bluuebunny/crossref_metadata_2025_split huggingface dataset:
Postsecretory Processing Generates Multiple Cathelicidins for Enhanced Topical Antimicrobial Defense
Authors: Murakami Masamoto , Lopez-Garcia Belen , Braff Marissa , Dorschner Robert A. , Gallo Richard L. 
Published: April 2014

Abstract
The production of antimicrobial peptides and proteins is essential for defense against infection. Many of the known human antimicrobial peptides are multifunctional, with stimulatory activities such as chemotaxis while simultaneously acting as natural antibiotics. In humans, eccrine appendages express DCD and CAMP, genes encoding proteins processed into the antimicrobial peptides dermcidin and LL-37. In this study we show that after secretion onto the skin surface, the CAMP gene product is processed by a serine protease-dependent mechanism into multiple novel antimicrobial peptides distinct from the cathelicidin LL-37. These peptides show enhanced antimicrobial action, acquiring the ability to kill skin pathogens such as Staphylococcus aureus and Candida albicans. Furthermore, although LL-37 may influence the host inflammatory response by stimulating IL-8 release from keratinocytes, this activity is lost in subsequently processed peptides. Thus, a single gene product encoding an important defense molecule alters structure and function in the topical environment to shift the balance of activity toward direct inhibition of microbial colonization.
Leishmania infantum Promotes Replication of HIV Type 1 in Human Lymphoid Tissue Cultured Ex Vivo by Inducing Secretion of the Proinflammatory Cytokines TNF-α and IL-1α
Authors: Zhao Chenqi , Papadopoulou Barbara , Tremblay Michel J. 
Published: April 2014

Abstract
Parasitic infections such as leishmaniasis can modulate the life cycle of HIV-1 and disease progression. Coinfection with HIV-1 and Leishmania has emerged as a serious threat in countries where both pathogenic agents are widespread. Although there are numerous clinical reports illustrating the cofactor role played by Leishmania in HIV-1-infected patients, there is still no information on the contribution of Leishmania to the biology of HIV-1 in human lymphoid tissue that is considered a major in vivo site of virus production. In this study we explored the modulatory effect of Leishmania on the process of HIV-1 infection using ex vivo cultured human tonsillar tissue. We found that the protozoan parasite Leishmania enhances both HIV-1 transcription and virus production after infection of human tonsillar tissue infected ex vivo with viral strains bearing various coreceptor usage profiles. Studies conducted with pentoxifylline and neutralizing Abs revealed that the Leishmania-mediated increase in HIV-1 production was linked to a higher production of TNF-α and IL-1α. Our findings help to unravel the molecular mechanism(s) through which the two microorganisms interact and provide information that may be useful for the design of more effective therapeutic strategies aimed at controlling disease progression in persons dually infected with HIV-1 and Leishmania. This work also indicates that histocultures of human lymphoid tissue infected by both pathogens represent an ideal experimental cell system to dissect interactions occurring between HIV-1 and an opportunist pathogen in a human microenvironment that approximates conditions prevailing under physiological situations.
Coordinate Expression of Cytokines and Chemokines by NK Cells during Murine Cytomegalovirus Infection
Authors: Dorner Brigitte G. , Smith Hamish R.C. , French Anthony R. , Kim Sungjin , Poursine-Laurent Jennifer , Beckman Diana L. , Pingel Jeanette T. , Kroczek Richard A. , Yokoyama Wayne M. 
Published: April 2014

AbstractCytokines and chemokines activate and direct effector cells during infection. We previously identified a functional group of five cytokines and chemokines, namely, IFN-γ, activation-induced T cell-derived and chemokine-related cytokine/lymphotactin, macrophage-inflammatory protein 1α, macrophage-inflammatory protein 1β, and RANTES, coexpressed in individual activated NK cells, CD8+ T cells, and CD4+ Th1 cells in vitro and during in vivo infections. However, the stimuli during infection were not known. In murine CMV (MCMV) infection, the DAP12/KARAP-associated Ly49H NK cell activation receptor is crucial for resistance through recognition of MCMV-encoded m157 but NK cells also undergo in vivo nonspecific responses to uncharacterized stimuli. In this study, we show that Ly49H ligation by m157 resulted in a coordinated release of all five cytokines/chemokines from Ly49H+ NK cells. Whereas other cytokines also triggered the release of these cytokines/chemokines, stimulation was not confined to the Ly49H+ population. At the single-cell level, the production of the five mediators showed strong positive correlation with each other. Interestingly, NK cells were a major source of these five cytokines/chemokines in vitro and in vivo, whereas infected macrophages produced only limited amounts of macrophage-inflammatory protein 1α, macrophage-inflammatory protein1β, and RANTES. These findings suggest that both virus-specific and nonspecific NK cells play crucial roles in activating and directing other inflammatory cells during MCMV infection.
Toll-Like Receptor 2 Plays a Role in the Early Inflammatory Response to Murine Pneumococcal Pneumonia but Does Not Contribute to Antibacterial Defense
Authors: Knapp Sylvia , Wieland Catharina W. , van ’t Veer Cornelis , Takeuchi Osamu , Akira Shizuo , Florquin Sandrine , van der Poll Tom 
Published: April 2014

Abstract
Toll-like receptors (TLR) are crucial pattern recognition receptors in innate immunity. The importance of TLR2 in host defense against Gram-positive bacteria has been suggested by the fact that this receptor recognizes major Gram-positive cell wall components, such as peptidoglycan and lipoteichoic acid. To determine the role of TLR2 in pulmonary Gram-positive infection, we first established that TLR2 is indispensable for alveolar macrophage responsiveness toward Streptococcus pneumoniae. Nonetheless, TLR2 gene-deficient mice intranasally inoculated with S. pneumoniae at doses varying from nonlethal (with complete clearance of the infection) to lethal displayed only a modestly reduced inflammatory response in their lungs and an unaltered antibacterial defense when compared with normal wild-type mice. These data suggest that TLR2 plays a limited role in the innate immune response to pneumococcal pneumonia, and that additional pattern recognition receptors likely are involved in host defense against this common respiratory pathogen.
Comprehensive Early and Lasting Loss of Memory CD8 T Cells and Functional Memory during Acute and Persistent Viral Infections
Authors: Kim Sung-Kwon , Welsh Raymond M. 
Published: April 2014

Abstract
Viral infections have been shown to induce lymphopenias that lower memory CD8 T cell frequencies, and they also have been shown to cause a permanent loss of memory cells specific to previously encountered pathogens. In this study, the patterns and significance of virus-induced memory CD8 T cell depletion were examined in mice immune to heterologous (Pichinde, vesicular stomatitis, vaccinia) viruses and subsequently challenged with acute or persistent lymphocytic choriomeningitis virus infections. Memory CD8 T cell loss was comprehensive and occurred in both lymphoid and peripheral tissues of the immune host. The impact of the loss of memory T cells was reflected by in vivo cytotoxicity assays, which showed decreased clearance of epitope-expressing targets. Memory CD8 T cell loss occurred very early (day 2) after infection, and was thereafter sustained, consistent more with an active deletion model than with a competition model. Cross-reactive T cells, in contrast, increased in number, but memory cells were reduced whether or not there was competition from cross-reactive T cells. Memory T cell loss was more profound during persistent infection than after acute infection. Adoptive transfer studies showed that, unlike the resolved acute infection, in which the reduced memory frequencies became stable, memory T cell loss was a continuously ongoing process during persistent infection. This study therefore links an early virus-induced lymphopenia to a subsequent long-term loss of CD8 T cell memory and offers a new mechanism for immune deficiency during persistent viral infections.
Depletion of CD4+ T Cells during Immunization with Nonviable Listeria monocytogenes Causes Enhanced CD8+ T Cell-Mediated Protection against Listeriosis
Authors: Kursar Mischo , Köhler Anne , Kaufmann Stefan H. E. , Mittrücker Hans-Willi 
Published: April 2014

Abstract
Immunization of mice with nonviable Listeria monocytogenes generates an insufficient CD8+ T cell response and consequently only limited protection against subsequent L. monocytogenes infection. We have recently demonstrated that depletion of regulatory CD4+ T cells during immunization significantly enhances CD8+ T cell responses. In the present study, we determined the impact of CD4+ T cell depletion on the CD8+ T cell response against heat-killed Listeria. Treatment of mice with anti-CD4 mAb during boost immunization with heat-killed Listeria significantly increased numbers of Listeria-specific CD8+ T cells and improved protection against subsequent infection with L. monocytogenes. During challenge infection, numbers of Listeria-specific CD8+ T cells were enhanced, and these cells expressed effector functions in terms of IFN-γ production. In summary, we demonstrate that combining nonviable L. monocytogenes vaccination and CD4+ T cell depletion improves generation of long-lasting and functional Listeria-specific CD8+ memory T cells.
Cryptic Epitope Identified in Rat and Human Cardiac Myosin S2 Region Induces Myocarditis in the Lewis Rat
Authors: Li Ya , Heuser Janet S. , Kosanke Stanley D. , Hemric Mark , Cunningham Madeleine W. 
Published: April 2014

Abstract
Myocarditis is a common cause of dilated cardiomyopathy leading to heart failure. Chronic stages of myocarditis may be initiated by autoimmune responses to exposed cardiac Ags after myocyte damage. Cardiac myosin, a heart autoantigen, induced experimental autoimmune myocarditis (EAM) in susceptible animals. Although cardiac myosin-induced myocarditis has been reported in Lewis rats, the main pathogenic epitope has not been identified. Using overlapping synthetic peptides of the S2 region of human cardiac myosin, we identified an amino acid sequence, S2–16 (residues 1052–1076), that induced severe myocarditis in Lewis rats. The myocarditic epitope was localized to a truncated S2–16 peptide (residues 1052–1073), which contained a sequence identical in human and rat cardiac myosin. The S2–16 peptide was not myocarditic for three other strains of rats, in which the lack of myocarditis was accompanied by the absence of strong S2–16-specific lymphocyte responses in vitro. For Lewis rats, S2–16 was characterized as a cryptic epitope of cardiac myosin because it did not recall lymphocyte and Ab responses after immunization with cardiac myosin. Lymphocytes from S2–16 immunized rats recognized not only S2–16, but also peptides in the S2–28 region. Furthermore, peptide S2–28 was the dominant epitope recognized by T cells from cardiac myosin immunized rats. S2–16 was presented by Lewis rat MHC class II molecules, and myocarditis induction was associated with an up-regulation of inflammatory cytokine production. S2–16-induced EAM provides a defined animal model to investigate mechanisms of EAM and modulation of immune responses to prevent autoimmune myocarditis.
Long-Term Suppression of Tumor Growth by TNF Requires a Stat1- and IFN Regulatory Factor 1-Dependent IFN-γ Pathway but Not IL-12 or IL-18
Authors: Wu Terry H. , Pabin Christine N. , Qin Zhihai , Blankenstein Thomas , Philip Mary , Dignam James , Schreiber Karin , Schreiber Hans 
Published: April 2014

Abstract
Tumor cells engineered to secrete TNF were used as a model to examine how persistently high local concentrations of TNF suppress tumor growth. TNF secretion had no effect on tumor cell proliferation in vitro but caused a very impressive growth arrest in vivo that was dependent on both bone marrow- and non-bone marrow-derived host cells expressing TNFR. Suppression also required an endogenous IFN-γ pathway consisting minimally of IFN-γ, IFN-γ receptor, Stat1, and IFN regulatory factor 1 since mice with targeted disruption of any of the four genes failed to arrest tumor growth. The ability of these mice to suppress tumor growth was restored after they were reconstituted with bone marrow cells from Wt mice. Interestingly, mice lacking the major IFN-γ-inducing cytokines IL-12 and IL-18 or T cells, B cells, and the majority of NK cells that are potential sources of IFN-γ nevertheless inhibited tumor development. Moreover, multiple lines of evidence indicated that local release of IFN-γ was not required to inhibit tumor formation. These results strongly suggest a novel function for the endogenous IFN-γ pathway that without measurable IFN-γ production or activity affects the ability of TNF to suppress tumor development.
Role of Specific CD8+ T Cells in the Severity of a Fulminant Zoonotic Viral Hemorrhagic Fever, Hantavirus Pulmonary Syndrome
Authors: Kilpatrick Elizabeth D. , Terajima Masanori , Koster Frederick T. , Catalina Michelle D. , Cruz John , Ennis Francis A. 
Published: April 2014

Abstract
We report on the role of specific CD8+ T cells in the pathogenesis of a highly lethal human viral disease, hantavirus pulmonary syndrome (HPS). HPS is a zoonotic disease caused by transmission of Sin Nombre virus (SNV) from chronically infected deer mice. In humans, this fulminant infection is characterized by lung capillary leakage, respiratory failure, and cardiogenic shock. Individuals with HLA-B*3501 have an increased risk of developing severe HPS, suggesting that CD8+ T cell responses to SNV contribute to pathogenesis. We identified three CD8+ T cell epitopes in SNV presented by HLA-B*3501 and quantitated circulating SNV-specific CD8+ T cells in 11 acute HPS patients using HLA/peptide tetramers. We found significantly higher frequencies of SNV-specific T cells in patients with severe HPS requiring mechanical ventilation (up to 44.2% of CD8+ T cells) than in moderately ill HPS patients hospitalized but not requiring mechanical ventilation (up to 9.8% of CD8+ T cells). These results imply that virus-specific CD8+ T cells contribute to HPS disease outcome. Intense CD8+ T cell responses to SNV may be induced by the encounter of the unnatural human host to this zoonotic virus without coevolution. This may also be the immunopathologic basis of other life-threatening human virus infections.
Human Memory B Cells Transferred by Allogenic Bone Marrow Transplantation Contribute Significantly to the Antibody Repertoire of the Recipient
Authors: Lausen Birgitte F. , Hougs Lotte , Schejbel Lone , Heilmann Carsten , Barington Torben 
Published: April 2014

AbstractThe bone marrow is an important source of Abs involved in long-term protection from recurrence of infections. Allogenic bone marrow transplantation (BMT) fails to restore this working memory. Attempts to overcome this immunodeficiency by immunization of the donor have not been very successful. More needs to be known about transfer of B cell memory by BMT. We tracked memory B cells from the donor to the recipient during BMT of a girl with leukocyte adhesion deficiency. Vaccination of her HLA-identical sibling donor 7 days before harvest induced Haemophilus influenzae type b (Hib) capsular polysaccharide (HibCP)-specific B cells readily detectable in marrow and blood. BMT did not lead to spontaneous production of HibCP Abs, but the recipient responded well to booster immunizations 9 and 11 mo after BMT. HibCP-specific B cells were obtained 7 days after the vaccinations, and their VH genes were sequenced and analyzed for rearrangements and unique patterns of somatic hypermutations identifying clonally related cells. Ninety (74%) of 121 sequences were derived from only 16 precursors. Twelve clones were identified in the donor, and representatives from all of them were detected in the recipient where they constituted 61 and 68% of the responding B cells after the first and second vaccinations, respectively. No evidence for re-entry of memory clones into the process of somatic hypermutation was seen in the recipient. Thus, memory B cells were transferred from the donor, persisted for at least 9 mo in the recipient, and constituted the major part of the HibCP-specific repertoire.
Cutting Edge: DGYW/WRCH Is a Better Predictor of Mutability at G:C Bases in Ig Hypermutation Than the Widely Accepted RGYW/WRCY Motif and Probably Reflects a Two-Step Activation-Induced Cytidine Deaminase-Triggered Process
Authors: Rogozin Igor B. , Diaz Marilyn 
Published: April 2014

AbstractA feature of Ig hypermutation is the presence of hypermutable DNA sequences that are preferentially found in the V regions of Ig genes. Among these, RGYW/WRCY is the most pronounced motif (G:C is a mutable position; R = A/G, Y = C/T, and W = A/T). However, a molecular basis for the high mutability of RGYW was not known until recently. The discovery that activation-induced cytidine deaminase targets the DNA encoding V regions, has enabled the analysis of its targeting properties when expressed outside of the context of hypermutation. We analyzed these data and found evidence that activation-induced cytidine deaminase is the major source of the RGYW mutable motif, but with a new twist: DGYW/WRCH (G:C is the mutable position; D = A/G/T, H = T/C/A) is a better descriptor of the Ig mutation hotspot than RGYW/WRCY. We also found evidence that a DNA repair enzyme may play a role in modifying the sequence of hypermutation hotspots.
Indirect Minor Histocompatibility Antigen Presentation by Allograft Recipient Cells in the Draining Lymph Node Leads to the Activation and Clonal Expansion of CD4+ T Cells That Cause Obliterative Airways Disease
Authors: Richards David M. , Dalheimer Stacy L. , Ehst Benjamin D. , Vanasek Tracy L. , Jenkins Marc K. , Hertz Marshall I. , Mueller Daniel L. 
Published: April 2014

AbstractAg recognition by OVA-reactive OT-II (I-Ab restricted) and DO11.10 (I-Ad restricted) TCR-Tg CD4+ T cells after heterotopic transplantation of OVA transgene-expressing tracheal grafts was examined as a model of minor histocompatibility Ag (mHAg)-induced chronic allograft rejection. In response to airway allotransplantation with grafts expressing the OVA transgene, these TCR-Tg CD4+ T cells expressed the activation markers CD69 and CD44, demonstrated evidence of blastogenesis, underwent multiple rounds of cell division leading to their clonal expansion in the draining lymph node, and proceeded to differentiate to a effector/memory T cell phenotype based on a reduction in the expression of CD45RB. These mHAg-specific TCR-Tg CD4+ T cells responded equally well to fully MHC-mismatched tracheas and to class II-deficient allografts, demonstrating that donor mHAg recognition by recipient CD4+ T cells does not rely on Ag presentation by donor-derived APC. The activation of mHAg-specific TCR-Tg CD4+ T cells after their adoptive transfer into recipient mice given MHC-matched, but mHAg-disparate, airway allografts was associated with their movement into the allograft and the near uniform destruction of the transplanted airway tissue secondary to the development of obliterative airways disease. These results demonstrate that an activation of mHAg-reactive CD4+ T cells in the draining lymph node by recipient APC that indirectly express graft mHAg-derived peptide/class II MHC complexes precedes responder T cell proliferation and differentiation, and leads to the eventual migration of these alloreactive T cells to the transplanted airway tissue and the promotion of chronic graft rejection.
Nasal Flt3 Ligand cDNA Elicits CD11c+CD8+ Dendritic Cells for Enhanced Mucosal Immunity
Authors: Kataoka Kosuke , McGhee Jerry R. , Kobayashi Ryoki , Fujihashi Keiko , Shizukuishi Satoshi , Fujihashi Kohtaro 
Published: April 2014

AbstractNasal immunization is an effective way to induce both mucosal and systemic immune responses. In this study, we assessed a cDNA vector for Flt3 ligand (FL) for its potential to enhance mucosal immunity or tolerance. Interestingly, tolerance was avoided and elevated levels of OVA-specific Ab responses were induced in nasal washes, fecal extracts, and saliva as well as in plasma when compared with mice given nasal OVA plus DNA plasmid without the FL gene. In addition, significant levels of OVA-specific CD4+ T cell proliferative responses and OVA-induced IL-4 and IL-2 production were noted in spleen and cervical lymph nodes. Further, marked increases in FL protein occurred in the nasal lamina propria and submandibular glands and the frequencies of CD11c+CD8+ dendritic cells (DCs) significantly increased in the mucosal tissues. Moreover, these DCs expressed high levels of CD40, CD80, CD86, and MHC class II molecules. Nasal delivery of plasmid FL with OVA resulted in FL expression in both mucosal inductive and effector sites and resulted in expanded activated lymphoid DCs. Thus, nasal plasmid FL prevents mucosal tolerance and enhances active immunity when given by a mucosal route.
A Major Allergen from Pollen Defines a Novel Family of Plant Proteins and Shows Intra- and Interspecie Cross-Reactivity
Authors: Barral Patricia , Batanero Eva , Palomares Oscar , Quiralte Joaquín , Villalba Mayte , Rodríguez Rosalía 
Published: April 2014

Abstract
Olive tree (Olea europaea) pollen is a main cause of allergy associated with extensive areas of Europe and North America. Ole e 10, a small (10.8 kDa) and acidic (pI 5.8) protein, has been identified as a major allergen from the olive pollen, isolated, and characterized. Circular dichroism analysis gave 17% α helix, 33% β sheet, and 21% β turn for its secondary structure. Based on amino acid sequences of tryptic peptides, the protein was cloned and sequenced. The allergen consists of a single polypeptide chain of 102 aa, with a signal peptide of 21 residues. Ole e 10 showed homology with the C-terminal domain of another olive allergen, Ole e 9 (1,3-β-glucanase, 53% identity), with deduced sequences from Arabidopsis thaliana genes (42–46% identity) and with polypeptide segments (Cys boxes) of proteins involved in yeast development (Epd1/Gas-1p/Phr2 families; 42–43% similarity). Ole e 10 showed 55% prevalence for olive-allergic patients and exhibited an IgE response dependent on its conformation. Remarkable IgE cross-reactivity was detected with Ole e 9, but no correlation was observed between the individual IgE responses to both allergens. Ole e 10 shares IgE B cell epitopes with proteins from Oleaceae, Gramineae, Betulaceae, Chenopodiaceae, Cupressaceae, Ambrosia, and Parietaria pollens, latex, and vegetable foods, such as tomato, kiwi, potato, and peach. These data indicate that Ole e 10 is a new pan-allergenic plant protein that shows notable intra- and interspecie IgE cross-reactivity and is a powerful candidate to be involved in pollen-latex-fruit syndrome.