The Roles of Neuropeptide Y in Respiratory Disease Pathogenesis via the Airway Immune Response.

The lungs are very complex organs, and the respiratory system performs the dual roles of repairing tissue while protecting against infection from various environmental stimuli. Persistent external irritation disrupts the immune responses of tissues and cells in the respiratory system, ultimately leading to respiratory disease. Neuropeptide Y (NPY) is a 36-amino-acid polypeptide and a neurotransmitter that regulates homeostasis. The NPY receptor is a seven-transmembrane-domain G-protein-coupled receptor with six subtypes (Y1, Y2, Y3, Y4, Y5, and Y6). Of these receptors, Y1, Y2, Y4, and Y5 are functional in humans, and Y1 plays important roles in the immune responses of many organs, including the respiratory system. NPY and the Y1 receptor have critical roles in the pathogenesis of asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. The effects of NPY on the airway immune response and pathogenesis differ among respiratory diseases. This review focuses on the involvement of NPY in the airway immune response and pathogenesis of various respiratory diseases.

Identification of Host Factors Associated with the Development of Equine Herpesvirus Myeloencephalopathy by Transcriptomic Analysis of Peripheral Blood Mononuclear Cells from Horses.

Equine herpesvirus-1 is the cause of respiratory disease, abortion, and equine herpesvirus myeloencephalopathy (EHM) in horses worldwide. EHM affects as many as 14% of infected horses and a cell-associated viremia is thought to be central for EHM pathogenesis. While EHM is infrequent in younger horses, up to 70% of aged horses develop EHM. The aging immune system likely contributes to EHM pathogenesis; however, little is known about the host factors associated with clinical EHM. Here, we used the "old mare model" to induce EHM following EHV-1 infection. Peripheral blood mononuclear cells (PBMCs) of horses prior to infection and during viremia were collected and RNA sequencing with differential gene expression was used to compare the transcriptome of horses that did (EHM group) and did not (non-EHM group) develop clinical EHM. Interestingly, horses exhibiting EHM did not show respiratory disease, while non-EHM horses showed significant respiratory disease starting on day 2 post infection. Multiple immune pathways differed in EHM horses in response to EHV-1. These included an upregulation of IL-6 gene expression, a dysregulation of T-cell activation through AP-1 and responses skewed towards a T-helper 2 phenotype. Further, a dysregulation of coagulation and an upregulation of elements in the progesterone response were observed in EHM horses.

The role of dectin-1 in health and disease.

Dendritic cell-associated C-type lectin-1 (Dectin-1), also known as ß-glucan receptor is an emerging pattern recognition receptor (PRR) which belongs to the family of C-type lectin receptor (CLR). This CLR identifies ligands independently of Ca2+ and is majorly involved in coupling of innate with adaptive immunity. Formerly, Dectin-1 was best known for its role in anti-fungal defense only. However, recent explorations suggested its wider role in defense against variety of infectious diseases caused by pathogens including bacteria, parasites and viruses. In fact, Dectin-1 signaling axis has been suggested to be targeted as an effective therapeutic strategy for cancers. Dectin-1 has also been elucidated ascetically in the heart, respiratory, intestinal, neurological and developmental disorders. Being a defensive PRR, Dectin-1 results in optimal immune responses in collaboration with other PRRs, but the overall evaluation reinforces the hypothesis of disease development on dis-regulation of Dectin-1 activity. This underscores the impact of Dectin-1 polymorphisms in modulating protein expression and generation of non-optimal immune responses through defective collaborations, further underlining their therapeutic potential. To add on, Dectin-1 influence autoimmunity and severe inflammation accredited to recognition of self T cells and apoptotic cells through unknown ligands. Few reports have also testified its redundant role in infections, which makes it a complicated molecule to be fully resolved. Thus, Dectin-1 is a hub that runs a complex collaborative network, whose interactive wire connections to different PRRs are still pending to be revealed. Alternatively, so far focus of almost all the researchers was the two major cell surface isoforms of Dectin-1, despite the fact that its soluble functional intracellular isoform (Dectin-1E) has already been dissected but is indefinable. Therefore, this review intensely recommends the need of future research to resolve the un-resolved and treasure the comprehensive role of Dectin-1 in different clinical outcomes, before determining its therapeutic prospective.

The Innate Lymphoid System Is a Critical Player in the Manifestation of Mucoinflammatory Airway Disease in Mice.

Innate lymphoid and adaptive immune cells are known to regulate epithelial responses, including mucous cell metaplasia (MCM), but their roles in mucoinflammatory airway diseases, such as cystic fibrosis, remain unknown. Scnn1b transgenic (Scnn1b-Tg+) mice, which recapitulate cystic fibrosis-like mucoinflammatory airway disease, deficient in innate lymphoid (Il2rg knockout mice [Il2rg KO]), adaptive immune (Rag1 knockout mice [Rag1 KO]), or both systems (Il2rg KO/Rag1 KO), were employed to investigate their respective contributions in the pathogenesis of mucoinflammatory airway disease. As previously reported, immunocompetent Tg+ juveniles exhibited spontaneous neonatal bacterial infections with robust mucoinflammatory features, including elevated expression of Th2-associated markers accompanied by MCM, elevated MUC5B expression, and airway mucus obstruction. The bacterial burden was increased in Il2rg KO/Tg+ juveniles but returned to significantly lower levels in Il2rg KO/Rag1 KO/Tg+ juveniles. Mechanistically, this improvement reflected reduced production of adaptive immunity-derived IL-10 and, in turn, increased activation of macrophages. Although all the mucoinflammatory features were comparable between the immunocompetent Tg+ and Rag1 KO/Tg+ juveniles, the Il2rg KO/Tg+ and Il2rg KO/Rag1 KO/Tg+ juveniles exhibited suppressed expression levels of Th2 markers, diminished MCM, suppressed MUC5B expression, and reduced mucus obstruction. Collectively, these data indicate that, in the context of airway mucus obstruction, the adaptive immune system suppresses antibacterial macrophage activation, whereas the innate lymphoid system contributes to MCM, mucin production, and mucus obstruction.

Role of Phosphodiesterase 7 (PDE7) in T Cell Activity. Effects of Selective PDE7 Inhibitors and Dual PDE4/7 Inhibitors on T Cell Functions.

Phosphodiesterase 7 (PDE7), a cAMP-specific PDE family, insensitive to rolipram, is present in many immune cells, including T lymphocytes. Two genes of PDE7 have been identified: PDE7A and PDE7B with three or four splice variants, respectively. Both PDE7A and PDE7B are expressed in T cells, and the predominant splice variant in these cells is PDE7A1. PDE7 is one of several PDE families that terminates biological functions of cAMP-a major regulating intracellular factor. However, the precise role of PDE7 in T cell activation and function is still ambiguous. Some authors reported its crucial role in T cell activation, while according to other studies PDE7 activity was not pivotal to T cells. Several studies showed that inhibition of PDE7 by its selective or dual PDE4/7 inhibitors suppresses T cell activity, and consequently T-mediated immune response. Taken together, it seems quite likely that simultaneous inhibition of PDE4 and PDE7 by dual PDE4/7 inhibitors or a combination of selective PDE4 and PDE7 remains the most interesting therapeutic target for the treatment of some immune-related disorders, such as autoimmune diseases, or selected respiratory diseases. An interesting direction of future studies could also be using a combination of selective PDE7 and PDE3 inhibitors.

Serum allergen-specific IgE reactivity: is there an association with clinical severity and airway eosinophilia in asthmatic cats?

OBJECTIVES: The aim of this study was to evaluate the results of serum allergen-specific IgE testing in cats with a clinical diagnosis of asthma and to determine if the number of allergens with positive IgE reactivity and magnitude of positive IgE responses would be associated with the severity of clinical signs or airway eosinophilia. METHODS: Medical records from 2008 to 2018 were retrospectively reviewed. Inclusion required a diagnosis of feline asthma based on consistent clinicopathologic features and bronchoalveolar lavage (BAL) cytology with >10% eosinophils; additionally, cats needed to have the results of serum allergen-specific IgE tests. RESULTS: Eighteen cases satisfied the inclusion criteria. Median age was 5 years and the most common presenting clinical sign was cough (n = 10/18). Most cats lived exclusively indoors (n = 13/18). The median percentage of BAL eosinophils was 47%. Serum allergen-specific IgE testing supported an underlying allergic etiology in 14/18 (78%) cats, with all but one having polysensitization. The severity of clinical signs and magnitude of airway eosinophilia did not correlate with the degree of positive IgE reactivity. CONCLUSIONS AND RELEVANCE: This study identified a strong association between the identification of allergen-specific IgE and cats with asthma, and the majority of these cats were polysensitized. However, larger numbers of allergens with positive IgE reactivity or magnitude of IgE reactivity were not significantly associated with clinical severity or airway eosinophilia. Knowledge of positive allergen-specific IgE results could guide allergen avoidance, regardless of the magnitude of IgE reactivity.

Targeting Evolutionary Conserved Oxidative Stress and Immunometabolic Pathways for the Treatment of Respiratory Infectious Diseases.

Significance: Up until recently, metabolism has scarcely been referenced in terms of immunology. However, emerging evidence has shown that immune cells undergo an adaptation of metabolic processes, known as the metabolic switch. This switch is key to the activation, and sustained inflammatory phenotype in immune cells, which includes the production of cytokines and reactive oxygen species (ROS) that underpin infectious diseases, respiratory and cardiovascular disease, neurodegenerative disease, as well as cancer. Recent Advances: There is a burgeoning body of evidence that immunometabolism and redox biology drive infectious diseases. For example, influenza A virus (IAV) utilizes endogenous ROS production via NADPH oxidase (NOX)2-containing NOXs and mitochondria to circumvent antiviral responses. These evolutionary conserved processes are promoted by glycolysis, the pentose phosphate pathway, and the tricarboxylic acid (TCA) cycle that drive inflammation. Such metabolic products involve succinate, which stimulates inflammation through ROS-dependent stabilization of hypoxia-inducible factor-1α, promoting interleukin-1ß production by the inflammasome. In addition, itaconate has recently gained significant attention for its role as an anti-inflammatory and antioxidant metabolite of the TCA cycle. Critical Issues: The molecular mechanisms by which immunometabolism and ROS promote viral and bacterial pathology are largely unknown. This review will provide an overview of the current paradigms with an emphasis on the roles of immunometabolism and ROS in the context of IAV infection and secondary complications due to bacterial infection such as Streptococcus pneumoniae. Future Directions: Molecular targets based on metabolic cell processes and ROS generation may provide novel and effective therapeutic strategies for IAV and associated bacterial superinfections.

Targeting neutrophils using novel drug delivery systems in chronic respiratory diseases.

Neutrophils are essential effector cells of immune system for clearing the extracellular pathogens during inflammation and immune reactions. Neutrophils play a major role in chronic respiratory diseases. In respiratory diseases such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, lung cancer and others, there occurs extreme infiltration and activation of neutrophils followed by a cascade of events like oxidative stress and dysregulated cellular proteins that eventually result in apoptosis and tissue damage. Dysregulation of neutrophil effector functions including delayed neutropil apoptosis, increased neutrophil extracellular traps in the pathogenesis of asthma, and chronic obstructive pulmonary disease enable neutrophils as a potential therapeutic target. Accounting to their role in pathogenesis, neutrophils present as an excellent therapeutic target for the treatment of chronic respiratory diseases. This review highlights the current status and the emerging trends in novel drug delivery systems such as nanoparticles, liposomes, microspheres, and other newer nanosystems that can target neutrophils and their molecular pathways, in the airways against infections, inflammation, and cancer. These drug delivery systems are promising in providing sustained drug delivery, reduced therapeutic dose, improved patient compliance, and reduced drug toxicity. In addition, the review also discusses emerging strategies and the future perspectives in neutrophil-based therapy.

Targeting defective pulmonary innate immunity - A new therapeutic option?

Chronic pulmonary conditions now account for 1 in 15 deaths in the US and mortality is increasing. Chronic obstructive pulmonary disease (COPD) is due to become the 3rd largest cause of mortality by 2030 and mortality from other respiratory conditions such as asthma, idiopathic pulmonary fibrosis and cystic fibrosis are not reducing. There is an urgent need for novel therapies to address this problem as many of the current strategies targeting inflammation are not sufficient. The innate immune system of the lung is an important defence against invading pathogens, but in many chronic pulmonary diseases, this system mounts an inappropriate response. In COPD, macrophages are increased in number, but fail to clear pathogens correctly and become highly activated. This leads to increased damage and remodelling of the airways. In idiopathic fibrosis, there is a switch of macrophage phenotype to a cell that promotes abnormal repair. Neutrophils also display dysfunction in COPD where aberrant migratory profiles may lead to increased damage to lung tissue and emphysema; while in cystic fibrosis the proteolytic lung environment damages neutrophil receptors leading to ineffective phagocytosis and migration. Targeting the innate immune system to restore 'normal function' could have enormous benefits. Improving phagocytosis of pathogens could reduce exacerbations and hence the associated decline in lung function, and novel therapeutics such as sulforaphane appear to do this in vitro. Other natural products such as resveratrol and derivatives also have anti-inflammatory properties. Statins have traditionally been used to manage cholesterol levels in hypercholesterolaemia, however these molecules also have beneficial effects on the innate immune cells. Statins have been shown to be anti-inflammatory and restore aberrant neutrophil chemotaxis in aged cells. Other possible agents that may be efficacious are senolytics. These compounds include natural products such as quercetin which have anti-inflammatory properties but can also suppress viral replication. As viruses have been shown to suppress phagocytosis of macrophages, it is possible that these compounds could have benefit during viral exacerbations to protect this innate response. These compounds demonstrate that it is possible to address defective innate responses in the lung but a better understanding of the mechanisms driving defective innate immunity in pulmonary disease may lead to improved therapeutics.

[Advances of studies on the occurrence of the upper respiratory disease correlative with immunity and tobacco].

SummaryTobacco smoke exposure has obvious and complex effects on the immune system of the human upper respiratory tract, including pro-inflammatory and anti-immune effects. Exposure to tobacco smoke is closely related to the occurrence and development of allergic rhinitis, the common rhinitis and sinusitis. The innate immune system is influenced by tobacco smoking through its effects on the respiratory mucosa and its adjuncts, natural killer cells, dendritic cells, neutrophils and innate immune receptors. Cigarette smoke can also affect the humoral immunity and cellular immunity, altering the acquired immune condition of the upper respiratory tract. Tobacco smoke exposure promotes the occurrence and development of the upper respiratory tract infectious diseases and allergic diseases by changing the composition of microflora in the upper respiratory tract.

Innate Lymphoid Cell-Dependent Airway Epithelial and Inflammatory Responses to Inhaled Ozone: A New Paradigm in Pathogenesis.

Epidemiological associations have been made between the new onset of childhood rhinitis/asthma and exposures to elevated ambient levels of ozone, a commonly encountered gaseous air pollutant. Our laboratory was the first to find that mice repeatedly exposed to ozone develop nasal type 2 immunity and eosinophilic rhinitis with mucous cell metaplasia. More recently, we have found that these ozone-induced upper airway alterations are mediated by group 2 innate lymphoid cells (ILC2s) and not by T and B cells that are important in adaptive immune responses typically associated with allergic rhinitis and asthma. Furthermore, repeated exposures of mice to ozone cause ILC2-mediated type 2 immunity and airway pathology in the lungs, like those found in the nasal airways. Our recent findings in ozone-exposed mice complement and extend previous reports of nonallergic nasal airway disease in ozone-exposed rats and nonhuman primates. Overall, these experimental results in laboratory animals suggest a plausible ILC2-dependent paradigm for the toxicologic pathobiology that underlies the development of nonallergic rhinitis/asthma in children who live in environments with repeated occurrences of high ambient concentrations of ozone.

Staphylococcus Aureus in chronic airway diseases: An overview.

This review investigates about the role of Staphylococcus Aureus (S. aureus) and S. aureus enterotoxins (SEs) in the pathogenesis of several chronic airway diseases. S. aureus is part of normal human flora and may colonize the skin and the upper airways. SEs acting as superantigens can induce an intense T cell activation and through the release of interleukin (IL) - 4, 5, and 13, can promote a polyclonal IgE response and eosinophilic inflammation. S. aureus can damage epithelial cells inducing the release of the so-called "alarmins" responsible of the activation of Type 2 innate lymphoid cells (ILC-2) linked to an IL-5 mediated airway eosinophilic inflammation. SEs sensitization has been recently associated with the eosinophilic endotypes of both nasal polyps and late onset severe asthma. Studies investigating the effect of biological therapies in SEs sensitized patients should be performed in order to better define the role played by S. aureus in the different endotypes of severe asthma and/or chronic rhinosinusitis.

[The significance of eosinophils in the correlation of upper and lower airway inflammation in patients with chronic rhinitis].

Objective: To explore the predictor of lower airway inflammation among the index of nasal inflammation by investigating the expression and association of eosinophils (EOS) in the upper-lower airways and blood of patients with chronic rhinitis. Methods: A total of 162 patients with allergic rhinitis (AR), 117 patients with non-allergic rhinitis (NAR) and 104 controls were enrolled from June 2010 to December 2013 from General Hospital of Eastern Theater Command, People's Liberation Army. All subjects were required detailed medical history collection and nasal resistance measurement. Skin prick test (SPT), blood total immunoglobin E (tIgE) and blood EOS, nasal lavage and induced sputum EOS, nasal provocation and bronchial provocation test (NPT, BPT), nasal and forced exhaled nitric oxide (NNO, FeNO) were performed in all patients. One-way analysis of variance was used for comparison between groups. LSD t test or Mann-Whitney U test was used for comparison between the two groups. Pearson or Spearman related parameter test was used for correlation analysis. Results: The nasal lavage EOS, NNO, induced sputum EOS, FeNO, blood EOS and tIgE were higher in the AR group than that in the NAR group (3.70[1.20, 14.23]/200 HP vs 1.40[0.20, 3.40]/200 HP, 673.50[466.80, 936.00] ppb vs 455.80[248.10, 705.60] ppb, 2.97[0.00, 10.63]% vs 1.00[0.23, 2.00]%, (49.28±26.37)ppb vs (34.07±19.11)ppb, 4.00[2.00, 7.00]% vs 2.00[1.00, 5.00]%, 208.01[61.70, 387.50] IU/ml vs 43.30[19.00, 122.00] IU/ml, F or χ(2) value was 11.442, 19.440, 70.727, 69.449, 47.453, 46.525, respectively, all P<0.05). But there was no significant difference in nasal resistance, NPT and BPT between the two groups. Nasal lavage EOS in AR group and NAR group was correlated with induced sputum EOS, FeNO, tIgE and blood EOS (r value of AR group was 0.448, 0.202, 0.159, 0.321, r value of NAR group was 0.442, 0.268, 0.268, 0.334, respectively, all P<0.05), but not with BPT. After adjustment for gender, age, height and weight, nasal EOS was positively correlated with sputum EOS. Multiple linear regression analysis showed that nasal EOS, blood EOS and SPT were factors affecting sputum EOS levels. The optimal threshold for nasal EOS to determine induced sputum EOS was 3.30/200 HP by (receiver operating characteristic,ROC) analysis. Conclusion: The nasal EOS is correlated with multiple lower airway and systemic inflammatory markers, and is a risk factor for the induced sputum EOS, which can be used as an inflammation biomarker to predict the lower air inflammation.

Mucosal IgE immune responses in respiratory diseases.

IgE is the less abundant immunoglobulin isotype in serum and displays higher affinity for its cognate Fc receptor (FcεRI) than the rest of antibody isotypes. Moreover, the class switch recombination and the generation of memory responses remarkably differ between IgE and other isotypes. Importantly, class switch recombination to IgE can occur in the mucosae, preferentially through the sequential switching from IgG. Therefore, resident effector cells get rapidly sensitized, and free IgE can be found in mucosal secretions. All these aspects explain the involvement of IgE in respiratory diseases. In allergic rhinitis and allergic asthma, the IgE-sensitization to environmental allergens triggers an eosinophilic inflammation of the airway mucosa of atopic patients. In recent years, growing evidence indicates that some non-atopic patients with nasal reactivity to allergens display nasal eosinophilic inflammation, which could be triggered by the local production of allergen-specific IgE. This phenotype has been termed local allergic rhinitis. Mucosal IgE is also implicated in the pathophysiology of chronic rhinosinusitis with nasal polyps, even though the mechanisms for IgE synthesis might differ in this case. The role of IgE as mediator of airway diseases identify this marker as a therapeutic target. Some biologicals antagonize IgE-mediated inflammation of the airway mucosa, but they have not shown a beneficial long-term effect after discontinuation. In contrast, allergen immunotherapy does not only control the symptoms of airway allergy, but it also induces a long-lasting effect after discontinuation, thus modifying the natural course of the disease.

Airway M Cells Arise in the Lower Airway Due to RANKL Signaling and Reside in the Bronchiolar Epithelium Associated With iBALT in Murine Models of Respiratory Disease.

Microfold (M) cells residing in the follicle-associated epithelium of mucosa-associated lymphoid tissues are specialized for sampling luminal antigens to initiate mucosal immune responses. In the past decade, glycoprotein 2 (GP2) and Tnfaip2 were identified as reliable markers for M cells in the Peyer's patches of the intestine. Furthermore, RANKL-RANK signaling, as well as the canonical and non-canonical NFκB pathways downstream, is essential for M-cell differentiation from the intestinal stem cells. However, the molecular characterization and differentiation mechanisms of M cells in the lower respiratory tract, where organized lymphoid tissues exist rarely, remain to be fully elucidated. Therefore, this study aimed to explore M cells in the lower respiratory tract in terms of their specific molecular markers, differentiation mechanism, and functions. Immunofluorescence analysis revealed a small number of M cells expressing GP2, Tnfaip2, and RANK is present in the lower respiratory tract of healthy mice. The intraperitoneal administration of RANKL in mice effectively induced M cells, which have a high capacity to take up luminal substrates, in the lower respiratory epithelium. The airway M cells associated with lymphoid follicles were frequently detected in the pathologically induced bronchus-associated lymphoid tissue (iBALT) in the murine models of autoimmune disease as well as pulmonary emphysema. These findings demonstrate that RANKL is a common inducer of M cells in the airway and digestive tracts and that M cells are associated with the respiratory disease. We also established a two-dimensional culture method for airway M cells from the tracheal epithelium in the presence of RANKL successfully. This model may be useful for functional studies of M cells in the sampling of antigens at airway mucosal surfaces.

Respuesta inmunoprotectora inducida por la glicoproteina D recombinante en el modelo de infección respiratoria de ratones BALB/c por alfaherpesvirus equino 1 / Immunoprotective response induced by recombinant glycoprotein D in the BALB/c respiratory mouse model " of Equid alphaherpesvirus 1 infection

Equid alphaherpesvirus 1 (EHV-1) infection causes abortion, respiratory disease, perinatal deaths and neurological disorders in horses. The natural infection and available vaccines provide only partial and short-lived protection against reinfections. In the present study, we analyzed the ability of purified baculovirus-expressed glycoprotein D (gD) administered by different routes to induce protective immunity in BALB/c mice after challenge with the EHV-1 AR8 strain. Clinical signs varied among the different groups of mice immunized by parenteral routes, and, although gD induced a specific serum IgG response, it did not prevent the virus from reaching the lungs. Intranasally immunized mice showed no clinical signs, and virus isolation from lungs, histological lesions and antigen detection by immunohistochemistry were negative. In addition, by this route, gD did not stimulate the production of serum IgG and IgA. However, a specific IgA response in the respiratory tract was confirmed in intranasally immunized mice. Thus, we conclude that the mucosal immune response could reduce the initial viral attachment and prevent the virus from reaching the lungs. Our findings provide additional data to further study new immunization strategies in the natural host.

La infección con alfaherpesvirus equino 1 (EHV-1) causa abortos, enfermedad respiratoria, muertes perinatales y desórdenes neurológicos en equinos. La infección natural y las vacunas disponibles solo proporcionan protección parcial y de corta duración contra las reinfecciones. En el presente estudio se analizó la inducción de inmunidad protectiva de la glicoproteina D (gD) expresada en baculovirus y purificada al ser administrada por diferentes rutas en ratones BALB/c desafiados con la cepa AR8 de EHV-1. Los signos clínicos fueron variables entre los grupos de ratones inmunizados por rutas parenterales y, aunque la gD indujo respuesta especifica de IgG en suero, no logró prevenir la llegada del virus al pulmón. En los ratones inmunizados intranasalmente no se observaron signos clinicos ni lesiones histopatológi-cas, y el aislamiento viral y la detección de antigenos por inmunohistoquímica en pulmón fueron negativos. Además, por esta ruta la gD no estimuló la producción de IgG y de IgA en suero. Sin embargo se confirmó la respuesta de IgA especifica en el tracto respiratorio de ratones inmunizados intranasalmente. Esta respuesta inmune mucosal podría haber reducido la unión inicial del virus a la célula huésped y, de este modo, prevenir la llegada del virus al pulmón. Nuestros hallazgos proporcionan un aporte para continuar estudiando nuevas estrategias de inmunización en el huésped natural.

Group 2 Innate Lymphoid Cells in Airway Diseases.

Group 2 innate lymphoid cells (ILC2s) are increasingly recognized as a key controller of type 2 inflammation, and are well known to be highly elevated in human airway type 2 inflammatory diseases including allergic rhinitis, chronic rhinosinusitis with nasal polyps, and asthma. ILC2-mediated production of type 2 cytokines initiates and amplifies airway inflammation via activation of eosinophils, B cells, mast cells, macrophages, fibroblasts, and epithelial cells in these diseases. ILC2s require at least three major signals to fully activate and robustly produce type 2 cytokines. IL-1 family cytokines (IL-1ß, IL-18, IL-33), IL-25, and TNF superfamilies (TNF, TL1A, GITR-L, RANK-L) activate the NF-κB and AP-1 pathways that initiate production of IL-5 and IL-13. Lipid mediators (LTC4, LTD4, PGD2) and neuropeptide NMU promote production of IL-4 through the NFAT pathway. IL-2 and IL-7 family cytokines (IL-2, IL-7, IL-9, TSLP) activate the STAT5 pathway that induces survival of ILC2s and enhances cytokine production. The activation of STAT5 is necessary to potently induce cytokine- and lipid mediator-mediated production of type 2 cytokines. Inhibitory pathways for ILC2s have also become clearer. Type I and II interferons and IL-27 inhibit ILC2 functions through the activation of STAT1. Suppression mediated via ß2-adrenergic receptor agonists, PGE2, and PGI2 occurs through cAMP and PKA. Glucocorticoid, testosterone, IL-10, and TGF-ß are also able to inhibit ILC2-mediated production of type 2 cytokines. Blockage of ILC2 activators, activation of inhibitory pathways of ILC2s, and suppression of ILC2-mediated pathways including type 2 cytokines (IL-5, IL-13, IL-4Ra) may become therapeutic strategies for airway type 2 inflammatory diseases.

Brevenal, a Marine Natural Product, is Anti-Inflammatory and an Immunomodulator of Macrophage and Lung Epithelial Cells.

Chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma, are some of the leading causes of illness and fatalities worldwide. The search for novel treatments led to the exploration of marine natural products as drug candidates to combat the debilitating effects of mucus accumulation and chronic inflammation. Previous research showed that an alga-derived compound, brevenal, could attenuate the effects of inflammatory agents, but the mechanisms by which it exerted its effects remained unclear. We investigated the effects of brevenal on lipopolysaccharide (LPS) induced cytokine/chemokine production from murine macrophages and human lung epithelial cells. It was found that brevenal reduces proinflammatory mediator secretion while preserving anti-inflammatory secretion from these cells. Furthermore, we found that brevenal does not alter cell surface Toll-like receptor 4 (TLR4) expression, thereby maintaining the cells' ability to respond to bacterial infection. However, brevenal does alter macrophage activation states, as demonstrated by reduced expression of both M1 and M2 phenotype markers, indicating this putative anti-inflammatory drug shifts innate immune cells to a less active state. Such a mechanism of action would be ideal for reducing inflammation in the lung, especially with patients suffering from chronic respiratory diseases, where inflammation can be lethal.

Immunogenicity of pneumococcal vaccines in comorbid autoimmune and chronic respiratory diseases.

Streptococcus pneumoniae causes pneumonia, meningitis, otitis media, and bacteremia. The mortality and morbidity of invasive pneumococcal disease are high among adults aged >65 years or those with underlying chronic or immunosuppressive conditions. A recent systematic review showed that patients treated with immunosuppressive agents have impaired immune responses to pneumococcal conjugate vaccine (PCV) and pneumococcal polysaccharide vaccine compared with healthy subjects. A more favorable response is observed in patients treated with tumor necrosis factor-alpha-blocking agents compared with those treated with other immunosuppressive agents. Low systemic corticosteroid doses do not affect the responses to pneumococcal vaccines. Patients with human immunodeficiency virus and idiopathic pulmonary fibrosis receiving immunosuppressive therapy exhibit decreased immunogenicity to pneumococcal vaccines. The effects of T-cell-dependent PCV possibly depend on host memory B cells in some disease conditions. Several immunosuppressive therapy types and disease conditions may affect the responses to pneumococcal vaccines. Immunization should be administered before immunosuppressive medication initiation whenever possible.