The dual role of innate immunity in the antiphospholipid syndrome.
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 beta(2)-glycoprotein I (beta(2)GPI) and lipopolysaccharide (LPS), a TLR ligand, produce high levels of aPL and other SLE-associated 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.
Rauch
J
J
Division of Rheumatology, The Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada. joyce.rauch@mcgill.ca
Dieudé
M
M
Subang
R
R
Levine
J S
JS
D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000276:immunology*; D016736:Antiphospholipid Syndrome / Q000150:complications / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D007113:Immunity, Innate; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000276:immunology; D051379:Mice; D013927:Thrombosis / Q000209:etiology / Q000276:immunology; D051193:Toll-Like Receptors / Q000378:metabolism
D017152:Antibodies, Antiphospholipid; D051193:Toll-Like Receptors