scholarly journals Proteo-transcriptomic profiling of nasal mononuclear phagocytic system cells in human controlled allergen challenge

2020 ◽  
Author(s):  
Astrid L Voskamp ◽  
Maarten L Gerdes ◽  
Roberta Menafra ◽  
Ellen Duijster ◽  
Szymon M Kielbasa ◽  
...  
Keyword(s):  
Immune Responses ◽  
Transcriptional Activation ◽  
Allergic Inflammation ◽  
Allergen Challenge ◽  
Clinical Score ◽  
Airway Disease ◽  
House Dust Mite Allergen ◽  
Mononuclear Phagocytic System ◽  
Environmental Antigens ◽  
Homeostatic Response

Immune homeostasis is essential to protect mucosal airway surfaces from unnecessary and damaging inflammation against inhaled harmless environmental antigens, such as allergens. However, in allergic individuals this protective homeostatic response seems absent. Innate cells part of the mononuclear phagocytic system (MPS) play an important role in these processes. Most of our knowledge on allergic immune responses comes from animal models or from peripheral blood immune responses. Information on human tissue-specific responses is scarce, however allergen-specific immune responses are initiated locally and this information is crucial for the development of novel therapies. Here we performed mass-cytometry proteomics and single cell RNA sequencing on immune cells from nasal biopsies of allergic rhinitis subjects and healthy controls, before and three days after repeated nasal challenge with House Dust Mite allergen. Following challenge, patients displayed an increased clinical score together with enhanced eosinophilia, a cardinal feature of allergic inflammation. Although clinically silent, we observed a distinct, local, innate immune response to allergen in healthy individuals, characterized by infiltration of HLA-DRlow CD14+ monocytes expressing anti-microbial genes (S100A8, S100A9, S100A12) as well as transcriptional activation in cDC2, including several tolerogenic genes (NR4A1, IL4I1, TIMP1). The innate response in allergic individuals indicated an inflammatory role for infiltrating HLA-DRhi CD14+ monocytes, CD16+ monocytes, and CD1A+ cDC2 (ALOX15, CD1A, CCL17), in the development/maintenance of an allergic response. Future therapies should be addressing those innate MPS populations, either enhancing or reducing their activity for the treatment of inflammatory airway disease.

scholarly journals CpG-ODN Signaling via Dendritic Cells-Expressing MyD88, but Not IL-10, Inhibits Allergic Sensitization

Vaccines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 743
Author(s):  
Ricardo Wesley Alberca ◽  
Eliane Gomes ◽  
Momtchilo Russo
Keyword(s):  
Dendritic Cells ◽  
Allergic Sensitization ◽  
Allergic Inflammation ◽  
Allergen Challenge ◽  
Lavage Fluid ◽  
Specific Cell ◽  
Cpg Odn ◽  
Allergic Lung Disease ◽  
Myd88 Pathway

Allergen-specific T helper (Th)2 cells orchestrate upon allergen challenge the development of allergic eosinophilic lung inflammation. Sensitization with alum adjuvant, a type 2 adjuvant, has been used extensively in animal models of allergic lung disease. In contrast, type 1 adjuvants like CpG-ODN, a synthetic toll-like receptor 9 agonist, inhibit the development of Th2 immunity. CpG-ODN induce type 1 and suppressive cytokines that influence Th2 cell differentiation. Here, we investigated the immune modulatory effect of CpG-ODN on allergic sensitization to OVA with alum focusing on dendritic cells (DCs) expressing the MyD88 molecule and the suppressive IL-10 cytokine. Using mice with specific cell deletion of MyD88 molecule, we showed that CpG-ODN suppressed allergic sensitization and consequent lung allergic inflammation signaling through the MyD88 pathway on dendritic cells, but not on B-cells. This inhibition was associated with an increased production of IL-10 in the bronchoalveolar lavage fluid. Sensitization to OVA with CpG-ODN of IL-10-deficient, but not wild-type mice, induced a shift towards Th1 pattern of inflammation. Employing bone marrow-derived dendritic cells (BM-DCs) pulsed with OVA for sensitizations with or without CpG-ODN, we showed that IL-10 is dispensable for the inhibition of allergic lung Th2 responses by CpG-ODN. Moreover, the lack of IL-10 on DCs was not sufficient for the CpG-ODN-induced immune-deviation towards a Th1 pattern. Accordingly, we confirmed directly the role of MyD88 pathway on DCs in the inhibition of allergic sensitization.

New perspectives on IL-33 and IL-1 family cytokines as innate environmental sensors

2018 ◽  
Vol 46 (5) ◽  
pp. 1345-1353 ◽  
Author(s):  
Ian C. Scott ◽  
D. Gareth Rees ◽  
E. Suzanne Cohen
Keyword(s):  
Immune Responses ◽  
Allergic Inflammation ◽  
Proteolytic Processing ◽  
Innate Immune ◽  
Environmental Sensors ◽  
Biological Functions ◽  
Soluble Receptors ◽  
Direct Sensing ◽  
Proteolytic Activities

Interleukin (IL)-1 family cytokines are important initiators of innate immunity and host defence; however, their uncontrolled activities can cause tissue-damaging inflammation. Consequently, IL-1 family cytokines have sophisticated regulatory mechanisms to control their activities including proteolytic processing for their activation and the deployment of soluble receptors and receptor antagonists to limit their activities. IL-33 is a promoter of type 2 immunity and allergic inflammation through its alarmin activity that can rapidly initiate local immune responses by stimulating innate immune cells following exposure to environmental insults, pathogens, or sterile injury. Recent publications have provided new insights into how the range and duration of IL-33 activity is regulated by direct sensing of host-derived and exogenous proteolytic activities as well as oxidative changes during tissue damage. Here, we discuss how this impacts our understanding of the roles of IL-33 in initiating immune responses and the evidence that these sensing mechanisms might regulate the activities of other IL-1 family cytokines and their biological functions. Finally, we discuss translational challenges these discoveries pose for the accurate detection of different forms of these cytokines.

scholarly journals ATP Induces IL-1βSecretion inNeisseria gonorrhoeae-Infected Human Macrophages by a Mechanism Not Related to the NLRP3/ASC/Caspase-1 Axis

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Killen García ◽  
Gisselle Escobar ◽  
Pablo Mendoza ◽  
Caroll Beltran ◽  
Claudio Perez ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Evasion ◽  
Transcriptional Activation ◽  
Pore Formation ◽  
Human Monocyte ◽  
Positive Staining ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Caspase 1

Neisseria gonorrhoeae(Ngo) has developed multiple immune evasion mechanisms involving the innate and adaptive immune responses. Recent findings have reported that Ngo reduces the IL-1βsecretion of infected human monocyte-derived macrophages (MDM). Here, we investigate the role of adenosine triphosphate (ATP) in production and release of IL-1βin Ngo-infected MDM. We found that the exposure of Ngo-infected MDM to ATP increases IL-1βlevels about ten times compared with unexposed Ngo-infected MDM (P<0.01). However, we did not observe any changes in inflammasome transcriptional activation of speck-like protein containing a caspase recruitment domain (CARD) (ASC,P>0.05) and caspase-1 (CASP1,P>0.05). In addition, ATP was not able to modify caspase-1 activity in Ngo-infected MDM but was able to increase pyroptosis (P>0.01). Notably ATP treatment defined an increase of positive staining for IL-1βwith a distinctive intracellular pattern of distribution. Collectively, these data demonstrate that ATP induces IL-1βsecretion by a mechanism not related to the NLRP3/ASC/caspase-1 axis and likely is acting at the level of vesicle trafficking or pore formation.

scholarly journals NITROGEN LIMITATION ADAPTATION functions as a negative regulator of Arabidopsis immunity

2021 ◽  
Author(s):  
Beatriz Val Torregrosa ◽  
Mireia Bundo ◽  
Tzyy Jen Chiou ◽  
Victor Flors ◽  
Blanca San Segundo
Keyword(s):  
Immune Responses ◽  
Transcriptional Activation ◽  
Fungal Pathogens ◽  
Nitrogen Limitation ◽  
Negative Regulator ◽  
Loss Of Function ◽  
Wild Type ◽  
Pathogen Infection ◽  
Fungal Elicitors ◽  
Resistance To Infection

Background: Phosphorus is an important macronutrient required for plant growth and development. It is absorbed through the roots in the form of inorganic phosphate (Pi). To cope with Pi limitation, plants have evolved an array of adaptive mechanisms to facilitate Pi acquisition and protect them from stress caused by Pi starvation. The NITROGEN LIMITATION ADAPTION (NLA) gene plays a key role in the regulation of phosphate starvation responses (PSR), its expression being regulated by the microRNA miR827. Stress caused by Pi limiting conditions might also affect the plant response to pathogen infection. However, cross-talk between phosphate signaling pathways and immune responses remains unclear. Results: In this study, we investigated whether NLA plays a role in Arabidopsis immunity. We show that loss-of-function of NLA and MIR827 overexpression causes an increase in phosphate (Pi) content which results in resistance to infection by the fungal pathogen Plectosphaerella cucumerina. The nla mutant plants accumulated callose in their leaves, a response that is also observed in wild-type plants that have been treated with high Pi. We also show that pathogen infection and treatment with fungal elicitors is accompanied by transcriptional activation of MIR827 and down-regulation of NLA. Upon pathogen challenge, nla plants exhibited higher levels of the phytoalexin camalexin compared to wild type plants. Camalexin level also increases in wild type plants treated with high Pi. Furthermore, the nla mutant plants accumulated salicylic acid (SA) and jasmonic acid (JA) in the absence of pathogen infection whose levels further increased upon pathogen. Conclusions: This study shows that NLA acts as a negative regulator of Arabidopsis immunity. Overaccumulation of Pi in nla plants positively affects resistance to infection by fungal pathogens. This piece of information reinforces the idea of signaling convergence between Pi and immune responses for the regulation of disease resistance in Arabidopsis.

scholarly journals Disulfide disruption reverses mucus dysfunction in allergic airway disease

2019 ◽  
Author(s):  
Leslie E. Morgan ◽  
Siddharth K. Shenoy ◽  
Dorota Raclawska ◽  
Nkechinyere A. Emezienna ◽  
Vanessa L. Richardson ◽  
...  
Keyword(s):  
Disulfide Bonds ◽  
Allergic Inflammation ◽  
Airway Disease ◽  
Airway Hyperreactivity ◽  
Allergic Airway Disease ◽  
Mucus Hypersecretion ◽  
Asthma Model ◽  
Targeted Treatments ◽  
Fungal Allergen ◽  
Respiratory Conditions

Airway mucus is essential for healthy lung defense1, but excessive mucus in asthma obstructs airflow, leading to severe and potentially fatal outcomes2–5. Current asthma therapies reduce allergic inflammation and relax airway smooth muscle, but treatments are often inadequate due to their minimal effects on mucus obstruction6,7. The lack of efficacious mucus-targeted treatments stems from a poor understanding of healthy mucus function and pathological mucus dysfunction at a molecular level. The chief macromolecules in mucus, polymeric mucins, are massive glycoproteins whose sizes and biophysical properties are dictated in part by covalent disulfide bonds that link mucin molecules into assemblies of 10 or more subunits8. Once secreted, mucin glycopolymers can aggregate to form plugs that block airflow. Here we show that reducing mucin disulfide bonds depolymerizes mucus in human asthma and reverses pathological effects of mucus hypersecretion in a mouse allergic asthma model. In mice challenged with a fungal allergen, inhaled mucolytic treatment acutely loosened mucus mesh, enhanced mucociliary clearance (MCC), and abolished airway hyperreactivity (AHR) to the bronchoprovocative agent methacholine. AHR reversal was directly related to reduced mucus plugging. Furthermore, protection in mucolytic treated mice was identical to prevention observed in mice lacking Muc5ac, the polymeric mucin required for allergic AHR in murine models9. These findings establish grounds for developing novel fast-acting agents to treat mucus hypersecretion in asthma10,11. Efficacious mucolytic therapies could be used to directly improve airflow, help resolve inflammation, and enhance the effects of inhaled treatments for asthma and other respiratory conditions11,12.

scholarly journals CURRENT CONCEPTS OF ATOPIC DERMATITIS IN CHILDREN: PROBLEMS AND PROSPECTS

2019 ◽  
Vol 20 (2) ◽  
pp. 99-107
Author(s):  
Galina I. Smirnova
Keyword(s):  
Atopic Dermatitis ◽  
Immune Responses ◽  
Proinflammatory Cytokines ◽  
Genetic Predisposition ◽  
Allergic Inflammation ◽  
Skin Lesions ◽  
Current Understanding ◽  
Epidermal Barrier ◽  
Barrier Integrity ◽  
Atopic Skin

There are presented modern data describing the current understanding of the pathogenesis of atopic dermatitis (AD): a genetic predisposition to atopy, disruptions of epidermal barrier integrity and a cascade of immune responses, contributing allergic inflammation in the skin. There are both described several mechanisms of acute and chronic phases of AD, the main directions of pathogenetically substantiated treatment of AD in children and indicated the prospects of new preparations specific blockers of proinflammatory cytokines involved in the development of AD - crisaborole, apremilast, dupilumab, lebrikizumab, tralokinumab, tezepelumab. There is especially presented in details external therapy of atopic skin lesions in children with the use of means of modern dermatological cosmetics.

Impact of gut microbiota on immune system

2021 ◽  
Author(s):  
Farhad Riazi-Rad ◽  
Ava Behrouzi ◽  
Hoora Mazaheri ◽  
Asal Katebi ◽  
Soheila Ajdary
Keyword(s):  
Immune System ◽  
Gut Microbiota ◽  
Immune Responses ◽  
Disease Susceptibility ◽  
Adaptive Immune System ◽  
Vital Role ◽  
Symbiotic Relationship ◽  
Adaptive Immune ◽  
Physiological Homeostasis ◽  
Environmental Antigens

AbstractThe commensal microflora collection known as microbiota has an essential role in maintaining the host's physiological homeostasis. The microbiota has a vital role in induction and regulation of local and systemic immune responses. On the other hand, the immune system involves maintaining microbiota compositions. Optimal microbiota-immune system cross-talk is essential for protective responses to pathogens and immune tolerance to self and harmless environmental antigens. Any change in this symbiotic relationship may cause susceptibility to diseases. The association of various cancers and auto-immune diseases with microbiota has been proven. Here we review the interaction of immune responses to gut microbiota, focusing on innate and adaptive immune system and disease susceptibility.

Pivotal role of STIM2, but not STIM1, in IL-4 production by IL-3–stimulated murine basophils

2019 ◽  
Vol 12 (576) ◽  
pp. eaav2060 ◽  
Author(s):  
Soichiro Yoshikawa ◽  
Masatsugu Oh-hora ◽  
Ryota Hashimoto ◽  
Toshihisa Nagao ◽  
Louis Peters ◽  
...  
Keyword(s):  
Immune Responses ◽  
Immune Complexes ◽  
Immunoglobulin E ◽  
Allergic Inflammation ◽  
Vital Role ◽  
Basophil Activation ◽  
Pivotal Role ◽  
Time Courses

Basophils have nonredundant roles in various immune responses that require Ca2+influx. Here, we examined the role of two Ca2+sensors, stromal interaction molecule 1 and 2 (STIM1 and STIM2), in basophil activation. We found that loss of STIM1, but not STIM2, impaired basophil IL-4 production after stimulation with immunoglobulin E (IgE)–containing immune complexes. In contrast, when basophils were stimulated with IL-3, loss of STIM2, but not STIM1, reduced basophil IL-4 production. This difference in STIM proteins was associated with distinct time courses of Ca2+influx and transcription of theIl4gene that were elicited by each stimulus. Similarly, basophil-specific STIM1 expression was required for IgE-driven chronic allergic inflammation in vivo, whereas STIM2 was required for IL-4 production after combined IL-3 and IL-33 treatment in mice. These data indicate that STIM1 and STIM2 have differential roles in the production of IL-4, which are stimulus dependent. Furthermore, these results illustrate the vital role of STIM2 in basophils, which is often considered to be less important than STIM1.

HSP27 elevated in mild allergic inflammation protects airway epithelium from H2SO4 effects

1997 ◽  
Vol 273 (2) ◽  
pp. L401-L409 ◽  
Author(s):  
A. T. Hastie ◽  
K. B. Everts ◽  
J. Zangrilli ◽  
J. R. Shaver ◽  
M. B. Pollice ◽  
...  
Keyword(s):  
Airway Epithelium ◽  
Stress Proteins ◽  
Stress Protein ◽  
Allergic Inflammation ◽  
Allergen Challenge ◽  
Bronchial Epithelium ◽  
Ciliary Activity ◽  
Normal Epithelium ◽  
Adverse Conditions ◽  
Before And After

Inflammation in allergic individuals is hypothesized to elevate stress proteins [heat shock proteins (HSP)] in airway epithelium, which may protect cells from further adverse conditions. Allergic, either asthmatic or not, and normal volunteers participated in a 2-day segmental allergen challenge bronchoscopic procedure. Bronchial epithelium was obtained before and after challenge. Epithelium was exposed to medium with H2SO4 (pH5), returned to medium at pH 7.4, and finally harvested for Western blotting with anti-27-kDa HSP (HSP27) antibody. Prechallenge epithelium of all subjects had significantly inhibited ciliary function by H2SO4 (pH 5) conditions (P < 0.001); only epithelium of normals recovered (P = 0.02). Allergic subjects with mild inflammation (< 50 micrograms/ml increase in albumin in bronchoalveolar lavage) had significantly increased HSP27 postchallenge (P = 0.01) and little ciliary dysfunction at pH 5, whereas subjects with severe inflammation (> 50 micrograms/ml increase in albumin) had little change in HSP27 and significant ciliary inhibition (P = 0.02). Normal epithelium had similar trends in HSP27 and equivalent inhibition of ciliary activity at pH 5 before and after allergen challenge. These data indicate that mild inflammation to allergen elevates HSP27 stress protein levels, thereby potentially protecting epithelial function from additional adverse conditions.

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