bluuebunny/crossref_metadata_2025 huggingface dataset:
Tinnitus Distress, Anxiety, Depression, and Hearing Problems among Cochlear Implant Patients with Tinnitus
Authors: Andersson Gerhard , Freijd Anders , Baguley David M. , Idrizbegovic Esma
Published: June 2009

Background: While several studies have investigated the presence and annoyance of tinnitus in cochlear implant (CI) recipients, few studies have probed the handicap experienced in association with tinnitus in this population. Purpose: The aim of this study was to use validated
self-report measures in a consecutive sample of CI patients who reported tinnitus in order to determine the extent of tinnitus handicap. Research Design: In a retrospective design, a total of 151 patients (80% response rate) responded to a postal questionnaire, and of these, 111 (74%)
reported that they currently experienced tinnitus and were asked to complete the full questionnaire. Sampling was performed at a point of a mean 2.9 years postsurgery (SD  =  1.8 years). Three established self-report questionnaires were included measuring tinnitus handicap (Tinnitus
Handicap Inventory [THI]), hearing problems (Gothenburg Profile), and finally, a measure of anxiety and depression (Hospital Anxiety and Depression Scale). We analyzed the data by means of Pearson product moment correlations, t-tests, ANOVAs, and chi-square. Results: Data from the validated
questionnaires showed relatively low levels of tinnitus distress, moderate levels of hearing problems, and low scores on the anxiety and depression scales. Using the criteria proposed for the THI (which was completed by 107 patients), 35% (N  =  38) had a score indicating “no
handicap,” 30% (N  =  32) “mild handicap” 18% (N  =  19) “moderate handicap”, and 17% (N  =  18) “severe handicap.” Thus 37 individuals from the total series of 151 reported moderate to severe tinnitus handicap (24.5%).
Tinnitus distress was associated with increased hearing problems, anxiety, and depression. Conclusion: Tinnitus can be a significant problem following CI, but that the experienced distress is often moderate. However, a quarter of CI recipients do demonstrate moderate/severe tinnitus
handicap, and thus are candidates for tinnitus specific therapy. The level of tinnitus handicap is associated with hearing problems and psychological distress.
Acute ST-Segment Elevation Myocardial Infarction Associated With Diclofenac-Induced Anaphylaxis: Case Report
Authors: de Groot J. W. B. , Gosselink A. T. M. , Ottervanger J. P.
Published: June 2009

A patient in whom acute myocardial infarction developed during diclofenac-induced anaphylaxis is described. ST-segment elevation myocardial infarction is a rare complication of anaphylactic reactions, but can occur even in patients with angiographically normal coronary arteries. Physicians should be aware of such a complication in order to diagnose it early and treat it properly. In the patient described here, according to the temporal relationship with diclofenac intake and the exclusion of coronary stenosis, it is probable that diclofenac caused the symptoms. To our knowledge, this is the first reported case of Kounis syndrome due to diclofenac. The patient’s recovery was uneventful.
Oral Care Interventions and Oropharyngeal Colonization in Children Receiving Mechanical Ventilation
Authors: Pedreira Mavilde L.G. , Kusahara Denise M. , de Carvalho Werther Brunow , Núñez Silvia Cristina , Peterlini Maria Angélica S.
Published: June 2009

Background Recent progress in identification of oral microorganisms has shown that the oropharynx can be a site of origin for dissemination of pathogenic organisms to distant body sites, such as the lungs.

Objective To compare the oropharyngeal microbiological profile, duration of mechanical ventilation, and length of stay in the intensive care unit of children receiving mechanical ventilation who had pharmacological or nonpharmacological oral care.

Methods A randomized and controlled study was performed in a pediatric intensive unit in São Paulo, Brazil. A total of 56 children were randomly assigned to an experimental group (n=27, 48%) that received oral care with use of 0.12% chlorhexidine digluconate or a control group (n=29, 52%) that received oral care without an antiseptic. Oropharyngeal secretions were collected and cultured on days 0, 2, and 4, and at discharge.

Results The 2 groups had similar demographic characteristics, preexisting underlying diseases, and pharmacological, nutritional, and ventilatory support. Gram-negative bacteria were the predominant pathogens: Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Enter-obacter species. The 2 groups did not differ significantly in the colonization of normal (P= .72) or pathogenic (P= .62) flora, in the duration of mechanical ventilation (P= .67), or in length of stay in the intensive care (P= .22).

Conclusion Use of chlorhexidine combined with nonpharmacological oral care did not decrease the colonization profile, duration of mechanical ventilation, or length of stay in critically ill children receiving mechanical ventilation.
Living With Depressive Symptoms: Patients With Heart Failure
Authors: Dekker Rebecca L. , Peden Ann R. , Lennie Terry A. , Schooler Mary P. , Moser Debra K.
Published: June 2009

Background Patients with heart failure often experience depressive symptoms that affect health-related quality of life, morbidity, and mortality. Researchers have not described the experience of patients with heart failure living with depressive symptoms. Understanding this experience will help in developing interventions to decrease depressive symptoms.

Objective To describe the experience of patients with heart failure living with depressive symptoms.

Methods This study was conducted by using a qualitative descriptive design. The sample consisted of 10 outpatients (50% female, mean age 63 [SD, 13] years, 70% New York Heart Association class III or IV) with heart failure who were able to describe depressive symptoms. Data were collected via taped, individual, 30- to 60-minute interviews. ATLAS ti (version 5) was used for content analysis.

Results Participants described emotional and somatic symptoms of depression. Negative thinking was present in all participants and reinforced their depressed mood. The participants experienced multiple stressors that worsened depressive symptoms. The overarching strategy for managing depressive symptoms was “taking my mind off of it.” Patients managed depressive symptoms by engaging in activities such as exercise and reading, and by using positive thinking, spirituality, and social support.

Conclusions Patients with heart failure experience symptoms of depression that are similar to those experienced by the general population. Clinicians should assess patients with heart failure for stressors that worsen depressive symptoms. Strategies that researchers and clinicians can use to reduce depressive symptoms in patients with heart failure include engaging patients in activities, positive thinking, and spirituality. Helping patients find enhanced social support may also be important.
TLR2 Is a Negative Regulator of Th17 Cells and Tissue Pathology in a Pulmonary Model of Fungal Infection
Authors: Loures Flávio V. , Pina Adriana , Felonato Maíra , Calich Vera L. G.
Published: June 2009

To study the role of TLR2 in a experimental model of chronic pulmonary infection, TLR2-deficient and wild-type mice were intratracheally infected with Paracoccidioides brasiliensis, a primary fungal pathogen. Compared with control, TLR2−/− mice developed a less severe pulmonary infection and decreased NO synthesis. Equivalent results were detected with in vitro-infected macrophages. Unexpectedly, despite the differences in fungal loads both mouse strains showed equivalent survival times and severe pulmonary inflammatory reactions. Studies on lung-infiltrating leukocytes of TLR2−/− mice demonstrated an increased presence of polymorphonuclear neutrophils that control fungal loads but were associated with diminished numbers of activated CD4+ and CD8+ T lymphocytes. TLR2 deficiency leads to minor differences in the levels of pulmonary type 1 and type 2 cytokines, but results in increased production of KC, a CXC chemokine involved in neutrophils chemotaxis, as well as TGF-β, IL-6, IL-23, and IL-17 skewing T cell immunity to a Th17 pattern. In addition, the preferential Th17 immunity of TLR2−/− mice was associated with impaired expansion of regulatory CD4+CD25+FoxP3+ T cells. This is the first study to show that TLR2 activation controls innate and adaptive immunity to P. brasiliensis infection. TLR2 deficiency results in increased Th17 immunity associated with diminished expansion of regulatory T cells and increased lung pathology due to unrestrained inflammatory reactions.
Significance of N-Terminal Proteolysis of CCL14a to Activity on the Chemokine Receptors CCR1 and CCR5 and the Human Cytomegalovirus-Encoded Chemokine Receptor US28
Authors: Richter Rudolf , Casarosa Paola , Ständker Ludger , Münch Jan , Springael Jean-Yves , Nijmeijer Saskia , Forssmann Wolf-Georg , Vischer Henry F. , Vakili Jalal , Detheux Michel , Parmentier Marc , Leurs Rob , Smit Martine J.
Published: June 2009

The CC chemokine CCL14a is constitutively expressed in a large variety of tissues and its inactive proform CCL14a(1–74) circulates in high concentrations in plasma. CCL14a(1–74) is converted into CCL14a(9–74) by the proteases urokinase-type plasminogen activator and plasmin and is a highly active agonist for the chemokine receptors CCR1 and CCR5. In this study, a new CCL14a analog, CCL14a(12–74), was isolated from blood filtrate. To elucidate the functional role of the N terminus, a panel of N-terminally truncated CCL14a analogs were tested on the receptors CCR1 to CCR5 and on the human cytomegalovirus (HCMV)-encoded chemokine receptor US28. The rank order of binding affinity to these receptors and of the activation of CCR1 and CCR5-mediated intracellular Ca2+ concentration mobilization is CCL14a(6–74)<(7–74)<(8–74)≪(9–74) = (10–74)≫(11–74)≫(12–74). The almost identical affinities of CCL14a(7–74), CCL14a(9–74), and CCL14a(10–74) for the US28 receptor and the inhibition of US28-mediated HIV infection of 293T cells by all of the N-terminally truncated CCL14a analogs support the promiscuous nature of the viral chemokine receptor US28. In high concentrations, CCL14a(12–74) did reveal antagonistic activity on intracellular Ca2+ concentration mobilization in CCR1- and CCR5-transfected cells, which suggests that truncation of Tyr11 might be of significance for an efficient inactivation of CCL14a. A putative inactivation pathway of CCL14a(9–74) to CCL14a(12–74) may involve the dipeptidase CD26/dipeptidyl peptidase IV (DPPIV), which generates CCL14a(11–74), and the metalloprotease aminopeptidase N (CD13), which displays the capacity to generate CCL14a(12–74) from CCL14a(11–74). Our results suggest that the activity of CCL14a might be regulated by stringent proteolytic activation and inactivation steps.
Expression of a Modified Form of CD4 Results in the Release of an Anti-HIV Factor Derived from the Env Sequence
Authors: Zaldívar Irene , Muñoz-Fernández María Ángeles , Alarcón Balbino , San José Ester
Published: June 2009

We have studied the inhibitory effect of a CD4 chimera (CD4ε15) on HIV replication. This chimera is retained in the endoplasmic reticulum and traps the HIV envelope precursor gp160, preventing its maturation. Retroviral expression of the chimera strongly inhibited HIV replication even when it is expressed by only a minority of the T cell population. This protective effect on bystander nontransduced cells is mediated by a soluble factor that we identified as a fragment of HIV gp120 envelope protein and accordingly, we named this factor Env-derived antiviral factor (EDAF). Biochemical and immunoreactivity data show that EDAF is comprised of the gp120 C3-C5 regions and indeed, a recombinant protein bearing this sequence reproduces the anti-HIV properties of EDAF. Surprisingly, three tryptic peptides derived from EDAF are homologous but not identical with the corresponding sequences of the HIV isolate used to generate EDAF. We propose that EDAF results from an alternative intracellular processing of the Env protein provoked by its association to CD4ε15 and the selection of the best fitted Env protein sequences contained within the HIV isolate. The presence of EDAF improves the therapeutic potential of the CD4ε15 gene and it opens new possibilities for antiviral treatment and vaccine development.
Identification of a Novel IL-1 Cytokine Family Member in Teleost Fish
Authors: Wang Tiehui , Bird Steve , Koussounadis Antonis , Holland Jason W. , Carrington Allison , Zou Jun , Secombes Christopher J.
Published: June 2009

A novel IL-1 family member (nIL-1F) has been discovered in fish, adding a further member to this cytokine family. The unique gene organization of nIL-1F, together with its location in the genome and low homology to known family members, suggests that this molecule is not homologous to known IL-1F. Nevertheless, it contains a predicted C-terminal β-trefoil structure, an IL-1F signature region within the final exon, a potential IL-1 converting enzyme cut site, and its expression level is clearly increased following infection, or stimulation of macrophages with LPS or IL-1β. A thrombin cut site is also present and may have functional relevance. The C-terminal recombinant protein antagonized the effects of rainbow trout rIL-1β on inflammatory gene expression in a trout macrophage cell line, suggesting it is an IL-1β antagonist. Modeling studies confirmed that nIL-1F has the potential to bind to the trout IL-1RI receptor protein, and may be a novel IL-1 receptor antagonist.
Propionic Acid Secreted from Propionibacteria Induces NKG2D Ligand Expression on Human-Activated T Lymphocytes and Cancer Cells
Authors: Andresen Lars , Hansen Karen Aagaard , Jensen Helle , Pedersen Stine Falsig , Stougaard Peter , Hansen Helle Rüsz , Jurlander Jesper , Skov Søren
Published: June 2009

We found that propionic acid secreted from propionibacteria induces expression of the NKG2D ligands MICA/B on activated T lymphocytes and different cancer cells, without affecting MICA/B expression on resting peripheral blood cells. Growth supernatant from propionibacteria or propionate alone could directly stimulate functional MICA/B surface expression and MICA promoter activity by a mechanism dependent on intracellular calcium. Deletion and point mutations further demonstrated that a GC-box motif around −110 from the MICA transcription start site is essential for propionate-mediated MICA promoter activity. Other short-chain fatty acids such as lactate, acetate, and butyrate could also induce MICA/B expression. We observed a striking difference in the molecular signaling pathways that regulate MICA/B. A functional glycolytic pathway was essential for MICA/B expression after exposure to propionate and CMV. In contrast, compounds with histone deacetylase-inhibitory activity such as butyrate and FR901228 stimulated MICA/B expression through a pathway that was not affected by inhibition of glycolysis, clearly suggesting that MICA/B is regulated through different molecular mechanisms. We propose that propionate, produced either by bacteria or during cellular metabolism, has significant immunoregulatory function and may be cancer prophylactic.
IL-33 Enhances Lipopolysaccharide-Induced Inflammatory Cytokine Production from Mouse Macrophages by Regulating Lipopolysaccharide Receptor Complex
Authors: Espinassous Quentin , Garcia-de-Paco Elvira , Garcia-Verdugo Ignacio , Synguelakis Monique , von Aulock Sonja , Sallenave Jean-Michel , McKenzie Andrew N. J. , Kanellopoulos Jean
Published: June 2009

Bacterial LPS triggers monocytes and macrophages to produce several inflammatory cytokines and mediators. However, once exposed to LPS, they become hyporesponsive to a subsequent endotoxin challenge. This phenomenon is defined as LPS desensitization or tolerance. Previous studies have identified some components of the biochemical pathways involved in negative modulation of LPS responses. In particular, it has been shown that the IL-1R-related protein ST2 could be implicated in LPS tolerance. The natural ligand of ST2 was recently identified as IL-33, a new member of the IL-1 family. In this study, we investigated whether IL-33 triggering of ST2 was able to induce LPS desensitization of mouse macrophages. We found that IL-33 actually enhances the LPS response of macrophages and does not induce LPS desensitization. We demonstrate that this IL-33 enhancing effect of LPS response is mediated by the ST2 receptor because it is not found in ST2 knockout mice. The biochemical consequences of IL-33 pretreatment of mouse macrophages were investigated. Our results show that IL-33 increases the expression of the LPS receptor components MD2 (myeloid differentiation protein 2) and TLR-4, the soluble form of CD14 and the MyD88 adaptor molecule. In addition, IL-33 pretreatment of macrophages enhances the cytokine response to TLR-2 but not to TLR-3 ligands. Thus, IL-33 treatment preferentially affects the MyD88-dependent pathway activated by the TLR.
SUMO Conjugation Contributes to Immune Deviation in Nonobese Diabetic Mice by Suppressing c-Maf Transactivation of IL-4
Authors: Leavenworth Jianmei W. , Ma Xiaojing , Mo Yin-yuan , Pauza Mary E.
Published: June 2009

It is not clear why the development of protective Th2 cells is poor in type 1 diabetes (T1D). c-Maf transactivates the IL-4 gene promoting Th2 cell development; therefore, abnormalities in c-Maf may contribute to reduced IL-4 production by CD4 cells from nonobese diabetic (NOD) mice. In this study we demonstrate that despite normal expression, c-Maf binds poorly to the IL-4 promoter (IL-4p) in NOD CD4 cells. Immunoblotting demonstrates that c-Maf can be modified at lysine 33 by SUMO-1 (small ubiquitin-like modifier 1). Sumoylation is facilitated by direct interaction with the E2-conjugating enzyme Ubc9 and increases following T cell stimulation. In transfected cells, sumoylation decreases c-Maf transactivation of IL-4p-driven luciferase reporter activity, reduces c-Maf binding to the IL-4p in chromatin immunoprecipitation assays, and enhances c-Maf localization into promyelocytic leukemia nuclear bodies. Sumoylation of c-Maf is increased in NOD CD4 cells as compared with CD4 cells from diabetes-resistant B10.D2 mice, suggesting that increased c-Maf sumoylation contributes to immune deviation in T1D by reducing c-Maf access to and transactivation of the IL-4 gene.
The Polarity Protein Par1b/EMK/MARK2 Regulates T Cell Receptor-Induced Microtubule-Organizing Center Polarization
Authors: Lin Joseph , Hou Kirk K. , Piwnica-Worms Helen , Shaw Andrey S.
Published: June 2009

Engagement of a T cell to an APC induces the formation of an immunological synapse as well as reorientation of the microtubule-organizing center (MTOC) toward the APC. How signals emanating from the TCR induce MTOC polarization is not known. One group of proteins known to play a critical role in asymmetric cell division and cell polarization is the partitioning defective (Par) family of proteins. In this study we found that Par1b, a member of the Par family of proteins, was inducibly phosphorylated following TCR stimulation. This phosphorylation resulted in 14-3-3 protein binding and caused the relocalization of Par1b from the membrane into the cytoplasm. Because a dominant-negative form of Par1b blocked TCR-induced MTOC polarization, our data suggest that Par1b functions in the establishment of T cell polarity following engagement to an APC.
Progesterone Inhibits Activation-Induced Deaminase by Binding to the Promoter
Authors: Pauklin Siim , Petersen-Mahrt Svend K.
Published: June 2009

Regulation of activation-induced deaminase (AID), an essential factor in Ig diversification, can alter not only somatic hypermutation and class switch recombination (CSR), but may also influence oncogenesis. AID deaminates cytosine to uracil in the Ig locus, thereby initiating Ig diversification. Unregulated AID can induce oncogenic DNA alterations in Ig and non-Ig loci, leading to mutations, recombination, and translocations. In this study, we demonstrate that AID mRNA production in activated mouse splenic B cells can be reduced by treatment with the sex hormone progesterone. This down-regulation is independent of translation or splicing and is predominantly achieved by inhibiting transcription. During cell treatment we could detect progesterone receptor bound to the AID promoter in proximity to NF-κB binding. Importantly, the progesterone-induced repression was also extended to the protein level of AID and its activity on somatic hypermutation and class switch recombination.
Annexin-1 Regulates Macrophage IL-6 and TNF via Glucocorticoid-Induced Leucine Zipper
Authors: Yang Yuan H. , Aeberli Daniel , Dacumos April , Xue Jin R. , Morand Eric F.
Published: June 2009

Annexin-1 (ANXA1) is a mediator of the anti-inflammatory actions of endogenous and exogenous glucocorticoids (GC). The mechanism of ANXA1 effects on cytokine production in macrophages is unknown and is here investigated in vivo and in vitro. In response to LPS administration, ANXA1−/− mice exhibited significantly increased serum IL-6 and TNF compared with wild-type (WT) controls. Similarly, LPS-induced IL-6 and TNF were significantly greater in ANXA1−/− than in WT peritoneal macrophages in vitro. In addition, deficiency of ANXA1 was associated with impairment of the inhibitory effects of dexamethasone (DEX) on LPS-induced IL-6 and TNF in macrophages. Increased LPS-induced cytokine expression in the absence of ANXA1 was accompanied by significantly increased LPS-induced activation of ERK and JNK MAPK and was abrogated by inhibition of either of these pathways. No differences in GC effects on MAPK or MAPK phosphatase 1 were observed in ANXA1−/− cells. In contrast, GC-induced expression of the regulatory protein GILZ was significantly reduced in ANXA1−/− cells by silencing of ANXA1 in WT cells and in macrophages of ANXA1−/− mice in vivo. GC-induced GILZ expression and GC inhibition of NF-κB activation were restored by expression of ANXA1 in ANXA1−/− cells, and GILZ overexpression in ANXA1−/− macrophages reduced ERK MAPK phosphorylation and restored sensitivity of cytokine expression and NF-κB activation to GC. These data confirm ANXA1 as a key inhibitor of macrophage cytokine expression and identify GILZ as a previously unrecognized mechanism of the anti-inflammatory effects of ANXA1.
A Subcytotoxic Dose of Subtilase Cytotoxin Prevents Lipopolysaccharide-Induced Inflammatory Responses, Depending on its Capacity to Induce the Unfolded Protein Response
Authors: Harama Daisuke , Koyama Kensuke , Mukai Mai , Shimokawa Naomi , Miyata Masanori , Nakamura Yuki , Ohnuma Yuko , Ogawa Hideoki , Matsuoka Shuji , Paton Adrienne W. , Paton James C. , Kitamura Masanori , Nakao Atsuhito
Published: June 2009

Subtilase cytotoxin (SubAB) is the prototype of a newly identified family of AB5 cytotoxins produced by Shiga toxigenic Escherichia coli. SubAB specifically cleaves the essential endoplasmic reticulum (ER) chaperone BiP (GRP78), resulting in the activation of ER stress-induced unfolded protein response (UPR). We have recently shown that the UPR following ER stress can suppress cellular responses to inflammatory stimuli during the later phase, in association with inhibition of NF-κB activation. These findings prompted us to hypothesize that SubAB, as a selective UPR inducer, might have beneficial effects on inflammation-associated pathology via a UPR-dependent inhibition of NF-κB activation. The pretreatment of a mouse macrophage cell line, RAW264.7, with a subcytotoxic dose of SubAB-triggered UPR and inhibited LPS-induced MCP-1 and TNF-α production associated with inhibition of NF-κB activation. SubAA272B, a SubAB active site mutant that cannot induce UPR, did not show such effects. In addition, pretreatment with a sublethal dose of SubAB, but not SubAA272B, protected the mice from LPS-induced endotoxic lethality associated with reduced serum MCP-1 and TNF-α levels and also prevented the development of experimental arthritis induced by LPS in mice. Collectively, although SubAB has been identified originally as a toxin associated with the pathogenesis of hemolytic uremic syndrome, the unique ability of SubAB to selectively induce the UPR may have the potential to prevent LPS-associated inflammatory pathology under subcytotoxic conditions.
IL-17 and IFN-γ Mediate the Elicitation of Contact Hypersensitivity Responses by Different Mechanisms and Both Are Required for Optimal Responses
Authors: He Donggou , Wu Lizhi , Kim Hee Kyung , Li Hui , Elmets Craig A. , Xu Hui
Published: June 2009

Hapten-induced contact hypersensitivity (CHS) in the skin is a delayed type cellular immune response that can be mediated by CD8+ T cells that produce IFN-γ or IL-17. However, mechanisms for these cytokines in the elicitation of CHS remain to be fully elucidated. In this study, we show that adoptive transfer of CHS with hapten-primed wild-type (WT) CD8+ T cells is reduced in IFN-γR−/− or IL-17R−/− mice compared with WT controls. The infiltration of granulocytes and macrophages in the hapten challenged skin of IL-17R−/− recipients is significantly reduced whereas it is less affected in IFN-γR−/− recipients although CD8+ T cell infiltration is inhibited in both recipients. In contrast, the activity of reactive oxidative species is significantly inhibited in IFN-γR−/− but is less affected in IL-17R−/− recipients. Further analysis reveals that the expression of chemokines and cytokines is differentially regulated in the hapten-challenged skin of IFN-γR−/− or IL-17R−/− recipients compared with WT controls. Interestingly, injection of rIL-17 in the skin induces inflammation with a high level of leukocyte infiltration whereas injection of IFN-γ induces inflammation with a high level of reactive oxidative species. Moreover, neutralization of IL-17 in IFN-γR−/− or IFN-γ in IL-17R−/− mice further suppresses the adoptive transfer of CHS by hapten-primed WT CD8+ T cells. The study demonstrates that IFN-γ and IL-17 mediate the elicitation of CHS by different mechanisms and that both cytokines are required for optimal responses. This outcome improves understanding of pathogenesis and provides new insights into therapeutic strategies for CHS.
Zymosan, but Not Lipopolysaccharide, Triggers Severe and Progressive Peritoneal Injury Accompanied by Complement Activation in a Rat Peritonitis Model
Authors: Mizuno Masashi , Ito Yasuhiko , Hepburn Natalie , Mizuno Tomohiro , Noda Yukihiro , Yuzawa Yukio , Harris Claire L. , Morgan B. Paul , Matsuo Seiichi
Published: June 2009

Fungal peritonitis is an important complication in peritoneal dialysis patients; either continuous or recurrent peritonitis may enhance peritoneal damage. Even when the peritoneal dialysis catheter is removed in patients with fungal peritonitis, peritoneal fibrosis can progress and evolve into encapsular peritoneal sclerosis. It is unclear why fungal infections are worse than bacterial in these respects. Zymosan is a cell wall component of yeast that strongly activates the complement system. In this study, we compared the effects of zymosan and bacterial LPS on peritoneal inflammation in a rat peritoneal injury model induced by mechanical scraping. Intraperitoneal administration of zymosan, but not LPS or vehicle, caused markedly enhanced peritonitis with massive infiltration of cells and deposition of complement activation products C3b and membrane attack complex on day 5. In rats administered zymosan and sacrificed on days 18 or 36, peritoneal inflammation persisted with accumulation of ED-1-positive cells, small deposits of C3b and membrane attack complex, exudation of fibrinogen, and capillary proliferation in subperitoneal tissues. When zymosan was administered daily for 5 days after peritoneal scrape, there was even greater peritoneal inflammation with peritoneal thickening, inflammatory cell accumulation, and complement deposition. Inhibition of systemic complement by pretreatment with cobra venom factor or local inhibition by i.p. administration of the recombinant complement regulator Crry-Ig reduced peritoneal inflammation in zymosan-treated rats. Our results show that yeast components augment inflammation in the injured peritoneum by causing complement activation within the peritoneal cavity. Local anticomplement therapy may therefore protect from peritoneal damage during fungal infection of the peritoneum.
Myeloid-Derived Suppressor Cells Down-Regulate L-Selectin Expression on CD4+ and CD8+ T Cells
Authors: Hanson Erica M. , Clements Virginia K. , Sinha Pratima , Ilkovitch Dan , Ostrand-Rosenberg Suzanne
Published: June 2009

Effective cell-mediated antitumor immunity requires the activation of tumor-reactive T cells and the trafficking of activated T cells to tumor sites. These processes involve the extravasation of lymphocytes from the blood and lymphatics, and their homing to lymph nodes and tumors. L-selectin (CD62L) is an important molecule in these processes. It directs naive lymphocytes to peripheral lymph nodes where they become activated and it traffics naive lymphocytes to inflammatory environments, such as tumors. Individuals with advanced cancer are immune suppressed due to myeloid-derived suppressor cells (MDSC), a population of immature myeloid cells that accumulate to high levels in response to tumor-secreted and proinflammatory factors. We now demonstrate that the reduction in T cell levels of L-selectin that is commonly seen in individuals with cancer inversely correlates with MDSC levels. Three lines of evidence demonstrate that MDSC directly down-regulate L-selectin on naive T cells: 1) naive T cells cocultured with tumor-induced MDSC have reduced L-selectin; 2) T cells in tumor-free aged mice with elevated levels of MDSC have reduced L-selectin, and 3) peritoneal exudate T cells of tumor-free mice treated with plasminogen activator urokinase to elevate MDSC have reduced levels of L-selectin. MDSC are likely to down-regulate L-selectin through their plasma membrane expression of ADAM17 (a disintegrin and metalloproteinase domain 17), an enzyme that cleaves the ectodomain of L-selectin. Therefore, MDSC down-regulate L-selectin levels on naive T cells, decreasing their ability to home to sites where they would be activated. This is another mechanism by which MDSC inhibit antitumor immunity.
IL-2 Regulates CD103 Expression on CD4+ T Cells in Scurfy Mice that Display Both CD103-Dependent and Independent Inflammation
Authors: Sharma Rahul , Sung Sun-sang Joe , Abaya Christian E. , Ju Angela Chiao-Ying , Fu Shu Man , Ju Shyr-Te
Published: June 2009

Scurfy (Sf) mice lack CD4+Foxp3+ regulatory T cells and develop fatal multiorgan inflammation (MOI) mediated by CD4+ T cells. Introducing Il2−/− gene into Sf mice (Sf.Il2−/−) inhibited inflammation in skin and lung. As a major integrin receptor for the organs, we compared CD103 expression on the CD4+ T cells of B6, Il2−/−, Sf, and Sf.Il2−/− mice. CD103+CD4+ T cells, but not CD8+ T cells or CD11c+ dendritic cells, were significantly up-regulated only in Sf mice, indicating Il2−/− dominantly and specifically inhibited CD103 up-regulation in Sf CD4+ T cells. In addition, CD4+Foxp3+ regulatory T cell CD103 expression was not reduced in Il2−/− mice. Introducing CD103−/− into Sf mice inhibited inflammation in skin and lung as compared with age-matched Sf mice, but they died at ∼7 wk old with inflammation developed in skin, lungs, and colon, demonstrating fatal MOI induced by CD103-independent mechanism. Transfer of Sf CD4+ T cells induced MOI more rapidly than CD103−CD4+ T cells, indicating the presence of CD103-dependent mechanism for inflammation. In vitro stimulation with anti-CD3 plus anti-CD28 beads confirmed that CD103 induction in the CD4+Foxp3− T cells in Il2−/− and Sf.Il2−/− is defective and cannot be restored by rIL-2 or rIL-15. The data indicate that IL-2 is required for optimal CD103 induction on CD4+ T cells in Sf mice and this effect contributes to inflammation in an organ-specific manner. IL-2 also has additional roles because the protection of skin and lung inflammation in Sf.Il2−/−, but not Sf.CD103−/− mice is lifelong and Sf.Il2−/− mice have longer lifespan than Sf.CD103−/− mice.
The Impact of TCR-Binding Properties and Antigen Presentation Format on T Cell Responsiveness
Authors: Chervin Adam S. , Stone Jennifer D. , Holler Phillip D. , Bai Ailin , Chen Jianzhu , Eisen Herman N. , Kranz David M.
Published: June 2009

TCR interactions with cognate peptide-MHC (pepMHC) ligands are generally low affinity. This feature, together with the requirement for CD8/CD4 participation, has made it difficult to dissect relationships between TCR-binding parameters and T cell activation. Interpretations are further complicated when comparing different pepMHC, because these can vary greatly in stability. To examine the relationships between TCR-binding properties and T cell responses, in this study we characterized the interactions and activities mediated by a panel of TCRs that differed widely in their binding to the same pepMHC. Monovalent binding of soluble TCR was characterized by surface plasmon resonance, and T cell hybridomas that expressed these TCR, with or without CD8 coexpression, were tested for their binding of monomeric and oligomeric forms of the pepMHC and for subsequent responses (IL-2 release). The binding threshold for eliciting this response in the absence of CD8 (KD = 600 nM) exhibited a relatively sharp cutoff between full activity and no activity, consistent with a switchlike response to pepMHC on APCs. However, when the pepMHC was immobilized (plate bound), T cells with the lowest affinity TCRs (e.g., KD = 30 μM) responded, even in the absence of CD8, indicating that these TCR are signaling competent. Surprisingly, even cells that expressed high-affinity (KD = 16 nM) TCRs along with CD8 were unresponsive to oligomers in solution. The findings suggest that to drive downstream T cell responses, pepMHC must be presented in a form that supports formation of appropriate supramolecular clusters.
Class Switch Recombination Efficiency and Junction Microhomology Patterns in Msh2-, Mlh1-, and Exo1-Deficient Mice Depend on the Presence of μ Switch Region Tandem Repeats
Authors: Eccleston Jennifer , Schrader Carol E. , Yuan Karen , Stavnezer Janet , Selsing Erik
Published: June 2009

The Msh2 mismatch repair (MMR) protein is critical for class switch recombination (CSR) events that occur in mice that lack the Sμ tandem repeat (SμTR) region (SμTR−/− mice). The pattern of microhomology among switch junction sites in Msh2-deficient mice is also dependent on the presence or absence of SμTR sequences. It is not known whether these CSR effects reflect an individual function of Msh2 or the function of Msh2 within the MMR machinery. In the absence of the SμTR sequences, Msh2 deficiency nearly ablates CSR. We now show that Mlh1 or Exo1 deficiencies also eliminate CSR in the absence of the SμTR. Furthermore, in SμTR−/− mice, deficiencies of Mlh1 or Exo1 result in increased switch junction microhomology as has also been seen with Msh2 deficiency. These results are consistent with a CSR model in which the MMR machinery is important in processing DNA nicks to produce double-stranded breaks, particularly in sequences where nicks are infrequent. We propose that double-stranded break paucity in MMR-deficient mice leads to increased use of an alternative joining pathway where microhomologies are important for CSR break ligation. Interestingly, when the SμTR region is present, deficiency of Msh2 does not lead to the increased microhomology seen with Mlh1 or Exo1 deficiencies, suggesting that Msh2 might have an additional function in CSR. It is also possible that the inability to initiate MMR in the absence of Msh2 results in CSR junctions with less microhomology than joinings that occur when MMR is initiated but then proceeds abnormally due to Mlh1 or Exo1 deficiencies.
A20 Attenuates Allergic Airway Inflammation in Mice
Authors: Kang Nam-In , Yoon Ha-Yong , Lee Young-Rae , Won Minho , Chung Myoung Ja , Park Jin-Woo , Hur Gang Min , Lee Hern-Ku , Park Byung-Hyun
Published: June 2009

TNF receptor 1 can activate signaling pathways leading to the activation of NF-κB. A20, an NF-κB-inducible protein, negatively regulates these signaling pathways and acts as an anti-inflammatory mediator. Therefore, A20 is viewed as a potential therapeutic target for inflammatory disease. In this study, we examined the effect of A20 on an OVA-induced allergic airway inflammation model in mice. We used an adenovirus containing A20 cDNA (Ad-A20) that was delivered intratracheally before OVA challenge. Single administration of Ad-A20 reduced airway inflammatory cell recruitment and peribronchiolar inflammation and suppressed the production of various cytokines in bronchoalveolar fluid. In addition, Ad-A20 suppressed mucus production and prevented the development of airway hyperresponsiveness. The protective effect of Ad-A20 was mediated by the inhibition of the NF-κB signaling pathway. Taken together, our results suggest that the development of an immunoregulatory strategy based on A20 may have therapeutic potential for the treatment of allergic asthma.
Lymphocytes in the Peritoneum Home to the Omentum and Are Activated by Resident Dendritic Cells
Authors: Carlow Douglas A. , Gold Michael R. , Ziltener Hermann J.
Published: June 2009

The omentum is of interest in the context of obesity-related metabolic disease where adipose tissue exhibits inflammatory changes; however, the immunology of the omentum is underexplored. The greater omentum is draped from the stomach and consists predominantly of adipose tissue studded with lymphoreticular aggregations (milky spots) that distinguish it from other visceral adipose tissues. Milky spots are thought to contain and conduct leukocytes in transit from the blood to the peritoneal cavity, particularly during peritonitis. We show here that both B and T lymphocytes counterflow from the peritoneal cavity to the omentum in mice. Residence in the omentum was brief with a t1/2 residence time of 6 h. Omentum access was pertussis toxin-sensitive, dependent on activation of the Rap1 GTPase, and on the integrin LFA-1. B cells and CD44high T cells accessed the omentum most efficiently, but homing of resting CD44low T cells was also observed. Omental tissue from normal healthy mice was found to contain CD8−CD11bhighMHC class IIhighCD11chigh dendritic cells that promoted the rapid activation of T cells entering the omentum and cross-presented soluble OVA or OVA acquired from either OVA-expressing Escherichia coli or OVA-pulsed spleen cells. We conclude that the omentum incorporates two key features of immunological sentinel function, actively supported lymphocyte traffic and dendritic cells, that reinforce a conceptual framework for function in stimulating adaptive immunity. These results extend basic understanding of omental and peritoneal cavity immunology and of how proinflammatory events occurring within the peritoneal cavity might affect adipocyte and hepatocyte metabolism.
Trans-Presentation of IL-15 by Intestinal Epithelial Cells Drives Development of CD8αα IELs
Authors: Ma Lisa J. , Acero Luis F. , Zal Tomasz , Schluns Kimberly S.
Published: June 2009

IL-15 is crucial for the development of intestinal intraepithelial lymphocytes (IEL) and delivery is mediated by a unique mechanism known as trans-presentation. Parenchymal cells have a major role in the trans-presentation of IL-15 to IELs, but the specific identity of this cell type is unknown. To investigate whether the intestinal epithelial cells (IEC) are the parenchymal cell type involved, a mouse model that expresses IL-15Rα exclusively by the IECs (Villin/IL-15Rα Tg) was generated. Exclusive expression of IL-15Rα by the IECs restored all the deficiencies in the CD8αα+TCRαβ+and CD8αα+TCRγδ+ subsets that exist in the absence of IL-15Rα. Interestingly, most of the IEL recovery was due to the preferential increase in Thy1low IELs, which compose a majority of the IEL population. The differentiation of Thy1highCD4−CD8− thymocytes into Thy1−CD8αα IELs was found to require IL-15Rα expression specifically by IECs and thus, provides evidence that differentiation of Thy1low IELs is one function of trans-presentation of IL-15 in the intestines. In addition to effects in IEL differentiation, trans-presentation of IL-15 by IECs also resulted in an increase in IEL numbers that was accompanied by increases in Bcl-2, but not proliferation. Collectively, this study demonstrates that trans-presentation of IL-15 by IECs alone is completely sufficient to direct the IL-15-mediated development of CD8αα+ T cell populations within the IEL compartment, which now includes a newly identified role of IL-15 in the differentiation of Thy1low IELs.
Initiation of Antigen Receptor-Dependent Differentiation into Plasma Cells by Calmodulin Inhibition of E2A
Authors: Hauser Jannek , Verma-Gaur Jiyoti , Wallenius Anders , Grundström Thomas
Published: June 2009

Differentiation of B lymphocytes into Ab-secreting plasmablasts and plasma cells is Ag driven. The interaction of Ag with the membrane-bound Ab of the BCR is critical in determining which clones enter the plasma cell response. However, not much is known about the coupling between BCR activation and the shift in transcription factor network from that of a B cell to that of ASC differentiation. Our genome-wide analysis shows that Ab-secreting cell differentiation of mouse B cells is induced by BCR activation through very fast regulatory events from the BCR. We identify activation of IFN regulatory factor-4 and down-regulation of Pax5, Bcl-6, MITF, Ets-1, Fli-1, and Spi-B gene expression as immediate early events. Furthermore, the transcription factor E2A is required for the rapid key down-regulations after BCR activation, and the Ca2+ sensor protein calmodulin has the corresponding regulatory effect as BCR activation. Moreover, mutants in the calmodulin binding site of E2A show that Ca2+ signaling through calmodulin inhibition of E2A is essential for the rapid down-regulation of immediate early genes after BCR activation in initiation of plasma cell differentiation.
An Anti-Inflammatory Role for Plasmacytoid Dendritic Cells in Allergic Airway Inflammation
Authors: Kool Mirjam , van Nimwegen Menno , Willart Monique A. M. , Muskens Femke , Boon Louis , Smit Joost J. , Coyle Anthony , Clausen Björn E. , Hoogsteden Henk C. , Lambrecht Bart N. , Hammad Hamida
Published: June 2009

It was previously shown that administration of recombinant human Fms-like tyrosine kinase receptor-3 ligand (Flt3L) before allergen challenge of sensitized mice suppresses the cardinal features of asthma through unclear mechanisms. Here, we show that Flt3L dramatically alters the balance of conventional to plasmacytoid dendritic cells (pDCs) in the lung favoring the accumulation of pDCs. Selective removal of pDCs abolished the antiinflammatory effect of Flt3L, suggesting a regulatory role for these cells in ongoing asthmatic inflammation. In support, we found that immature pDCs are recruited to the lungs of allergen-challenged mice irrespective of Flt3L treatment. Selective removal of pDCs during allergen challenge enhanced airway inflammation, whereas adoptive transfer of cultured pDCs before allergen challenge suppressed inflammation. Experiments in which TLR9 agonist CpG motifs were administered in vitro or in vivo demonstrated that pDCs were antiinflammatory irrespective of their maturation state. These effects were mediated through programmed death-1/programmed death ligand 1 interactions, but not through ICOS ligand, IDO, or IFN-α. These findings suggest a specialized immunoregulatory role for pDCs in airway inflammation. Enhancing the antiinflammatory properties of pDCs could be employed as a novel strategy in asthma treatment.
Direct Antigen Presentation and Gap Junction Mediated Cross-Presentation during Apoptosis
Authors: Pang Baoxu , Neijssen Joost , Qiao Xiaohang , Janssen Lennert , Janssen Hans , Lippuner Christoph , Neefjes Jacques
Published: June 2009

MHC class I molecules present peptides from endogenous proteins. Ags can also be presented when derived from extracellular sources in the form of apoptotic bodies. Cross-presentation of such Ags by dendritic cells is required for proper CTL responses. The fate of Ags in cells initiated for apoptosis is unclear as is the mechanism of apoptosis-derived Ag transfer into dendritic cells. Here we show that novel Ags can be generated by caspases and be presented by MHC class I molecules of apoptotic cells. Since gap junctions function until apoptotic cells remodel to form apoptotic bodies, transfer and cross-presentation of apoptotic peptides by neighboring and dendritic cells occurs. We thus define a novel phase in classical Ag presentation and cross-presentation by MHC class I molecules: presentation of Ags created by caspase activities in cells in apoptosis.
Cathepsin S Regulates Class II MHC Processing in Human CD4+ HLA-DR+ T Cells
Authors: Costantino Cristina Maria , Ploegh Hidde L. , Hafler David A.
Published: June 2009

Although it has long been known that human CD4+ T cells can express functional class II MHC molecules, the role of lysosomal proteases in the T cell class II MHC processing and presentation pathway is unknown. Using CD4+ T cell clones that constitutively express class II MHC, we determined that cathepsin S is necessary for invariant chain proteolysis in T cells. CD4+HLA-DR+ T cells down-regulated cathepsin S expression and activity 18 h after activation, thereby ceasing nascent class II MHC product formation. This blockade resulted in the loss of the invariant chain fragment CLIP from the cell surface, suggesting that—like professional APC—CD4+ HLA-DR+ cells modulate self-Ag presentation as a consequence of activation. Furthermore, cathepsin S expression and activity, and concordantly cell surface CLIP expression, was reduced in HLA-DR+ CD4+ T cells as compared with B cells both in vitro and ex vivo.
Ncf1-Associated Reduced Oxidative Burst Promotes IL-33R+ T Cell-Mediated Adjuvant-Free Arthritis in Mice
Authors: Hagenow Kristin , Gelderman Kyra A. , Hultqvist Malin , Merky Patrick , Bäcklund Johan , Frey Oliver , Kamradt Thomas , Holmdahl Rikard
Published: June 2009

Reactive oxygen species (ROS) are important in the immune defense against invading pathogens, but they are also key molecules in the regulation of inflammatory reactions. Low levels of ROS production due to a polymorphism in the neutrophil cytosolic factor 1 (Ncf1) gene are associated with autoimmunity and arthritis severity in mouse models induced with adjuvant. We established an adjuvant-free arthritis model in which disease is induced by injection of the autoantigen collagen type II (CII) and depends on IL-5-producing T cells and eosinophils. In addition, the transgenic expression of mutated mouse CII allowed us to investigate an autoreactive immune response to an autologous Ag and by that natural tolerance mechanism. We show that a deficient ROS production, due to a spontaneous mutation in Ncf1, leads to increased autoantibody production and expansion of IL-33R-expressing T cells, impaired T cell tolerance toward tissue-specific CII, and severe arthritis in this unique model without disturbing adjuvant effects. These results demonstrate that the insufficient production of ROS promotes the breakdown of immune tolerance and development of autoimmune and adjuvant-free arthritis through an IL-5- and IL33R-dependent T cell activation pathway.