, MD; the GACI Study GroupBackground-Generalized arterial calcification of infancy has been reported to be frequently lethal, and the efficiency of any therapy, including bisphosphonates, is unknown. A phosphate-poor diet markedly increases survival of NPP1 null mice, a model of generalized arterial calcification of infancy. Methods and Results-We performed a multicenter genetic study and retrospective observational analysis of 55 subjects affected by generalized arterial calcification of infancy to identify prognostic factors. Nineteen (34%) patients survived the critical period of infancy. In all 8 surviving patients tested, hypophosphatemia due to reduced renal tubular phosphate reabsorption developed during childhood. Eleven of 17 (65%) patients treated with bisphosphonates survived. Of 26 patients who survived their first day of life and were not treated with bisphosphonates only 8 (31%) patients survived beyond infancy. Forty different homozygous or compound heterozygous mutations, including 16 novel mutations in ENPP1, were found in 41 (75%) of the 55 patients. Twenty-nine (71%) of these 41 patients died in infancy (median, 30 days). Seven of the 14 (50%) patients without ENPP1 mutations died in infancy (median, 9 days). When present on both alleles, the mutation p.P305T was associated with death in infancy in all 5 cases; otherwise, no clear genotype-phenotype correlation was seen. Conclusion-ENPP1 coding region mutations are associated with generalized arterial calcification of infancy in Ϸ75% of subjects. Except for the p.P305T mutation, which was universally lethal when present on both alleles, the identified ENPP1 mutations per se have no discernable effect on survival. However, survival seems to be associated with hypophosphatemia linked with hyperphosphaturia and also with bisphosphonate treatment. ENPP1 encodes a type II transmembrane glycoprotein ectoenzyme that forms homodimers of identical disulfidebonded subunits. 7 NPP1 has an extracellular catalytic domain as well as somatomedin B-like and substrate-binding or substrate-specifying nuclease-like domains. 8 NPP1 regulates soft tissue calcification and bone and joint cartilage mineralization by generating PP i , which not only serves as an essential physiological inhibitor of hydroxyapatite crystal growth 9 but also is a suppressor of chondrogenesis. 10 In artery smooth muscle cells, deficiencies of NPP1 (or of extracellular PP i without NPP1 deficiency in ank/ank mice homozygous for functional inactivation of the PP i transporter ANK) promote chondrogenic transdifferentiation in vivo and also in vitro under circumstances where excess of an inorganic phosphate (P i ) source is provided. 10,11 Although the pathophysiologic role of NPP1-mediated PP i generation in GACI has come to light within recent years, the factors accounting for the variation of the GACI phenotype including the presence or absence of intracerebral artery calcification and periarticular calcification, early death in utero and long-term survival are not known. 12 PP i and ...

Endocytic segregation of gliadin peptide AA 31-49 seems to be a constitutive process. It explains why this peptide cannot stimulate gluten-sensitive T cells. Presentation of gliadin peptides by HLA-DR proteins via late endosomes within enterocytes might induce a tolerogenic effect and constitutes a potentially promising therapeutic approach for induction of tolerance towards gliadin.

S phingosine 1-phosphate (S1P) is a pleiotropic lipid mediator produced by phosphorylation of sphingosine by sphingosine kinases 1 and 2 in response to a variety of stimuli.1,2 S1P interacts with 5 related G-protein-coupled receptors termed S1P receptor (S1PR) types 1 to 5, which regulate a wide spectrum of cellular functions, including proliferation and survival, cytoskeletal rearrangements, and cell motility, and exert potent cytoprotective effects. 3,4 In the vasculature, S1PR1, 2, and 3 were identified on endothelial surface, whereas S1PR2 and S1PR3 are present on smooth muscle cells. Through these receptors S1P is believed to provide essential contribution to the new vessel formation and the maintenance of vascular barrier integrity. 5,6 In addition, S1P was demonstrated to interfere with proliferation, migration, and activation of lymphocytes and monocytes/macrophages and to regulate their recruitment to sites of inflammation. 7-9 These immunomodulatory activities, which are mediated by S1PR1 and 4 on lymphocytes and S1PR1, 2, 3, and 4 on macrophages, likely account for beneficial effects exerted by S1P and its analogues in animal models of inflammatory diseases, such as ulcerating colitis, viral myocarditis, endotoxin-induced lung injury, or autoimmune encephalomyelitis. 10-13Erythrocytes and platelets are major sources of S1P in plasma, where it is associated with a subfraction(s) of high-density lipoprotein (HDL)-a potent plasma-borne antiatherogenic factor. [14][15][16] There is substantial evidence © 2013 American Heart Association, Inc. Objective-Sphingosine 1-phosphate (S1P) partly accounts for antiatherogenic properties of high-density lipoproteins. We previously demonstrated that FTY720, a synthetic S1P analog targeting all S1P receptors but S1P receptor type 2, inhibits murine atherosclerosis. Here, we addressed the identity of S1P receptor mediating atheroprotective effects of S1P. Approach and Results-Low-density lipoprotein receptor-deficient mice on cholesterol-rich diet were given selective S1P receptor type 1 agonist KRP-203 ( T cells in peripheral lymphoid organs, and interfered with lymphocyte function, as evidenced by decreased T-cell proliferation and interleukin-2 and interferon-γ production in activated splenocytes. Cyto-and chemokine (tumor necrosis factor-α, regulated and normal T cell expressed and secreted) levels in plasma and aortas were reduced by KRP-203 administration. Moreover, macrophages from KRP-203-treated mice showed reduced expression of activation marker MCH-II and poly(I:C)-elicited production of tumor necrosis factor-α, monocyte chemoattractant protein-1, and interleukin-6. In vitro studies demonstrated that KRP-203 reduced tumor necrosis factor-α, interleukin-6, and interferon-γ-induced protein-10 production; IκB and signal transducer and activator of transcription-1 phosphorylation; and nuclear factor κB and signal transducer and activator of transcription-1 activation in poly(I:C)-, lipopolysaccharide-, or interferon-γ-stimulated bone marrow macrophages, respec...