Abstract
The anti-phospholipid syndrome (APS) is characterized by recurrent thrombosis and occurrence of anti-phospholipid antibodies (aPL). aPL are necessary, but not sufficient for the clinical manifestations of APS. Growing evidence suggests a role of innate immune cells, in particular polymorphonuclear neutrophils (PMN) and Toll-like receptors (TLR) to be additionally involved. aPL activate endothelial cells and monocytes through a TLR4-dependent signalling pathway. Whether this is also relevant for PMN in a similar way is currently not known. To address this issue, we used purified PMN from healthy donors and stimulated them in the presence or absence of human monoclonal aPL and the TLR4 agonist LPS monitoring neutrophil effector functions, namely the oxidative burst, phagocytosis, L-Selectin shedding and IL-8 production. aPL alone were only able to induce minor activation of PMN effector functions at high concentrations. However, in the additional presence of LPS the activation threshold was markedly lower indicating a synergistic activation pathway of aPL and TLR in PMN. In summary, our results indicate that PMN effector functions are directly activated by aPL and boosted by the additional presence of microbial products. This highlights a role for PMN as important innate immune effector cells that contribute to the pathophysiology of APS.
Highlights
The anti-phospholipid syndrome (APS) is a systemic autoimmune disease characterized by an adaptive immune response against self membrane anionic phospholipids or associated plasma proteins resulting in the generation of anti-phospholipid specific antibodies [1] and APS patients show a high risk for venous or arterial thrombosis. 2% of the general population develop APS affecting in particular females [2,3]
Since polymorphonuclear neutrophils (PMN) are important participants of innate immune responses and express various Toll-like receptors (TLR) [32], there might be a direct role for TLR mediated activation of PMN in the course of disease
We show that human purified aPL had an impact on PMN function, namely on the induction of phagocytosis
Summary
The anti-phospholipid syndrome (APS) is a systemic autoimmune disease characterized by an adaptive immune response against self membrane anionic phospholipids or associated plasma proteins resulting in the generation of anti-phospholipid specific antibodies (aPL) [1] and APS patients show a high risk for venous or arterial thrombosis. 2% of the general population develop APS affecting in particular females [2,3]. The anti-phospholipid syndrome (APS) is a systemic autoimmune disease characterized by an adaptive immune response against self membrane anionic phospholipids or associated plasma proteins resulting in the generation of anti-phospholipid specific antibodies (aPL) [1] and APS patients show a high risk for venous or arterial thrombosis. Analyzing the participation of aPL in pregnancy loss during APS in more detail revealed that aPL apparently have a direct impact on complement activation as shown in animal models, where LPS pretreated rats received transfer of polyclonal IgG aPL from patients with APS [5]. Thrombus is induced dependent on the activation of C5 and C6 as well as on b2-GPI-reactive aPL. In line with these results, Girardi et al showes that C5-deficient mice are protected from aPL-
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