Subscribe: pubmed: 0091-6749
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pubmed: 0091-6749



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Substance P activates Mas-related G-protein coupled receptors to induce itch.
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Substance P activates Mas-related G-protein coupled receptors to induce itch.

J Allergy Clin Immunol. 2017 Feb 17;:

Authors: Azimi E, Reddy VB, Pereira PJ, Talbot S, Woolf CJ, Lerner EA

Abstract
BACKGROUND: Substance P (SP) is linked to itch and inflammation through activation of receptors on mast cells and sensory neurons. There is increasing evidence that SP functions through Mas-related G protein-coupled receptors (Mrgprs) in addition to its conventional receptor, neurokinin-1.
OBJECTIVE: Because Mrgprs mediate some aspects of inflammation that had been considered mediated by neurokinin-1 receptor (NK-1R), we sought to determine whether itch induced by SP can also be mediated by Mrgprs.
METHODS: Genetic and pharmacologic approaches were used to evaluate the contribution of Mrgprs to SP-induced scratching behavior and activation of cultured dorsal root ganglion neurons from mice.
RESULTS: SP-induced scratching behavior and activation of cultured dorsal root ganglion neurons was dependent on Mrgprs rather than NK-1R.
CONCLUSION: We deduce that SP activates MrgprA1 on sensory neurons rather than NK-1R to induce itch.

PMID: 28219706 [PubMed - as supplied by publisher]




Substance P represents a novel first-line defense mechanism in the nose.
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Substance P represents a novel first-line defense mechanism in the nose.

J Allergy Clin Immunol. 2017 Feb 17;:

Authors: Larsson O, Tengroth L, Xu Y, Uddman R, Georén SK, Cardell LO

Abstract
BACKGROUND: Neuropeptides, such as substance P (SP), have long been seen as mediators of widespread, continuous airway inflammation, a process known as neurogenic inflammation. However, this has been difficult to demonstrate clinically, suggesting an alternative role for these signaling molecules.
OBJECTIVES: To examine the role of SP in nasal infection, by assessing the release of SP in response to viral stimulation and characterizing the effects of SP on innate immunity, the latter reflected in changes in local Toll-like receptor (TLR) expression.
METHODS: The distribution of SP and TLRs in the nasal mucosa and in local airway neurons was assessed with immunohistochemistry. The TLR7 agonists R-837 and R-848 were used to mimic a viral insult in upper airways, represented by primary human and mouse nasal epithelial cells (HNEC, MNEC) and isolated murine trigeminal ganglia (TGN). SP release from HNEC, MNEC and TGN was quantified with EIA. The effects of SP on TLR expression on HNEC were determined using flow cytometry and confocal microscopy.
RESULTS: SP was released from the sensory neurons, MNEC and HNEC within 15 minutes of local TLR7 stimulation. Subsequently, stimulation with SP induced upregulation of TLR expression in HNEC within 30 minutes, via induction of TLR movement within HNEC. Upregulation of TLR expression was not evident when cells were treated with the neurokinin 1 receptor (NK1R) antagonist aprepitant prior to SP stimulation.
CONCLUSIONS: This highlights a novel role for sensory neuropeptides as acute and local mediators of pathogen-driven inflammation, rapidly priming innate immune defenses in the airway.

PMID: 28219705 [PubMed - as supplied by publisher]




β-lactam hypersensitivity involves expansion of circulating and skin-resident Th22 cells.
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β-lactam hypersensitivity involves expansion of circulating and skin-resident Th22 cells.

J Allergy Clin Immunol. 2017 Feb 17;:

Authors: Sullivan A, Wang E, Farrell J, Whitaker P, Faulkner L, Peckham D, Park BK, Naisbitt DJ

Abstract
BACKGROUND: β-lactam hypersensitivity has been classified according to the phenotype and function of drug-specific T-cells; however, new T-cell subsets have not been considered.
OBJECTIVE: The objective of this study was use piperacillin as a model of β-lactam hypersensitivity to study the nature of the drug-specific T-cell response induced in the blood and skin of hypersensitive patients and healthy volunteers.
METHODS: Drug-specific T-cells were cloned from blood and inflamed skin and cellular phenotype and function was explored. Naïve T cells from healthy volunteers were primed to piperacillin, cloned and subjected to the similar analyses.
RESULTS: PBMC and T-cell clones (n=570, 84% CD4+) from blood of piperacillin hypersensitive patients proliferated and secreted Th1/2 cytokines alongside IL-22 following drug stimulation. IL-17A secretion was not detected. Drug-specific clones from inflamed skin (n=96, 83% CD4+) secreted a similar profile of cytokines, but displayed greater cytolytic activity, secreting perforin, granzyme B and Fas L when activated. Blood- and skin-derived clones expressed high levels of skin-homing chemokine receptors and migrated in the presence of the ligands CCL17 and CCL27. Piperacillin-primed naïve T-cells from healthy volunteers also secreted IFN-γ, IL-13, IL-22 and cytolytic molecules. Aryl hydrocarbon (ArH) receptor blockade prevented differentiation of the naïve T-cells into antigen-specific Il-22 secreting cells.
CONCLUSION: Together our results reveal that circulating and skin resident antigen-specific IL-22 secreting T-cells are detectable in patients with β-lactam hypersensitivity. Furthermore, differentiation of naïve T-cells into antigen-specific Th22 cells is dependent on ArH receptor signalling.

PMID: 28219704 [PubMed - as supplied by publisher]




Extracellular eosinophilic traps in association with Staphylococcus aureus at the site of epithelial barrier defects in severe airway inflammation.
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Extracellular eosinophilic traps in association with Staphylococcus aureus at the site of epithelial barrier defects in severe airway inflammation.

J Allergy Clin Immunol. 2017 Feb 16;:

Authors: Gevaert E, Zhang N, Krysko O, Lan F, Holtappels G, De Ruyck N, Nauwynck H, Yousefi S, Simon HU, Bachert C

Abstract
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by a Th2-biased eosinophilic inflammation. Eosinophils have been shown to generate so-called extracellular eosinophilic traps (EETs) under similar pathological conditions.
OBJECTIVE: Our aim was to investigate a possible link between EET formation and the presence of Staphylococcus aureus, an organism frequently colonizing the upper airways, at the human mucosal site of the disease.
METHODS: Tissue slides were investigated for the presence of EETs and S. aureus, using immunofluorescent staining and PNA-fish assay respectively. An ex vivo human mucosal disease tissue model was used for artificial infection with S. aureus. Cell markers were analyzed using immunohistochemistry, luminex Multiplex assay, ELISA, PCR, immunobloting and linked to the presence of EETs.
RESULTS: About 8.8 ± 4.8 % of the infiltrating eosinophils exhibited EETs in patient's nasal polyp tissues. The formation of EETs was associated with increased IL-5 (p < 0.05) and periostin (p < 0.05) tissue levels, and colonization with S. aureus (p < 0.05). Using an ex vivo human mucosal disease tissue model, EET formation was induced (4.2 ± 0.9 fold) upon exposure to S. aureus, but not to S. epidermidis. Eosinophils were shown to migrate (p < 0.01) towards S. aureus and entrap the bacteria both inside and outside the mucosal tissue. Blocking NAPDH oxidase activity, led to a complete inhibition (p < 0.05) of EET formation by S. aureus.
CONCLUSION: Eosinophils are likely to be specifically recruited to and form EETs at sites of airway epithelial damage to protect the host from infections with S. aureus and possibly other microorganisms in CRSwNP.

PMID: 28216437 [PubMed - as supplied by publisher]




Group 2 innate lymphoid cell activation in the neonatal lung drives type 2 immunity and allergen sensitization.
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Group 2 innate lymphoid cell activation in the neonatal lung drives type 2 immunity and allergen sensitization.

J Allergy Clin Immunol. 2017 Feb 16;:

Authors: Steer CA, Martinez-Gonzalez I, Ghaedi M, Allinger P, Mathä L, Takei F

Abstract
Neonatal lung immunity is unique due to allergen-independent endogenous IL-33 mediated activation of group 2 innate lymphoid cells (ILC2s) that promote Th2 cell responses, making neonates prone to allergen sensitization and allergic lung diseases.

PMID: 28216436 [PubMed - as supplied by publisher]




Morpholino-based correction of hypomorphic ZAP70 mutation in an adult with combined immunodeficiency.
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Morpholino-based correction of hypomorphic ZAP70 mutation in an adult with combined immunodeficiency.

J Allergy Clin Immunol. 2017 Feb 16;:

Authors: Gavino C, Landekic M, Zeng J, Wu N, Jung S, Zhong MC, Cohen-Blanchet A, Langelier M, Neyret O, Lejtenyi D, Rochefort C, Cotton-Montpetit J, McCusker C, Mazer B, Veillette A, Vinh DC

Abstract
An adult with hypomorphic ZAP-70 deficiency due to de novo donor splice site mutation manifested autoimmunity, infections especially with DNA-based viruses and lymphoproliferation. Morpholino interference of mutant splice site increased expression of wild-type protein, significantly improving T cell responses.

PMID: 28216435 [PubMed - as supplied by publisher]




Human NLRP3 inflammasome activity is regulated by and potentially targetable via BTK.
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Human NLRP3 inflammasome activity is regulated by and potentially targetable via BTK.

J Allergy Clin Immunol. 2017 Feb 16;:

Authors: Liu X, Pichulik T, Wolz OO, Dang TM, Stutz A, Dillen C, Delmiro Garcia M, Kraus H, Dickhöfer S, Daiber E, Münzenmayer L, Wahl S, Rieber N, Kümmerle-Deschner J, Yazdi A, Franz-Wachtel M, Macek B, Radsak M, Vogel S, Schulte B, Walz JS, Hartl D, Latz E, Stilgenbauer S, Grimbacher B, Miller L, Brunner C, Wolz C, Weber AN

Abstract
BACKGROUND: The Nod-like receptor, NACHT, LRR and PYD domains-containing protein 3 (NLRP3), and Bruton's tyrosine kinase (BTK) are protagonists in innate and adaptive immunity, respectively: NLRP3 senses exogenous and endogenous insults leading to inflammasome activation, which occurs spontaneously in Muckle-Wells Syndrome (MWS); BTK mutations cause the genetic immunodeficiency X-linked agammaglobulinemia (XLA). However, to date few proteins that regulate NLRP3 inflammasome activity in human primary immune cells have been identified and clinically promising pharmacological targeting strategies remain elusive.
OBJECTIVE: We therefore sought to identify novel regulators of the NLRP3 inflammasome in human cells with a view to exploring interference with inflammasome activity at the level of such regulators.
METHODS: Following proteome-wide phospho-proteomics, an identified novel regulator, BTK, was studied in human and murine cells using pharmacological and genetic BTK ablation.
RESULTS: We here show that BTK is a critical regulator of NLRP3 inflammasome activation: Pharmacological (using the Food and Drug Administration (FDA)-approved inhibitor, ibrutinib) and genetic (in XLA patients and Btk-knockout mice) BTK ablation in primary immune cells led to reduced Interleukin (IL)-1β processing and secretion in response to Nigericin and the Staphylococcus aureus toxin, Leukocidin (Luk) AB. BTK affected Apoptosis-associated speck-like protein containing a CARD (ASC) speck formation and caspase-1 cleavage and interacted with NLRP3 and ASC. S. aureus infection control in vivo and IL-1β release from MWS patient cells were impaired by ibrutinib. Notably, IL-1β processing and release from immune cells isolated from cancer patients on ibrutinib therapy was reduced.
CONCLUSION: Our data suggest that XLA may partially result from genetic inflammasome deficiency and that NLRP3 inflammasome-linked inflammation could potentially be targeted pharmacologically via BTK.

PMID: 28216434 [PubMed - as supplied by publisher]




Lifelong Memory Responses Perpetuate Humoral Th2 Immunity and Anaphylaxis in Food Allergy.
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Lifelong Memory Responses Perpetuate Humoral Th2 Immunity and Anaphylaxis in Food Allergy.

J Allergy Clin Immunol. 2017 Feb 16;:

Authors: Jiménez-Saiz R, Chu DK, Mandur TS, Walker TD, Gordon ME, Chaudhary R, Koenig J, Saliba S, Galipeau HJ, Utley A, King IL, Lee K, Ettinger R, Waserman S, Kolbeck R, Jordana M

Abstract
BACKGROUND: A number of food allergies (e.g. fish, shellfish, nuts) are lifelong, without any disease-transforming therapies and unclear in their underlying immunology. Clinical manifestations of food allergy are largely mediated by IgE. Although persistent IgE titres have conventionally been attributed to long-lived IgE(+) plasma cells (PCs), this has not been directly and comprehensively tested.
OBJECTIVE: To evaluate mechanisms underlying persistent IgE and allergic responses to food allergens.
METHODS: We used a model of peanut allergy and anaphylaxis, various knockout mice, adoptive transfer experiments and in vitro assays, to identify mechanisms underlying persistent IgE humoral immunity over almost the entire life-span of the mouse (18-20 months).
RESULTS: Contrary to conventional paradigms, our data show that clinically relevant lifelong IgE titres are not sustained by long-lived IgE(+) PCs. Instead, lifelong reactivity is conferred by allergen-specific long-lived memory B cells that replenish the IgE(+) PC compartment. B cell re-activation requires allergen re-exposure and IL-4 production by CD4 T cells. We define the half-lives of antigen-specific: germinal centers (23.3 days); IgE(+) and IgG1(+) PCs (60 days and 234.4 days respectively) and clinically-relevant cell-bound IgE (67.3 days).
CONCLUSIONS: These findings can explain lifelong food allergies observed in humans as the consequence of allergen exposures that recurrently activate memory B cells and identify these as a therapeutic target with disease-transforming potential.

PMID: 28216433 [PubMed - as supplied by publisher]