The dual role of innate immunity in the antiphospholipid syndrome

Abstract

The antiphospholipid syndrome (APS), as both a primary syndrome and a syndrome in association with systemic lupus erythematosus (SLE), can be a devastating disease. It is unclear what factors (genetic and/or environmental) lead to the generation of antiphospholipid antibodies (aPL). It is equally unclear why only certain individuals with aPL develop clinical events. We hypothesize that innate immune activation plays a critical role at two distinct stages of APS, namely, the initiation phase, in which aPL first appear, and the effector phase, in which aPL precipitate a thrombotic event. According to the model we propose, aPL alone are insufficient to cause thrombosis and a concomitant trigger of innate immunity, e.g. a toll-like receptor (TLR) ligand, must be present for thrombosis to occur. Here, we discuss our findings that mice immunized with β 2 -glycoprotein I (β 2 GPI) and lipopolysaccharide (LPS), a TLR ligand, produce high levels of aPL and other SLEassociated autoantibodies, and develop lupus-like glomerulonephritis. We also discuss our data showing that autoantibodies to heat shock protein 60 (HSP60), an 'endogenous TLR ligand', promote thrombus generation in a murine model of arterial injury. Thus, both pathogen-derived TLR ligands (e.g. LPS) and endogenous TLR ligands (e.g. HSP60) may contribute to the pathogenesis of APS. This putative dual role of innate immunity provides new insight into the generation of aPL as well as the enigma of why some individuals with aPL develop APS, while others do not.

Pathogenic Mechanisms of Thrombosis in Antiphospholipid Syndrome (APS)

“…It remains unclear why only some people with aPL develop clinical manifestations of disease. It has been argued by several researchers that the activation of innate immunity plays a critical role in two separate stages: a) the "immune" phase, critical for aPL production and b) the "pathological "phase, in which autoantibodies become involved in the induction of thrombosis [ 123 ]. According to this model, aPL alone is insufficient to cause thrombosis and thus requires the concomitant triggering of innate immunity (e.g., a ligand for TLRs).…”

Antiphospholipid Syndrome: Changing Knowledge During the Time – The ”Four P” Pattern

“…The most recent knowledge in pathophysiology of antiphospholipid antibodies was widely discussed at the 13 th international congress on anthiphospholipid antibodies, which was held in April 2010 at Galveston, Texas, USA. The role of innate immunity was described by Rauch (Rauch J, et al;2010). The role of tissue factor was summarised by Boles and Mackman (Boles J, Mackman N;2010).…”

The role of TLR4 in pathophysiology of antiphospholipid syndrome‐associated thrombosis and pregnancy morbidity

“…In this autoimmune spiral, the human b2GPI-specific T cell can provide help to any B cell that internalizes an apoptotic cell binding human b2GPI on its surface. In this way, multiple autoreactive B cells can be activated by a single human b2GPI-specific T-cell and produce high titres of aPL and other SLE autoantibodies (Levine et al, 2006;Rauch et al, 2010).…”