On a strict GFD, children report greater rates of both GI and EI symptom resolution as compared to adults with greater rates of improvement in GI over EI symptoms. Early recognition of CeD and close attention to diet adherence may help in symptom resolution.
Heparin-induced thrombocytopenia (HIT)is caused by antibodies that recognize complexes between platelet factor 4 (PF4) and heparin or glycosaminoglycan side chains. These antibodies can lead to a limb-and life-threatening prothrombotic state. We now show that HIT antibodies are able to inhibit generation of activated protein C (aPC) by thrombin/ thrombomodulin (IIa/TM) in the presence of PF4. Tetrameric PF4 potentiates aPC generation by formation of complexes with chondroitin sulfate (CS) on TM. Formation of these complexes occurs at a specific molar ratio of PF4 to glycosaminoglycan. This observation and the finding that the effect of heparin on aPC generation depends on the concentration of PF4 suggest similarity between PF4/CS complexes and those that bind HIT antibodies. HIT antibodies reduced the ability of PF4 to augment aPC formation. Cationic protamine sulfate, which forms similar complexes with heparin, also enhanced aPC generation, but its activity was not blocked by HIT antibodies. Our studies provide evidence that complexes formed between PF4 and TM's CS may play a physiologic role in potentiating aPC generation. IntroductionMany of the biologic effects of platelet factor 4 (PF4) result from its ability to bind to cell-surface glycosaminoglycans (GAGs) and other negatively charged molecules. 1 GAGs bind with high affinity to an equatorial band of positively charged residues on the surface of the PF4 homotetramer. 2 Using PF4 mutant K50E, we have previously shown that interfering with tetramer formation between PF4 dimers results in a marked loss in affinity for GAGs. 3 Tetrameric PF4 bound to negatively charged molecules, such as heparin, forms large complexes at a specific molar ratio that dissociate in the presence of excess of either PF4 or the negatively charged molecule. 3,4 At least 2 populations of PF4/heparin complexes were observed depending on the PF4 to heparin molar ratio. 3 The ultralarge (Ͼ 670 kDa) complexes formed at 1:1 ratio are stable and have been visualized using rotary shadowed electron microscopy. 3 They are also the colloidal complexes at neutralizing molar ratios of PF4 and heparin. 4 Similar large, colloidal complexes form between heparin or GAGs and other small positively charged proteins, including protamine sulfate (PRT), 5 supporting an electrostatic basis for this interaction. These PF4/heparin complexes are an antigenic target in heparin-induced thrombocytopenia (HIT), and each complex is capable of binding multiple HIT-like monoclonal antibodies KKO. 3 The observation that these complexes form only over a narrow range of PF4 to heparin ratio probably explains why binding of HIT antibodies and KKO to PF4/heparin mixture follows a bell-shaped curve that depends on the molar ratio of PF4 and heparin. 3,6 KKO and patients' HIT antibodies also recognize PF4 bound to surface GAGs on platelets 7 and monocytes, 8 following a similar bell-shaped curve with maximal binding observed at an exogenous PF4 concentration of 1.6M. Others have shown similar results for surface GAGs o...
Objective-Core2 1-6-N-glucosaminyltransferase-I (C2GlcNAcT-I) modification of adhesion molecules is required for optimal binding to target ligands. The objective of this study was to determine the role of C2GlcNAcT-I in the recruitment of Ly-6C hi monocytes to atherosclerotic lesions and in lesion formation in mice. Methods and Results-In a whole-blood binding assay, Ly-6C hi monocytes and certain lymphocytes and natural killer cells from wild-type mice bound to P-and E-selectin. C2GlcNAcT-I deficiency abrogated leukocyte binding to P-and E-selectin in this assay as well as in an in vitro flow chamber assay. Moreover, C2GlcNAcT-I deficiency decreased Ly-6C hi monocyte interactions with atherosclerotic arteries under physiological flow conditions and also inhibited monocyte recruitment to the peritoneal cavity in mice challenged with thioglycollate. In apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice, lack of C2GlcNAcT-I resulted in fewer and smaller atherosclerotic lesions in mouse aortas. Atherosclerosis was also suppressed in C2GlcNAcT-I Ϫ/Ϫ /apoE Ϫ/Ϫ chimeric mice transplanted with C2GlcNAcT-I Cell-cell interactions are mediated by a wide variety of adhesion molecules, including P-, E-, and L-selectins as well as P-selectin glycoprotein ligand 1 (PSGL-1), CD43, CD44,  2 integrins, and a 4 b 1 , and many others. Most adhesion molecules, such as PSGL-1, CD43, and CD44, are glycoproteins that are modified by Core2 1-6-N-glucosaminyltransferase-I (C2GlcNAcT-I). The role of these C2GlcNAcT-I-modified adhesion molecules in cell-cell interactions has been extensively studied. [3][4][5][6][7] Ly-6C hi monocytes are key contributors to the development of atherosclerosis in mice. 8 Our recent work has demonstrated that PSGL-1 is highly expressed on Ly-6C hi monocytes and is a major determinant for Ly-6C hi monocyte recruitment to sites of atherosclerosis in mice. Deficiency of PSGL-1, a C2GlcNAcT-I-modified molecule, dramatically inhibits the formation of spontaneous atherosclerotic lesions and neointima formation after arterial injury in apoE Ϫ/Ϫ mice. 9 The role of C2GlcNAcT-I deficiency in monocyte homing to the arterial wall and the formation of atherosclerotic lesions has not been studied, however.PSGL-1 contains sialylated and fucosylated oligosaccharides (O-glycans) and has at least one sulfated tyrosine near the N terminus. 10,11 Attachment of the O-glycan to PSGL-1 requires C2GlcNAcT-I, and this modification is crucial for optimal binding of PSGL-1 to selectins as demonstrated by in vitro gene transfer studies. 12,13 The role of C2GlcNAcT-I in leukocyte homing varies under different pathological conditions. For example, C2GlcNAcT-I Ϫ/Ϫ mice are defective in eosinophil and neutrophil trafficking to the peritoneum but not to the lung. 14 Therefore, the role of C2GlcNAcT-I in the regulation of Ly-6C hi monocyte PSGL-1 binding, monocyte recruitment, and formation of atherosclerotic lesions in vivo remains to be clarified.Here, we used Ly-6C hi monocytes from C2GlcNAcT-I monocyte homing. We bred C2GlcNAcT-I Ϫ/Ϫ mice wi...
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