Epigenetic Regulation of Early- and Late-Response Genes in Acute Pancreatitis [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Chromatin remodeling seems to regulate the patterns of proinflammatory genes. Our aim was to provide new insights into the epigenetic mechanisms that control transcriptional activation of early- and late-response genes in initiation and development of severe acute pancreatitis as a model of acute inflammation. Chromatin changes were studied by chromatin immunoprecipitation analysis, nucleosome positioning, and determination of histone modifications in promoters of proinflammatory genes in vivo in the course of taurocholate-induced necrotizing pancreatitis in rats and in vitro in rat pancreatic AR42J acinar cells stimulated with taurocholate or TNF-α. Here we show that the upregulation of early and late inflammatory genes rely on histone acetylation associated with recruitment of histone acetyltransferase CBP. Chromatin remodeling of early genes during the inflammatory response in vivo is characterized by a rapid and transient increase in H3K14ac, H3K27ac, and H4K5ac as well as by recruitment of chromatin-remodeling complex containing BRG-1. Chromatin remodeling in late genes is characterized by a late and marked increase in histone methylation, particularly in H3K4. JNK and p38 MAPK drive the recruitment of transcription factors and the subsequent upregulation of early and late inflammatory genes, which is associated with nuclear translocation of the early gene Egr-1. In conclusion, specific and strictly ordered epigenetic markers such as histone acetylation and methylation, as well as recruitment of BRG-1–containing remodeling complex are associated with the upregulation of both early and late proinflammatory genes in acute pancreatitis. Our findings highlight the importance of epigenetic regulatory mechanisms in the control of the inflammatory cascade.

http://ift.tt/2fkwKkZ

Differential Role of Hematopoietic and Nonhematopoietic Cell Types in the Regulation of NK Cell Tolerance and Responsiveness [INNATE IMMUNITY AND INFLAMMATION]

Many NK cells express inhibitory receptors that bind self-MHC class I (MHC I) molecules and prevent killing of self-cells, while enabling killing of MHC I–deficient cells. But tolerance also occurs for NK cells that lack inhibitory receptors for self-MHC I, and for all NK cells in MHC I–deficient animals. In both cases, NK cells are unresponsive to MHC I–deficient cells and hyporesponsive when stimulated through activating receptors, suggesting that hyporesponsiveness is responsible for self-tolerance. We generated irradiation chimeras, or carried out adoptive transfers, with wild-type (WT) and/or MHC I–deficient hematopoietic cells in WT or MHC I–deficient C57BL/6 host mice. Unexpectedly, in WT hosts, donor MHC I–deficient hematopoietic cells failed to induce hyporesponsiveness to activating receptor stimulation, but did induce tolerance to MHC I–deficient grafts. Therefore, these two properties of NK cells are separable. Both tolerance and hyporesponsiveness occurred when the host was MHC I deficient. Interestingly, infections of mice or exposure to inflammatory cytokines reversed the tolerance of NK cells that was induced by MHC I–deficient hematopoietic cells, but not the tolerance induced by MHC I–deficient nonhematopoietic cells. These data have implications for successful bone marrow transplantation, and suggest that tolerance induced by hematopoietic cells versus nonhematopoietic cells may be imposed by distinct mechanisms.

http://ift.tt/2fDyWaN

Blood Stem Cell Activity Is Arrested by Th1-Mediated Injury Preventing Engraftment following Nonmyeloablative Conditioning [TRANSPLANTATION]

T cells are widely used to promote engraftment of hematopoietic stem cells (HSCs) during an allogeneic hematopoietic cell transplantation. Their role in overcoming barriers to HSC engraftment is thought to be particularly critical when patients receive reduced doses of preparative chemotherapy and/or radiation compared with standard transplantations. In this study, we sought to delineate the effects CD4⁺ cells on engraftment and blood formation in a model that simulates clinical hematopoietic cell transplantation by transplanting MHC-matched, minor histocompatibility–mismatched grafts composed of purified HSCs, HSCs plus bulk T cells, or HSCs plus T cell subsets into mice conditioned with low-dose irradiation. Grafts containing conventional CD4⁺ T cells caused marrow inflammation and inhibited HSC engraftment and blood formation. Posttransplantation, the marrows of HSCs plus CD4⁺ cell recipients contained IL-12–secreting CD11c⁺ cells and IFN-–expressing donor Th1 cells. In this setting, host HSCs arrested at the short-term stem cell stage and remained in the marrow in a quiescent cell cycling state (G₀). As a consequence, donor HSCs failed to engraft and hematopoiesis was suppressed. Our data show that Th1 cells included in a hematopoietic allograft can negatively impact HSC activity, blood reconstitution, and engraftment of donor HSCs. This potential negative effect of donor T cells is not considered in clinical transplantation in which bulk T cells are transplanted. Our findings shed new light on the effects of CD4⁺ T cells on HSC biology and are applicable to other pathogenic states in which immune activation in the bone marrow occurs such as aplastic anemia and certain infectious conditions.

http://ift.tt/2fDxs0r

Cell-Extrinsic TNF Collaborates with TRIF Signaling To Promote Yersinia-Induced Apoptosis [INNATE IMMUNITY AND INFLAMMATION]

Innate immune responses that are crucial for control of infection are often targeted by microbial pathogens. Blockade of NF-B and MAPK signaling by the Yersinia virulence factor YopJ inhibits cytokine production by innate immune cells but also triggers cell death. This cell death requires RIPK1 kinase activity and caspase-8, which are engaged by TLR4 and the adaptor protein TRIF. Nevertheless, TLR4- and TRIF-deficient cells undergo significant apoptosis, implicating TLR4/TRIF-independent pathways in the death of Yersinia-infected cells. In this article, we report a key role for TNF/TNFR1 in Yersinia-induced cell death of murine macrophages, which occurs despite the blockade of NF-B and MAPK signaling imposed by Yersinia on infected cells. Intriguingly, direct analysis of YopJ injection revealed a heterogeneous population of injection-high and injection-low cells, and demonstrated that TNF expression came from the injection-low population. Moreover, TNF production by this subpopulation was necessary for maximal apoptosis in the population of highly injected cells, and TNFR-deficient mice displayed enhanced susceptibility to Yersinia infection. These data demonstrate an important role for collaboration between TNF and pattern recognition receptor signals in promoting maximal apoptosis during bacterial infection, and demonstrate that heterogeneity in virulence factor injection and cellular responses play an important role in promoting anti-Yersinia immune defense.

http://ift.tt/2fDwi5b

GM-CSF Induces Inflammatory Macrophages by Regulating Glycolysis and Lipid Metabolism [INNATE IMMUNITY AND INFLAMMATION]

GM-CSF induces proinflammatory macrophages, but the underlying mechanisms have not been studied thus far. In this study, we investigated the mechanisms of how GM-CSF induces inflammatory macrophages. First, we observed that GM-CSF increased the extent of LPS-induced acute glycolysis in murine bone marrow–derived macrophages. This directly correlates with an inflammatory phenotype because glycolysis inhibition by 2-deoxyglucose abolished GM-CSF–mediated increase of TNF-α, IL-1β, IL-6, and IL-12p70 synthesis upon LPS stimulation. Increased glycolytic capacity is due to de novo synthesis of glucose transporter (GLUT)-1, -3, and -4, as well as c-myc. Meanwhile, GM-CSF increased 3-hydroxy-3-methyl-glutaryl-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway. Inhibition of acute glycolysis or 3-hydroxy-3-methyl-glutaryl-CoA reductase abrogated the inflammatory effects of GM-CSF priming in macrophages. Finally, mice with inflamed colons exposed to dextran sodium sulfate containing GLUT-1^high macrophages led to massive uptake of [¹⁸F]-fluorodeoxyglucose, but GM-CSF neutralization reduced the positron-emission tomography signal in the intestine and also decreased GLUT-1 expression in colonic macrophages. Collectively, our results reveal glycolysis and lipid metabolism created by GM-CSF as the underlying metabolic constructs for the function of inflammatory macrophages.

http://ift.tt/2fkyvhK

RAGE Enhances TLR Responses through Binding and Internalization of RNA [INNATE IMMUNITY AND INFLAMMATION]

Nucleic acid recognition is an important mechanism that enables the innate immune system to detect microbial infection and tissue damage. To minimize the recognition of self-derived nucleic acids, all nucleic acid–sensing signaling receptors are sequestered away from the cell surface and are activated in the cytoplasm or in endosomes. Nucleic acid sensing in endosomes relies on members of the TLR family. The receptor for advanced glycation end-products (RAGE) was recently shown to bind DNA at the cell surface, facilitating DNA internalization and subsequent recognition by TLR9. In this article, we show that RAGE binds RNA molecules in a sequence-independent manner and enhances cellular RNA uptake into endosomes. Gain- and loss-of-function studies demonstrate that RAGE increases the sensitivity of all ssRNA-sensing TLRs (TLR7, TLR8, TLR13), suggesting that RAGE is an integral part of the endosomal nucleic acid–sensing system.

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Menin Plays a Critical Role in the Regulation of the Antigen-Specific CD8+ T Cell Response upon Listeria Infection [INFECTIOUS DISEASE AND HOST RESPONSE]

Menin, a tumor suppressor protein, is encoded by the MEN1 gene in humans. Certain germinal mutations of MEN1 induce an autosomal-dominant syndrome that is characterized by concurrent parathyroid adenomas and several other tumor types. Although menin is also expressed in hematopoietic lineages, its role in CD8⁺ T cells remains unclear. We generated Menin^flox/flox CD4-Cre (Menin-KO) mice by crossing Menin^flox/flox mice with CD4-Cre transgenic (Tg) mice to determine the role of menin in CD8⁺ T cells. Wild-type (WT) and Menin-KO mice were infected with Listeria monocytogenes expressing OVA to analyze the immune response of Ag-specific CD8⁺ T cells. Menin deficiency resulted in an impaired primary immune response by CD8⁺ T cells. On day 7, there were fewer Menin-KO OVA-specific CD8⁺ T cells compared with WT cells. Next, we adoptively transferred WT and Menin-KO OT-1 Tg CD8⁺ T cells into congenic recipient mice and infected them with L. monocytogenes expressing OVA to determine the CD8⁺ T cell–intrinsic effect. Menin-KO OT-1 Tg CD8⁺ T cells were outcompeted by the WT cells upon infection. Increased expression of Blimp-1 and T-bet, cell cycle inhibitors, and proapoptotic genes was observed in the Menin-KO OT-1 Tg CD8⁺ T cells upon infection. These data suggest that menin inhibits differentiation into terminal effectors and positively controls proliferation and survival of Ag-specific CD8⁺ T cells that are activated upon infection. Collectively, our study uncovered an important role for menin in the immune response of CD8⁺ T cells to infection.

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Distinct Roles for Human Cytomegalovirus Immediate Early Proteins IE1 and IE2 in the Transcriptional Regulation of MICA and PVR/CD155 Expression [INFECTIOUS DISEASE AND HOST RESPONSE]

Elimination of virus-infected cells by cytotoxic lymphocytes is triggered by activating receptors, among which NKG2D and DNAM-1/CD226 play an important role. Their ligands, that is, MHC class I–related chain (MIC) A/B and UL16-binding proteins (ULBP)1–6 (NKG2D ligand), Nectin-2/CD112, and poliovirus receptor (PVR)/CD155 (DNAM-1 ligand), are often induced on virus-infected cells, although some viruses, including human CMV (HCMV), can block their expression. In this study, we report that infection of different cell types with laboratory or low-passage HCMV strains upregulated MICA, ULBP3, and PVR, with NKG2D and DNAM-1 playing a role in NK cell–mediated lysis of infected cells. Inhibition of viral DNA replication with phosphonoformic acid did not prevent ligand upregulation, thus indicating that early phases of HCMV infection are involved in ligand increase. Indeed, the major immediate early (IE) proteins IE1 and IE2 stimulated the expression of MICA and PVR, but not ULBP3. IE2 directly activated MICA promoter via its binding to an IE2-responsive element that we identified within the promoter and that is conserved among different alleles of MICA. Both IE proteins were instead required for PVR upregulation via a mechanism independent of IE DNA binding activity. Finally, inhibiting IE protein expression during HCMV infection confirmed their involvement in ligand increase. We also investigated the contribution of the DNA damage response, a pathway activated by HCMV and implicated in ligand regulation. However, silencing of ataxia telangiectasia mutated, ataxia telangiectasia and Rad3–related protein, and DNA-dependent protein kinase did not influence ligand expression. Overall, these data reveal that MICA and PVR are directly regulated by HCMV IE proteins, and this may be crucial for the onset of an early host antiviral response.

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Neutrophil Necroptosis Is Triggered by Ligation of Adhesion Molecules following GM-CSF Priming [INNATE IMMUNITY AND INFLAMMATION]

Apoptosis is the most common form of neutrophil death under both physiological and inflammatory conditions. However, forms of nonapoptotic neutrophil death have also been observed. In the current study, we report that human neutrophils undergo necroptosis after exposure to GM-CSF followed by the ligation of adhesion receptors such as CD44, CD11b, CD18, or CD15. Using a pharmacological approach, we demonstrate the presence of a receptor-interacting protein kinase-3 (RIPK3)—a mixed lineage kinase–like (MLKL) signaling pathway in neutrophils which, following these treatments, first activates p38 MAPK and PI3K, that finally leads to the production of high levels of reactive oxygen species (ROS). All these steps are required for necroptosis to occur. Moreover, we show that MLKL undergoes phosphorylation in neutrophils in vivo under inflammatory conditions. This newly identified necrosis pathway in neutrophils would imply that targeting adhesion molecules could be beneficial for preventing exacerbation of disease in the neutrophilic inflammatory response.

http://ift.tt/2fDy8Ts

Secreted NS1 Protects Dengue Virus from Mannose-Binding Lectin-Mediated Neutralization [INFECTIOUS DISEASE AND HOST RESPONSE]

Flavivirus nonstructural protein 1 (NS1) is a unique secreted nonstructural glycoprotein. Although it is absent from the flavivirus virion, intracellular and extracellular forms of NS1 have essential roles in viral replication and the pathogenesis of infection. The fate of NS1 in insect cells has been more controversial, with some reports suggesting it is exclusively cell associated. In this study, we confirm NS1 secretion from cells of insect origin and characterize its physical, biochemical, and functional properties in the context of dengue virus (DENV) infection. Unlike mammalian cell–derived NS1, which displays both high mannose and complex type N-linked glycans, soluble NS1 secreted from DENV-infected insect cells contains only high mannose glycans. Insect cell–derived secreted NS1 also has different physical properties, including smaller and more heterogeneous sizes and the formation of less stable NS1 hexamers. Both mammalian and insect cell–derived NS1 bind to complement proteins C1s, C4, and C4-binding protein, as well as to a novel partner, mannose-binding lectin. Binding of NS1 to MBL protects DENV against mannose-binding lectin–mediated neutralization by the lectin pathway of complement activation. As we detected secreted NS1 and DENV together in the saliva of infected Aedes aegypti mosquitoes, these findings suggest a mechanism of viral immune evasion at the very earliest phase of infection.

http://ift.tt/2fkz7UD

HIV-1 Nef Impairs the Formation of Calcium Membrane Territories Controlling the Signaling Nanoarchitecture at the Immunological Synapse [INFECTIOUS DISEASE AND HOST RESPONSE]

The ability of HIV-1 to replicate and to establish long-term reservoirs is strongly influenced by T cell activation. Through the use of membrane-tethered, genetically encoded calcium (Ca²⁺) indicators, we were able to detect for the first time, to our knowledge, the formation of Ca²⁺ territories and determine their role in coordinating the functional signaling nanostructure of the synaptic membrane. Consequently, we report a previously unknown immune subversion mechanism involving HIV-1 exploitation, through its Nef accessory protein, of the interconnectivity among three evolutionarily conserved cellular processes: vesicle traffic, signaling compartmentalization, and the second messenger Ca²⁺. We found that HIV-1 Nef specifically associates with the traffic regulators MAL and Rab11b compelling the vesicular accumulation of Lck. Through its association with MAL and Rab11b, Nef co-opts Lck switchlike function driving the formation Ca²⁺ membrane territories, which, in turn, control the fusion of LAT-transporting Rab27 and Rab37 vesicles and the formation of LAT nanoclusters at the immunological synapse. Consequently, HIV-1 Nef disengages TCR triggering from the generation of p-LAT and p-SLP nanoclusters driving TCR signal amplification and diversification. Altogether our results indicate that HIV-1 exploits the interconnectivity among vesicle traffic, Ca²⁺ membrane territories, and signaling nanoclusters to modulate T cell signaling and function.

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DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV [IMMUNOTHERAPY AND VACCINES]

HIV sequence diversity and the propensity of eliciting immunodominant responses targeting variable regions of the HIV proteome are hurdles in the development of an effective AIDS vaccine. An HIV-derived conserved element (CE) p24^gag plasmid DNA (pDNA) vaccine is able to redirect immunodominant responses to otherwise subdominant and often more vulnerable viral targets. By homology to the HIV immunogen, seven CE were identified in SIV p27^Gag. Analysis of 31 rhesus macaques vaccinated with full-length SIV gag pDNA showed inefficient induction (58% response rate) of cellular responses targeting these CE. In contrast, all 14 macaques immunized with SIV p27CE pDNA developed robust T cell responses recognizing CE. Vaccination with p27CE pDNA was also critical for the efficient induction and increased the frequency of Ag-specific T cells with cytotoxic potential (granzyme B⁺ CD107a⁺) targeting subdominant CE epitopes, compared with the responses elicited by the p57^gag pDNA vaccine. Following p27CE pDNA priming, two booster regimens, gag pDNA or codelivery of p27CE+gag pDNA, significantly increased the levels of CE-specific T cells. However, the CE+gag pDNA booster vaccination elicited significantly broader CE epitope recognition, and thus, a more profound alteration of the immunodominance hierarchy. Vaccination with HIV molecules showed that CE+gag pDNA booster regimen further expanded the breadth of HIV CE responses. Hence, SIV/HIV vaccine regimens comprising CE pDNA prime and CE+gag pDNA booster vaccination significantly increased cytotoxic T cell responses to subdominant highly conserved Gag epitopes and maximized response breadth.

http://ift.tt/2fDC9an

Soluble RANKL Cleaved from Activated Lymphocytes by TNF-{alpha}-Converting Enzyme Contributes to Osteoclastogenesis in Periodontitis [IMMUNE REGULATION]

Host immune responses play a key role in promoting bone resorption in periodontitis via receptor activator of NF-B ligand (RANKL)–dependent osteoclastogenesis. Both membrane-bound RANKL (mRANKL) expressed on lymphocytes and soluble RANKL (sRANKL) are found in periodontal lesions. However, the underlying mechanism and cellular source of sRANKL release and its biological role in periodontitis are unclear. TNF-α–converting enzyme (TACE) is reported to cleave the following: 1) precursor TNF-α with release of mature, soluble TNF-α and 2) mRANKL with release of sRANKL. Both soluble TNF-α and sRANKL are found in the periodontitis lesion, leading to the hypothesis that TACE expressed on lymphocytes is engaged in RANKL shedding and that the resulting sRANKL induces osteoclastogenesis. In the current study, upon stimulating PBLs with mitogens in vitro, RANKL expression, sRANKL secretion, and TACE expression were all upregulated. Among the four putative mRANKL sheddases examined in neutralization assays, TACE was the only functional sheddase able to cleave mRANKL expressed on PBL. Moreover, PBL culture supernatant stimulated with mitogens in the presence of anti-TACE Ab or anti-RANKL Ab showed a marked reduction of osteoclastogenesis from osteoclast precursors, indicating that TACE-mediated sRANKL may possess sufficient osteoclastogenic activity. According to double-color confocal microscopy, B cells expressed a more pronounced level of RANKL and TACE expression than T cells or monocytes in periodontally diseased gingiva. Conditioned medium of patients' gingival lymphocyte culture increased in vitro osteoclastogenic activity, which was suppressed by the addition of anti-TACE Ab and anti-RANKL Ab. Therefore, TACE-mediated cleavage of sRANKL from activated lymphocytes, especially B cells, can promote osteoclastogenesis in periodontitis.

http://ift.tt/2fkx1nX

Water-in-Oil-Only Adjuvants Selectively Promote T Follicular Helper Cell Polarization through a Type I IFN and IL-6-Dependent Pathway [IMMUNE REGULATION]

T follicular helper (Tfh) cells are a subset of CD4⁺ T lymphocytes that promote the development of humoral immunity. Although the triggers required for the differentiation of the other major Th subsets are well defined, those responsible for Tfh cell responses are still poorly understood. We determined that mice immunized with peptide or protein Ags emulsified in IFA or related water-in-oil adjuvants develop a highly polarized response in which the majority of the Ag-specific CD4⁺ T cells are germinal center–homing CXCR5⁺Bcl6⁺ Tfh cells. Despite the absence of exogenous microbial pathogen-associated molecular patterns, the Tfh cell responses observed were dependent, in part, on MyD88. Importantly, in addition to IL-6, T cell–intrinsic type I IFN signaling is required for optimal Tfh cell polarization. These findings suggest that water-in-oil adjuvants promote Tfh cell–dominated responses by triggering endogenous alarm signals that, in turn, induce type I IFN–dependent differentiation pathway functioning in T cells.

http://ift.tt/2fDx7uI

Endothelial Plasmalemma Vesicle-Associated Protein Regulates the Homeostasis of Splenic Immature B Cells and B-1 B Cells [IMMUNE SYSTEM DEVELOPMENT]

Plasmalemma vesicle-associated protein (Plvap) is an endothelial protein with roles in endothelial diaphragm formation and maintenance of basal vascular permeability. At the same time, Plvap has roles in immunity by facilitating leukocyte diapedesis at inflammatory sites and controlling peripheral lymph node morphogenesis and the entry of soluble Ags into lymph node conduits. Based on its postulated role in diapedesis, we have investigated the role of Plvap in hematopoiesis and show that deletion of Plvap results in a dramatic decrease of IgM⁺IgD^lo B cells in both the spleen and the peritoneal cavity. Tissue-specific deletion of Plvap demonstrates that the defect is B cell extrinsic, because B cell and pan-hematopoietic Plvap deletion has no effect on IgM⁺IgD^lo B cell numbers. Endothelial-specific deletion of Plvap in the embryo or at adult stage recapitulates the full Plvap knockout phenotype, whereas endothelial-specific reconstitution of Plvap under the Chd5 promoter rescues the IgM⁺IgD^lo B cell phenotype. Taken together, these results show that Plvap expression in endothelial cells is important in the maintenance of IgM⁺ B cells in the spleen and peritoneal cavity.

http://ift.tt/2fDqGYq

Loss of Neurokinin-1 Receptor Alters Ocular Surface Homeostasis and Promotes an Early Development of Herpes Stromal Keratitis [INFECTIOUS DISEASE AND HOST RESPONSE]

Substance P neuropeptide and its receptor, neurokinin-1 receptor (NK1R), are reported to present on the ocular surface. In this study, mice lacking functional NK1R exhibited an excessive desquamation of apical corneal epithelial cells in association with an increased epithelial cell proliferation and increased epithelial cell density, but decreased epithelial cell size. The lack of NK1R also resulted in decreased density of corneal nerves, corneal epithelial dendritic cells (DCs), and a reduced volume of basal tears. Interestingly, massive accumulation of CD11c⁺CD11b⁺ conventional DCs was noted in the bulbar conjunctiva and near the limbal area of corneas from NK1R^–/– mice. After ocular HSV-1 infection, the number of conventional DCs and neutrophils infiltrating the infected corneas was significantly higher in NK1R^–/– than C57BL/6J mice. This was associated with an increased viral load in infected corneas of NK1R^–/– mice. As a result, the number of IFN-–secreting virus-specific CD4 T cells in the draining lymph nodes of NK1R^–/– mice was much higher than in infected C57BL/6J mice. An increased number of CD4 T cells and mature neutrophils (CD11b⁺Ly6g^high) in the inflamed corneas of NK1R^–/– mice was associated with an early development of severe herpes stromal keratitis. Collectively, our results show that the altered corneal biology of uninfected NK1R^–/– mice along with an enhanced immunological response after ocular HSV-1 infection causes an early development of herpes stromal keratitis in NK1R^–/– mice.

http://ift.tt/2fDyPMo

NKT Cell Hyporesponsiveness Leads to Unrestrained Accumulation of Marginal Zone B Cells in Hypercholesterolemic Apolipoprotein E-Deficient Mice [IMMUNE REGULATION]

Recently, the role of B cells in atherosclerosis has gained more attention but studies have mainly focused on B1 and follicular B cell subsets. Therefore, the contribution of marginal zone (MZ) B cells in experimental atherosclerosis remains elusive. In the current study, we examined the MZ B cell compartment in atherosclerotic apoE-deficient (apoE^–/–) mice and found that hypercholesterolemia in these mice was associated with an increased number and percentage of MZ B cells. This aberrant accumulation of MZ B cells was not associated with alterations in their development or increased proliferation but was due to decreased apoptotic cell death. This decrease in MZ B cell death in apoE^–/– mice was associated with the reduced capacity of invariant NKT (iNKT) cells to produce IFN- and IL-4 after activation. Lowering cholesterol plasma levels with ezetimibe in apoE^–/– mice reversed iNKT function and MZ B cell accumulation. To elucidate the mechanism whereby iNKT cells control MZ B cell accumulation in apoE^–/– mice, we performed an adoptive transfer of iNKT cells and found that only wild-type iNKT cells but not IFN-^–/– iNKT cells reversed MZ B cell accumulation in apoE^–/– recipient mice. Our findings reveal that lipid changes associated with atherosclerotic disease induce decreased production of IFN- by iNKT, which in turn leads to aberrant accumulation of MZ B cells. This study further extends the importance of iNKT cells in regulating MZ B cell compartment.

http://ift.tt/2fkwann

Correlation between flexural and indirect tensile strength of resin composite cements

To evaluate a potential correlation between flexural strength and indirect tensile strength in assessing the mechanical strength of resin composite cements.

http://ift.tt/2f2nDqX

Pen-type laser fluorescence device versus bitewing radiographs for caries detection on approximal surfaces

The accurate detection of approximal caries is generally difficult. The aim of this study was to assess the ability of the pen-type laser fluorescence device (LF pen) to detect approximal carious lesions in co...

http://ift.tt/2fnfBHE

The expression of Bcl-6 in circulating follicular helper-like T cells positively correlates with the disease activity in systemic lupus erythematosus

Publication date: Available online 3 November 2016
Source:Clinical Immunology
Author(s): Xin Huang, Haijing Wu, Hong Qiu, Huilan Yang, Yaxiong Deng, Ming Zhao, Hairong Luo, Xiang Zhou, Yubin Xie, Vera Chan, Chak-Sing Lau, Qianjin Lu
Increased circulating follicular helper-like T cells (cTfh) are reported in systemic lupus erythematosus (SLE) patients. However, whether B-cell lymphoma 6 (Bcl-6) is expressed in cTfh cells remains to be clarified. In this study, we found that the frequencies of CD4⁺CXCR5^hiPD-1^hicTfh, CD4⁺CXCR5^hiPD-1^hiICOS^hi, and CD4⁺CXCR5^hiPD-1^hiBcl-6⁺ populations were significantly increased in SLE patients (n=70) when compared with healthy controls (n=48). Surprisingly, only CD4⁺CXCR5^hiPD-1^hiBcl-6⁺ cTfh cells, rather than CD4⁺CXCR5^hiPD-1^hi population, were positively correlated with SLEDAI and anti-dsDNA antibodies. An elevated level of IL-21 was found in SLE CD4⁺ T cells. Moreover, IL-21 promoted the enrichment of TET2 in Bcl-6 promoter region and induced Bcl-6 expression. Therefore, Bcl-6 expression in cTfh cells may represent a reliable marker for the disease activity in SLE.



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Stratum corneum profiles of inflammatory mediators in patch test reactions to common contact allergens and sodium lauryl sulfate

Abstract

Background

Recent studies demonstrated allergen-specific differences in the gene-expression of inflammatory mediators in patch-tested skin.

Objectives

To determine levels of various inflammatory mediators in the stratum corneum (SC) after patch testing with common contact allergens and the skin irritant sodium lauryl sulfate (SLS).

Methods

Twenty-seven individuals with previous positive patch test to nickel (Ni), chromium (Cr), methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) or p-phenylenediamine (PPD) were retested and furthermore patch tested with SLS and petrolatum, with petrolatum serving as patch test controls. At 72 hours, test sites were clinically graded and SC samples collected by adhesive tapes.

Results

The levels of eighteen out of thirty-two quantified mediators differed significantly from that of control patches for at least one of the tested substances. SLS and MCI/MI induced the largest number of immunomediators. The levels of IL-16 were significantly higher in patch test reactions to all allergens than in the controls, while no significant difference was detected for SLS. Furthermore, a strong negative correlation was found between clinical severity and levels of IL-1α.

Conclusion

Cytokine profiles in the SC of patch tested skin did not show a distinct allergen-specific pattern. However, MCI/MI induced a larger and broader immune response than the other allergens, perhaps due to its irritant potency. The levels of IL-16 were significantly increased in patch test reactions to all allergens but not to SLS, and thus, may help to differentiate between allergic contact dermatitis and irritant contact dermatitis.

This article is protected by copyright. All rights reserved.

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Responsiveness of the German Version of the Neck Disability Index (NDI-G)

Condition:   Neck Pain Chronic
Intervention:   Other: Manual Therapy
Sponsors:   Balgrist University Hospital;   Maastricht University
Recruiting - verified November 2016

http://ift.tt/2foMpyu

Cervical Range of Motion in Neck Pain Patients: A Mixed Methods Study

Condition:   Neck Pain
Intervention:   Other: Measurement of the range of motion of the cervical spine
Sponsors:   Balgrist University Hospital;   Maastricht University
Recruiting - verified November 2016

http://ift.tt/2evk9fH

Endscopically-assisted reduction of a fracture of the anterior wall of the frontal sinus using a Foley catheter

Publication date: Available online 3 November 2016
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): T. Spindler, M. Cairns, M. Halsnad




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Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5
Author(s): Steven de Maat, Jenny Björkqvist, Chiara Suffritti, Chantal P. Wiesenekker, Willem Nagtegaal, Arnold Koekman, Sanne van Dooremalen, Gerard Pasterkamp, Philip G. de Groot, Marco Cicardi, Thomas Renné, Coen Maas
BackgroundPatients with angioedema experience unpredictable attacks of tissue swelling in which bradykinin is implicated. Several distinct mutations in Factor XII (FXII) are associated with hereditary angioedema (HAE) in the presence of normal C1 esterase inhibitor activity (FXII-HAE). The underlying disease mechanisms are unclear, which complicates diagnosis and treatment.ObjectiveWe sought to identify the natural trigger for FXII activation, which causes uncontrolled bradykinin production in patients with FXII-HAE.MethodsWe generated recombinant variants of FXII, representing health and disease, and studied their behavior in functional studies. We investigated bradykinin-forming pathways in blood plasma with newly developed nanobody-based analytic methods.ResultsWe here report that FXII-HAE mutations collectively introduce new sites that are sensitive to enzymatic cleavage by plasmin. These FXII mutants rapidly activate after cleavage by plasmin, escape from inhibition through C1 esterase inhibitor, and elicit excessive bradykinin formation. Furthermore, our findings indicate that plasmin modulates disease activity in patients with FXII-HAE. Finally, we show that soluble lysine analogs attenuate this mechanism, explaining their therapeutic value in patients with HAE.ConclusionOur findings indicate a new pathway for bradykinin formation in patients with HAE, in which FXII is cleaved and activated by plasmin. This should lead to the identification of new markers for diagnosis and targets for treatment.

Graphical abstract

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Brief Overview of This Month's JACI

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5





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Table of Contents

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5





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Editorial Board

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5





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Information for Readers

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5





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News & Notes

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5





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Cover 1

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5





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CME Activities Calendar

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5





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News Beyond Our Pages

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5
Author(s): Marc E. Rothenberg, Jean Bousquet




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Immune modules shared by innate lymphoid cells and T cells

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5
Author(s): Michelle L. Robinette, Marco Colonna
In recent years, innate lymphoid cells (ILCs) have emerged as innate correlates to T cells. The similarities between ILCs and T cells indicate that lymphocytes of fundamentally distinct lineages can share core "immune modules" that encompass transcriptional circuitry and effector functions while using nonredundant complementary mechanisms of pattern recognition to enact these functions. We review modules currently recognized to be shared between ILCs and T cells.



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Immune modules shared by innate lymphoid cells and T cells

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5





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Innate lymphoid cells in allergic and nonallergic inflammation

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5
Author(s): Hideaki Morita, Kazuyo Moro, Shigeo Koyasu
In the last decade, the full picture of the role of innate lymphoid cells (ILCs) has been gradually revealed. ILCs are classified into 3 groups based on their transcription factors and cytokine production patterns, which mirror helper T-cell subsets. Unlike T cells and B cells, ILCs do not have antigen receptors. They promptly respond to multiple tissue-derived factors, such as cytokines and alarmins, and produce multiple proinflammatory and immunoregulatory cytokines. It has been reported that ILC-derived cytokines are important for the induction and regulation of inflammation. Accumulating evidence suggests that ILCs play substantial roles in protection against infection and the pathogenesis of inflammatory diseases, such as allergic diseases and autoimmune diseases. Different ILC subsets localize in distinct tissue/organ niches and receive tissue-derived signals on different types of inflammation, which allows them to acquire diverse phenotypes with specialized effector capacities. In this review we highlight the roles of ILCs in a variety of organs, such as the airway, skin, and gastrointestinal tract, in the context of allergic and nonallergic inflammation.



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Advances in rhinitis and rhinosinusitis in 2015

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5
Author(s): Claus Bachert, Elien Gevaert
The last year has seen great progress in the understanding of upper airway disease and in its management. For allergic rhinitis, authors focused on the prediction of and effect on the natural course of disease. New evidence was published for the disease-modifying effect of allergen immunotherapy in terms of avoidance of new sensitizations and prevention of asthma in either randomized or real-life studies. Specifically, for patients with house dust mite allergies, which are often underestimated and difficult to diagnose, the efficacy of SQ house dust mite sublingual immunotherapy tablets has been demonstrated in patients with allergic rhinitis and asthma. For the first time, allergen immunotherapy significantly reduced asthma exacerbations. In patients with chronic rhinosinusitis, a novel endotyping approach purely based on T helper cell biomarkers has been developed and has shown clinical relevance through associations with asthma comorbidity and recurrence after surgery. Severe nasal polyposis with high risk for asthma comorbidity and disease recurrence is characterized by type 2 inflammatory patterns, including IgE antibodies to staphylococcal superantigens; several studies using biologic agents have targeted exactly this spectrum of mediators. This goes in parallel with new knowledge on even more type 2 mediators derived from epithelial cells, which will expand the number of possible candidates for innovative intervention.



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Advances in allergen immunotherapy in 2015

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5
Author(s): Robert K. Bush
The year 2015 saw a significant number of advances in allergen immunotherapy (AIT), and several of these are reviewed in this report. Although AIT has been used for more than 100 years, investigations into optimal treatment approaches and mechanisms are ongoing. Among the highlights was a report by an international group of experts who reviewed AIT guidelines from the major specialty societies and addressed potential unmet needs. Herein, advances in the effectiveness, safety, and mechanisms of sublingual and oral immunotherapy are reviewed. Development of hypoallergenic vaccines to enhance safety, newer routes and regimens to improve efficacy, and biomarkers to monitor immunotherapy are also discussed.



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The Editors' Choice

Publication date: November 2016
Source:Journal of Allergy and Clinical Immunology, Volume 138, Issue 5
Author(s): Cezmi A. Akdis, Zuhair K. Ballas




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Resolution of left ventricular postinfarction thrombi in patients undergoing percutaneous coronary intervention using rivaroxaban in addition to dual antiplatelet therapy

Constantinos Andreas Makrides<br />Oct 26, 2016; 2016:201621784-201621784<br />case-report

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Coexisting pulmonary haemorrhage and venous thrombosis: a tricky but novel case

Alexandra Fielding, Mira Pecheva, Aser Farghal, Russell Phillips<br />Oct 20, 2016; 2016:201621716-201621716<br />case-report

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Native valve Proteus mirabilis endocarditis: successful treatment of a rare entity formulated by in vitro synergy antibiotic testing

Caroline R Brotzki, Kari A Mergenhagen, Zackery P Bulman, Brian T Tsuji, Charles S Berenson<br />Oct 20, 2016; 2016:201621595-201621595<br />case-report

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Role of diagnostic laparoscopy in penetrating anterior abdominal wall trauma

David Parizh, Vadim Meytes, Anthony Kopatsis<br />Oct 14, 2016; 2016:201621764-201621764<br />case-report

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Ascites: it is not all alcohol--a case of constrictive pericarditis

Asgher Champsi, Muzzammil Ali<br />Oct 8, 2016; 2016:201621502-201621502<br />case-report

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Bleeding manifestations in a patient with amyloidosis

Luai Alhazmi, Abdulelah Nuqali, Ragheb Assaly<br />Oct 8, 2016; 2016:201621694-201621694<br />case-report

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Severe hypercalcaemia in a child secondary to use of alternative therapies

Catriona Boyd, Abdul Moodambail<br />Oct 6, 2016; 2016:201621584-201621584<br />case-report

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Aortic valve replacement for Libman-Sacks endocarditis

Jack B Keenan, Rajesh Janardhanan, Brandon T Larsen, Zain Khalpey<br />Oct 4, 2016; 2016:201621591-201621591<br />case-report

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Successful Treatment of Vitiligo on the Scalp of a 9-Year-Old Girl Using Autologous Cultured Pure Melanocyte Transplantation

Abstract

Leukotrichia frequently accompanies vitiligo on hairy areas such as the scalp. Treatment with conventional medical therapy is usually unsuccessful because of deficiencies in the melanocyte reservoir. We describe transplantation of autologous cultured pure melanocytes for scalp vitiligo with leukotrichia in a 9-year-old girl, resulting in almost complete and stable repigmentation of skin and hair.

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Invasive Melanoma in a Patient with Congenital Ichthyosiform Erythroderma

Abstract

We describe the case of a 26-year-old woman with a history of congenital ichthyosiform erythroderma (CIE) who initially presented with a stage IIA amelanotic melanoma on her forearm that was surgically excised. We also review the literature on CIE-associated skin cancers and discuss the possible contribution of ichthyosis to the risk of cutaneous malignancies. Our findings emphasize the importance of close lifelong skin cancer screening in individuals with CIE and highlight the unique malignancy risk of these individuals.

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A Cutaneous Lupus Erythematosus-Like Eruption Induced by Hydroxyurea

Abstract

Hydroxyurea is a medication with many well-described cutaneous side effects, notably the dermatomyositis-like eruption known as hydroxyurea dermopathy. Although systemic lupus erythematosus has been reported with hydroxyurea use, cutaneous lupus has not. We report a novel case of chronic cutaneous lupus induced by hydroxyurea and propose that this is a side effect that is distinct from hydroxyurea dermopathy.

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