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β2 glycoprotein I (β2GPI)-dependent anti-phospholipid antibodies (aPL) induce thrombosis and affect pregnancy. The CMV-derived synthetic peptide TIFI mimics the PL-binding site of β2GPI and inhibits β2GPI cell-binding in vitro and aPL-mediated thrombosis in vivo. Here we investigated the effect of TIFI on aPL-induced fetal loss in mice. TIFI inhibitory effect on in vitro aPL binding to human trophoblasts was evaluated by indirect immunofluorescence and ELISA. TIFI effect on aPL-induced fetal loss was investigated in pregnant C57BL/6 mice treated with aPL or normal IgG (NHS). Placenta/fetus weight and histology and RNA expression were analyzed. TIFI, but not the control peptide VITT, displayed a dose-dependent inhibition of aPL binding to trophoblasts in vitro. Injection of low doses of aPL at day 0 of pregnancy caused growth retardation and increased fetal loss rate, both significantly reduced by TIFI but not VITT. Consistent with observations in humans, histological analysis showed no evidence of inflammation in this model, as confirmed by the absence of an inflammatory signature in gene expression analysis, which in turn revealed a TIFI-dependent modulation of molecules involved in differentiation and development processes. These findings support the non-inflammatory pathogenic role of aPL and suggest innovative therapeutic approaches to aPL-dependent fetal loss., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Pentraxins are a family of multimeric pattern recognition proteins highly conserved in evolution. On the basis of the primary structure of the protomer, pentraxins are divided into two groups: short pentraxins and long pentraxins. C reactive protein, the first pattern recognition receptor identified, and serum amyloid P component are classic short pentraxins produced in the liver in response to IL-6. Long pentraxins, including the prototype PTX3, are expressed in a variety of tissues. PTX3 is produced by a variety of cells and tissues, most notably dendritic cells and macrophages, in response to Toll-like receptor (TLR) engagement and inflammatory cytokines. Through interaction with several ligands, including selected pathogens and apoptotic cells, pentraxins play a role in complement activation, pathogen recognition and apoptotic cell clearance. In addition, PTX3 is involved in the deposition of extracellular matrix and female fertility. Unlike the classic short pentraxins CRP and SAP, PTX3 primary sequence and regulation are highly conserved in man and mouse. Thus, gene targeting identified PTX3 (and presumably other members of the family) as multifunctional soluble pattern recognition receptors acting as a nonredundant component of the humoral arm of innate immunity and involved in tuning inflammation, matrix deposition, and female fertility. (c) 2009 International Union of Biochemistry and Molecular Biology, Inc.

Other than signalling receptors sustaining leucocyte recruitment during inflammatory reactions, the chemokine system includes 'silent' receptors with distinct specificity and tissue distribution. The best-characterized molecule of this subgroup is the CC chemokine receptor D6, which binds most inflammatory CC chemokines and targets them to degradation via constitutive ligand-independent internalization. Structure-function analysis and recent results with gene-targeted animals indicate that D6 has unique functional and structural features, which make it ideally adapted to act as a chemokine decoy and scavenger receptor, strategically located on lymphatic endothelium and placenta to dampen inflammation in tissues and draining lymph nodes.