title: A role for Toll-like receptor mediated signals in neutrophils in the pathogenesis of the anti-phospholipid syndrome.
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.
authors.affiliation: Institute of Immunology, Johannes Gutenberg-University Medical Center, Mainz, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Gladigau
authors.forename: Philipp
authors.initials: P
authors.lastname: Haselmayer
authors.forename: Inge
authors.initials: I
authors.lastname: Scharrer
authors.forename: Markus
authors.initials: M
authors.lastname: Munder
authors.forename: Nadine
authors.initials: N
authors.lastname: Prinz
authors.forename: Karl
authors.initials: K
authors.lastname: Lackner
authors.forename: Hansjörg
authors.initials: H
authors.lastname: Schild
authors.forename: Pamela
authors.initials: P
authors.lastname: Stein
authors.forename: Markus P
authors.initials: MP
authors.lastname: Radsak
mesh_terms: D016736:Antiphospholipid Syndrome / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D017209:Apoptosis; D039481:CD11b Antigen / Q000276:immunology; D005434:Flow Cytometry; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D019041:L-Selectin / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D018375:Neutrophil Activation; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D010587:Phagocytosis; D016897:Respiratory Burst; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D039481:CD11b Antigen; D016209:Interleukin-8; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D019041:L-Selectin