Autoimmunity beyond antibodies: alternative roles of beta-2-glycoprotein I in and out of antiphospholipid syndrome?

The term autoimmune disease refers to autoantibody-dependent pathophysiological conditions, in which characterising the autoantibodies is essential, as is studying their target(s), the (auto)antigen(s), which represent the other side of the coin. In this review, we aimed to go further inside the ultimate experimental works on the pathophysiology of Beta-2-Glycoprotein I (B2GPI), the main target of the antiphospholipid antibodies (aPL) in Antiphospholipid Syndrome (APS). This protein is almost unique in the body. It is able to up and down regulate the complement and the coagulative cascade and displays pleiotropic functions that are still to be fully understood. Many recent omics-based experimental approaches have found B2GPI among the proteins involved in both acute and chronic disease conditions. These range from inflammatory diseases to cancer. The protein's ability to modulate biological processes like apoptosis, redox impairment, cardiolipin binding, lipopolysacharide, and circulating mitochondria scavenging suggests its role in homeostasis, both as an acute phase modulator and a tolerogenic spark. We imagined B2GPI as a sentinel protein, patrolling tissues as part of a complex system of interacting molecules: the fine-tuning regulation of its threshold in circulation and on solid-target tissues may hold the key to its reactivity. The aPL might represent the prototypical way of this threshold dysfunction. The change in focus towards the antigen might help APS therapeutic approaches and aid in understanding different clinical outcomes. Moreover, it reveals a fascinating protein, acting like a safety net in the body, whose disruption can lead to a wide range of pathophysiological conditions.