bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intestinal T Cell Responses to Gluten Peptides Are Largely Heterogeneous: Implications for a Peptide-Based Therapy in Celiac Disease
Authors: Camarca Alessandra , Anderson Robert P. , Mamone Gianfranco , Fierro Olga , Facchiano Angelo , Costantini Susan , Zanzi Delia , Sidney John , Auricchio Salvatore , Sette Alessandro , Troncone Riccardo , Gianfrani Carmen 
Published: March 2009

Abstract
The identification of gluten peptides eliciting intestinal T cell responses is crucial for the design of a peptide-based immunotherapy in celiac disease (CD). To date, several gluten peptides have been identified to be active in CD. In the present study, we investigated the recognition profile of gluten immunogenic peptides in adult HLA-DQ2+ celiac patients. Polyclonal, gliadin-reactive T cell lines were generated from jejunal mucosa and assayed for both proliferation and IFN-γ production in response to 21 peptides from wheat glutenins and α-, γ-, and ω-gliadins. A magnitude analysis of the IFN-γ responses was performed to assess the hierarchy of peptide potency. Remarkably, 12 of the 14 patients recognized a different array of peptides. All α-gliadin stimulatory peptides mapped the 57–89 N-terminal region, thus confirming the relevance of the known polyepitope 33-mer, although it was recognized by only 50% of the patients. By contrast, γ-gliadin peptides were collectively recognized by the great majority (11 of 14, 78%) of CD volunteers. A 17-mer variant of 33-mer, QLQPFPQPQLPYPQPQP, containing only one copy of DQ2-α-I and DQ2-α-II epitopes, was as potent as 33-mer in stimulating intestinal T cell responses. A peptide from ω-gliadin, QPQQPFPQPQQPFPWQP, although structurally related to the α-gliadin 17-mer, is a distinct epitope and was active in 5 out of 14 patients. In conclusion, these results showed that there is a substantial heterogeneity in intestinal T cell responses to gluten and highlighted the relevance of γ- and ω-gliadin peptides for CD pathogenesis. Our findings indicated that α-gliadin (57–73), γ-gliadin (139–153), and ω-gliadin (102–118) are the most active gluten peptides in DQ2+ celiac patients.
Novel Subset of CD8α+ Dendritic Cells Localized in the Marginal Zone Is Responsible for Tolerance to Cell-Associated Antigens
Authors: Qiu Chun-Hong , Miyake Yasunobu , Kaise Hitomi , Kitamura Hiroshi , Ohara Osamu , Tanaka Masato 
Published: March 2009

Abstract
Apoptotic cell clearance by dendritic cells (DCs) plays a crucial role in the maintenance of self-tolerance. In spleen, CD8α+ DCs are thought to be responsible for this phenomenon by phagocytosing circulating apoptotic cells. However, as CD8α+ DCs are believed to be predominantly localized in the T cell zone, it remains unclear how these DCs phagocytose blood-borne apoptotic cells accumulated in the marginal zone (MZ). In this study, we identified a subpopulation of CD8α+ DCs responsible for tolerance induction to cell-associated Ags. Among splenic CD8α+ DCs, the CD103+,CD207+ subset was preferentially localized in the MZ and dominantly phagocytosed blood-borne apoptotic cells. After phagocytosis of apoptotic cells, this DC subset migrated into the T cell zone for cross-presentation of cell-associated Ags. Stimulation of TLRs induced the disappearance of this DC subset. Consequently, CD8α+ DCs neither phagocytosed injected apoptotic cells nor presented cell-associated Ags in mice treated with TLR ligands. Transient ablation of this DC subset by cytochrome c injection resulted in a failure of tolerance induction to cell-associated Ags, indicating that this DC subset is essential for tolerance induction by apoptotic cell clearance.
Modulation of T Lymphocyte Replicative Senescence via TNF-α Inhibition: Role of Caspase-3
Authors: Parish Stanley T. , Wu Jennifer E. , Effros Rita B. 
Published: March 2009

Abstract
Expanded populations of CD8+ T lymphocytes lacking CD28 expression are associated with a variety of deleterious clinical outcomes, including early mortality in the elderly, more rapid progression to AIDS, cardiovascular disease, and enhanced tumor cell growth. In cell culture, irreversible loss of CD28 expression correlates with increased production of TNF-α as CD8+ T cells are driven to the nonproliferative end stage of replicative senescence by multiple rounds of Ag-driven cell division. Interestingly, in patients with rheumatoid arthritis, inhibition or neutralization of TNF-α reduces the proportion of T cells lacking CD28 in the disease joints, consistent with studies showing a direct involvement of this cytokine in CD28 gene transcription. Here, we show that modulation of TNF-α levels in long-term cultures of human CD8+ T lymphocytes, by chronic exposure either to a neutralizing Ab or to an inhibitor of the TNF-α receptor-1, increases proliferative potential, delays loss of CD28 expression, retards cytokine profile changes, and enhances telomerase activity. We also show that constitutive caspase-3, one of the downstream effectors of TNF-αR1 binding, increases in parallel with the loss of CD28 in long-term cultures, but this effect is blunted in the presence of the TNF-α inhibitors. Consistent with the in vitro culture data, CD8+CD28− T lymphocytes tested immediately ex vivo also show significantly higher levels of caspase-3 compared with their CD28+ counterparts. These findings help elucidate the complex nature of CD28 gene regulation, and may ultimately lead to novel therapeutic approaches for diseases associated with increased proportions of CD28− T lymphocytes.
Cutting Edge: Acute Lung Allograft Rejection Is Independent of Secondary Lymphoid Organs
Authors: Gelman Andrew E. , Li Wenjun , Richardson Steven B. , Zinselmeyer Bernd H. , Lai Jiaming , Okazaki Mikio , Kornfeld Christopher G. , Kreisel Friederike H. , Sugimoto Seiichiro , Tietjens Jeremy R. , Dempster John , Patterson G. Alexander , Krupnick Alexander S. , Miller Mark J. , Kreisel Daniel 
Published: March 2009

Abstract
It is the prevailing view that adaptive immune responses are initiated in secondary lymphoid organs. Studies using alymphoplastic mice have shown that secondary lymphoid organs are essential to initiate allograft rejection of skin, heart, and small bowel. The high immunogenicity of lungs is well recognized and allograft rejection remains a major contributing factor to poor outcomes after lung transplantation. We show in this study that alloreactive T cells are initially primed within lung allografts and not in secondary lymphoid organs following transplantation. In contrast to other organs, lungs are acutely rejected in the absence of secondary lymphoid organs. Two-photon microscopy revealed that recipient T cells cluster predominantly around lung-resident, donor-derived CD11c+ cells early after engraftment. These findings demonstrate for the first time that alloimmune responses following lung transplantation are initiated in the graft itself and therefore identify a novel, potentially clinically relevant mechanism of lung allograft rejection.
Vitamin D-Directed Rheostatic Regulation of Monocyte Antibacterial Responses
Authors: Adams John S. , Ren Songyang , Liu Philip T. , Chun Rene F. , Lagishetty Venu , Gombart Adrian F. , Borregaard Niels , Modlin Robert L. , Hewison Martin 
Published: March 2009

Abstract
The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) enhances innate immunity by inducing the cathelicidin antimicrobial peptide (hCAP). In monocytes/macrophages, this occurs primarily in response to activation of TLR, that induce expression of the vitamin D receptor and localized synthesis of 1,25(OH)2D from precursor 25-hydroxyvitamin D3 (25OHD). To clarify the relationship between vitamin D and innate immunity, we assessed changes in hCAP expression in vivo and ex vivo in human subjects attending a bone clinic (n = 50). Of these, 38% were vitamin D-insufficient (&lt;75 nM 25OHD) and received supplementation with vitamin D (50,000 IU vitamin D2 twice weekly for 5 wk). Baseline 25OHD status or vitamin D supplementation had no effect on circulating levels of hCAP. Therefore, ex vivo changes in hCAP for each subject were assessed using peripheral blood monocytes cultured with 10% autologous serum (n = 28). Under these vitamin D “insufficient” conditions the TLR2/1 ligand 19 kDa lipopeptide or the TLR4 ligand LPS, monocytes showed increased expression of the vitamin D-activating enzyme CYP27b1 (5- and 5.5-fold, respectively, both p &lt; 0.01) but decreased expression of hCAP mRNA (10-fold and 30-fold, both p &lt; 0.001). Following treatment with 19 kDa, expression of hCAP: 1) correlated with 25OHD levels in serum culture supplements (R = 0.649, p &lt; 0.001); 2) was significantly enhanced by exogenous 25OHD (5 nM); and 3) was significantly enhanced with serum from vivo vitamin D-supplemented patients. These data suggest that a key role of vitamin D in innate immunity is to maintain localized production of antibacterial hCAP following TLR activation of monocytes.
Vascular Endothelial Growth Factor C Facilitates Immune Tolerance and Endovascular Activity of Human Uterine NK Cells at the Maternal-Fetal Interface
Authors: Kalkunte Satyan S. , Mselle Teddy F. , Norris Wendy E. , Wira Charles R. , Sentman Charles L. , Sharma Surendra 
Published: March 2009

Abstract
Although replete with cytotoxic machinery, uterine NK (uNK) cells remain tolerant at the maternal-fetal interface. The mechanisms that facilitate the uNK cell tolerance are largely unknown. In this study, we demonstrate that vascular endothelial growth factor (VEGF) C, a proangiogenic factor produced by uNK cells, is responsible for their noncytotoxic activity. VEGF C-producing uNK cells support endovascular processes as demonstrated in a three-dimensional coculture model of capillary tube formation on Matrigel. Peripheral blood NK cells fail to produce VEGF C and remain cytotoxic. This response can be reversed by exogenous VEGF C. We show that cytoprotection by VEGF C can be related to induction of the TAP-1 expression and MHC class I assembly in target cells. Small interfering RNA-mediated silencing of TAP-1 expression abolished the VEGF C-imparted protection. Overall, these results demonstrate that empowerment of uNK cells with angiogenic factors keeps them noncytotoxic. This phenotype is critical to their pregnancy-compatible immunovascular role during placentation and fetal development.
Uneven Colonization of the Lymphoid Periphery by T Cells That Undergo Early TCRα Rearrangements
Authors: Hendricks Deborah W. , Fink Pamela J. 
Published: March 2009

Abstract
A sparse population of thymocytes undergoes TCRα gene rearrangement early in development, before the double-positive stage. The potential of these cells to contribute to the peripheral T cell pool is unknown. To examine the peripheral T cell compartment expressing a repertoire biased to early TCR gene rearrangements, we developed a mouse model in which TCRα rearrangements are restricted to the double-negative stage of thymocyte development. These mice carry floxed RAG2 alleles and a Cre transgene driven by the CD4 promoter. As expected, conventional T cell development is compromised in such Cre+ RAG2fl/fl mice, and the TCRαβ+ T cells that develop are limited in their TCRα repertoire, preferentially using early rearranging Vα genes. In the gut, the Thy-1+TCRαβ+ intraepithelial lymphocyte (IEL) compartment is surprisingly intact, whereas the Thy-1−TCRαβ+ subset is almost completely absent. Thus, T cells expressing a TCRα repertoire that is the product of early gene rearrangements can preferentially populate distinct IEL compartments. Despite this capacity, Cre+ RAG2fl/fl T cell progenitors cannot compete with wild-type T cell progenitors in mixed bone marrow chimeras, suggesting that in normal mice, there is only a small contribution to the peripheral T cell pool by cells that have undergone early TCRα rearrangements. In the absence of wild-type competitors, aggressive homeostatic proliferation in the IEL compartment can promote a relatively normal Thy-1+ TCRαβ+ T cell pool from the limited population derived from Cre+ RAG2fl/fl progenitors.
Cutting Edge: TLR-Dependent Viral Recognition Along with Type I IFN Positive Feedback Signaling Masks the Requirement of Viral Replication for IFN-α Production in Plasmacytoid Dendritic Cells
Authors: Kumagai Yutaro , Kumar Himanshu , Koyama Shohei , Kawai Taro , Takeuchi Osamu , Akira Shizuo 
Published: March 2009

Abstract
Plasmacytoid dendritic cells (pDCs) recognize RNA virus infection via TLRs and consequently produce vast amounts of type I IFN. Because nucleic acid-sensing TLRs reside in the intracellular membrane compartment, it is presumable that pDCs do not require cytoplasmic viral replication to recognize the infection. By checking Newcastle disease virus (NDV) RNA abundance in GFP+ and GFP− pDCs from Ifna6gfp mice, we found that NDV replication was not detected in IFN-producing pDCs. GFP+ pDC was induced in response to replication-incompetent NDV. In contrast, the replication-incompetent NDV failed to induce IFN-producing pDCs in type I IFNR-deficient mice. The lack of IFNR signaling led to the replication of NDV and the subsequent RIG-I-like helicase-dependent IFN-α production in pDCs. These results showed that detection of viruses via TLRs together with a type I IFN feedback system circumvents the requirement for viral replication-dependent recognition in pDCs.
Subtle Affinity-Enhancing Mutations in a Myelin Oligodendrocyte Glycoprotein-Specific TCR Alter Specificity and Generate New Self-Reactivity
Authors: Udyavar Akshata , Alli Rajshekhar , Nguyen Phuong , Baker Lesley , Geiger Terrence L. 
Published: March 2009

Abstract
We describe a simple iterative approach to augment TCR affinity, which we studied using a myelin oligodendrocyte glycoprotein-specific TCR. We hypothesized that single amino acid modifications in TCR CDR3 could enhance TCR sensitivity through focal interactions with antigenic peptide while minimizing the risk of cross-reactivity observed previously in TCR more broadly mutagenized using in vitro evolution techniques. We show that this iterative method can indeed generate TCR with Ag sensitivity 100-fold greater than the parental receptor and can endow TCR with coreceptor independence. However, we also find that single amino acid mutations in the CDR3 can alter TCR fine specificity, affecting recognition requirements for Ag residues over most of the length of the MHC binding groove. Furthermore, minimal changes in surface-exposed CDR3 amino acids, even the addition of a single hydroxyl group or conversion of a methyl or sulfhydryl moiety to a hydroxyl, can confer modified Ag-specific TCR with new self-reactivity. In vivo modeling of modified TCR through retroviral TCR gene transfer into Rag−/− mice confirmed the biological significance of these altered reactivities, although it also demonstrated the feasibility of producing Ag-specific, positively selecting, coreceptor-independent receptors with markedly increased Ag sensitivity. These results affirm the possibility of readily generating affinity-enhanced TCR for therapeutic purposes but demonstrate that minimal changes in TCR CDR3 structure can promote self reactivity and thereby emphasize the importance of caution in validating receptors with even subtle alterations before clinical application.
pH‐Responsive Flower‐Type Micelles Formed by a Biotinylated Poly(2‐vinylpyridine)‐block‐poly(ethylene oxide)‐block‐poly(ε‐caprolactone) Triblock Copolymer
Authors: Van Butsele Kathy , Cajot Sébastien , Van Vlierberghe Sandra , Dubruel Peter , Passirani Catherine , Benoit Jean‐Pierre , Jérôme Robert , Jérôme Christine 
Published: March 2009

AbstractIn the present work, a method is proposed to assemble pH‐responsive, flower‐like micelles that can expose a targeting unit at their periphery upon a decrease in pH. The micelles are composed of a novel biotinylated triblock copolymer of poly(εε‐caprolactone)‐block‐poly(ethylene oxide)‐block‐poly(2‐vinylpyridine) (PCL‐b‐PEO‐b‐P2VP) and the non‐biotinylated analogue. The block copolymers are synthesized by sequential anionic and ring‐opening polymerization. The pH‐dependent micellization behaviour in aqueous solution of the triblock copolymers developed is studied using dynamic light scattering, zeta potential, transmission electron microscopy (TEM), and fluorimetric measurements. The shielding of the biotin at neutral pH and their availability at the micelle surface upon protonation is established by TEM and surface plasmon resonance with avidin and streptavidin‐coated gold surfaces. The preliminary stealthy behavior of these pH‐responsive micelles is examined using the complement activation (CH50) test.
Polymer Films Composed of Surface‐Bound Nanofilaments with a High Aspect Ratio, Molecularly Imprinted with Small Molecules and Proteins
Authors: Linares Ana Valvanuz , Vandevelde Fanny , Pantigny Jacques , Falcimaigne‐Cordin Aude , Haupt Karsten 
Published: March 2009

AbstractHierarchically nanostructured materials that combine two or more levels of structuring and that exhibit a combination of useful features have gained considerable interest over recent years. Here, the generation of surface‐bound nanofilaments with a high aspect ratio by nanomolding on a nanoporous template surface is described. The filaments, at the same time, carry molecularly imprinted binding sites. The dye fluorescein and the protein myoglobin are used as model templates for imprinting. The surfaces exhibit specific binding as revealed by fluorescence microscopy. The wetting properties of the surfaces depend on the dimensions of the nanofilaments and on the nature of the polymer. It is believed that these materials can potentially be useful for applications in biosensors and biochips.
Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis
Authors: Piepers Sanne , Veldink Jan H. , De Jong Sonja W. , Van Der Tweel Ingeborg , Van Der Pol W‐Ludo , Uijtendaal Esther V. , Schelhaas H. Jurgen , Scheffer Hans , De Visser Marianne , De Jong J. M. B. Vianney , Wokke John H. J. , Groeneveld Geert Jan , Van Den Berg Leonard H. 
Published: March 2009

AbstractObjectiveTo determine whether valproic acid (VPA), a histone deacetylase inhibitor that showed antioxidative and antiapoptotic properties and reduced glutamate toxicity in preclinical studies, is safe and effective in amyotrophic lateral sclerosis (ALS) using a sequential trial design.MethodsBetween April 2005 and January 2007, 163 ALS patients received VPA 1,500mg or placebo daily. Primary end point was survival. Secondary outcome measure was decline of functional status measured by the revised ALS Functional Rating Scale. Analysis was by intention to treat and according to a sequential trial design. This trial was registered with ClinicalTrials.gov (number NCT00136110).ResultsVPA did not affect survival (cumulative survival probability of 0.72 in the VPA group [standard error (SE), 0.06] vs 0.88 in the placebo group [SE, 0.04] at 12 months, and 0.59 in the VPA group [SE, 0.07] vs 0.68 in the placebo group [SE, 0.08] at 16 months) or the rate of decline of functional status. VPA intake did not cause serious adverse reactions.InterpretationOur finding that VPA, at a dose used in epilepsy, does not show a beneficial effect on survival or disease progression in patients with ALS has implications for future trials with histone deacetylase inhibitors in ALS and other neurodegenerative diseases. The use of a sequential trial design allowed inclusion of only half the number of patients required for a classic trial design and prevented patients from unnecessarily continuing potentially harmful study medication. Ann Neurol 2009;66:227–234
Digit‐specific aberrations in the primary somatosensory cortex in Writer's cramp
Authors: Nelson Aimee J. , Blake David T. , Chen Robert 
Published: March 2009

AbstractObjectiveOne approach to the treatment of focal hand dystonia (FHD) is via sensory‐based training regimes. It is known that FHD patients demonstrate a reduced distance between the representations of digits 1 and 5 and also digits 2 and 5 in primary somatosensory cortex. However, we lack information on the spatial relationships among digits, such as reduced inter‐digit spacing or shifts of representations within the cortical areas, and whether aberrations are specific to symptomatic digits. Our aim was to characterize the spatial relationships among individual digits to determine the types of aberrations that exist and whether these are specific to symptomatic digits only.MethodsUsing high‐resolution fMRI over a limited volume and surface‐based mapping techniques, the cortical representations of all digits of the dystonia‐affected hand within the sub‐regions of the postcentral gyrus were mapped in patients with task‐specific Writer's cramp (WC).ResultsIn area 3b, digits directly involved in writing (D1, D2 and D3) show reduced inter‐digit separation, reversals, and overlapping activation. The thumb representation occupies territory normally occupied by digit 2 in controls. Asymptomatic digits 4 and 5 preserve their inter‐digit separation yet shift towards the D1/D2/D3 cluster, suggesting that reduced spacing, not simply digit shifts, are associated with dystonia symptoms. Area 3a was less responsive to sensory input in WC patients providing evidence of reduced afferent drive or top‐down modulation to this sub‐region.InterpretationTherapeutic regimes aimed at facilitating inter‐digit separation of digits 1, 2 and 3 may promote beneficial plasticity in WC patients. Ann Neurol 2009;66:146–154.
SNCA variants are associated with increased risk for multiple system atrophy
Authors: Scholz Sonja W. , Houlden Henry , Schulte Claudia , Sharma Manu , Li Abi , Berg Daniela , Melchers Anna , Paudel Reema , Gibbs J. Raphael , Simon‐Sanchez Javier , Paisan‐Ruiz Coro , Bras Jose , Ding Jinhui , Chen Honglei , Traynor Bryan J. , Arepalli Sampath , Zonozi Ryan R. , Revesz Tamas , Holton Janice , Wood Nick , Lees Andrew , Oertel Wolfgang , Wüllner Ullrich , Goldwurm Stefano , Pellecchia Maria Teresa , Illig Thomas , Riess Olaf , Fernandez Hubert H. , Rodriguez Ramon L. , Okun Michael S. , Poewe Werner , Wenning Gregor K. , Hardy John A. , Singleton Andrew B. , Gasser Thomas 
Published: March 2009

AbstractTo test whether the synucleinopathies Parkinson's disease and multiple system atrophy (MSA) share a common genetic etiology, we performed a candidate single nucleotide polymorphism (SNP) association study of the 384 most associated SNPs in a genome‐wide association study of Parkinson's disease in 413 MSA cases and 3,974 control subjects. The 10 most significant SNPs were then replicated in additional 108 MSA cases and 537 controls. SNPs at the SNCA locus were significantly associated with risk for increased risk for the development of MSA (combined p = 5.5 × 1012; odds ratio 6.2). Ann Neurol 2009;65:610–614
Closed and Open Clamlike Structures Formed by Hydrogen‐Bonded Pairs of Cyclotricatechylene Anions that Contain Cationic “Meat”
Authors: Abrahams Brendan F. , FitzGerald Nicholas J. , Hudson Timothy A. , Robson Richard , Waters Tom 
Published: March 2009

AbstractClamming up: The hexaphenolic compound cyclotricatechylene, which has a bowl‐shaped cavity, forms clamlike pairs that encapsulate cations (see picture). Variable hydrogen bonding allows two linked cyclotricatechylene clamshells to be in a closed arrangement when smaller cations such Rb+ or Cs+ provide the clam meat, whereas larger cations such as NMe4+ and NEt4+ cause the clam to be partially opened.magnified image
Perfluoropentaphenylborole: A New Approach to Lewis Acidic, Electron‐Deficient Compounds
Authors: Huynh Keith , Vignolle Joan , Tilley T. Don 
Published: March 2009

AbstractZirconocene is the key: A new synthetic method, which utilizes zirconocene‐mediated coupling of alkynes, has been developed for the preparation of a new class of highly Lewis acidic boroles (see scheme). Such compounds hold potential for applications in catalysis and the field of electron‐deficient organic materials.magnified image