Mast Cell Stabilizer Research Articles

KOUNIS SYNDROME, THE ALLERGIC HEART ATTACK

<h3>Introduction</h3> Seldom do allergic reactions progress to involve the heart. Kounis Syndrome is the occurrence of acute coronary syndrome associated with conditions of mast cell activation such as allergy hypersensitivities (1). Here, we describe a case in which an allergic reaction to injected Lidocaine and Kenalog leads to myocardial infarction. <h3>Case Description</h3> A 67-year-old female with cardiac risk factors and osteoarthritis underwent injection of her right ankle with Lidocaine and Kenalog. She developed diffuse erythematous rash with symptoms of lightheadedness, altered mentation, and chest discomfort. Upon admission, she received epinephrine. Electrocardiogram (EKG) demonstrated ST-segment elevation in inferior leads II, III, and aVF. Labs revealed serum tryptase level of 74.8 ug/L. The patient received intravenous (IV) Norepinephrine, IV diphenhydramine, IV Famotidine, IV methylprednisolone, Aspirin, and continuous IV heparin for emergent coronary angiography. The distal right coronary artery revealed occlusive thrombus burden, causing 95% stenosis. Percutaneous coronary intervention was performed with drug-eluting stent placement. Her symptoms resolved, and she was referred to an outpatient allergist. <h3>Discussion</h3> This case illustrates the type II variant of Kounis Syndrome in which inflammatory mediators from an allergic reaction induce atherosclerotic plaque destabilization and rupture in underlying coronary artery disease (CAD). Cardiovascular manifestations associated with allergic conditions are more common than initially perceived, suggesting a causal relationship between allergies and heart disease. This remains underdiagnosed by clinicians in practice (1,2). Biomarkers in allergies, such as serum tryptase, may provide a potential marker of CAD. Novel medications that stabilize mast cells and reduce inflammation known to control allergies may ultimately reduce cardiovascular events (4).

OMALIZUMAB: A POTENTIAL LONG-TERM THERAPEUTIC ALTERNATIVE FOR REFRACTORY DELAYED PRESSURE URTICARIA?

<h3>Introduction</h3> Delayed pressure urticaria (DPU) can go unrecognized due to its delayed onset. While most are antihistamine resistant, this case illustrates a complete response to omalizumab as a potential long-term therapeutic alternative. <h3>Case Description</h3> A 44 year-old man who works at a weapons disposal arsenal presents for chronic spontaneous delayed pressure urticaria. Exam reveals lesions on his trunk and extremities with redness and oozing blisters. Triggers include using his hands, wearing a respirator backpack, or leaning against an object for longer than 5 minutes. Skin biopsy reveals nonspecific eosinophilic infiltrate and labs showed mildly elevated CRP. He is treated with cephalexin for presumed cellulitis and high dose antihistamines, famotidine, and montelukast without relief. Given recurrent episodes, the patient is started on monthly omalizumab with complete resolution after the first injection. <h3>Discussion</h3> DPU is a physical urticaria that presents with erythematous, pruritic painful swellings, occasionally with blisters, after prolonged pressure on the skin. The incidence is 2% and occurs in up to 37% of patients with chronic spontaneous urticaria (CSU). Pathophysiology is due to late phase reaction from mast cell activation and upregulation of E selectin leading to an inflammatory response with cytokines and cellular infiltrates. Management is generally unsatisfactory and consists mainly of antihistamine, NSAIDs, colchicine, TNF-a blocker, IVIG, and montelukast. Oral steroids are the most effective treatment, but should not be used long-term. This case illustrates a favorable response to omalizumab, normally used in CSU. Proposed mechanism in a bullous DPU case involves inhibition of cutaneous mast cells, resulting in decreased eosinophil degranulation.

A CASE OF DIFFICULT TO DIAGNOSE C1INH NORMAL HAE

<h3>Introduction</h3> Hereditary Angioedema (HAE) is characterized by recurrent swellings of the face, tongue, oropharynx, extremities, and abdomen. Typically beginning in the second decade of life, these swells often require emergent treatment and may result in intubation. Unchecked production of bradykinin, typically due to low levels of C1 esterase inhibitor (C1INH), results in bradykinin mediated vascular leakage and swelling. Type I and II can be diagnosed by checking C1INH levels and function but C1INH Normal continues to be difficult to diagnose. We present a challenging case detailing the diagnosis and management of probable C1INH normal HAE in a 42-year-old female. <h3>Case Description</h3> A 42-year-old woman with a history of hypothyroidism, GERD, migraine, obesity, and borderline personality disorder, presented to our clinic with a 10-year history of three or more weekly episodes of throat and eyelid angioedema, accompanied by intermittent urticaria. Her controller therapy included montelukast, fexofenadine, cetirizine, zyflo, famotidine, and cromolyn. Despite this regimen, she continued her thrice weekly episodes, so cyclosporine was added without improvement in flare frequency or severity. C1INH level and function, along with her physical exam, were unremarkable. A trial of recombinant C1INH resolved an acute swell, so she was started on C1INH replacement, with significant reduction in her swell frequency. <h3>Discussion</h3> C1INH normal HAE continues to be difficult to diagnose with currently available assays. For patients with recurrent swells, not responding to mast cell stabilizers or antihistamines, a trial of recombinant C1INH or a bradykinin receptor antagonist, may aid in the diagnosis of C1INH Normal HAE.

Blockade of the BLT1-LTB4 axis does not affect mast cell migration towards advanced atherosclerotic lesions in LDLr−/− mice

Mast cells have been associated with the progression and destabilization of advanced atherosclerotic plaques. Reducing intraplaque mast cell accumulation upon atherosclerosis progression could be a potent therapeutic strategy to limit plaque destabilization. Leukotriene B4 (LTB4) has been reported to induce mast cell chemotaxis in vitro. Here, we examined whether antagonism of the LTB4-receptor BLT1 could inhibit mast cell accumulation in advanced atherosclerosis. Expression of genes involved in LTB4 biosynthesis was determined by single-cell RNA sequencing of human atherosclerotic plaques. Subsequently, Western-type diet fed LDLr−/− mice with pre-existing atherosclerosis were treated with the BLT1-antagonist CP105,696 or vehicle control three times per week by oral gavage. In the spleen, a significant reduction in CD11b+ myeloid cells was observed, including Ly6Clo and Ly6Chi monocytes as well as dendritic cells. However, atherosclerotic plaque size, collagen and macrophage content in the aortic root remained unaltered upon treatment. Finally, BLT1 antagonism did not affect mast cell numbers in the aortic root. Here, we show that human intraplaque leukocytes may be a source of locally produced LTB4. However, BLT1-antagonism during atherosclerosis progression does not affect either local mast cell accumulation or plaque size, suggesting that other mechanisms participate in mast cell accumulation during atherosclerosis progression.

AT9283, 1-Cyclopropyl-3-(3-(5-(Morpholinomethyl)-1H-Benzo[d]Imidazole-2-yl)-1H-Pyrazol-4-yl) Urea, Inhibits Syk to Suppress Mast Cell-Mediated Allergic Response.

Mast cells are an effector cell that plays a pivotal role in type I hypersensitive immune responses. Mast cells exist in connective tissues, such as skin and mucosal tissue, and contain granules which contain bioactive substances such as histamine and heparin in cells. The granules of mast cells are secreted by antigen stimulation to cause the type I allergic hypersensitivity. In addition, stimulated by antigen, mast cells synthesize and secrete various eicosanoids and cytokines. While AT9283 is known to have anticancer effects, the therapeutic effect of AT9283 on allergic disorders is completely unknown. In this study, it was found that AT9283 reversibly inhibited antigen-IgE binding-induced degranulation in mast cells (IC50, approx. 0.58 μM) and suppressed the secretion of the inflammatory cytokines IL-4 (IC50, approx. 0.09 μM) and TNF-α (IC50, approx. 0.19 μM). For a mechanism of mast cell inhibition, while not inhibiting Syk phosphorylation, AT9283 suppressed the activation of LAT, a downstream substrate protein of Syk, in a dose-dependent manner. As expected, AT9283 also inhibited the activation of PLCγ1 and Akt, downstream signaling molecules of Syk/LAT, and MAP kinases such as JNK, Erk1/2, and P38. In an in vitro protein tyrosine kinase assay, AT9283 directly inhibited Syk activity. Next, AT9283 dose-dependently inhibited passive cutaneous anaphylaxis (PCA), an IgE-mediated allergic acute response, in mice (ED50, approx. 34 mg/kg, p.o.). These findings suggest that AT9283 has potential to use as a new drug for alleviating the symptoms of IgE-mediated allergic disorders.

Cetirizine more potently exerts mast cell-stabilizing property than diphenhydramine.

Cetirizine, a second-generation antihistamine, and diphenhydramine, a first-generation antihistamine, are among the most widely used anti-allergic drugs. In addition to longer duration of action and less incidence of sedative side effects, recent clinical studies also indicate a higher potency of cetirizine than diphenhydramine in the treatment or prevention of allergic disorders. In the present study, using the differential-interference contrast (DIC) microscopy, we examined the effects of cetirizine and diphenhydramine (1 μM to 1 mM) on the degranulation from rat peritoneal mast cells. Using fluorescence imaging of a water-soluble dye, lucifer yellow, we also examined their effects on the deformation of the plasma membrane. At relatively higher concentrations (100 μM, 1 mM), both cetirizine and diphenhydramine significantly reduced the numbers of degranulating mast cells. Of note, at 1 mM, cetirizine more markedly reduced the number than diphenhydramine, almost entirely suppressing the degranulation of mast cells. Additionally, 1 mM cetirizine and levocetirizine, another second-generation antihistamine, almost totally inhibited the process of exocytosis in mast cells and washed out the trapping of the lucifer yellow on the cell surface, while diphenhydramine and chlorpheniramine, another first-generation antihistamine, did not. This study provided in vitro evidence for the first time that cetirizine more potently inhibited the process of exocytosis in mast cells than diphenhydramine, indicating its higher potency as a mast cell-stabilizer. Such mast cell-stabilizing property of cetirizine could be ascribed to its counteracting effect on the plasma membrane deformation in degranulating mast cells.

A Mysterious Case of Abdominal Pain

A Mysterious Case of Abdominal Pain

Pretreatment with propofol restores intestinal epithelial cells integrity disrupted by mast cell degranulation in vitro

Propofol has been shown to against intestinal reperfusion injury when treated either before or after ischemia, during which mast cell could be activated. The aim of this study was to evaluate the role of propofol in restoring the intestinal epithelial cells integrity disrupted by mast cell activation or the released tryptase after activation in vitro. We investigated the effect of: (1) tryptase on Caco-2 monolayers in the presence of PAR-2 inhibitor or propofol, (2) mast cell degranulation in a Caco-2/LAD-2 co-culture model in the presence of propofol, and (3) propofol on mast cell degranulation. Epithelial integrity was detected using transepithelial resistance (TER) and permeability to fluorescein isothiocyanate (FITC)-dextran (the apparent permeability coefficient, Papp). The expression of junctional proteins zonula occludens-1 (ZO-1/TJP1) and occludin were determined using western blot analysis and immunofluorescence microscopy. The intracellular levels of reactive oxidative species (ROS) and Ca2+ were measured using flow cytometry. Tryptase directly enhanced intestinal barrier permeability as demonstrated by significant reductions in TER, ZO-1, and occludin protein expression and concomitant increases in Papp. The intestinal barrier integrity was restored by PAR-2 inhibitor but not by propofol. Meanwhile, mast cell degranulation resulted in epithelial integrity disruption in the Caco-2/LAD-2 co-culture model, which was dramatically attenuated by propofol. Mast cell degranulation caused significant increases in intracellular ROS and Ca(2+) levels, which were blocked by propofol and NAC. Propofol pretreatment can inhibit mast cell activation via ROS/Ca(2+) and restore the intestinal barrier integrity induced by mast cell activation, instead of by tryptase.

Oral Intervention of Narirutin Ameliorates the Allergic Response of Ovalbumin Allergy.

A new intervention was investigated for the induction of oral tolerance (OT) of OVA using narirutin by in vivo and in vitro experiments combined with network pharmacology and structural analysis of molecular docking. Narirutin (and its metabolism naringenin) has effects on OT by affecting B cell function, DCs, and T cell response by prediction. It was verified that narirutin could affect B cell function of secreting antibodies, thereby reducing the ability of DCs to absorb antigens by affecting GATA3, CCR7, STAT5, and MHCII expression and regulating T cell response by suppressing Th2 and improving Treg cells in vivo. Molecular docking showed that steric hindrance effects may be the reason for weaker binding energy with targets of narirutin. However, this does not mean that it has no bioactivity, for it can inhibit mast cell degranulation. This finding is interesting because it offers the possibility of using natural compounds to promote oral tolerance.

Oral administration of Forsythiasides-rich extract from Forsythiae fructus decreases the IgE production through suppressing Th2 response in shrimp protein-sensitized BALB/c mice

BackgroundIgE-mediated allergic diseases are characterized by an overreaction of type 2 response which promotes B cell differentiation and IgE production via Th2 cytokines. Forsythiae Fructus, a well-known traditional Chinese medicine, has been clinically used for relieving IgE-mediated type I allergy by continuous treatment for several days. PurposeWe aimed to investigate the effect of continuous oral administration with Forsythiasides-rich extract (FRE) from Forsythiae Fructus on type 2 response and the underlying mechanism in shrimp protein (SP)-sensitized mice. Study design and methodsWe established a SP-sensitized mice model and investigated effect of FRE both in vivo and ex vivo. Serum total IgE (tIgE), specific IgE (sIgE), mouse mast cell protease 1 (mMCP-1) and supernatant Th2 cytokines (IL-4, IL-5 and IL-13) were determined by ELISA. The cell viability was examined by MTS assay. ResultsContinuous oral administration of FRE could significantly lower the levels of serum tIgE, sIgE and mMCP-1 in SP-sensitized mice. Ex vivo study indicated that a single treatment of FRE could potently suppress the release of Th2 cytokines (IL-4, IL-5 and IL-13) in isolated mesenteric lymph nodes cells and splenocytes of SP-sensitized mice in a concentration-dependent manner. ConclusionFRE can suppress Th2 cytokines (IL-4, IL-5 and IL-13) to decrease the production of IgE in SP-sensitized mice. In view of its another ability to stabilize mast cells, Forsythiae Fructus is reasonably suitable for treating IgE-mediated allergic diseases.

Mast cell-T cell axis alters development of colitis-dependent and colitis-independent colorectal tumours: potential for therapeutically targeting via mast cell inhibition

BackgroundColorectal cancer (CRC) has a high mortality rate and can develop in either colitis-dependent (colitis-associated (CA)-CRC) or colitis-independent (sporadic (s)CRC) manner. There has been a significant debate about whether mast...

S3495 What Do These Eosinophils Mean? Treatment Naive Systemic Lupus Erythematosus Presenting With Eosinophilic Ascites, Eosinophilic Pleural Fluid, and Enteritis of Unclear Etiology

Introduction: Eosinophilic ascites (EA), lupus enteritis (LE), and eosinophilic enteritis (EE) are rare systemic lupus erythematosus (SLE) complications. When they do occur, overlapping diagnostic criteria causes problems in distinguishing between a SLE-related etiology or EE. For example, intestinal eosinophil infiltration associated with EE is also consistently found in disseminated SLE autopsy case reports. Although both conditions are treated with steroids, therapies after treatment failure are different. We present a rare case of a SLE patient with this diagnostic dilemma with suboptimal response to SLE therapies, questioning whether an EE treatment algorithm may be more appropriate. Case Description/Methods: An afebrile 55 year old female with untreated SLE presented with constipation and a mildly tender distended abdomen. Imaging described moderate ascites, continuous small bowel thickening, ileus, and bilateral pulmonary infiltrates with pleural effusions. Significant results included a white blood cell count of 3.8 without eosinophils, erythrocyte sedimentation rate 5, C-reactive protein < 1, positive ANA (1:160), positive double stranded DNA, and low C3/C4 complement. Paracentesis yielded an exudative eosinophilic (71%) ascitic fluid with a low serum-ascites albumin gradient of 0.9 g/dL, high protein of 3.9 g/dL, and no evidence of malignancy or infection. She also had exudative eosinophilic pleural fluid. Endoscopy revealed mild cecal ischemia, mild gastritis, and a normal terminal ileum without eosinophils. Rheumatology diagnosed her with SLE serositis with peritoneal and pleural involvement complicated by LE, but they were unable to rule out EE. She responded to intravenous steroids but deteriorated when she was switched to oral prednisone. She then failed a regimen of hydroxychloroquine and oral prednisone. During her most recent hospitalization, the patient was transitioned to a regimen of hydroxychloroquine, mycophenolate mofetil, and oral prednisone. Discussion: It is unclear whether our patient’s sub-optimal therapy response is due to SLE or EE, with our case illustrating the difficulties in determining a diagnosis. Determining a diagnosis influences treatment and the patient's clinical course. In EE, treatment includes dietary therapy, antihistamines, leukotriene antagonists, and mast-cell stabilizers. However, our patient’s symptoms are attributed to serositis, leading to a focus on escalating her SLE immunosuppressive therapy rather than re-examine the diagnosis.

Mast cell stabilizer disodium cromoglycate improves long-term cognitive impairment after general anesthesia exposure in neonatal mice.

BackgroundProlonged exposure to general anesthesia (GA) results in long-lasting cognitive impairment, especially during critical stages of brain development. An exaggerated neuroinflammation induced by anesthesia is generally considered to be a key cause of cognitive impairment.Materials and methodsPostnatal day 7 (PND 7) mice were exposed to GA by isoflurane inhalation for 6 h or mock anesthesia. Disodium cromoglycate (DSCG) was intraperitoneally injected daily for 2 weeks, beginning from 30 min before anesthesia. The post-anesthesia evaluation included behavioral tests, toluidine blue staining, immunofluorescence and western blot.ResultsOur results demonstrated the long-term cognition were impaired after 6 h GA exposure in neonatal mice. DSCG treatment ameliorated early mast cells (MCs) degranulation and mast cell tryptase (MCT) expression, which helps to attenuate subsequent neuroinflammation, activation of microglia and astrocytes, and damage to oligodendrocytes and synapses to improve cognitive impairment.ConclusionDisodium cromoglycate could effectively improve long-term cognitive impairment after GA exposure in neonatal mice.

A fully human anti-c-Kit monoclonal antibody 2G4 inhibits proliferation and degranulation of human mast cells

Given that mast cells are pivotal contributors to allergic diseases, various allergy treatments have been developed to inhibit them. Omalizumab, an anti-immunoglobulin E antibody, is a representative therapy that can alleviate allergy symptoms by inhibiting mast cell degranulation. However, omalizumab cannot reduce the proliferation and accumulation of mast cells, which is a fundamental cause of allergic diseases. c-Kit is essential for the proliferation, survival, and differentiation of mast cells. Excessive c-Kit activation triggers various mast cell diseases, such as asthma, chronic spontaneous urticaria, and mastocytosis. Herein, we generated 2G4, an anti-c-Kit antibody, to develop a therapeutic agent for mast cell diseases. The therapeutic efficacy of 2G4 antibody was evaluated in LAD2, a human mast cell line. 2G4 antibody completely inhibited c-Kit signaling by blocking the binding of stem cell factor, known as the c-Kit ligand. Inhibition of c-Kit signaling led to the suppression of proliferation, migration, and degranulation in LAD2 cells. Moreover, 2G4 antibody suppressed the secretion of pro-inflammatory cytokines, including granulocyte–macrophage colony-stimulating factor, vascular endothelial growth factor, C–C motif chemokine ligand 2, brain-derived neurotrophic factor, and complement component C5/C5a, which can exacerbate allergy symptoms. Taken together, these results suggest that 2G4 antibody has potential as a novel therapeutic agent for mast cell diseases.

Nematode galectin binds IgE and modulates mast cell activity

Mast cell degranulation is the major mechanism influencing establishment and survival of the abomasal nematode Teladorsagia circumcincta and probably many other gastrointestinal nematodes. Host galectins-3 and -9 have been shown to bind IgE and positively and negatively influence mast cell degranulation. As incoming nematodes produce large amounts of galectin, we hypothesised that nematode galectin competes with host galectin and inhibits mast cell degranulation. ELISA was used to show that nematode galectin reduced total IgE activity. Galectin also reduced the binding of sheep IgE to the surface of a mast cell line and decreased the release of LCT-4 and Beta hexosaminidase but not MMP-9. These results indicate that nematode galectin influences mast cell degranulation and identify a potential immunomodulatory mechanism used by nematodes to enhance their establishment and survival.

Protease inhibitor from Libidibia ferrea seeds attenuates inflammatory and nociceptive responses in mice

Ethnopharmacological relevanceLibidibia ferrea (Mart. ex. Tul.) L.P. Queiroz is a Brazilian native tree locally known as jucá and pau-ferro, and it has been used in folk medicine for relieving, asthma, bronchitis, sore throat, rheumatism, enterocolitis and fever. The anti-inflammatory properties of L. ferrea were confirmed for its stem, fruit, leaves, bark and seeds extracts, however little is known about the natural compounds that may be associated with that response. Aim of this studyIn a normal physiological condition, many enzymes play an important role in catalyzing biological functions. Among them, proteases are of great interest. Although they take part of many biological systems, as the inflammatory process, when deregulated, proteases may cause system malfunctions, such as under- or overproduction of cytokines, or immune cells activation. Thus, protease inhibitors prevent these immune responses by regulating proteases. The objective of this study was to evaluate the anti-inflammatory and anti-nociceptive response of a protease inhibitor purified from L. ferrea seeds (LfTI). Materials and methodsIn vitro (5, 50 and 250 μg/mL of LfTI) and in vivo (0.6, 3 e 15 mg/kg of LfTI) assays were performed. Male Swiss mice weighing 18–25 g were used for cell harvesting and for the in vivo assays. The anti-inflammatory activity was analyzed in vitro by macrophage cytotoxicity, hydrogen peroxide (H2O2) production, and cell adhesion assays; and in vivo by leukocyte recruitment, nitric oxide (NO) production, vascular permeability, paw edema and mast cell degranulation assays. The anti-nociceptive activity was evaluated through abdominal writhing test induced by acetic acid and formalin sensitization. ResultsOur results showed that, in vitro, LfTI is not cytotoxic. Also, LfTI (50 μg/mL) inhibited macrophage H2O2 production (48.2%), and adhesion (48.4%). LfTI (0.6, 3 e 15 mg/kg) decreased polymorphonuclear cell recruitment dose-dependently, and it inhibited NO production (53%), vascular permeability (40.7%) and paw edema at 3 mg/kg at different time, but it did not inhibit mast cell degranulation. Besides, LfTI did not inhibit either the number of writhing or the licking time in the formalin test in the second phase (inflammatory). However, LfTI (3 mg/kg) inhibited licking time at the first phase (neurogenic) in the formalin sensitization (46.1%). ConclusionsOur results show that LfTI has anti-inflammatory and antinociceptive (neurogenic pain) effects, and these effects might be associated with the inhibition of inflammatory proteases and/or protease-activated receptors activation hindering.

The combined use of photobiomodulation and curcumin-loaded iron oxide nanoparticles significantly improved wound healing in diabetic rats compared to either treatment alone

This experimental study examined the effects of curcumin-loaded iron oxide nanoparticles (CUR), photobiomodulation (PBM), and CUR + PBM treatments on mast cells (MC)s numbers and degranulation, inflammatory cells (macrophages, neutrophils), and wound strength in the last step of the diabetic wound repair process (maturation phase) in a rat model of type one diabetes mellitus (T1DM). T1DM was induced in 24 rats, and 1month later, an excisional wound was created on each rat's back skin. The rats were then distributed into four groups: (1) untreated diabetic control group (UDCG); (2) rats treated with CUR (CUR); (3) rats exposed to PBM (890nm, 80Hz, 0.2J/cm2) (PBM); (4) rats treated with CUR plus PBM (CUR + PBM). Fifteen days after surgery, skin tissue samples were taken for biomechanical and stereological evaluations. The biomechanical factor of maximum force was observed to be considerably improved in the CUR + PBM (p = 0.000), PBM (p = 0.014), and CUR (p = 0.003) groups compared to the UDCG. CUR + PBM, PBM, and CUR groups had significantly decreased total numbers of MC compared with the UDCG (all, p = 0.001). The results were significantly better in the CUR + PBM (p = 0.000) and PBM (p = 0.003) groups than in the CUR group. Inflammatory cell counts were significantly lower in the CUR + PBM, PBM, and CUR groups than in the UDCG (all, p = 0.0001). In all evaluating methods, the usage of CUR + PBM produced better results than the use of CUR or PBM alone (almost all tests, p = 0.0001). CUR + PBM, PBM, and CUR significantly improved the repair of diabetic skin wounds in type 1 DM rats through significant decreases of MC number, degranulation, and inflammatory cells as well as a noteworthy improvement in wound strength. The impact of CUR + PBM was superior to that of either PBM or CUR alone. It is suggested that CUR + PBM could be used as a MC stabilizer for the effective treatment of some related human diseases.

The Meat of the Matter: Understanding and Managing Alpha-Gal Syndrome.

Alpha-gal syndrome is an unconventional food allergy, characterized by IgE-mediated hypersensitivity responses to the glycan galactose-alpha-1,3-galactose (alpha-gal) and not to a food-protein. In this review, we discuss how alpha-gal syndrome reframes our current conception of the mechanisms of pathogenesis of food allergy. The development of alpha-gal IgE is associated with tick bites though the possibility of other parasites promoting sensitization to alpha-gal remains. We review the immune cell populations involved in the sensitization and effector phases of alpha-gal syndrome and describe the current understanding of why allergic responses to ingested alpha-gal can be delayed by several hours. We review the foundation of management in alpha-gal syndrome, namely avoidance, but also discuss the use of antihistamines, mast cell stabilizers, and the emerging role of complementary and alternative therapies, biological products, and oral immunotherapy in the management of this condition. Alpha-gal syndrome influences the safety and tolerability of medications and medical devices containing or derived from mammalian products and impacts quality of life well beyond food choices.

The ketone body β-hydroxybutyrate mitigates ILC2-driven airway inflammation by regulating mast cell function.

Ketone bodies are increasingly understood to have regulatory effects on immune cell function, with β-hydroxybutyrate (BHB) exerting a predominantly anti-inflammatory response. Dietary strategies to increase endogenous ketone body availability such as the ketogenic diet (KD) have recently been shown to alleviate inflammation of the respiratory tract. However, the role of BHB has not been addressed. Here, we observe that BHB suppresses group 2 innate lymphoid cell (ILC2)-mediated airway inflammation. Central to this are mast cells, which support ILC2 proliferation through interleukin-2 (IL-2). Suppression of the mast cell/IL-2 axis by BHB attenuates ILC2 proliferation and the ensuing type 2 cytokine response and immunopathology. Mechanistically, BHB directly inhibits mast cell function in part through GPR109A activation. Similar effects are achieved with either the KD or 1,3-butanediol. Our data reveal the protective role of BHB in ILC2-driven airway inflammation, which underscores the potential therapeutic value of ketone body supplementation for the management of asthma.

PD-1+ mast cell enhanced by PD-1 blocking therapy associated with resistance to immunotherapy

BackgroundProgrammed cell death protein 1 (PD-1) antibody has been approved for a variety of tumors, but its effective rate is unsatisfactory. New evidence suggests that mast cells are an important component of the tumor microenvironment and are associated with resistance to immunotherapy, but the underlying mechanism is not clear.MethodsBioinformatics analysis of patients with melanoma in TCGA-SKCM and GSE91061 was used to determine the prognostic value of mast cells and their association with anti-PD-1 immunotherapy. HMC-1 cells (mast cell line) and bone marrow-derived mast cells (BMMCs) were used to verify the effect of PD-1 antibody and cromolyn sodium in vitro. The mouse subcutaneous melanoma model was used to verify the effect of the PD-1 antibody on mast cells in vivo.ResultsBioinformatics analysis showed that mast cells were a poor prognostic factor associated with resistance to anti-PD-1 immunotherapy. PD-1 was expressed on the mast cell membrane. The PD-1 antibody promoted the release of histamine and cytokines from mast cells via the PI3K/AKT pathway and calcium signaling pathway. The activation of mast cells induced by PD-1 antibody could be partially inhibited by cromolyn sodium. In vivo, cromolyn sodium increased the efficacy of PD-1 antibody and decreased the infiltration of mast cells and the density of microvessels.ConclusionPD-1+ mast cell activated by PD-1 antibody plays a negative role in the tumor microenvironment via the enhanced function of releasing histamine and cytokines. Inhibition of mast cell may provide a new solution to solve the low response rate of anti-PD-1 immunotherapy.