IgE Hyperproduction Research Articles

Markers of allergy and immunoregulation in children under conditions of aerogenic exposure to aluminum

Introduction. The study of sensitization under conditions of aerogenic exposure to aluminum is relevant for preventing the formation of the risk of disorders of the immunological health in the child population. Materials and methods. Preschool three hundred fifty three children living in Eastern Siberia were examined. Observation group included 199 children living in the zone exposed to emissions from non-ferrous metallurgy enterprises, comparison group – 154 children living in a “conditionally clean” area. In the observation area, the average daily dose of aerogenic exposure to aluminum was 0.292 ∙ 10–3 mg/(kg ∙ day), in the comparison area – 0.0376 ∙ 10–3mg/(kg ∙ day). The work used sanitary-hygienic, chemical-analytical, enzyme-linked immunosorbent and allergosorbent research methods. Results. In children living under conditions of aluminum exposure, a twofold excess of aluminum content was identified in biological environments relative to the comparison group (p = 0.001), hyperproduction of IgG to aluminum, CD19+ and CD3+CD8+ lymphocytes (1.6 times), and NKT lymphocytes (2 times) and CD11a+ lymphocytes 1.4 times (p=0.001) was noted, which reflects an imbalance of immunoregulation and the formation of autoallergy. A significant relationship was established between hyperproduction of total IgE and IgG to aluminum (OR=2.29–5.98; 95% CI 1.76–9.52), (RR=1.93–2.66; 95% CI: 1.41–3.54) Limitations of the study. Limited sample size. Conclusion. As markers of allergy and imbalance of immunoregulation in children under conditions of aerogenic exposure to aluminum and with its increased content in biological media, it is necessary to recommend IgG to aluminum as a marker of sensitivity, as well as CD11a+, reflecting the likelihood of developing a risk of developing immunological disadaptation and autosensitization (OR = 2.29–5.98), (RR=1.93–2.66).

RESULTS OF IMMUNE STATUS IN SICK CHILDREN WITH ATOPIC DERMATITIS USING ACUNE REFLEX THERAPY AND EXTERNAL THERAPY

Increasing the effectiveness of the treatment of dermatological patients with atopic dermatitis is an important social task. Purpose of the study. To study immunological indicators in children with atopic dermatitis and develop a method of corrective therapy in the process of acupuncture with the use of Broncho-munal. Materials and research methods. 32 children with atopic dermatitis aged 12 to 14 years were under observation. The results of the studies allow us to conclude that acupuncture has a normalizing effect on the parameters of the humoral link of the immune system of girls with atopic dermatitis. The question arises about the possible mechanisms of such action of acupuncture. Research results: The mean values ​​of the levels of immunoglobulins A, G, M in children with atopic dermatitis before treatment did not significantly differ from normal values. An increase in the level of IgG was found in 14 (43.7%) patients. Of particular interest was the study of total IgE in patients with atopic dermatitis. In most patients during the period of exacerbation, a pronounced hyperproduction of IgE was found. The highest average level of IgE was observed in sick children with moderate severity of the disease. Findings: In the pathogenesis of sick children with atopic dermatitis, there is a change in the functional activity of the humoral link of immunity, expressed in an increase in the level of serum IgE.

IL-7 Deficiency Exacerbates Atopic Dermatitis in NC/Nga Mice.

Interleukin-7 (IL-7) plays a vital role in the homeostasis of CD4+ and CD8+ T cells. Although IL-7 has been implicated in T helper (Th)1- and Th17-mediated autoinflammatory diseases, its role in Th2-type allergic disorders, such as atopic dermatitis (AD), remains unclear. Thus, to elucidate the effects of IL-7 deficiency on AD development, we generated IL-7-deficient AD-prone mice by backcrossing IL-7 knockout (KO) B6 mice onto the NC/Nga (NC) mouse strain, a model for human AD. As expected, IL-7 KO NC mice displayed defective development of conventional CD4+ and CD8+ T cells compared with wild type (WT) NC mice. However, IL-7 KO NC mice presented with enhanced AD clinical scores, IgE hyperproduction, and increased epidermal thickness compared with WT NC mice. Moreover, IL-7 deficiency decreased Th1, Th17, and IFN-γ-producing CD8+ T cells but increased Th2 cells in the spleen of NC mice, indicating that a reduced Th1/Th2 ratio correlates with severity of AD pathogenesis. Furthermore, significantly more basophils and mast cells infiltrated the skin lesions of IL-7 KO NC mice. Taken together, our findings suggest that IL-7 could be a useful therapeutic target for treating Th2-mediated skin inflammations, such as AD.

Protective Effects of Topical Administration of Laminarin in Oxazolone-Induced Atopic Dermatitis-like Skin Lesions.

Laminarin is a polysaccharide isolated from brown marine algae and has a wide range of bioactivities, including immunoregulatory and anti-inflammatory properties. However, the effects of laminarin on atopic dermatitis have not been demonstrated. This study investigated the potential effects of topical administration of laminarin using a Balb/c mouse model of oxazolone-induced atopic dermatitis-like skin lesions. Our results showed that topical administration of laminarin to the ear of the mice improved the severity of the dermatitis, including swelling. Histological analysis revealed that topical laminarin significantly decreased the thickening of the epidermis and dermis and the infiltration of mast cells in the skin lesion. Serum immunoglobulin E levels were also significantly decreased by topical laminarin. Additionally, topical laminarin significantly suppressed protein levels of oxazolone-induced proinflammatory cytokines, such as interleukin-1β, tumor necrosis factor-α, monocyte chemoattractant protein-1, and macrophage inflammatory protein-1α in the skin lesion. These results indicate that topical administration of laminarin can alleviate oxazolone-induced atopic dermatitis by inhibiting hyperproduction of IgE, mast cell infiltration, and expressions of proinflammatory cytokines. Based on these findings, we propose that laminarin can be a useful candidate for the treatment of atopic dermatitis.

Association of Gln27Glu Polymorphism of the β2-adrenoreceptor Gene with Specific Parameters of the Immunoregulatory Cytokine Cascade and IgE Production in Patients with Bronchial Asthma

The objective: to study the level of serum cytokines IL-4, IFN-γ and the activity of IgE production in patients with bronchial asthma (BA) with the consideration of the Gln27Glu-polymorphism of the β2-AR gene.Subjects and Methods. 130 people of Uzbek ethnicity were examined including 83 patients with BA. BA patients were divided into groups according to the international classification of the World Health Organization and the GINA 2006 diagnostic criteria. Genotyping was performed by polymerase chain reaction technology and restriction fragment analysis.Results. In the group with allergic BA, patients with the Gln27Gln-polymorphic variant of the β2-adrenergic receptor gene had an average IgE value (1,664.20 ± 293.29 pg/ml) higher versus patients with the Gln27Glu genotype (338.40 ± 121.33 pg/ml; p < 0.01). No significant relationship between the Gln27Glu polymorphism of the β2-adrenergic receptor gene and the activity of inductor cytokines was found. The Gln27Gln genotype of the β2-adrenergic receptor gene in patients with bronchial asthma, especially in the allergic form of the disease, is associated with hyperproduction of IgE.

Features of external therapy of allergic skin diseases in children

The development of inflammatory process in the skin has proven to be primarily associated with the immune system defects, in particular T-lymphocytes: the Th2 response predominates during the acute phase of the disease, when Th2 cells are stimulated with the subsequent hyperproduction of IgE; during the chronic phase, the Th2- shifts to Th1-immune response. At the same time, a significant amount of pro-inflammatory cytokines IL-4, IL-5, IL-13, IL-31 and IFN-γ move into this process. In addition, it is known that skin reactions can be induced not only by food allergens, but also by other allergens (house dust mites, Staphylococcus aureus enterotoxins, mold fungi). The prevalence of atopic dermatitis among the children’s population is up to 20%, while half of the children have skin lesions characterized by a severe long-term course, which violates their quality of life. The main goal of external therapy of dermatoses is to achieve control over subjective symptoms (especially skin itching), as well as regression of inflammatory manifestations with subsequent persistent remission of the allergic process. Local therapy of manifestations of atopic dermatitis is based on the adequate use of various external forms, as well as means in accordance with the inflammatory manifestations and localization of the inflammatory process. The article describes clinical cases of treatment of atopic dermatitis with various variants of its course using methylprednisolone aceponate cream with ceramides, emollient agents. It has been shown that the combined use of topical corticosteroids and emollients contributes to a rapid reduction of inflammation, dry skin and itching. The absence of toxic and side effects on this type of therapy in children with high treatment efficiency is emphasized.

Alleviation effects of Rubus coreanus Miquel root extract on skin symptoms and inflammation in chronic atopic dermatitis.

Atopic dermatitis (AD) is an inflammatory skin disease characterized by chronic inflammatory dermatitis with immunological manifestations. The aim of this study was to investigate the effects of polyphenol-containing Rubus coreanus Miquel root extract on skin allergy and AD. The protective effects of R. coreanus root ethanol extract against AD were investigated using the human keratinocyte cell line HaCaT, human mast cell line HMC-1, and the 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin NC/Nga mouse model. Treatment with R. coreanus root ethanol extracts reduced β-hexosaminidase and histamine release from HMC-1 cells stimulated with compound 48/80 compared to treatment with R. coreanus fruit ethanol extract. Furthermore, topical application of R. coreanus root ethanol extract dramatically reduced the severity of skin symptoms and the thickening and swelling of the dorsal skin and ear in DNCB-treated NC/Nga mice. The protein and mRNA expression of several cytokines (IL-4, IL-5, IL-12, IFN-γ, TNF-α, and TARC) and IgE was significantly lowered upon application of the R. coreanus root ethanol extract. The promising candidate for the active ingredient of R. coreanus root polyphenols was revealed to be ellagic acid. These findings clearly indicate that the R. coreanus root polyphenols show strong anti-allergic effects and suppress the symptoms of AD. Therefore, polyphenol-containing R. coreanus root ethanol extract could be a novel therapeutic candidate for the treatment of allergy and AD.

Repeated α-GalCer Administration Induces a Type 2 Cytokine-Biased iNKT Cell Response and Exacerbates Atopic Skin Inflammation in Vα14Tg NC/Nga Mice.

We have previously shown that Vα14 TCR Tg (Vα14Tg) NC/Nga (NC) mice contain increased numbers of double-negative (DN) invariant natural killer T (iNKT) cells that protect against spontaneous development of atopic dermatitis (AD). iNKT cells can regulate immune responses by producing various cytokines such as IFNγ and IL4 rapidly upon stimulation with α-galactosylceramide (α-GalCer), a prototypical iNKT cell agonist. However, the precise role of α-GalCer-activated iNKT cells in AD development remains unclear. Therefore, we examined whether repeated activation of iNKT cells with α-GalCer can regulate the pathogenesis of AD in Vα14Tg NC mice. We found that Vα14Tg NC mice injected repeatedly with α-GalCer display exacerbated AD symptoms (e.g., a higher clinical score, IgE hyperproduction, and increased numbers of splenic mast cells and neutrophils) compared with vehicle-injected Vα14Tg NC mice. Moreover, the severity of AD pathogenesis in α-GalCer-injected Vα14Tg NC mice correlated with increased Th2 cells but reduced Th1 and Foxp3+ Treg cells. Furthermore, the resulting alterations in the Th1/Th2 and Treg/Th2 balance were strongly associated with a biased expansion of type 2 cytokine-deviated iNKT cells in α-GalCer-treated Vα14Tg NC mice. Collectively, our results have demonstrated the adverse effect of repeated α-GalCer treatment on skin inflammation mediated by type 2 immunity.

FEATURES OF CHANGES IN IMMUNE HOMEOSTASIS IN PATIENTS WITH BRONCHIAL ASTHMA

92 patients with bronchial asthma (BA) were examined. Among them, 48 patients with allergic BA (52.2%), 12 patients with non-allergic BA (NBA) (13%) and 28 patients with mixed BA (SBA) (26.8%). In 71 (77.2%) patients, the hereditary history was delayed. Determination of total IgE in blood serum was carried out by the ELISA method using a set of the company Hema-Media, the level of IFN-γ, IL-4 in blood serum using test systems for quantitative determination by the solid-phase ELISA method (CJSC Vector-Best, Russia). Genotyping of DNA samples was performed by PCR amplification. The results obtained show a certain dependence of the levels of total IgE, IL-4, and IFN-g in patients with BA with a pathogenetic variant of the disease, the distinctness of which is more pronounced in patients with ABA. In patients with ABA and SBA, there is a pronounced inhibition of IFN-γ production, while in patients with BA with a predominantly allergic mechanism of the disease, a significant increase in the level of IL-4 is recorded. According to the results of our studies, there was no significant relationship between the Gln27Glu polymorphism of the β2-BArenoreceptor gene and the activity of inductive cytokines. The Gln27Gln genotype of the β2-BArenoreceptor gene in patients with BA and, especially, in the allergic form of the disease, is associated with IgE hyperproduction.

Phenotypes of immune status in children with recurrent respiratory infections

We have observed 98 children and evaluated certain laboratory parameters, including cell counts of peripheral blood, the phagocytic activity of neutrophils, the concentration of the C3 and the C4 components of the complement, immunoglobulins (IgM, IgG, IgA, IgE) and circulating immune complexes of the serum. Leukocyte markers of CD3+, CD3+CD4+, CD3+CD8+, CD3-CD19+, CD3-CD56+, CD3+CD56+, CD3+CD25+, CD3+HLA-DR were determined by flow cytometry. In the group with reccurent respiratory infections, abnormalities of the humoral aspect of immunity were determined in 53.1% of children, with depressed IgA levels being present in 37.76% and a decrease in IgG – in 13.27%, IgE hyperproduction - in 11% (p <0,05). We have identified the main phenotypes of the immune status in children with reccurent respiratory infections – allergic – in 14.3%, immunodeficient – in 27.6%, infectious - in 6.1%, infectious-allergic – in 6.1% of children. Decrease in the level of B-lymphocytes and T-helper lymphocytes was found with a frequency of 16.39% each. 17.72 and 29.1% of children, respectively, had decreased indicators of the phagocytic index and phagocytic number, the C3 complement component levels were reduced in 8.75% of children, and 8.2% of children had a lower counts of NK cells (CD3-CD16 + CD56 +).

IL-4 and IL-17 Are Required for House Dust Mite-Driven Airway Hyperresponsiveness in Autoimmune Diabetes-Prone Non-Obese Diabetic Mice.

Allergic asthma is characterized by airway inflammation with a Th2-type cytokine profile, hyper-IgE production, mucus hypersecretion, and airway hyperreactivity (AHR). It is increasingly recognized that asthma is a heterogeneous disease implicating complex immune mechanisms resulting in distinct endotypes observed in patients. In this study, we showed that non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, undergo more severe allergic asthma airway inflammation and AHR than pro-Th2 BALB/c mice upon house dust mite (HDM) sensitization and challenge. The use of IL-4-deficient NOD mice and the in vivo neutralization of IL-17 demonstrated that both IL-4 and IL-17 are responsible by the exacerbated airway inflammation and AHR observed in NOD mice. Overall, our findings indicate that autoimmune diabetes-prone NOD mice might become useful as a new HDM-induced asthma model to elucidate allergic dysimmune mechanisms involving Th2 and Th17 responses that could better mimic some asthmatic endoytpes.

Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials

Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by IgE hyperproduction and eosinophilic inflammation. The anti-IgE antibody, omalizumab, has demonstrated efficacy in patients with CRSwNP and comorbid asthma previously. Our aim was to determine omalizumab safety and efficacy in CRSwNP in phase 3 trials (POLYP 1 and POLYP 2). Adults with CRSwNP with inadequate response to intranasal corticosteroids were randomized (1:1) to omalizumab or placebo and intranasal mometasone for 24 weeks. Coprimary end points included change from baseline to week 24 in Nasal Polyp Score (NPS) and Nasal Congestion Score. Secondary end points included change from baseline to week 24 in Sino-Nasal Outcome Test-22 (SNOT-22) score, University of Pennsylvania Smell Identification Test, sense of smell, postnasal drip, runny nose, and adverse events. Patients in POLYP 1 (n= 138) and POLYP 2 (n= 127) exhibited severe CRSwNP and substantial quality of life impairment evidenced by a mean NPS higher than 6 and SNOT-22 score of approximately 60. Both studies met both the coprimary end points. SNOT-22 score, University of Pennsylvania Smell Identification Test score, sense of smell, postnasal drip, and runny nose were also significantly improved for omalizumab versus placebo. In POLYP 1 and POLYP 2, the mean changes from baseline at week 24 for omalizumab versus placebo were as follows: NPS, -1.08 versus 0.06 (P< .0001) and -0.90 versus -0.31 (P= .0140); Nasal Congestion Score, -0.89 versus -0.35 (P= .0004) and -0.70 versus -0.20 (P= .0017); and SNOT-22 score, -24.7 versus -8.6 (P< .0001) and -21.6 versus -6.6 (P< .0001). Adverse events were similar between groups. Omalizumab significantly improved endoscopic, clinical, and patient-reported outcomes in severe CRSwNP with inadequate response to intranasal corticosteroids, and it was well tolerated.

MARCH1 plays an indispensable role in the development of airway allergic immunity and asthma

Abstract Membrane associated RING-CH-1 (MARCH1) is an E3 ubiquitin ligase expressed mostly by antigen presenting cells (APCs) of the hematopoietic lineage. MARCH1 ubiquitinates surface MHCII and CD86 targeting these molecules for lysosomal degradation. MARCH1-mediated MHCII ubiquitination is crucial for thymic regulatory T cell generation. Whether MARCH1 plays a role in airway allergic inflammation remains unknown. We interrogated the function of MARCH1 in a well-established house dust mite (HDM) driven allergic inflammation mouse model of asthma. Despite displaying higher levels of MHCII and CD86 in APCs, MARCH1-deficient mice were incapable of developing allergic airway inflammation comprising of lung eosinophil accumulation, Th2 cell production of IL-4 and IL-13 cytokines, serum IgE responses, airway hyper-reactivity and mucus production. MARCH1-deficient mice failed to elicit IL-4 production from naïve CD4+ T cells in the lung draining lymph node during HDM sensitization. In addition, MARCH1-deficient mice did not effectively expand effector Th2 cells in the lungs after HDM challenge. Importantly, ablation of MARCH1 expression protected HDM sensitized mice from developing airway inflammation and hyper-production of IgE following re-exposure to HDM. These findings indicate that MARCH1 plays a crucial role in the initiation and progression of allergic airway inflammation, raising the possibility that modulating MARCH1 function might be therapeutically beneficial in asthma treatment.

The Role of Proteasome Inhibitor MG132 in 2,4-Dinitrofluorobenzene-Induced Atopic Dermatitis in NC/Nga Mice

Background: Although immunosuppressants for therapy of atopic dermatitis (AD) are still being sought, proteasome inhibitors are also potential candidates for the treatment of AD. Proteasome inhibitors exert various effects by blocking proteasomal degradation and help regulate processes such as apoptosis induction via caspase-9, cell cycle progression via cyclins, NF-κB inactivation via IκB, and downregulation of antigen cross-presentation. The cells targeted by proteasome inhibitors are therefore activated cells undergoing proliferation or differentiation, and antigen-presenting cells carrying out protein degradation. Objectives: This study investigated the therapeutic effects and side effects of a proteasome inhibitor, MG132, on the treatment of AD. Methods: AD-like disease in NC/Nga mice housed under specific pathogen-free conditions was induced by repeated application of 2,4-dinitrofluorobenzene (DNFB). Disease progression was evaluated by inflammation score, histopathology, and serum IgE level, and the effects of systemic MG132 administration were investigated. The percentages and absolute numbers for each population of Th1, Th2, and Th17 cells in the axillary lymph nodes were analyzed by flow cytometry. Results: DNFB application increased the expression of a unique major histocompatibility complex class I mutant molecule D/L^dm7 in dendritic cells (DCs), and increased Th1 and Th17 cells in NC/Nga mice. In vivo MG132 administration to NC/Nga mice with DNFB-induced dermatitis reduced Th17 cells but maintained the level of Th1 cells, resulting in the alleviation of dermatitis lesions by decreasing both serum IgE hyperproduction and mast cell migration. To understand the mechanisms maintaining Th1 cell levels following in vivo MG132-administration, we focused on the role of proteasomes regulating D/L^dm7 expression. Interestingly, 20S proteasome activity was higher in NC/Nga DCs than in BALB/c DCs. In vitro MG132 administration partially increased D/L^dm7 expression in a dose-dependent manner during DC maturation, and induced IFN-γ production from autoreactive CD8+ T cells but not from CD4+ T cells following coculturing with D/L^dm7-upregulated DCs. Conclusion: Although MG132 administration temporarily alleviated AD pathogenesis in NC/Nga mice, prolonged MG132 treatment may result in immunopathogenesis leading to chronic AD due to its side effect of maintaining Th1 levels via autoreactive CD8+ T cells.

Maintenance pharmacotherapy of atopic dermatitis

Atopic dermatitis (AD) - multifactorial inflammatory disease of skin characterized by pruritus, chronic recurrent process and age-related features of localization and morphology of lesions. This is one of most spread disease of skin up to 40%, meeting in all countries, in both sexes, in different age groups. The aim. Prevention of severe forms of AD and complications. Methods. To estimate the degree of atopic dermatitis was used international scale SCORAD (Scoring of Atopic Dermatitis). Results and discussion. At present time the pathogenesis of atopic dermatitis is discussed in terms of heredity resulting in disturbance of skin barrier, deficiency of immune system. The later means the stimulation of Th2-cells resulting in hyperproduction of IgE, hypersensitivity to allergens and nonspecific stimulants, colonization by pathogenic microorganism such as Staphylococcus aureus, Malassezia furfur and so on. The imbalance of autonomous nerve system with increased production of inflammatory mediators is strongly considered in the pathogenesis of atopic dermatitis too. Conclusion. Considering the multifactoriality of atopic dermatitis the maintenance pharmacotherapy is of particular importance. (For citation: Petrova IV, Omarov NN, Sargsyan МS, et al. Maintenance pharmacotherapy of atopic dermatitis. Reviews on Clinical Pharmacology and Drug Therapy. 2018;16(1):60-63. doi: 10.17816/RCF16160-63).

Physiological effects of brominated flame retardants on NC/Nga mice

Purpose: Brominated flame retardants (BFRs) are used as an additive or reactive components in various materials. Regarding their health concerns, their immunotoxicity have not been clarified yet.Materials and methods: In the current study, we examined the effects of systemic exposure to two types of BFRs, DE71 and DE79, on pathophysiologic traits of murine atopic dermatitis (AD). Male NC/Nga mice were repeatedly injected intraperitoneally with DE71 and DE79 and/or mite allergen (Dermatophagoides pteronyssinus: Dp) into their right ears. Thereafter, clinical scores, macroscopic findings of inflammatory foci, and Ig values in serum were examined.Results: Both DEs significantly aggravated clinical scores induced by mite allergen including skin dryness and edema. Total IgE titer was significantly greater in the Dp + DE79 group than in the Dp group.Conclusions: Taken together, exposure to BFRs can exacerbate AD-like skin lesions related to mite allergen in mice. The accentuating effects may be mediated, at least in part, through hyperproduction of IgE.

Effect of administrating polysaccharide from black currant (Ribes nigrum L.) on atopic dermatitis in NC/Nga mice.

Atopic dermatitis (AD) is a chronic inflammatory skin disease that causes dry skin and functional disruption of the skin barrier. AD is often accompanied by allergic inflammation. AD patient suffer from heavy itching, and their quality of life is severely affected. Some pharmaceuticals for AD have some side effects such as skin atrophy. So it is necessary to develop mild solutions such as food ingredients without side effects. There are various causes of AD. It is especially induced by immunological imbalances such as IFN-γ reduction. IFN-γ has an important role in regulating IgE, which can cause an allergy reaction. NC/Nga mice develop AD and IgE hyperproduction. In a previous study, we revealed that administration of polysaccharide from black currant (R. nigrum) has an effect on immunomodulation. It induces IFN-γ production from myeloid dendritic cells. We named this polysaccharide cassis polysaccharide (CAPS). In this report, we studied the effect of administering CAPS on atopic dermatitis in NC/Nga mice. Thirty NC/Nga mice that developed symptoms of atopic dermatitis were used. We divided them into three groups (control, CAPS administration 12 mg/kg/day, CAPS administration 60 mg/kg/day). For 4 weeks, we evaluated clinical score, serum IgE levels, gene expression of spleen, and skin pathology. We revealed that CAPS administration improves atopic dermatitis symptoms. We also found that CAPS administration suppresses IgE hyperproduction and induces IFN-γ gene transcription in the spleen. Finally, we confirmed that CAPS administration suppresses mast cell migration to epidermal skin. These results indicated that CAPS has an effect on AD.

Poly (ADP) Ribose Polymerase (PARP)‐1 Is A critical Determinant of Atopic Dermatitis through Control of Allergen‐Induced Th2 And T‐regulatory Responses And Expression of The Matricellular Protein Periostin

BackgroundAtopic dermatitis (AD) is a complex and multi‐factorial chronic inflammatory skin disorder. Individuals with AD have limited treatment options and, thus, identifying the key molecular mechanisms that participate in the pathogenesis of the disease will increase the likelihood of establishing precise strategies to prevent/combat the debilitating symptoms of AD. Immune system defects, including deregulated Th2 responses and hyperproduction of IgE, play a key role in the progression of the disease. Increasing evidence shows that the extracellular matrix (ECM) protein periostin plays an equally important role in AD. Our laboratory has extensively examined the role of PARP‐1 in the pathogenesis of several inflammatory diseases including chronic allergic asthma. PARP‐1 inhibition genetically or pharmacologically by Olaparib, a drug that is currently being used as a monotherapy against human ovarian cancer, provides a significant protection against the onset of the disease by blocking Th2 cytokines and IgE production and several other related factors.ObjectiveTo examined the efficacy of PARP‐1 inhibition by gene deletion or by Olaparib against AD traits using both an in vitro and an animal model of the disease.MethodsWild type and PARP‐1−/− mice were epicutaneously exposed to ovalbumin (OVA) 3 times a week for 3 weeks; each week was separated by a 2‐week resting period. Olparib (5mg/kg) was injected to WT mice. At the end of the protocol, the severity of dermatitis was evaluated using a clinical skin scoring (CSS) system. Mice were euthanized; skin biopsies were analyzed for immunohistopathologic features. Serum were collected and assessed for OVA‐specific IgE and cytokines levels. Spleen‐derived cells were assessed by FACS. WT or PARP‐1−/− skin fibroblasts were treated with LPS or IL‐13 for different time intervals then subjected to RT‐PCR or immunoblot analysis.ResultsPARP inhibition by gene knockout or pharmacologically by Olaparib provided a robust reduction in the manifestation of all traits of the disease including Redness, thickness, scratching and lichenification as assessed by the Eczema Area and Severity Index (EASI). The protective effects of PARP inhibition may be mediated by a differential regulation of Th1/Th2 cytokines production. Indeed, while PARP inhibition suppressed production of Th2 cytokines (e.g. IL‐4/IL‐5/GM‐CSF) and allergen‐specific IgE, it exerted no effect on production of the anti‐inflammatory cytokine IL‐10 or the Th1 cytokine, IFN‐γ. Such differential effects occurred with a statistically significant increase in T‐regulatory cell population. Remarkably, PARP‐1 appeared to play a critical role in periostin protein expression both in vitro using skin fibroblasts and in the skin of mice using the AD animal model. PARP‐1 inhibition may not only alter the function and ability of T cells to produce Th2 cytokines but also regulate the production of the ECM proteins as periostin.ConclusionOur results show for the first time that PARP‐1 plays a critical role in atopic dermatitis. These findings provide evidence for the potential of PARP‐1 inhibitors as a novel therapeutic strategy and Olaparib as a likely candidate to be tested in human clinical trials.Support or Funding InformationNIH

IMMUNOLOGICAL MARKERS OF UNCONTROLLED ATOPIC BRONCHIAL ASTHMA IN CHILDREN

Bronchial asthma is a prevalent chronic allergic disease of lungs at early ages. A priority task in allergology is to search biological markers related to uncontrolled atopic bronchial asthma. Cytokines fulfill their distinct function in pathogenesis of atopic bronchial asthma, participating at the initiation, development and persistence of allergic inflammation in airways, causing different variations of clinical course of the disease (with respect to its acuteness, severity, frequency of exacerbations). The present work has studied indices of cellular and humoral links of immunity, as well as levels of some pro and anti-inflammatory cytokines in peripheral blood serum (IL-4, IL-10, IL-2 and TNFα), aiming to determine potential markers of uncontrolled atopic bronchial asthma in children. A group of Caucasian (European) children was involved into the research: Cohort 1, moderate atopic bronchial asthma with controlled course during the last 3 months (n = 59); Cohort 2, severe/moderate-severe atopic bronchial asthma with uncontrolled course of the disease within last 3 months (n = 51), Cohort 3 – control, practically healthy children without signs of atopy (n = 33). All the children included in the group with atopic bronchial asthma underwent regular mono/combined basic therapy at high/ intermediate therapeutic doses. We performed a comparative analysis of cell population indices reflecting certain cellular immunity links, and determined significantly lower levels of CD3 + lymphocytes, as well as decrease in relative and absolute contents of CD4 + and CD8+ cells in the cohort with uncontrolled course of atopic bronchial asthma, as compared with controlled-course cohort. When evaluating concentrations of cytokines in peripheral blood serum of the patients with controlled and uncontrolled atopic bronchial asthma, we revealed significantly higher levels of IL-2, IL-4, and IL-10, as compared to control group. It was found that TNFα concentration is considerably higher in both cohorts of the patients, being 2to 3-fold higher than the levels of this cytokine in control group. When comparing the cohorts with different control of the disease course, we have found that TNFα concentration in the cohort with uncontrolled bronchial asthma is statistically higher than among children with controllable course of the disease. Hence, the following parameters may serve as potential markers of pediatric atopic bronchial asthma with uncontrolled course: low levels of total Т lymphocyte numbers in peripheral blood, and decreased counts of CD4 + , CD8 + cells; IgE hyperproduction; low contents of common IgA, and high concentration of TNFα in peripheral blood serum.

Increased Expression of Three Types of Transient Receptor Potential Channels (TRPA1, TRPV4 and TRPV3) in Burn Scars with Post-burn Pruritus

Post-burn pruritus is a common distressing consequence of burn wounds. Empirical treatment often fails to have a satisfactory outcome on post-burn pruritus, as the mechanism of post-burn pruritus has not been fully elucidated. The aim of this study was to evaluate the manifestation of transient receptor potential (TRP) channels in post-burn pruritus. Fifty-one burn patients with (n=33) or without (n=18) pruritus were investigated, including skin biopsies. Not unexpectedly, the scarred body area was larger in the former group. In immunohistochemistry, TPRV3 was significantly elevated in the epidermis of burn scars with pruritus. Furthermore, real time- PCR showed that mRNA of TRPA1 and TRPV4 was increased in itching burn scars. Staining for substance P and CGRP did not differ between the 2 grouped, but the former neuropeptide was increased in burn scars. These results may help determine a specific therapeutic approach for post-burn pruritus.