Oral immunotherapy for food allergy.

Food allergy is a pathological, potentially deadly cascade of immune responses to molecules or molecular fragments that are normally innocuous when encountered in foods, such as milk, egg, or peanut. As the incidence and prevalence of food allergy rise, the standard of care is poised to advance beyond food allergen avoidance coupled with injectable epinephrine treatment of allergen-induced systemic reactions. Recent studies provide evidence that oral immunotherapy may effectively redirect the atopic immune responses of food allergy patients as they ingest small but gradually increasing allergen doses over many months, eliciting safer immune responses to these antigens. Research into the molecular and cellular bases of pathological and therapeutic immune responses, and into the possibilities for their safe and effective modulation, is generating tremendous interest in basic and clinical immunology. We synthesize developments, innovations, and key challenges in our understanding of the immune mechanisms associated with atopy and oral immunotherapy for food allergy.

Th2 and Th17 Induce Dry Skin in a Mouse Model of Arthritis.

Skin dryness is a characteristic of rheumatoid arthritis (RA) model mice. However, the mechanism underlying the induction of dry skin by RA is unclear. We hypothesized that T helper (Th)2 and Th17 cells mediate this process. A mouse model of DBA/1JJmsSlc collagen-induced arthritis was treated with Th2 or Th17 cell inhibitor, and transepidermal water loss (TEWL) and the expression of markers associated with allergic reaction and inflammation were evaluated. TEWL and plasma levels of thymic stromal lymphopoietin, interleukin (IL)-6 and -17, and tumor necrosis factor (TNF)-α were increased in the arthritis mouse model compared to that in control mice. Administration of Th2 cell inhibitor abolished the increase in TEWL, IL-6, and TNF-α levels, whereas Th17 cell inhibitor reversed TEWL and decreased IL-17 level. Th2 and Th17 cells contribute to the induction of dry skin, but via distinct mechanisms.

The profile of IL-4, IL-5, IL-10 and GATA3 in patients with LRBA deficiency and CVID with no known monogenic disease: Association with disease severity.

BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic form of primary immunodeficiency (PID). LPS-responsive beige-like anchor protein (LRBA) deficiency is an autosomal recessive disease characterized by a CVID-like phenotype. T cell abnormality was reported in patients with CVID and LRBA deficiency. The study's aim was to evaluate IL-4, IL-5, IL-10 and GATA3 expression in patients with LRBA deficiency and CVID with no known monogenic disease, and further evaluate its relevance with immunological futures and clinical complications of patients. METHODS: The study population comprised patients with CVID, LRBA deficiency and age-sex matched healthy controls. Mutation analysis was done by whole exome sequencing in CVID patients to rule out monogenic PIDs. After CD4+ T cell stimulation with anti-CD3 and anti-CD28 monoclonal antibodies, gene expression of IL-4, IL-5, IL-10 and transcription factor GATA3 was evaluated by real-time polymerase chain reaction. The protein of mentioned cytokines was assessed by enzyme-linked immunosorbent assay. RESULTS: The main clinical presentations of CVID patients were infections only and lymphoproliferations phenotypes, but in LRBA patients were autoimmune and enteropathy phenotype. The frequencies of CD4+ T cells were significantly reduced in LRBA and CVID patients. There were no statistically significant differences among GATA3, IL4, and IL5 gene expressions by CD4+ T cells of patients and controls, however, the IL10 expressions in CVID patients was significantly lower than in LRBA patients and HCs. As compared with HCs, CVID patients showed a prominent decrease in IL-4 and IL-10 production by CD4+ T cells. CONCLUSIONS: Our findings demonstrated that patients with CVID and LRBA deficiency (even with severe infectious and inflammatory complications) have not imbalance in Th2 response, which is in parallel with lower frequency of allergy and asthma in these patients.

The Roles of Sex Hormones in the Course of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by T helper 2 cell (Th2)-shifted abnormal immunity, skin barrier impairment, and pruritus. The prevalence of AD in childhood is slightly higher in boys than in girls; after puberty, the sexual difference is reversed. The female preponderance in all generations exists in intrinsic AD with enhanced Th1 activity and nickel allergy, lacking increased serum IgE or filaggrin mutation. AD is often deteriorated before menstruation. We review the effects of sex hormones on immune responses and skin permeability barrier and propose possible hypotheses for the above phenomena. After puberty, the immune responses of patients are remarkably influenced by sex hormones. Estrogen and progesterone enhance the activities of Th2/regulatory T cell (Treg) but suppress Th1/Th17. Androgens suppress Th1/Th2/Th17 and induce Treg. The skin permeability barrier is fortified by estrogen but is impaired by progesterone and androgens. Dehydroepiandrosterone suppresses Th2 but enhances Th1. The amount of steroid sulfatase converting dehydroepiandrosterone sulfate to dehydroepiandrosterone is higher in women than in men, and thus, women might be more susceptible to the influence of dehydroepiandrosterone. The balance of modulatory effects of sex hormones on immune responses and skin barrier might regulate the course of AD.

miR-146a Mimics Attenuate Allergic Airway Inflammation by Impacted Group 2 Innate Lymphoid Cells in an Ovalbumin-Induced Asthma Mouse Model.

BACKGROUND: The prevalence of allergic asthma has increased dramatically. Previous studies have found that the microRNA 146a (miR-146a) expression in asthma inhibits cell proliferation and promotes apoptosis of bronchial smooth muscle cells. We aimed to investigate the effect of miR-146a mimics on ovalbumin (OVA)-induced asthma in a mouse model. METHODS: Inflammatory cell infiltration in bronchoalveolar lavage fluid (BALF) was measured by flow cytometry. Levels of OVA-specific immunoglobulin E (IgE) in serum and cytokines in BALF were examined by enzyme-linked immunosorbent assay. For monitoring the airway, the Penh value (% baseline) was measured using a whole-body plethysmograph. RESULTS: In OVA-induced asthmatic mice, miR-146a significantly suppressed the infiltration of inflammatory cells in BALF and decreased the levels of OVA-specific IgE and T helper 2 cell type cytokines. In addition, miR-146a inhibited the OVA-induced airway hyperresponsiveness and the group 2 innate lymphoid cell responses. Moreover, the effects of miR-146a mimics were dependent on interleukin 33 stimulation. CONCLUSIONS: Our results suggest that miR-146a mimics might serve as an attractive candidate for further preclinical studies as an anti-inflammatory treatment of asthma.

Up-regulation of serum periostin and squamous cell carcinoma antigen levels in infants with acute bronchitis due to respiratory syncytial virus.

BACKGROUND: Periostin and squamous cell carcinoma antigen (SCCA) are involved in the pathogenesis of asthma. Acute bronchitis due to respiratory syncytial virus (RSV) infection during infancy exhibits an asthma-like pathogenesis, suggesting that it may be associated with the subsequent development of asthma. However, the mechanism by which RSV infection leads to development of asthma has not yet been fully elucidated. METHODS: Infants younger than 36 months were enrolled and classified into three groups. Group I included patients hospitalized with RSV-induced bronchitis. These patients were further stratified into two sub-groups according to whether the criteria for the modified Asthma Predictive Index (mAPI) had been met: Group I consisted of mAPI (+) and mAPI (-) patients; Group II included patients with food allergy as a positive control group; and Group III included children with no allergy as a negative control group. Serum periostin and SCCA levels were measured in the groups. This study was registered as a clinical trial (UMIN000012339). RESULTS: We enrolled 14 subjects in Group I mAPI (+), 22 in Group I mAPI (-), 18 in Group II, and 18 in Group III. In Group I, the serum periostin and SCCA levels were significantly higher during the acute phase compared with the recovery phase. However, no significant differences were found between Group I mAPI (+) and mAPI (-). CONCLUSIONS: The serum periostin and SCCA levels increased during acute RSV bronchitis. Both periostin and SCCA may play a role in the pathogenesis of acute bronchitis due to RSV.

Elevation of IgE in patients with psoriasis: Is it a paradoxical phenomenon?

Immunoglobulin E (IgE) elevation is a hallmark of allergic conditions such as atopic dermatitis (AD). The pathogenesis of AD is typically associated with high levels of IL-4 and IL-13 produced by activated T helper 2 (Th2) cells. Psoriasis, on the other hand, is an inflammatory skin disease mainly driven by Th17 cells and their related cytokines. Although the immunopathologic reactions and clinical manifestations are often easily distinguished in the two skin conditions, patients with psoriasis may sometimes exhibit AD-like manifestations, such as elevated IgE and persistent pruritic lesions. Given the fact that the effective T cells have great plasticity to re-differentiate in response to innate and environmental factors, this unusual skin condition could be a consequence of a cross-reaction between distinct arms of T-cell and humoral immunity. Here we review the literature concerning the roles of IgE in the development of AD and psoriasis, showing that elevated IgE seems to be an important indicator for this non-typical psoriasis.

NFE2L3 as a Novel Biomarker Associated With IL-2/STAT5/NLRP3 Signaling Pathway in Malignant Pleural Mesothelioma and Other Cancers.

Background: Malignant pleural mesothelioma (MPM) is a malignant tumor originating from pleural mesothelial cells and has a high mortality rate worldwide. With the advent of immunotherapy in MPM treatment, there is an urgent need to elucidate the immune-related mechanisms in this caner. Methods: Single-sample gene set enrichment analysis (ssGSEA) was used to score the immunocytes infiltration of data from different database sources. Identification of immunocyte-related genes was performed with weighted gene co-expression network analysis (WGCNA), differentially expressed genes (DEGs) analysis, and correlation analysis. Pan-caner analysis was performed using "DiffExp" and "Correlation" modules in TIMER. Results: T-helper 2 (Th2) cell was found to be a poor prognostic factor for patients with MPM. Then a transcription factor, NFE2L3, was identified as a biomarker that showed a strong positive correlation with Th2 cell infiltration, and was highly expressed in MPM tissues and was related to the poor prognosis of these patients. At the same time, multiple NFE2L3 methylation sites were negatively correlated with Th2 cell infiltration, and patients with a high degree of methylation enjoy a better prognosis. Pan-caner analysis indicated that NFE2L3 might promote the differentiation of Th2 cells through the IL-2/STAT5/NLRP3 signaling pathway in MPM and many other cancers. Conclusion: We believe that NFE2L3 can serve as a potential biomarker related to the diagnosis and prognosis of patients with MPM, and speculate that NFE2L3 could promote Th2 cell differentiation via IL-2/STAT5/NLRP3 signaling pathway in MPM and many other cancers.

Group 2 innate lymphoid cells (ILC2s) are important in typical type 2 immune-mediated diseases and an essential therapeutic target.

The prevalence rate of allergic diseases, such as asthma, atopic rhinitis (AR), and atopic dermatitis (AD), has been significantly increasing over the years because of environmental changes. Type 2 immunity is mediated by allergic inflammation initiated by an innate immune response. This response is orchestrated by type 2 cytokines (interleukin [IL]-4, IL-5, IL-9, and IL-13) together with other cells. The dendritic cell [DC]-T helper 2 (Th2) cell axis is the conventional type 2 immune pathway, and is currently known as the group 2 innate lymphoid cell (ILC2)-DC-Th2 axis that mediates type 2 inflammation. ILC2s strongly mediate type 2 inflammation in allergic diseases. ILC2s are activated by epithelial cell-derived cytokines, such as IL-25 and IL-33, and thymic stromal lymphopoietin. Additionally, ILC2s are activated by mast cell lipid inflammatory mediators, such as cysteinyl leukotrienes and prostaglandin D2. ILC2s produce a large amount of type 2 cytokines. The important role of ILC2s in the pathogenesis of type 2-mediated disease has resulted in ILC2-derived cytokines being a target for therapeutic development. In this review, we discuss type 2 immunity, mainly the ILC2-DC-Th2 axis, and other immune cells, the dominant role of ILC2s in asthma, AR, and AD, and therapeutic targets against type 2 cytokines.

Ex vivo expansion of regulatory T cell and T helper 2 cells using a hematosphere culture.

Regulatory T cells (T-reg) are important components of immune system required to understand the mechanistic details of cancer immunity and autoimmune diseases. However, reliable and efficient methods of regulatory T cell expansion have not been established yet. Here, we show that a human peripheral blood mononuclear cell (PBMNC) derived blood-born hematosphere (BBHS) culture without cytokine treatment increased T-reg and T helper 2 cell (Th2) populations in the cell suspension. We found that the isolated cells suspended around the hematospheres expressed T helper cell markers. Importantly, the Foxp3+/CD25+ T-reg and IL-4+/CD25+ Th2 cell populations in the cell suspension were greatly expanded during hematosphere culture. Through ELISA analysis of the supernatant, we showed that secretion of Th2-related cytokines such as IL-5, IL-10, and IL-13 also increased. Taken together, hematosphere culture is a good method for ex vivo expansion of T-reg and Th2, which can provide therapeutic benefits for the treatment of immune disorders.

Alterations of CD4+T Cell Subsets in Blood and Peritoneal Fluid in Different Stages of Endometriosis.

BACKGROUND: Endometriosis is a chronic inflammatory disorder with known immune disturbances. The aim of this study was to compare the frequency of different CD4+ T cells [T helper (Th)1, Th2, Th17 and regulatory T cells (Tregs)] in peripheral blood (PB) and peritoneal fluid (PF) of patients that have early and advanced stages of endometriosis with a control group. MATERIALS AND METHODS: In this case control study, PB and PF samples were collected from women aged 24-40 years who underwent laparoscopy procedures. The frequency of CD4+ T subsets were analysed by flow cytometry and compared between three study groups; early endometriosis (stage I, II), advanced endometriosis (stage III, IV) and control (no endometriosis). T cell numbers were compared between the PB and PF in each of the aforementioned groups. RESULTS: No statistically significant difference was found between the study groups regarding the numbers of Th1, Th2 and Th17 cells in PB. The PF of patients with advanced endometriosis had increased numbers of Th17 cells compared to the control group (P=0.003), with P values of 0.059 and 0.045 in both menstrual phases. Increased numbers of Th2 cells in PF from early compared to advanced stages of endometriosis were detected exclusively in the luteal phase (P=0.035). The control group had increased numbers of Treg and Th2 cells in the PF compared to PB (both, P value=0.046). However, in the early stages of endometriosis there were more Th2, Th17 and Treg cells in the PF compared to PB (P values: 0.005, 0.047 and 0.013, respectively), while the number of Th17 cells was higher in the PF compared with PB in the advanced stages of endometriosis (P= 0.013). CONCLUSION: There were increased numbers of Th17 cells in the PF of patients with advanced stages of endometriosis, which could be related to the severity of this disease.

Data on arsenic trioxide modulates Treg/Th17/Th1/Th2 cells in treatment-naïve rheumatoid arthritis patients and collagen-induced arthritis model mice.

In this article, we share the raw protein and mRNA data obtained from basal and stimulated human peripheral blood mononuclear cells (PBMCs) derived from 15 individual treatment-naïve rheumatoid arthritis (RA) patients and synovial fluid mononuclear cells (SFMCs). In treatment-naïve RA patients, PBMCs were treated with a gradient of concentrations of As2O3 (0, 0.1, 0.5, 1.0, 2.0, 4.0 µM) for 48 hours. We found that 2.0 µM As2O3 promoted the apoptosis of PBMCs significantly, and 0.5 µM As2O3 was the lowest and effective concentration that contributed to Treg cell generation but it prevented Th17 cell differentiation, as assessed by flow cytometry. Furthermore, As2O3 decreased the transcription factor STAT3 mRNA expression of Th17 cells but increased the transcription factor Foxp3 of Treg cells. In synovial fluid from RA patients, consistent with PBMCs, As2O3 inhibited Th17 cell differentiation but promoted Treg cell generation. In an animal experiment, we analyzed the body-weight of mice as the indicator of As2O3 toxicity and calculated the spleen index. As2O3 significantly decreased the hematoxylin and eosin score in Type II collagen-induced arthritis in mice. Furthermore, As2O3 downregulated the frequency of Th1 but upregulated Th2 cells. For more insight please see Arsenic trioxide improves Treg and Th17 balance by modulating STAT3 in treatment-naive rheumatoid arthritis patients [1].

Human umbilical cord-derived mesenchymal stem cells ameliorate the enteropathy of food allergies in mice.

Food allergy prevalence has steadily increased worldwide over the past decades and immunotherapeutic treatment strategies are gaining attention. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) exhibit similar immune regulatory properties to bone marrow-derived MSCs. hUC-MCSs can be prepared with fewer ethical constraints and are potential candidates for allergic disorder therapies. The current study aimed to investigate potential antiallergic properties of hUC-MSCs in mice with ovalbumin (OVA)-induced food allergy. Administration of hUC-MSCs cells intraperitoneally combined with oral gavage of the culture medium significantly alleviated OVA-induced diarrhea symptoms. Additionally, this treatment significantly decreased IgE levels and the percentage of T helper 2 cells in the blood, which were increased in mice with OVA-induced food allergy. The mRNA levels of the inflammatory cytokines interleukin-4 and tumor necrosis factor-α, and inflammatory cell infiltration in mouse colons were significantly decreased in hUC-MSCs-treated animals compared with mice with OVA-induced food allergy. Goblet cells were detected in colons of allergy-induced mice and their numbers were reduced following treatment with hUC-MSCs. In addition, treatment with hUC-MSCs reestablished the gut flora. The results revealed that hUC-MSCs may have a potential application in food allergy therapy.

Peucedanum japonicum extract attenuates allergic airway inflammation by inhibiting Th2 cell activation and production of pro-inflammatory mediators.

ETHNOPHARMACOLOGICAL RELEVANCE: The root of Peucedanum japonicum Thunberg is traditionally used to treat coughs, colds, headache and inflammatory diseases in Korea and Japan. Its effects on allergic lung inflammation have not been investigated. AIM OF THE STUDY: To investigate the anti-asthmatic effects of Peucedanum japonicum extract (PJE) using a murine model of asthma and a lipopolysaccharide (LPS)-stimulated macrophage cell line. MATERIALS AND METHODS: Mice underwent two rounds of sensitization with ovalbumin 1 week apart followed by four intranasal ovalbumin challenges on days 13-16. The control group received saline only. Two ovalbumin-sensitized groups were orally administered vehicle or PJE (200mg/kg) 5 days a week starting 1 week before the first ovalbumin sensitization. The third group was orally administered the asthma medication Montelukast (10mg/kg) on days 12-16. All animals were sacrificed on day 17. The lungs were assessed for histological features, inflammatory cell infiltration, Th2 cell activation and GATA-binding protein-3 (GATA-3) expression. The bronchoalveolar lavage fluid (BALF) was assessed for type 2 cytokine levels. The effect of PJE on the in vitro Th2 polarization of naïve CD4+ splenocytes and the production of pro-inflammatory mediators and cytokines by LPS-stimulated RAW 264.7 cells was evaluated. RESULTS: PJE treatment inhibited OVA-induced inflammatory cell infiltration, eosinophilia, Th2 activation, and GATA-3 expression in the lung, reduced the interleukin (IL)-5 and IL-13 levels in BALF, down-regulated Th2 activation in vitro, and inhibited the macrophage production of inducible nitric oxide, cyclooxygenase-2, tumor necrosis factor-α, and IL-6. CONCLUSION: PJE attenuated allergic airway inflammation by inhibiting Th2 cell activation and macrophage production of inflammatory mediators. Peucedanum japonicum may be candidate therapy for allergic lung inflammation.

Regression of eosinophil counts after diagnosis of chronic graft-versus-host disease as a potential marker for improved clinical outcome.

Eosinophilia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been associated with the development of acute and chronic graft-versus-host disease (cGVHD). However, a limited number of studies have investigated the course of eosinophil counts in relation to the onset of cGVHD. In this study, the course of relative eosinophil counts (RECs) was retrospectively analyzed in 64 patients who developed cGVHD following allogeneic HSCT in relation to overall survival (OS), relapse rate and clinical course of cGVHD. At onset of cGVHD, eosinophilia was observed in 45% of the patients and developed one week prior to cGVHD diagnosis. Furthermore, a trend towards improved OS in patients with eosinophilia was observed. Beneficial effects were most evident in patients who exhibited decreasing eosinophil counts one week after diagnosis of cGVHD. By contrast, an increase in or stable eosinophil counts one week after diagnosis were associated with significantly impaired OS and a significantly higher rate of later aggravation of cGVHD. Findings of this study suggested that the course of eosinophil counts may provide a useful parameter in the assessment of cGVHD development and activity allowing the potential identification of patient subpopulations with a good outcome and reduced cGVHD-related mortality.