Lifestyle Changes and Industrialization in the Development of Allergic Diseases.

PURPOSE OF REVIEW: Modernization and Westernization in industrialized and developing nations is associated with a substantial increase in chronic noncommunicable diseases. This transformation has far-reaching effects on lifestyles, impacting areas such as economics, politics, social life, and culture, all of which, in turn, have diverse influences on public health. Loss of contact with nature, alternations in the microbiota, processed food consumption, exposure to environmental pollutants including chemicals, increased stress and decreased physical activity jointly result in increases in the frequency of inflammatory disorders including allergies and many autoimmune and neuropsychiatric diseases. This review aims to investigate the relationship between Western lifestyle and inflammatory disorders. RECENT FINDINGS: Several hypotheses have been put forth trying to explain the observed increases in these diseases, such as 'Hygiene Hypothesis', 'Old Friends', and 'Biodiversity and Dysbiosis'. The recently introduced 'Epithelial Barrier Theory' incorporates these former hypotheses and suggests that toxic substances in cleaning agents, laundry and dishwasher detergents, shampoos, toothpastes, as well as microplastic, packaged food and air pollution damage the epithelium of our skin, lungs and gastrointestinal system. Epithelial barrier disruption leads to decreased biodiversity of the microbiome and the development of opportunistic pathogen colonization, which upon interaction with the immune system, initiates local and systemic inflammation. Gaining a deeper comprehension of the interplay between the environment, microbiome and the immune system provides the data to assist with legally regulating the usage of toxic substances, to enable nontoxic alternatives and to mitigate these environmental challenges essential for fostering a harmonious and healthy global environment.

Recent advances in the epithelial barrier theory.

The epithelial barrier theory links the recent rise in chronic non-communicable diseases, notably autoimmune and allergic disorders, to environmental agents disrupting the epithelial barrier. Global pollution and environmental toxic agent exposure have worsened over six decades because of uncontrolled growth, modernization, and industrialization, affecting human health. Introducing new chemicals without any reasonable control of their health effects through these years has led to documented adverse effects, especially on the skin and mucosal epithelial barriers. These substances, such as particulate matter, detergents, surfactants, food emulsifiers, micro- and nano-plastics, diesel exhaust, cigarette smoke, and ozone, have been shown to compromise the epithelial barrier integrity. This disruption is linked to the opening of the tight-junction barriers, inflammation, cell death, oxidative stress, and metabolic regulation. Consideration must be given to the interplay of toxic substances, underlying inflammatory diseases, and medications, especially in affected tissues. This review article discusses the detrimental effect of environmental barrier-damaging compounds on human health and involves cellular and molecular mechanisms.

How does global warming contribute to disorders originating from an impaired epithelial barrier?

The epithelial barrier represents the point of contact between the host and the external environment. It is the first line of defense against external insults in the skin and in the gastrointestinal and upper and lower respiratory tracts. The steep increase in chronic disorders in recent decades, including allergies and autoimmune disorders, has prompted studies to investigate the immune mechanisms of their underlying pathogeneses, all of which point to a thought-provoking shared finding: disrupted epithelial barriers. Climate change with global warming has increased the frequency of unpredictable extreme weather events, such as wildfires, droughts, floods, and aberrant and longer pollination seasons, among many others. These increasingly frequent natural disasters can synergistically damage the epithelial barrier integrity in the presence of environmental pollution. A disrupted epithelial barrier induces proinflammatory activation of epithelial cells and alarmin production, namely, epithelitis. The "opened" epithelial barrier facilitates the entry of the external exposome into and underneath the epithelium, triggering an expulsion response driven by inflammatory cells in the area and chronic inflammation. These changes are associated with microbial dysbiosis with colonizing opportunistic pathogens and decreased commensals. These cellular and molecular events are key mechanisms in the pathogenesis of numerous chronic inflammatory disorders. This review summarizes the impact of global warming on epithelial barrier functions in the context of allergic diseases. Further studies in the impact of climate change on the dysfunction of the epithelial barriers are warranted to improve our understanding of epithelial barrier-related diseases and raise awareness of the environmental insults that pose a threat to our health.

Mechanisms of gut epithelial barrier impairment caused by food emulsifiers polysorbate 20 and polysorbate 80.

BACKGROUND: The rising prevalence of many chronic diseases related to gut barrier dysfunction coincides with the increased global usage of dietary emulsifiers in recent decades. We therefore investigated the effect of the frequently used food emulsifiers on cytotoxicity, barrier function, transcriptome alterations, and protein expression in gastrointestinal epithelial cells. METHODS: Human intestinal organoids originating from induced pluripotent stem cells, colon organoid organ-on-a-chip, and liquid-liquid interface cells were cultured in the presence of two common emulsifiers: polysorbate 20 (P20) and polysorbate 80 (P80). The cytotoxicity, transepithelial electrical resistance (TEER), and paracellular-flux were measured. Immunofluorescence staining of epithelial tight-junctions (TJ), RNA-seq transcriptome, and targeted proteomics were performed. RESULTS: Cells showed lysis in response to P20 and P80 exposure starting at a 0.1% (v/v) concentration across all models. Epithelial barrier disruption correlated with decreased TEER, increased paracellular-flux and irregular TJ immunostaining. RNA-seq and targeted proteomics analyses demonstrated upregulation of cell development, signaling, proliferation, apoptosis, inflammatory response, and response to stress at 0.05%, a concentration lower than direct cell toxicity. A proinflammatory response was characterized by the secretion of several cytokines and chemokines, interaction with their receptors, and PI3K-Akt and MAPK signaling pathways. CXCL5, CXCL10, and VEGFA were upregulated in response to P20 and CXCL1, CXCL8 (IL-8), CXCL10, LIF in response to P80. CONCLUSIONS: The present study provides direct evidence on the detrimental effects of food emulsifiers P20 and P80 on intestinal epithelial integrity. The underlying mechanism of epithelial barrier disruption was cell death at concentrations between 1% and 0.1%. Even at concentrations lower than 0.1%, these polysorbates induced a proinflammatory response suggesting a detrimental effect on gastrointestinal health.

Gut epithelial barrier damage caused by dishwasher detergents and rinse aids.

BACKGROUND: The increased prevalence of many chronic inflammatory diseases linked to gut epithelial barrier leakiness has prompted us to investigate the role of extensive use of dishwasher detergents, among other factors. OBJECTIVE: We sought to investigate the effects of professional and household dishwashers, and rinse agents, on cytotoxicity, barrier function, transcriptome, and protein expression in gastrointestinal epithelial cells. METHODS: Enterocytic liquid-liquid interfaces were established on permeable supports, and direct cellular cytotoxicity, transepithelial electrical resistance, paracellular flux, immunofluorescence staining, RNA-sequencing transcriptome, and targeted proteomics were performed. RESULTS: The observed detergent toxicity was attributed to exposure to rinse aid in a dose-dependent manner up to 1:20,000 v/v dilution. A disrupted epithelial barrier, particularly by rinse aid, was observed in liquid-liquid interface cultures, organoids, and gut-on-a-chip, demonstrating decreased transepithelial electrical resistance, increased paracellular flux, and irregular and heterogeneous tight junction immunostaining. When individual components of the rinse aid were investigated separately, alcohol ethoxylates elicited a strong toxic and barrier-damaging effect. RNA-sequencing transcriptome and proteomics data revealed upregulation in cell death, signaling and communication, development, metabolism, proliferation, and immune and inflammatory responses of epithelial cells. Interestingly, detergent residue from professional dishwashers demonstrated the remnant of a significant amount of cytotoxic and epithelial barrier-damaging rinse aid remaining on washed and ready-to-use dishware. CONCLUSIONS: The expression of genes involved in cell survival, epithelial barrier, cytokine signaling, and metabolism was altered by rinse aid in concentrations used in professional dishwashers. The alcohol ethoxylates present in the rinse aid were identified as the culprit component causing the epithelial inflammation and barrier damage.

Involvement and therapeutic implications of airway epithelial barrier dysfunction in type 2 inflammation of asthma.

ABSTRACT: Type 2 inflammation is a complex immune response and primary mechanism for several common allergic diseases including allergic rhinitis, allergic asthma, atopic dermatitis, and chronic rhinosinusitis with nasal polyps. It is the predominant type of immune response against helminths to prevent their tissue infiltration and induce their expulsion. Recent studies suggest that epithelial barrier dysfunction contributes to the development of type 2 inflammation in asthma, which may partly explain the increasing prevalence of asthma in China and around the globe. The epithelial barrier hypothesis has recently been proposed and has received great interest from the scientific community. The development of leaky epithelial barriers leads to microbial dysbiosis and the translocation of bacteria to inter- and sub-epithelial areas and the development of epithelial tissue inflammation. Accordingly, preventing the impairment and promoting the restoration of a deteriorated airway epithelial barrier represents a promising strategy for the treatment of asthma. This review introduces the interaction between type 2 inflammation and the airway epithelial barrier in asthma, the structure and molecular composition of the airway epithelial barrier, and the assessment of epithelial barrier integrity. The role of airway epithelial barrier disruption in the pathogenesis of asthma will be discussed. In addition, the possible mechanisms underlying the airway epithelial barrier dysfunction induced by allergens and environmental pollutants, and current treatments to restore the airway epithelial barrier are reviewed.

Epithelial barrier hypothesis: Effect of the external exposome on the microbiome and epithelial barriers in allergic disease.

Environmental exposure plays a major role in the development of allergic diseases. The exposome can be classified into internal (e.g., aging, hormones, and metabolic processes), specific external (e.g., chemical pollutants or lifestyle factors), and general external (e.g., broader socioeconomic and psychological contexts) domains, all of which are interrelated. All the factors we are exposed to, from the moment of conception to death, are part of the external exposome. Several hundreds of thousands of new chemicals have been introduced in modern life without our having a full understanding of their toxic health effects and ways to mitigate these effects. Climate change, air pollution, microplastics, tobacco smoke, changes and loss of biodiversity, alterations in dietary habits, and the microbiome due to modernization, urbanization, and globalization constitute our surrounding environment and external exposome. Some of these factors disrupt the epithelial barriers of the skin and mucosal surfaces, and these disruptions have been linked in the last few decades to the increasing prevalence and severity of allergic and inflammatory diseases such as atopic dermatitis, food allergy, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, and asthma. The epithelial barrier hypothesis provides a mechanistic explanation of how these factors can explain the rapid increase in allergic and autoimmune diseases. In this review, we discuss factors affecting the planet's health in the context of the 'epithelial barrier hypothesis,' including climate change, pollution, changes and loss of biodiversity, and emphasize the changes in the external exposome in the last few decades and their effects on allergic diseases. In addition, the roles of increased dietary fatty acid consumption and environmental substances (detergents, airborne pollen, ozone, microplastics, nanoparticles, and tobacco) affecting epithelial barriers are discussed. Considering the emerging data from recent studies, we suggest stringent governmental regulations, global policy adjustments, patient education, and the establishment of individualized control measures to mitigate environmental threats and decrease allergic disease.

Primary Immun Deficiency in Patients with Non-Cystic Fibrosis Bronchiectasis and Its Relationship with Clinical Parameters.

OBJECTIVE: Bronchiectasis is characterized by chronic respiratory infection. The role of immunodeficiency in this disease is poorly studied in relation to clinical indices. The primary aim of this study was to determine the frequency of these neglected altered immune status by evaluating immunoglobulins, lymphocyte subsets, complement levels, and neutrophil function, and to assess its relationship with clinical parameters in adult patients with non-cystic fibrosis bronchiectasis (NCFB). MATERIAL AND METHODS: A total of 74 (30 men and 44 women with a mean age of 47±17 years) adult patients with stable NCFB were enrolled in this study. The bronchiectasis severity index (BSI) and FACED (F:FEV1, A: Age, C: Chronic colonization, E: Extension, D: Dyspnea) scores were assessed. Peripheral blood samples were collected for the detection of total IgG, IgA, IgM, IgE, and IgG subclasses and C3 and C4 levels. The counts of CD3, CD4, CD8, CD19, CD16/56 expressing peripheral blood lymphocytes and neutrophil oxidative function were evaluated. RESULTS: In the study population, BSI and FACED severity index scores increased with longer duration of the disease (p=0.01 and p=0.040, respectively). Of the 74 patients, 27 (37%) showed humoral aberrations. The number of male patients were higher in this group (p=0.03). High serum total IgE levels were associated with high scores in BSI (moderate-severe group versus mild group, p=0.030). Patients with bronchiectasis demonstrated lower CD3+ T cell count, lower CD4+ T helper cell percentage, and lower CD4+ T cell count (p=0.031, p=0.030, p=0.029, respectively) than healthy subjects. A significant negative correlation was found between the percentage and count of CD16/56+ natural killer (NK) cells and the number of exacerbations within the past year (r=-0.230, p=0.049 and r=-0.264, p=0.023, respectively). CONCLUSION: Humoral aberrations in adult patients with NCFB were found to be frequent. IgE levels were related to high scores for disease severity indices. Furthermore, patients with low percentage and counts of NK cells had higher rates of exacerbations. These results emphasize the importance of immune function assessment in adult patients with NCFB.

Reference values for T and B lymphocyte subpopulations in Turkish children and adults

Background/aim: Established reference values are critical for the interpretation of immunologic assessments. In particular, the proportion and absolute counts of T- and B- cell subpopulations are subject to change with age and ethnicity. We aimed to establish age- specific reference values for lymphocyte subsets using updated immunophenotyping panels. Materials and methods: We studied a total of 297 healthy Turkish subjects aged 0 to 50 years, stratified into major age brackets in a cluster factor of 10 per age-group. The predetermined age intervals contained randomly allocated participants enrolled over a period of 6 months, who were homogenously distributed by sex. We analyzed a complete blood count test and simultaneously with detailed immunophenotyping enumerated the percent and absolute cell counts of lymphocyte subsets. Results: The percentage and absolute counts of lymphocyte subsets show a marked surge across the age-span. T helper, T cytotoxic, and the natural killer cell numbers were increasing from birth until 6 months, followed by a gradual decrease thereafter. B cell numbers were rising until 2 years, followed by a gradual decrease for the upcoming years, accompanied by a steady expansion of unclass-switched- and class-switched- B cells. Conclusion: We provide updated extensive reference intervals for lymphocyte subpopulations in Turkish people.

Parents of ataxia-telangiectasia patients display a distinct cellular immune phenotype mimicking ATM-mutated patients.

BACKGROUND: Heterozygous relatives of ataxia-telangiectasia (AT) patients are at an increased risk for certain AT-related manifestations. We also show that there is an increase of infection frequency in parents of AT patients. Thus, we hypothesized that the parents might exhibit immune alterations similar to their affected children. METHODS: Lymphocyte phenotyping to enumerate T- and B-cell subsets was performed. Functional analyses included in vitro quantified γ-H2AX, poly (ADP-ribose) polymerase (PARP) and caspase-9 proteins. Chromosomal instability was determined by comet assay. RESULTS: We analyzed 20 AT patients (14F/6M), 31 parents (16F/15M), and 35 age-matched healthy controls. The AT patients' parents exhibited low frequency of naive CD4+ T- (n = 14, 45%) and recent thymic emigrants (n = 11, 35%) in comparison with the age-matched healthy donors. Interestingly, parents with low naive T cells also demonstrated high rate of recurrent infections (9/14, 64%). In comparison with age-matched controls, parents who had recurrent infections and low naive T cells showed significantly higher baseline γ-H2AX levels and H2 O2 -induced DNA damage as well as increased cleaved caspase-9 and PARP proteins. CONCLUSION: Parents of AT patients could present with recurrent infections and display cellular defects that mimic AT patients. The observed immunological changes could be associated with increased DNA double-strand breaks.

Diagnostic Modalities Based on Flow Cytometry for Chronic Granulomatous Disease: A Multicenter Study in a Well-Defined Cohort.

BACKGROUND: Chronic granulomatous disease (CGD) is characterized by defective microbial killing due to mutations affecting subunits of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Definitive genetic identification of disease subtypes may be delayed or not readily available. OBJECTIVE: Sought to investigate the role of intracellular staining of NADPH oxidase enzyme subunits in predicting the respective genetic defects in patients with CGD and carriers. METHODS: Thirty-four patients with genetically inherited CGD, including 12 patients with X-linked CGD (gp91phagocyte oxidase (phox) deficiency due to cytochrome b-245, beta polypeptide [CYBB] mutations) and 22 patients with autosomal-recessive CGD (p22phox, p47phox, and p67phox deficiency due to cytochrome b-245, alpha polypeptide [CYBA], neutrophil cytosolic factor 1 [NCF1] and NCF2 mutations, respectively) were recruited from different immunology centers and followed up prospectively. Dihydrorhodamine testing and NADPH oxidase subunit expression in white blood cells were determined by flow cytometry. RESULTS: gp91phox and p22phox defects, which result in simultaneous loss of both proteins due to their complex formation, were differentiated only by comparative analysis of patients' and mothers' intracellular staining. p47phox and p67phox protein expression was almost undetectable in patients compared with carrier mothers and healthy controls. The expression values of the respective subunits were found to be significantly higher in all controls as compared with carrier mothers, which in turn were higher than those of patients. CONCLUSIONS: Analysis of NADPH oxidase enzyme subunits by flow cytometry in patients and carriers is useful in the rapid prediction of the genetic defect of patients with CGD, thus guiding targeted sequencing and aiding in their early diagnosis.

Lymphocyte Subset Abnormalities in Pediatric-Onset Common Variable Immunodeficiency.

INTRODUCTION: Common variable immunodeficiency (CVID) is characterized by recurrent infections, autoimmunity, lymphoproliferation, hypogammaglobulinemia, and defective antibody production. In CVID, B-cell abnormalities were described to predict end organ involvement and prognosis. Pediatric-onset CVID is much rarer than adult CVID, and lymphocyte subset abnormalities have not been thoroughly evaluated. OBJECTIVE: We sought to determine lymphocyte subset abnormalities and their association with end organ involvement in pediatric-onset CVID patients. METHODS: The clinical manifestations and laboratory findings including absolute numbers and percentages of B-, T-, and NK cell populations were assessed in pediatric-onset CVID patients and compared to age-matched healthy controls. The patients were divided into 2 groups according to age at assessment (pediatric CVID patients: 10-16 years, n = 9; and adult CVID patients: >16 years, n = 13). The comparisons between lymphocyte subsets and organ involvement were also evaluated. RESULTS: Mean age at symptom onset was 18 (3-204) months. All CVID patients with pediatric onset had decreased levels of total and memory B cells, CD4+ T cells, CD4+CD45RA+ naive T cells, and recent thymic emigrant (RTE) cells. On the other hand, they had increases in CD8+CD45RO+ memory T cells. Interestingly, adult CVID patients demonstrated high frequencies of activated and double-negative T cells, which were unique only for this group of patients. Specific cellular abnormalities associated with the reduction in B and NK cells and increase in CD8+ T cells were found in patients with bronchiectasis. Moreover, in pediatric CVID patients, low serum IgA levels and decreased numbers of naive T and RTE cells were determined as risk factors for chronic diarrhea. CONCLUSIONS: Specific abnormalities in B- and T-lymphocyte compartments were identified in pediatric-onset CVID patients and appear to be associated with end organ manifestations.

Abatacept as a Long-Term Targeted Therapy for LRBA Deficiency.

BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. The long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established. OBJECTIVE: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations. METHODS: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry. RESULTS: The mean age of the patients was 13.4 ± 7.9 years, and the follow-up period was 3.4 ± 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. The long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy. CONCLUSIONS: Long-term abatacept therapy is effective in most patients with LRBA deficiency.

House Dust Mites Confer a Distinct Immunological Feature among Dermatitis.

Atopic dermatitis (AD) is a heterogeneous disease with regard to clinical phenotype and natural history. We investigated T cell subtypes and cytokine responses in peripheral blood and skin lesions of AD patients with various sensitivities. Immunological studies were performed in 27 subjects: 9 house dust mite (HDM)-sensitized; 6 subjects with sensitizations other than HDM; 7 non-allergic AD patients and 5 healthy controls. Among those, skin biopsy samples of 13 subjects were evaluated for immunohistochemical analyses, as well. The mean age was 8.93±5.17 years. HDM-allergic AD emerged as a distinct immunologic phenotype, with higher production of interleukin (IL)-4, -5, -2 both at rest and when stimulated by Der p1 or SEB along with higher Th17. As for TH17 cell percentage, it was increased in all AD groups compared to healthy controls, while HDM-allergic group was distinguished with a significantly lower production of IL-17. Patients with sensitizations other than HDM were mostly similar to non-allergic AD, with increased Th17 and CD4+CD69+interferon-gamma (IFN-γ)+ T cells percentage. The biopsy of lesional skin showed that HDM-allergic AD had lower IFN-γ and IFN-γ co-expressing CD8+ T cells compared to patients with other sensitizations (p=0.03 and p=0.04, respectively). Among the HDM allergic patients, pairwise comparison of lesional versus non-lesional skin revealed higher CD4+ T cells numbers, expression of forkhead box P3 (Foxp3) and T-cell-specific transcription factor (T-bet) (p=0.018, p=0.018, p=0.018, respectively). HDM-allergic AD is a distinct subtype with a predominant skewing in Th2 and higher Th17 cell percentage along with a blunted Th1 response in the skin, all of which may have therapeutic implications.

The effect of systemic corticosteroids on the innate and adaptive immune system in children with steroid responsive nephrotic syndrome.

UNLABELLED: The severity and duration of immunosuppression caused by corticosteroids (CSs) usage have not been extensively studied. We aimed to investigate the effects of CSs on the various compartments of immune system in relation to timing of initiation and persistence of therapy. Pediatric patients with idiopathic nephrotic syndrome (NS) treated with 2 mg/kg/day prednisolone and healthy control (HC) were enrolled. Blood samples were drawn for immunologic analyses at baseline and at the first and second weeks and first, second, and third months of CS therapy in addition to first and second weeks and first, second, and third months of discontinuation. Fourteen patients (M/F, 7/7) between 1 and 8 years old were evaluated. Untreated NS exhibited high absolute lymphocyte count (ALC)(p = 0.010), absolute CD3(+) T cells (p = 0.020) and absolute CD8(+) T cells (p = 0.006) compared to HC. Suppression in ALC was observed and nadir value was noted at first month of therapy compared to baseline (p = 0.002). The CD4(+) (p = 0.036) and CD8(+) T cell (p = 0.013) counts decreased significantly at the first week of treatment compared to baseline. While baseline B cell counts was indifferent from HC, gradually increased in 2 weeks of CS initiation and decreased during the treatment with a statistical significance compared to HC (p = 0.010). However, after cessation of CS, B cell counts continued to decline and found to be significantly different than baseline at first week (p = 0.008) and at third month (p = 0.040). CONCLUSION: Apart from baseline lymphocyte subset changing observed in untreated NS patients, our data implies that T cells were suppressed very early in the CS treatment. Interestingly, depressed B cell counts were detected later but persisted even after CS cessation. Due to early decrease in T cells, it would be beneficial to assume the patients as immunosuppressed at the very beginning of CS treatment to avoid infections. WHAT IS KNOWN: • Corticosteroids (CSs) are widely used for a variety of diseases including nephrotic syndrome, which is related with complex immune disturbance including T and B cells dysfunctions. • CSs induce neutrophilic leukocytosis concomitant with lymphopenia and eosinopenia leading to immunosupression. What is New: • T cell subsets and proliferation are susceptible to CSs more than B cells; however, the reversibility is faster with dose reduction in CS. • The change of B cells and B cell subtypes (CD27 (+) memory) shows prolonged effect of CSs on B cells which may alter antibody production even after 3 months of CSs cessation.

G6PC3 Deficiency: Primary Immune Deficiency Beyond Just Neutropenia.

Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency was recently defined as a new severe congenital neutropenia subgroup remarkable with congenital heart defects, urogenital malformations, endocrine abnormalities, and prominent superficial veins. Here, we report 3 patients with G6PC3 deficiency presenting with recurrent diarrhea, failure to thrive, and sinopulmonary infections leading to bronchiectasis. In patient I and II, a combined immune deficiency was suspected due to early-onset disease with lymphopenia, neutropenia, and thrombocytopenia, along with variable reductions in lymphocyte subpopulations and favorable response to intravenous γ-globulin therapy. Apart from neutropenia, all 3 patients had intermittent thrombocytopenia, anemia, and lymphopenia. All patients had failure to thrive and some of the classic syndromic features of G6PC3 deficiency, including cardiac abnormalities and visibility of superficial veins in all, endocrinologic problems in PI and PIII, and urogenital abnormalities in PII. Our experience suggests that a diagnosis of congenital neutropenia due to G6PC3 may not be as straightforward in such patients with combined lymphopenia and thrombocytopenia. A high index of suspicion and the other syndromic features of G6PC3 were clues to diagnosis. Screening of all combined immune deficiencies with neutropenia may help to uncover the whole spectra of G6PC3 deficiency.

Potentially Beneficial Effect of Hydroxychloroquine in a Patient with a Novel Mutation in Protein Kinase Cδ Deficiency.

Protein kinase C delta (PRKCD) has essential functions in controlling B-cell proliferation and apoptosis, development of B-cell tolerance and NK-cell cytolitic activity. Human PRKCD deficiency was recently identified to be causative for an autoimmune lymphoproliferative syndrome like disorder with significant B-cell proliferation particularly of immature B cells. Here we report a child with a novel mutation in PRKCD gene who presented with CMV infection and an early onset SLE-like disorder which was successfully treated with hydroxychloroquine.

Allogeneic pluripotent stem cells suppress airway inflammation in murine model of acute asthma.

New strategies are needed to suppress airway inflammation and prevent or reverse airway remodeling in asthma. Reprogramming induced pluripotent stem cells (iPSCs) have the potential of embryonic stem cells (ESCs) and provide a resource for stem cell-based utility. The aim of this study was to evaluate the histopathological and immunomodulatory effects of ESCs and iPSCs for potential allogenic application in a murine model of acute asthma. BALB/c mice were sensitized with alum-absorbed ovalbumin (OVA) and then challenged with 1% aerosolized OVA. 5×10(5) ESCs and iPSCs were administrated intranasally on the last day of nebulization. Mice were sacrificed after 24 h, and serum allergen specific antibody level, airway remodeling, cytokine levels in lung supernatants, and eosinophilic infiltration in BAL fluid were examined. As a result, more ESCs and iPSCs integrated into the lungs of mice in OVA groups than those of the controls. Epithelial, smooth muscle and basal membrane thicknesses as well as goblet cell hyperplasia occurring in airway remodeling were significantly suppressed by pluripotent stem cells in both distal and proximal airways. Percentage of eosinophils decreased significantly in BAL fluid as well as serum allergen-specific IgE and IL-4 levels in lung supernatants. On the contrary, regulatory cytokine - IL-10 level - was enhanced. Application of especially ESCs significantly increased the percentage of Treg subsets. Our comparative results showed that i.n. delivery of miRNA-based reprogrammed iPSCs is beneficial in attenuating airway inflammation in a murine model of acute asthma, and that cells also have similar immunomodulatory effects in mice.

Suppressive effect of compact bone-derived mesenchymal stem cells on chronic airway remodeling in murine model of asthma.

New therapeutic strategies are needed in the treatment of asthma besides vaccines and pharmacotherapies. For the development of novel therapies, the use of mesenchymal stem cells (MSCs) is a promising approach in regenerative medicine. Delivery of compact bone (CB) derived MSCs to the injured lungs is an alternative treatment strategy for chronic asthma. In this study, we aimed to isolate highly enriched population of MSCs from mouse CB with regenerative capacity, and to investigate the impact of these cells in airway remodeling and inflammation in experimental ovalbumin-induced mouse model of chronic asthma. mCB-MSCs were isolated, characterized, labeled with GFP and then transferred into mice with chronic asthma developed by ovalbumin (OVA) provocation. Histopathological changes including basement membrane, epithelium, subepithelial smooth thickness and goblet cell hyperplasia, and MSCs migration to lung tissues were evaluated. These histopathological alterations were increased in ovalbumin-treated mice compared to PBS group (P<0.001). Intravenous administration of mCB-MSC significantly reduced these histopathological changes in both distal and proximal airways (P<0.001). We showed that GFP-labeled MSCs were located in the lungs of OVA group 2weeks after intravenous induction. mCB-MSCs also significantly promoted Treg response in ovalbumin-treated mice (OVA+MSC group) (P<0.037). Our studies revealed that mCB-MSCs migrated to lung tissue and suppressed histopathological changes in murine model of asthma. The results reported here provided evidence that mCB-MSCs may be an alternative strategy for the treatment of remodeling and inflammation associated with chronic asthma.