Examining how antiphospholipid antibodies activate intracellular signaling pathways: a systematic review.

Objectives: Diverse experimental evidence exists implicating the activation of various different cell surface receptors and intracellular pathways by antiphospholipid antibodies (aPL). This evidence has been generated using a number of different cell types with varying numbers of aPL from different sources and disease subtypes. This experimental variability complicates the comparison of results from different studies. We therefore undertook a systematic review of the literature to provide a critical analysis of the strength of the evidence that specific receptors and signaling pathways are important in the pathogenesis of antiphospholipid syndrome.

Methods: We searched PubMed and EMBASE for studies in which the effects of aPL on cell surface receptors or intracellular signaling pathways were measured in vitro or in vivo. Each publication was systematically examined to note the following points: antibody type and source, outcome measures, use of receptor/signaling pathway inhibitors, and cell type and origin.

Results: We identified 10 original studies on toll-like receptors (TLR), 14 on protein kinases, and 13 on nuclear factor kappa B (NFκB). There was considerable heterogeneity between studies. Nevertheless, convincing evidence from multiple approaches implicates TLR4, p38 mitogen-activated protein kinase (MAPK), and NFκB in mediating pathogenic effects of antiphospholipid antibodies.

Conclusions: TLR4, p38 MAPK and NFκB are involved in mediating pathogenic effects of aPL on different cell types and may be potential therapeutic targets in antiphospholipid syndrome.