IL-2-Agonist-Induced IFN-γ Exacerbates Systemic Anaphylaxis in Food Allergen-Sensitized Mice

Food allergies are common, costly and potentially life-threatening disorders. They are driven by Th2, but inhibited by Th1 reactions. There is also evidence indicating that IL-2 agonist treatment inhibits allergic sensitization through expansion of regulatory T cells. Here, we tested the impact of an IL-2 agonist in a novel model for food allergy to hen´s egg in mice sensitized without artificial adjuvants. Prophylactic IL-2 agonist treatment expanded Treg populations and inhibited allergen-specific sensitization. However, IL-2 agonist treatment of already sensitized mice increased mast cell responses and allergic anaphylaxis upon allergen re-challenge. These effects depended on allergen-specific IgE and were mediated through IFN-γ, as shown by IgE transfer and blockade of IFN-γ with monoclonal antibodies. These results suggest that although shifting the allergic reaction toward a Treg/Th1 response inhibits allergic sensitization, the prototypic Th1 cytokine IFN-γ promotes mast cell activation and allergen-induced anaphylaxis in individuals that are already IgE-sensitized. Hence, while a Th1 response can prevent the development of food allergy, IFN-γ has the ability to exacerbate already established food allergy.

Download Full-text

Thermoneutrality Alters Gastrointestinal Antigen Passage Patterning and Predisposes to Oral Antigen Sensitization in Mice

Frontiers in Immunology ◽

10.3389/fimmu.2021.636198 ◽

2021 ◽

Vol 12 ◽

Author(s):

Taeko K. Noah ◽

Jee-Boong Lee ◽

Christopher A. Brown ◽

Amnah Yamani ◽

Sunil Tomar ◽

...

Keyword(s):

Mast Cell ◽

Food Allergy ◽

Cell Activation ◽

Oral Challenge ◽

Mast Cell Activation ◽

Oral Exposure ◽

Standard Temperature ◽

Cellular Patterning ◽

The Impact ◽

Egg Antigen

Food allergy is an emerging epidemic, and the underlying mechanisms are not well defined partly due to the lack of robust adjuvant free experimental models of dietary antigen sensitization. As housing mice at thermoneutrality (Tn) - the temperature of metabolic homeostasis (26–30°C) – has been shown to improve modeling various human diseases involved in inflammation, we tested the impact of Tn housing on an experimental model of food sensitization. Here we demonstrate that WT BALB/c mice housed under standard temperature (18–20°C, Ts) conditions translocated the luminal antigens in the small intestine (SI) across the epithelium via goblet cell antigen passages (GAPs). In contrast, food allergy sensitive Il4raF709 mice housed under standard temperature conditions translocated the luminal antigens in the SI across the epithelium via secretory antigen passages (SAPs). Activation of SI antigen passages and oral challenge of Il4raF709 mice with egg allergens at standard temperature predisposed Il4raF709 mice to develop an anaphylactic reaction. Housing Il4raF709 mice at Tn altered systemic type 2 cytokine, IL-4, and the landscape of SI antigen passage patterning (villus and crypt involvement). Activation of SI antigen passages and oral challenge of Il4raF709 mice with egg antigen under Tn conditions led to the robust induction of egg-specific IgE and development of food-induced mast cell activation and hypovolemic shock. Similarly, Tn housing of WT BALB/c mice altered the cellular patterning of SI antigen passage (GAPs to SAPs). Activation of SI antigen passages and the oral challenge of WT BALB/c mice with egg antigen led to systemic reactivity to egg and mast cell activation. Together these data demonstrate that Tn housing alters antigen passage cellular patterning and landscape, and concurrent oral exposure of egg antigens and SAP activation is sufficient to induce oral antigen sensitization.

Download Full-text

Case 73: Dysautonomia Due to Mast Cell Activation Syndrome or Psoriatic Arthritis?

Autonomic Testing ◽

10.1093/med/9780190889227.003.0078 ◽

2019 ◽

pp. 374-377

Author(s):

Peter Novak

Keyword(s):

Mast Cell ◽

Psoriatic Arthritis ◽

Cell Activation ◽

Mast Cell Activation ◽

Food Allergies ◽

Postural Tachycardia Syndrome ◽

Mast Cell Activation Syndrome ◽

Autonomic Testing ◽

Postural Tachycardia ◽

Activation Syndrome

The patient presents with fatigue, postprandial nausea, diarrhea, food allergies, and nighttime tachycardia. She was diagnosed with mast cell syndrome (MCAS). Autonomic testing has shown anxiety; mild postural tachycardia syndrome (POTS), neuropathic form; and small fiber neuropathy, mixed, length-dependent.

Download Full-text

Beyond IgE: Alternative Mast Cell Activation Across Different Disease States

International Journal of Molecular Sciences ◽

10.3390/ijms21041498 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1498 ◽

Cited By ~ 7

Author(s):

David O. Lyons ◽

Nicholas A. Pullen

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Activation ◽

Autoimmune Disorders ◽

Receptor Expression ◽

Mast Cell Activation ◽

Food Allergies ◽

Type I ◽

Disease States ◽

Ige Mediated

Mast cells are often regarded through the lens of IgE-dependent reactions as a cell specialized only for anti-parasitic and type I hypersensitive responses. However, recently many researchers have begun to appreciate the expansive repertoire of stimuli that mast cells can respond to. After the characterization of the interleukin (IL)-33/suppression of tumorigenicity 2 (ST2) axis of mast cell activation—a pathway that is independent of the adaptive immune system—researchers are revisiting other stimuli to induce mast cell activation and/or subsequent degranulation independent of IgE. This discovery also underscores that mast cells act as important mediators in maintaining body wide homeostasis, especially through barrier defense, and can thus be the source of disease as well. Particularly in the gut, inflammatory bowel diseases (Crohn’s disease, ulcerative colitis, etc.) are characterized with enhanced mast cell activity in the context of autoimmune disease. Mast cells show phenotypic differences based on tissue residency, which could manifest as different receptor expression profiles, allowing for unique mast cell responses (both IgE and non-IgE mediated) across varying tissues as well. This variety in receptor expression suggests mast cells respond differently, such as in the gut where immunosuppressive IL-10 stimulates the development of food allergy or in the lungs where transforming growth factor-β1 (TGF-β1) can enhance mast cell IL-6 production. Such differences in receptor expression illustrate the truly diverse effector capabilities of mast cells, and careful consideration must be given toward the phenotype of mast cells observed in vitro. Given mast cells’ ubiquitous tissue presence and their capability to respond to a broad spectrum of non-IgE stimuli, it is expected that mast cells may also contribute to the progression of autoimmune disorders and other disease states such as metastatic cancer through promoting chronic inflammation in the local tissue microenvironment and ultimately polarizing toward a unique Th17 immune response. Furthermore, these interconnected, atypical activation pathways may crosstalk with IgE-mediated signaling differently across disorders such as parasitism, food allergies, and autoimmune disorders of the gut. In this review, we summarize recent research into familiar and novel pathways of mast cells activation and draw connections to clinical human disease.

Download Full-text

Stress-Induced Mast Cell Activation in Glabrous and Hairy Skin

Mediators of Inflammation ◽

10.1155/2014/105950 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 25

Author(s):

Constantin Căruntu ◽

Daniel Boda ◽

Sorin Musat ◽

Ana Căruntu ◽

Eugen Mandache

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Activation ◽

Prolonged Exposure ◽

Mast Cell Degranulation ◽

Mast Cell Activation ◽

Glabrous Skin ◽

Stress Exposure ◽

Hairy Skin ◽

The Impact

Mast cells play a key role in modulation of stress-induced cutaneous inflammation. In this study we investigate the impact of repeated exposure to stress on mast cell degranulation, in both hairy and glabrous skin. Adult male Wistar rats were randomly divided into four groups: Stress 1 day(n=8), Stress 10 days(n=7), Stress 21 days(n=6), and Control(n=8). Rats in the stress groups were subjected to 2 h/day restraint stress. Subsequently, glabrous and hairy skin samples from animals of all groups were collected to assess mast cell degranulation by histochemistry and transmission electron microscopy. The impact of stress on mast cell degranulation was different depending on the type of skin and duration of stress exposure. Short-term stress exposure induced an amplification of mast cell degranulation in hairy skin that was maintained after prolonged exposure to stress. In glabrous skin, even though acute stress exposure had a profound stimulating effect on mast cell degranulation, it diminished progressively with long-term exposure to stress. The results of our study reinforce the view that mast cells are active players in modulating skin responses to stress and contribute to further understanding of pathophysiological mechanisms involved in stress-induced initiation or exacerbation of cutaneous inflammatory processes.

Download Full-text

PD-L1 Blockade During Allergen Sensitization Inhibits the Synthesis of Specific Antibodies and Decreases Mast Cell Activation in a Murine Model of Active Cutaneous Anaphylaxis

Frontiers in Immunology ◽

10.3389/fimmu.2021.655958 ◽

2021 ◽

Vol 12 ◽

Author(s):

Rafael Bonamichi-Santos ◽

Marcelo Vivolo Aun ◽

Jorge Kalil ◽

Mariana Concepcion Castells ◽

Pedro Giavina-Bianchi

Keyword(s):

Mast Cell ◽

Murine Model ◽

Cell Activation ◽

Allergic Diseases ◽

Specific Ige ◽

Inhibitory Effect ◽

Positive Control ◽

Negative Control ◽

Mast Cell Activation ◽

Allergen Sensitization

Programmed cell death ligand 1(PDL-1) is known for its inhibitory effect on the cellular immune response. Even though it is expressed on the surface of mast cells, its role in allergic diseases is unknown. We analyzed the effects of PD-L1 blockade in a murine model of active cutaneous anaphylaxis (ACA). C57BL/6 mice were sensitized and challenged with ovalbumin (OVA). Blood samples were collected to measure specific immunoglobulins. The mice were divided into six groups that underwent the active cutaneous anaphylaxis procedure. Group 1 (negative control) received 50 μl of phosphate-buffered saline (PBS) subcutaneously, and the other five groups were sensitized with 50 μg of OVA subcutaneously. Group 2 was the positive control, and the others received the anti-PD-L1 antibody or its isotype during sensitization (groups 3 and 4) or during the challenge (groups 5 and 6). All animals that underwent ACA on the ears with OVA and PBS were sacrificed, and the reaction was evaluated by extravasation of Evans blue (measured by spectrophotometry) and histological analysis of the collected fragments. Anti-PD-L1 blockade during the sensitization phase led to a reduction in specific IgE and IgG1 levels, allergic reaction intensity at the ACA site, and mast cell degranulation in the tissue. There was no significant biological effect of anti-PD-L1 administration on the challenge phase. PD-L1 blockade during allergen sensitization inhibited the synthesis of specific IgE and IgG1 and decreased mast cell activation in this murine model of anaphylaxis.

Download Full-text

Adjuvant Activity of Poly-ε-caprolactone/Chitosan Nanoparticles Characterized by Mast Cell Activation and IFN-γ and IL-17 Production

Molecular Pharmaceutics ◽

10.1021/acs.molpharmaceut.7b00730 ◽

2017 ◽

Vol 15 (1) ◽

pp. 72-82 ◽

Cited By ~ 17

Author(s):

Sandra Jesus ◽

Edna Soares ◽

Gerrit Borchard ◽

Olga Borges

Keyword(s):

Mast Cell ◽

Cell Activation ◽

Chitosan Nanoparticles ◽

Mast Cell Activation ◽

Adjuvant Activity ◽

Ifn Γ

Download Full-text

Aspergillus oryzae Lectin Induces Anaphylactoid Oedema and Mast Cell Activation Through its Interaction With Fucose of Mast Cell-Bound Non-specific IgE

Scandinavian Journal of Immunology ◽

10.1111/j.1365-3083.2011.02598.x ◽

2011 ◽

Vol 74 (5) ◽

pp. 445-453 ◽

Cited By ~ 5

Author(s):

K. Yamaki ◽

S. Yoshino

Keyword(s):

Mast Cell ◽

Aspergillus Oryzae ◽

Cell Activation ◽

Specific Ige ◽

Mast Cell Activation

Download Full-text

Novel Approaches in the Inhibition of IgE-Induced Mast Cell Reactivity in Food Allergy

Frontiers in Immunology ◽

10.3389/fimmu.2021.613461 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chiara Tontini ◽

Silvia Bulfone-Paus

Keyword(s):

Mast Cell ◽

Monoclonal Antibodies ◽

Food Allergy ◽

Mast Cells ◽

Specific Ige ◽

Mast Cell Activation ◽

Type I ◽

Allergen Specific Immunotherapy ◽

Immunological Mechanisms ◽

Novel Approaches

Allergy is an IgE-dependent type-I hypersensitivity reaction that can lead to life-threatening systemic symptoms such as anaphylaxis. In the pathogenesis of the allergic response, the common upstream event is the binding of allergens to specific IgE, inducing cross-linking of the high-affinity FcεRI on mast cells, triggering cellular degranulation and the release of histamine, proteases, lipids mediators, cytokines and chemokines with inflammatory activity. A number of novel therapeutic options to curb mast cell activation are in the pipeline for the treatment of severe allergies. In addition to anti-IgE therapy and allergen-specific immunotherapy, monoclonal antibodies targeted against several key Th2/alarmin cytokines (i.e. IL-4Rα, IL-33, TSLP), active modification of allergen-specific IgE (i.e. inhibitory compounds, monoclonal antibodies, de-sialylation), engagement of inhibitory receptors on mast cells and allergen-specific adjuvant vaccines, are new promising options to inhibit the uncontrolled release of mast cell mediators upon allergen exposure. In this review, we critically discuss the novel approaches targeting mast cells limiting allergic responses and the immunological mechanisms involved, with special interest on food allergy treatment.

Download Full-text