The association of the persistent presence of circulating antiphospholipid antibodies (aPLs) and recurrent vascular thrombosis and/or pregnancy morbidity is known as anti-phospholipid syndrome (APS). Although aPLs were originally thought to be directed against anionic phospholipids (PLs), evidence shows that PL-binding plasma proteins such as β2-glycoprotein I (β2GPI) and prothrombin are the dominant antigenic targets in APS.1
The autoantibody pathogenicity of APS is one of the clearest among the autoimmune diseases. Numerous studies on the pathophysiology of APS have analyzed the mechanism by which aPLs produce thrombophilia or pregnancy morbidity. It is now accepted that procoagulant cells exposed to aPLs via β2GPI or other PL-binding proteins produce thrombophilic substances such as tissue factor, followed by thrombin generation. Recently, great interest has arisen concerning the intracellular signal transduction mechanisms involved in the increased expression of procoagulant substances in response to aPLs, and several groups revealed the essential role of p38 mito-gen activated protein kinase (MAPK) pathway in aPL-mediated cell activation.2,3 Currently, researchers exploring the “entrance” of such activation in the signal transduction pathway have unveiled some candidates of the receptor for β2GPI. A series of those studies have been designed to focus the therapeutic target molecules in APS for preventing thrombotic complications. However, this type of therapeutic strategy requires life-long treatment, since patients with persistent aPLs would have a sustained potential of thrombosis.
In the last few years, Kuwana et al4,5 have been performing interesting research in the APS field, investigating T cells responsible for the development of APS, and have identified CD4+ T cells responsive to β2GPI or to the peptides derived from β2GPI. In this issue of Blood, Yamaguchi and colleagues have focused on the role of aPLs in T-cell response. They examine the potential cellular and molecular factors required for the sustained activation of β2GPI reactive CD4+ T cells in APS and elegantly demonstrate that β2GPI-reactive CD4+ T-cell proliferation depends on monocytes as antigen-presenting cells (APCs). The reaction was observed only in the presence of anti-β2GPI antibodies and was mediated by Fcγreceptor I. This result suggests that the opsonization of the β2GPI/phosphatidylserine complex by the IgG anti-β2GPI antibody is essential for efficient antigen presentation from monocytes to T cells and eventually for maintaining the pathogenic anti-β2GPI antibody response in patients with APS. The findings are the first evidence of uptake and presentation of β2GPI by APCs. Antigen uptake, processing, and presentation are the first steps following the exposure of antigen to the immune system. If we could artificially control this procedure to reduce β2GPI-reactive CD4+ T-cell response, the subsequent reactions, including anti-β2GPI antibody production, would not occur, thus curing the disease. These novel findings and this research mark a significant advance in understanding the most fundamental immunological reactions in APS and open a new insight into possible therapeutical approaches to APS, focusing on the blockage of the autoimmune loop carried out by monocytes, β2GPI-reactive CD4+ T cells, and B cells. This type of treatment would be specific to and curative for the autoimmune dependent diseases.
Conflict-of-interest disclosure: The author declares no competing financial interests. ■