cells better receiving signals from both B cell antigen receptor (BCR) and CD40, thus promoting B cell activation, surface molecules expression, anti-β₂GPI Ab production, and cytokines secretion and making B cell functioning like an antigen presenting cell (APC). At the same time, TLR4 also promotes B cells producing antibodies by upregulating the expression of B-cell activating factor (BAFF). In this paper, we aim to review the functions of TLR4 in B cell immune response and antibody production in autoimmune disease APS and try to find a new way for the prevention and treatment of APS.

Figure 1

The model for antigen-triggered B cell activation. A model was proposed for B cell-mediated, TLR4-dependent roles of phospholipid-binding protein (human β ₂GPI), and innate immune activation in the development of APS-related autoantibodies. This figure outlines two approaches in the process leading to the development of anti-β ₂GPI autoantibodies: (a) TD-Ag pathway: Stage 1, activation of DCs and human β ₂GPI-specific T cells, Stage 2, activation of human β ₂GPI-specific B cells, and Stage 3, the production of anti-β ₂GPI autoantibodies and cytokine. (b) TI-Ag pathway: B cell tolerance is broken down in human β ₂GPI-specific B cells that recognize self-Ags (human β ₂GPI). Then, these B cells present human β ₂GPI to any human β ₂GPI-specific T cells that can recognize a self-Ag epitope recognized by the B cells, leading to the activation of human β ₂GPI-specific T cells. These activated T cells provide help to the cognate B cells, leading to the production of anti-β ₂GPI autoantibodies. At last, the activated B cells can present various self-Ag epitopes to T cells with different specificity allowing them in turn to promote the activation of additional human β ₂GPI-specific B cells.