[Show abstract][Hide abstract] ABSTRACT: Background
Food-induced anaphylaxis is triggered by specific IgE antibodies. Paradoxically, some subjects with significant IgE levels can ingest allergenic foods without incident. Similarly, subjects completing oral immunotherapy (OIT) tolerate food challenges despite persistent high-titer food-specific IgE.
We sought to test whether IgG antibodies induced by food immunotherapy prevent food-induced anaphylaxis and whether this occurs through the inhibitory receptor FcγRIIb.
Food allergy–susceptible Il4raF709 mice were enterally sensitized to ovalbumin (OVA). Similarly sensitized IgE-deficient (IgE−/−) Il4raF709 mice, which can ingest OVA without anaphylaxis, were subjected to a high-dose enteral OVA desensitization protocol (OIT). Sera from both groups were tested for the ability to activate or inhibit bone marrow mast cells (BMMCs) exposed to allergen or to passively transfer allergy to naive hosts. In parallel experiments sera obtained from patients with peanut allergy before and after undergoing OIT were interrogated for their ability to enhance or suppress peanut-induced activation in an indirect assay by using basophils from nonallergic donors.
Il4raF709 mice exhibited strong OVA-specific IgE responses. Their sera efficiently sensitized BMMCs for activation by antigen challenge. Sera from Il4raF709/IgE−/− mice subjected to OVA OIT suppressed BMMC responses. This inhibition was IgG mediated and FcγRIIb dependent. Similarly, pre-OIT but not post-OIT sera from patients efficiently sensitized basophils for peanut-induced activation. IgG antibodies in post-OIT sera suppressed basophil activation by pre-OIT sera. This inhibition was blocked by antibodies against FcγRII.
Food-specific IgG antibodies, such as those induced during OIT, inhibit IgE-mediated reactions. Strategies that favor IgG responses might prove useful in the management of food allergy.
Journal of Allergy and Clinical Immunology 12/2014; · 11.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The lung is a gas exchange organ that contends with a large array of environmental factors, including allergens, infectious microbes and reactive oxygen species. A number of innate immune mechanisms have evolved to rapidly respond to these elements, and can mediate lung inflammation and asthma, a very heterogeneous disease with several distinct phenotypes. Indeed, several of different forms of asthma can develop independently of adaptive immunity, and appear to involve Type 2 as well as Type 3 innate lymphoid cells (ILCs), producing IL-5, IL-9, IL-13 or IL-17 and IL-22. Type 2 ILCs respond to allergen and to influenza infection, and can lead to airway hyperreactivity (AHR), a cardinal feature of asthma. In contrast, in obesity, which is associated with a steroid resistant form of severe asthma, CCR6+ Type 3 ILC3s expand in the lungs in response to IL-1β produced via the NLRP3 pathway in lung macrophages. Administration of IL-1β directly into the lungs of mice resulted in the expansion of lung ILC3s, and directly induced AHR. Furthermore, blockade of IL-1β with an IL-1 receptor antagonist reduced the number of lung ILC3 cells and abolished obesity-induced AHR in mice. Obesity-associated AHR was independent of adaptive immunity, as it occurred in obese Rag1−/− mice, and was dependent on interleukin-17A (IL-17A) and the NLRP3 inflammasome, as it did not develop in obese Il17a−/− or Nlrp3−/− mice, respectively. These studies suggest an important role for Type 2 and Type 3 ILCs in different forms of allergic and non-allergic asthma.
[Show abstract][Hide abstract] ABSTRACT: Innate lymphoid cells (ILCs) are a recently discovered family of innate immune cells belonging to the lymphoid lineage, yet lacking antigen-specific receptors. ILCs were first identified in the intestinal tract, where they contribute to epithelial barrier integrity and host responses to commensal microbes. Teunissen et al. (in the current issue) and Villanova et al. (2014) now suggest an important role for type 3 ILCs (ILC3s) in the skin, particularly in psoriasis. Both groups found an increased frequency of IL-22- and/or IL-17A-producing ILCs in psoriatic skin and blood. These cells are activated in response to IL-1β and IL-23, correlate with disease severity, and are decreased following antitumor necrosis factor-α (anti-TNFα) treatment. The presence of a novel ILC population in psoriatic skin, one that responds to biologic therapeutics, suggests that dysregulation of ILCs is a contributing factor to psoriasis pathogenesis.
Journal of Investigative Dermatology 09/2014; 134(9):2305-7. · 6.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Food allergy is a major public health problem without satisfactory treatment options. Of several new treatments being studied, oral immunotherapy (OIT) appears to be the most promising. Unfortunately, OIT is associated with an unacceptably high frequency of allergic reactions. However, recent studies suggest that OIT might be made safer and faster when performed in conjunction with anti-IgE monoclonal antibody as an adjunctive treatment.
[Show abstract][Hide abstract] ABSTRACT: The lung, while functioning as a gas exchange organ, encounters a large array of environmental factors, including particulate matter, toxins, reactive oxygen species, chemicals, allergens, and infectious microbes. To rapidly respond to and counteract these elements, a number of innate immune mechanisms have evolved that can lead to lung inflammation and asthma, which is the focus of this review. These innate mechanisms include a role for two incompletely understood cell types, invariant natural killer T (iNKT) cells and innate lymphoid cells (ILCs), which together produce a wide range of cytokines, including interleukin-4 (IL-4), IL-5, IL-13, interferon-γ, IL-17, and IL-22, independently of adaptive immunity and conventional antigens. The specific roles of iNKT cells and ILCs in immunity are still being defined, but both cell types appear to play important roles in the lungs, particularly in asthma. As we gain a better understanding of these innate cell types, we will acquire great insight into the mechanisms by which allergic and non-allergic asthma phenotypes develop.
[Show abstract][Hide abstract] ABSTRACT: We report that programmed death ligand 2 (PD-L2), a known ligand of PD-1, also binds to repulsive guidance molecule b (RGMb), which was originally identified in the nervous system as a co-receptor for bone morphogenetic proteins (BMPs). PD-L2 and BMP-2/4 bind to distinct sites on RGMb. Normal resting lung interstitial macrophages and alveolar epithelial cells express high levels of RGMb mRNA, whereas lung dendritic cells express PD-L2. Blockade of the RGMb-PD-L2 interaction markedly impaired the development of respiratory tolerance by interfering with the initial T cell expansion required for respiratory tolerance. Experiments with PD-L2-deficient mice showed that PD-L2 expression on non-T cells was critical for respiratory tolerance, but expression on T cells was not required. Because PD-L2 binds to both PD-1, which inhibits antitumor immunity, and to RGMb, which regulates respiratory immunity, targeting the PD-L2 pathway has therapeutic potential for asthma, cancer, and other immune-mediated disorders. Understanding this pathway may provide insights into how to optimally modulate the PD-1 pathway in cancer immunotherapy while minimizing adverse events.
Journal of Experimental Medicine 04/2014; · 13.91 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Asthma is a complex and heterogeneous disease with several phenotypes, including an allergic asthma phenotype characterized by TH2 cytokine production and associated with allergen sensitization and adaptive immunity. Asthma also includes nonallergic asthma phenotypes, such as asthma associated with exposure to air pollution, infection, or obesity, that require innate rather than adaptive immunity. These innate pathways that lead to asthma involve macrophages, neutrophils, natural killer T cells, and innate lymphoid cells, newly described cell types that produce a variety of cytokines, including IL-5 and IL-13. We review the recent data regarding innate lymphoid cells and their role in asthma.
The Journal of allergy and clinical immunology 04/2014; 133(4):943-950. · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The prevalence of asthma has increased alarmingly in the past 2 to 3 decades. Increased antibiotic use in infancy has been suggested to limit exposure to gastrointestinal microbes and to predispose to asthma in later life.
To evaluate the association between antibiotic exposure during the first year of life and the development of asthma up to the age of 7 years.
A retrospective population-based study of a cohort of children enrolled in a nationwide employer-provided health insurance plan from January 1, 1999, through December 31, 2006, in the United States (n = 62,576). We evaluated the association between antibiotic exposure during the first year of life and subsequent development of 3 asthma phenotypes: transient wheezing (began and resolved before 3 years of age), late-onset asthma (began after 3 years of age), and persistent asthma (began before 3 years of age and persisted through 4-7 years of age).
Antibiotic use in the first year of life was associated with the development of transient wheezing (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.9-2.2; P < .001) and persistent asthma (OR, 1.6; 95% CI, 1.5-1.7; P < .001). A dose-response effect was observed. When 5 or more antibiotic courses were received, the odds of persistent asthma doubled (OR, 1.9; 95% CI, 1.5-2.6; P < .001). There is no association between antibiotic use and late-onset asthma.
Antibiotic use in the first year life is associated with an increased risk of early-onset childhood asthma that began before 3 years of age. The apparent effect has a clear dose response. Heightened caution about avoiding unnecessary use of antibiotics in infants is warranted.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 03/2014; · 2.75 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The gene encoding the cytoskeletal regulator DIAPH3 is lost at high frequency in metastatic prostate cancer, and DIAPH3 silencing evokes a transition to an amoeboid tumor phenotype in multiple cell backgrounds. This amoeboid transformation is accompanied by increased tumor cell migration, invasion, and metastasis. DIAPH3 silencing also promotes the formation of atypically large (> 1 μm) membrane blebs that can be shed as extracellular vesicles (EV) containing bioactive cargo. Whether loss of DIAPH3 also stimulates the release of nano-sized EV (e.g., exosomes) is not established. Here we examined the mechanism of release and potential biological functions of EV shed from DIAPH3-silenced and other prostate cancer cells. We observed that stimulation of LNCaP cells with the prostate stroma-derived growth factor heparin-binding EGF-like growth factor (HB-EGF), combined with p38MAPK inhibition caused EV shedding, a process mediated by ERK1/2 hyperactivation. DIAPH3 silencing in DU145 cells also increased rates of EV production. EV isolated from DIAPH3-silenced cells activated AKT1 and androgen signaling, increased proliferation of recipient tumor cells, and suppressed proliferation of human macrophages and peripheral blood mononuclear cells. DU145 EV contained miR-125a, which suppressed AKT1 expression and proliferation in recipient human peripheral blood mononuclear cells and macrophages. Our findings suggest that EV produced as a result of DIAPH3 loss or growth factor stimulation may condition the tumor microenvironment through multiple mechanisms, including the proliferation of cancer cells and suppression of tumor-infiltrating immune cells.
Cancer biology & therapy 01/2014; 15(4). · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Food allergy has a significant impact on child and family quality of life. Although there is currently no cure for food allergy, oral immunotherapy (OIT) has shown promise in desensitizing patients to food allergens. The primary aim of this paper was to examine the psychological impact of participation in OIT for children and families, including both perceived benefits and treatment burden. Semistructured interviews about the OIT experience were conducted with 10 children receiving OIT for milk allergy and their parents, and an inductive, grounded process was used to identify the most common categories of interview responses. Research documents were reviewed in a sample of 13 children receiving OIT for peanut allergy, to identify the nature and frequency of visits with a pediatric psychologist who was included as a member of the interdisciplinary research team. Following OIT for milk allergy, positive changes including increased dietary options, increased inclusion in social situations, and decreased anxiety about reactions were reported. Sources of treatment burden included anxiety about ingesting milk and injection-related distress. During OIT for peanut allergy, 69.2% of children met with the psychologist, with the most common presenting concerns including aversion to the taste of peanut, anxiety about ingestion of peanut, and injection-related distress. Children and families report perceived psychosocial benefits following OIT; however, there is also burden associated with the treatment itself. Preliminary experience suggests a role for pediatric psychologists to help children and families cope with and enhance adherence to OIT protocols. (PsycINFO Database Record (c) 2014 APA, all rights reserved)
Clinical Practice in Pediatric Psychology. 01/2014; 2(1):13.
[Show abstract][Hide abstract] ABSTRACT: Adiponectin is an adipose-derived hormone with anti-inflammatory activity. Following subacute ozone exposure (0.3 ppm for 24-72 h), neutrophilic inflammation and IL-6 are augmented in adiponectin deficient (Adipo(-/-)) mice. The IL-17/G-CSF axis is required for this increased neutrophilia. We hypothesized that elevated IL-6 in Adipo(-/-) mice contributes to their augmented responses to ozone via effects on IL-17A expression. Therefore, we generated mice deficient in both adiponectin and IL-6 (Adipo(-/-)IL-6(-/-)) and exposed them to ozone or air. In ozone exposed mice, BAL neutrophils, IL-6, and G-CSF, and pulmonary Il17α mRNA expression were greater in Adipo(-/-) versus wildtype mice, but reduced in Adipo(-/-)IL-6(-/-) versus Adipo(-/-) mice. IL-17A+ F4/80+ cells and IL-17A(+) γδ T-cells were also reduced in Adipo(-/-)IL-6(-/-) versus Adipo(-/-) mice exposed to ozone. Only BAL neutrophils were reduced in IL-6(-/-) versus WT mice. In wildtype mice, IL-6 was expressed in Gr-1(+)F4/80(-)CD11c(-) cells, whereas in Adipo-/- mice, F4/80(+)CD11c(+) cells also expressed IL-6, suggesting that IL-6 is regulated by adiponectin in these alveolar macrophages. Transcriptomic analysis identified serum amyloid A3 (Saa3), which promotes IL-17A expression, as the gene most differentially augmented by ozone in Adipo(-/-) versus wildtype mice. After ozone, Saa3 mRNA expression was markedly greater in Adipo(-/-) versus wildtype mice, but reduced in Adipo(-/-)/IL-6(-/-) versus Adipo(-/-) mice. In conclusion, our data support a pivotal role of IL-6 in the hyperinflammatory condition observed in Adipo(-/-) mice after ozone exposure, and suggest that this role of IL-6 involves its ability to induce Saa3, IL-17A and G-CSF.
[Show abstract][Hide abstract] ABSTRACT: Obesity is associated with the development of asthma, which is often difficult to control. To understand the immunological pathways that lead to obesity-associated asthma, we fed mice a high-fat diet for 12 weeks, which resulted in obesity and the development of airway hyperreactivity (AHR), a cardinal feature of asthma. This AHR was independent of adaptive immunity, as it occurred in obese Rag1(-/-) mice, which lack B and T cells, and was dependent on interleukin-17A (IL-17A) and the NLRP3 inflammasome, as it did not develop in obese Il17a(-/-) or Nlrp3(-/-) mice. AHR was also associated with the expansion of CCR6(+) type 3 innate lymphoid cells (ILCs) producing IL-17A (ILC3 cells) in the lung, which could by themselves mediate AHR when adoptively transferred into Rag2(-/-); Il2rg(-/-) mice treated with recombinant IL-1β. Macrophage-derived IL-1β production was induced by HFD and expanded the number of lung ILC3 cells. Blockade of IL-1β with an IL-1 receptor antagonist abolished obesity-induced AHR and reduced the number of ILC3 cells. As we found ILC3-like cells in the bronchoalveolar lavage fluid of individuals with asthma, we suggest that obesity-associated asthma is facilitated by inflammation mediated by NLRP3, IL-1β and ILC3 cells.
[Show abstract][Hide abstract] ABSTRACT: Peanut allergy is a major public health problem that affects 1% of the population and has no effective therapy.
To examine the safety and efficacy of oral desensitization in peanut-allergic children in combination with a brief course of anti-IgE mAb (omalizumab [Xolair]).
We performed oral peanut desensitization in peanut-allergic children at high risk for developing significant peanut-induced allergic reactions. Omalizumab was administered before and during oral peanut desensitization.
We enrolled 13 children (median age, 10 years), with a median peanut-specific IgE level of 229 kUA/L and a median total serum IgE level of 621 kU/L, who failed an initial double-blind placebo-controlled food challenge at peanut flour doses of 100 mg or less. After pretreatment with omalizumab, all 13 subjects tolerated the initial 11 desensitization doses given on the first day, including the maximum dose of 500 mg peanut flour (cumulative dose, 992 mg, equivalent to >2 peanuts), requiring minimal or no rescue therapy. Twelve subjects then reached the maximum maintenance dose of 4000 mg peanut flour per day in a median time of 8 weeks, at which point omalizumab was discontinued. All 12 subjects continued on 4000 mg peanut flour per day and subsequently tolerated a challenge with 8000 mg peanut flour (equivalent to about 20 peanuts), or 160 to 400 times the dose tolerated before desensitization. During the study, 6 of the 13 subjects experienced mild or no allergic reactions, 5 subjects had grade 2 reactions, and 2 subjects had grade 3 reactions, all of which responded rapidly to treatment.
Among children with high-risk peanut allergy, treatment with omalizumab may facilitate rapid oral desensitization and qualitatively improve the desensitization process.
The Journal of allergy and clinical immunology 10/2013; · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The relationship between mold and asthma has been recognized for decades, but the molecular triggers of asthma generated by molds have not been fully elucidated. A glycolipid generated by Aspergillus species has recently been identified that triggers airway hyperreactivity via natural killer T cell activation. The synthesis of this glycolipid and structural variants designed to allow identification of the features of this glycolipid required for recognition by natural killer T cells is described.
[Show abstract][Hide abstract] ABSTRACT: Aspergillus fumigatus is a saprophytic fungus that is ubiquitous in the environment and is commonly associated with allergic sensitization and severe asthma in humans. Although A. fumigatus is recognized by multiple microbial pattern-recognition receptors, we found that an A. fumigatus-derived glycosphingolipid, asperamide B, directly activates invariant natural killer T (iNKT) cells in vitro in a CD1d-restricted, MyD88-independent and dectin-1-independent fashion. Moreover, asperamide B, when loaded onto CD1d, directly stained, and was sufficient to activate, human and mouse iNKT cells. In vivo, asperamide B rapidly induced airway hyperreactivity, which is a cardinal feature of asthma, by activating pulmonary iNKT cells in an interleukin-33 (IL-33)-ST2-dependent fashion. Asperamide B is thus the first fungal glycolipid found to directly activate iNKT cells. These results extend the range of microorganisms that can be directly detected by iNKT cells to the kingdom of fungi and may explain how A. fumigatus can induce severe chronic respiratory diseases in humans.
[Show abstract][Hide abstract] ABSTRACT: Background: Severe refractory atopic dermatitis (AD) is a chronic, debilitating condition that is associated with elevated serum immunoglobulin E (IgE) levels. Thymic stromal lymphopoietin (TSLP), thymus and activation-regulated chemokine (TARC) and OX40 ligand (OX40L) are important immunologic factors involved in the pathogenesis of AD. Omalizumab, an anti-IgE antibody indicated for use in allergic asthma, is implicated in regulating allergen presentation by dendritic cells and the T cell response during the effector phases of allergic disease. We investigated if anti-IgE therapy modulates the allergen-specific responses mediated by the TSLP pathway in young patients with severe refractory AD. Methods: This was a randomized, double-blind, placebo-controlled study of 8 patients between the ages of 4 and 22 years (mean = 11.6 years) with severe refractory AD (clinical trials.gov NCT01678092). Serum IgE ranged from 218 to 1,890 (mean = 1,068 IU/ml). Subjects received omalizumab (n = 4) or placebo (n = 4) every 2-4 weeks over 24 weeks using a regimen extrapolated from the package insert. TSLP, TARC, OX40L and other cytokines involved in AD were measured by using cytometric bead arrays. Results: All patients receiving omalizumab had strikingly decreased levels of TSLP, OX40L, TARC (involved in Th2 polarization) and interleukin (IL)-9 compared to placebo. In addition, there was a marked increase in IL-10, a tolerogenic cytokine, in the omalizumab-treated group. Patients on anti-IgE therapy had an improvement in clinical outcomes as measured by the SCORAD system; however, these effects were comparable to improvements in the control group. Conclusions: Anti-IgE therapy with omalizumab decreases levels of cytokines that are involved in Th2 polarization and allergic inflammation, including TSLP, TARC and OX40L.
International Archives of Allergy and Immunology 06/2013; 162(1):89-93. · 2.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Asthma is a complex and heterogeneous disease with several phenotypes, including an allergic asthma phenotype, characterized by Th2 cytokine production and associated with allergen sensitization and adaptive immunity. Asthma also includes nonallergic asthma phenotypes that require innate rather than adaptive immunity. These innate pathways to asthma involve macrophages, neutrophils, as well as ILCs, newly described cell types that produce a variety of cytokines, including IL-5 and IL-13. We review the recent data regarding ILCs and their role in asthma.
Journal of leukocyte biology 06/2013; · 4.99 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Studies of asthma have been limited by a poor understanding of how nonallergic environmental exposures, such as air pollution and infection, are translated in the lung into inflammation and wheezing. OBJECTIVE: Our goal was to understand the mechanism of nonallergic asthma that leads to airway hyperreactivity (AHR), a cardinal feature of asthma independent of adaptive immunity. METHOD: We examined mouse models of experimental asthma in which AHR was induced by respiratory syncytial virus infection or ozone exposure using mice deficient in T-cell immunoglobulin and mucin domain 1 (TIM1/HAVCR1), an important asthma susceptibility gene. RESULTS: TIM1(-/-) mice did not have airways disease when infected with RSV or when repeatedly exposed to ozone, a major component of air pollution. On the other hand, the TIM1(-/-) mice had allergen-induced experimental asthma, as previously shown. The RSV- and ozone-induced pathways were blocked by treatment with caspase inhibitors, indicating an absolute requirement for programmed cell death and apoptosis. TIM-1-expressing, but not TIM-1-deficient, natural killer T cells responded to apoptotic airway epithelial cells by secreting cytokines, which mediated the development of AHR. CONCLUSION: We defined a novel pathway in which TIM-1, a receptor for phosphatidylserine expressed by apoptotic cells, drives the development of asthma by sensing and responding to injured and apoptotic airway epithelial cells.
The Journal of allergy and clinical immunology 05/2013; · 12.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human T-cell Immunoglobulin and Mucin-domain containing proteins (TIM1, 3, and 4) specifically bind phosphatidylserine (PS). TIM1 has been proposed to serve as a cellular receptor for hepatitis A virus and Ebola virus and as an entry factor for dengue virus. Here we show that TIM1 promotes infection of retroviruses and virus-like particles (VLPs) pseudotyped with a range of viral entry proteins, in particular those from the filovirus, flavivirus, New World arenavirus and alphavirus families. TIM1 also robustly enhanced the infection of replication-competent viruses from the same families, including dengue, Tacaribe, Sindbis and Ross River viruses. All interactions between TIM1 and pseudoviruses or VLPs were PS-mediated, as demonstrated with liposome blocking and TIM1 mutagenesis experiments. In addition, other PS-binding proteins, such as Axl and TIM4, promoted infection similarly to TIM1. Finally, the blocking of PS receptors on macrophages inhibited the entry of Ebola VLPs, suggesting that PS receptors can contribute to infection in physiologically relevant cells. Notably, infection mediated by the entry proteins of Lassa fever virus, influenza A virus and SARS coronavirus was largely unaffected by TIM1 expression. Taken together our data show that TIM1 and related PS-binding proteins promote infection of diverse families of enveloped viruses, and may therefore be useful targets for broad-spectrum antiviral therapies.
[Show abstract][Hide abstract] ABSTRACT: Food allergy has increased dramatically in prevalence over the past decade in westernized countries, and is now a major public health problem. Unfortunately for patients with food allergy, there is no effective therapy beyond food allergen avoidance, and rapid medical treatment for accidental exposures. Recently, oral immunotherapy (OIT) has been investigated as a treatment for this problem. In this review, we will discuss the progress in developing OIT for food allergy, including a novel approach utilizing Xolair (anti-IgE monoclonal antibody, omalizumab) in combination with OIT. This combination may enhance both the safety and efficacy of oral immunotherapy, and could lead to a widely available and safe therapy for food allergy.