Fine particulate matter (PM2.5) promotes IgE-mediated mast cell activation through ROS/Gadd45b/JNK axis.

BACKGROUND: Mast cells play an important role in allergic responses and persistently exposure to environmental fine particulate matter (PM2.5) exacerbates allergic diseases,but the details remained elucidative. OBJECTIVES: To investigate the effect of PM2.5 on IgE-mediated mast cell responses through an IgE-mediated mouse model and mast cell activation. METHODS: The ß-hexosaminidase release and a BALB/c model of passive cutaneous anaphylaxis (PCA) was used to test IgE-mediated mast cells activation in vitro and in vivo. RNA-Seq technique was conducted to study the gene expression profile. Reactive oxygen species (ROS) production was measured by flow-cytometry. RT-PCR,WB and ELISA were performed to examine targeting molecules expression. RESULTS: PM2.5 facilitated IgE-mediated degranulation and increased cytokines expression in mast cells. Meanwhile, the Evan's blue extravasation as well as serum cytokines in mice was increased after treatment with PM2.5. Furthermore, PM2.5 treatment dramatically increased the expression of Gadd45b which is an oxidative stress molecule that directly activates down-stream pathway, such as MEKK4/JNK. PM2.5 treatment activated MEKK4, JNK1/2 but not ERK1/2 and p38. Meanwhile, Knockdown of Gadd45b significantly attenuated PM2.5-mediated JNK1/2 activation and expression of cytokines. In addition, a JNK1/2-specific inhibitor SP600125 blocked IgE-mediated mast cell activation and cytokine release in PCA model mice. Moreover, PM2.5 treatment increased the ROS level and ROS inhibitor dramatically blocked the PM2.5-induced ROS production and reversed the PM2.5-mediated gene expression in the mitochondrial respiratory chain. CONCLUSIONS: PM2.5 regulates ROS production through Gadd45b/MEKK4/JNK pathway, facilitating IgE-mediated mast cell activation.

Glycan-specific IgG anti-IgE autoantibodies are protective against allergic anaphylaxis in a murine model.

BACKGROUND: IgE causes anaphylaxis in type I hypersensitivity diseases by activating degranulation of effector cells such as mast cells and basophils. The mechanisms that control IgE activity and prevent anaphylaxis under normal conditions are still enigmatic. OBJECTIVE: We aimed to unravel how anti-IgE autoantibodies are induced and we aimed to understand their role in regulating serum IgE level and allergic anaphylaxis. METHODS: We immunized mice with different forms of IgE and tested anti-IgE autoantibody responses and their specificities. We then analyzed the effect of those antibodies on serum kinetics and their in vitro and in vivo impact on anaphylaxis. Finally, we investigated anti-IgE autoantibodies in human sera. RESULTS: Immunization of mice with IgE-immune complexes induced glycan-specific anti-IgE autoantibodies. The anti-IgE autoantibodies prevented effector cell sensitization, reduced total IgE serum levels, protected mice from passive and active IgE sensitization, and resulted in cross-protection against different allergens. Furthermore, glycan-specific anti-IgE autoantibodies were present in sera from subjects with allergy and subjects without allergy. CONCLUSION: In conclusion, this study provided the first evidence that in the murine model, the serum level and anaphylactic activity of IgE may be downregulated by glycan-specific IgG anti-IgE autoantibodies.

In vivo safety profile of a CSPG4-directed IgE antibody in an immunocompetent rat model.

IgE monoclonal antibodies hold great potential for cancer therapy. Preclinical in vivo systems, particularly those in which the antibody recognizes the host species target antigen and binds to cognate Fc receptors, are often the closest approximation to human exposure and represent a key challenge for evaluating the safety of antibody-based therapies. We sought to develop an immunocompetent rat system to assess the safety of a rodent anti-tumor IgE, as a surrogate for the human therapeutic candidate. We generated a rat IgE against the human tumor-associated antigen chondroitin sulfate proteoglycan 4 (CSPG4) and cross-reactive for the rat antigen. We analyzed CSPG4 distribution in normal rat and human tissues and investigated the in vivo safety of the antibody by monitoring clinical signs and molecular biomarkers after systemic administration to immunocompetent rats. Human and rat CSPG4 expression in normal tissues were comparable. Animals receiving antibody exhibited transient mild to moderate adverse events accompanied by mild elevation of serum tryptase, but not of angiotensin II or cytokines implicated in allergic reactions or cytokine storm. In the long term, repeated antibody administration was well tolerated, with no changes in animal body weight, liver and kidney functions or blood cell counts. This model provides preclinical support for the safety profiling of IgE therapeutic antibodies. Due to the comparable antigen tissue distribution in human and rat, this model may also comprise an appropriate tool for proof-of-concept safety evaluations of different treatment approaches targeting CSPG4.

Biological and epidemiological evidence of anti-allergic effects of traditional Japanese food ume (Prunus mume).

Japanese apricot (Prunus mume; ume) is a traditional food in Japan that has been shown to have various beneficial health effects. There is some evidence to suggest that ume is also effective against allergic disease. Here, we conducted a cross-sectional epidemiological pilot study to examine the association between ume intake frequency and allergic symptoms including rhinitis in 563 adults (288 men and 275 women) who resided in Wakayama, Japan. After adjusting for age, present illness and medication, women with high ume intake had significantly lower odds ratio (OR) for the presence of symptoms of allergy [OR: 0.49 with 95% confidence interval (CI): 0.25-0.97]. Therefore, we investigated the anti-allergic effect of ume on passive cutaneous anaphylaxis (PCA) reaction in immunoglobulin E (IgE)-sensitized mice. The animal study demonstrated that oral administration of ume extract attenuated the PCA reaction and mast cell degranulation. Furthermore, RBL-2H3 mast cells were used to identify anti-allergic ume compounds. The following ume compounds inhibited IgE-mediated mast cell degranulation: vanillin, syringic acid, protocatechuic aldehyde, lyoniresinol and p-coumaric acid. These results suggested that ume has the potential to inhibit mast cell degranulation and may be associated with reduced risk of allergic symptoms in women.

The effects of imidacloprid combined with endosulfan on IgE-mediated mouse bone marrow-derived mast cell degranulation and anaphylaxis.

Low levels of endosulfan are known to stimulate mast cells to release allergic mediators, while imidacloprid can inhibit IgE-mediated mast cell degranulation. However, little information about the effects of both pesticides together on mast cell degranulation is available. To measure the effects, IgE-activated mouse bone marrow-derived mast cells (BMMCs) were treated with imidacloprid and endosulfan, individually, and simultaneously at equi-molar concentrations in tenfold steps ranging from 10-4 to 10-11 M, followed by measuring several allergy-related parameters expressed in BMMCs: the mediator production and influx of Ca2+, the phosphorylation content of NF-κB in the FcεRI signaling pathway. Then, the effects of the mixtures on IgE-induced passive systemic anaphylaxis (PSA) of BALB/c was detectded. This study clearly showed that the application of equi-molar mixtures of both pesticides with 10-4-10-5 M significantly inhibited the IgE-mediated mouse bone marrow-derived mast cells degranulation in vitro and 10-4 M of them decreased IgE-mediated PSA in vivo, as the application of imidacloprid at the same concentration alone did. Morever endosulfan alone had no remarkable stimulatory effects on any of the factors measured. In conclusion, simultaneous application of equi-molar concentrations of both pesticides generally showed highly similar responses compared to the responses to imidacloprid alone, suggesting that the effects of the mixture could be solely attributed to the effects of imidacloprid.

An immunologically relevant rodent model demonstrates safety of therapy using a tumour-specific IgE.

BACKGROUND: Designing biologically informative models for assessing the safety of novel agents, especially for cancer immunotherapy, carries substantial challenges. The choice of an in vivo system for studies on IgE antibodies represents a major impediment to their clinical translation, especially with respect to class-specific immunological functions and safety. Fcε receptor expression and structure are different in humans and mice, so that the murine system is not informative when studying human IgE biology. By contrast, FcεRI expression and cellular distribution in rats mirror that of humans. METHODS: We are developing MOv18 IgE, a human chimeric antibody recognizing the tumour-associated antigen folate receptor alpha. We created an immunologically congruent surrogate rat model likely to recapitulate human IgE-FcεR interactions and engineered a surrogate rat IgE equivalent to MOv18. Employing this model, we examined in vivo safety and efficacy of antitumour IgE antibodies. RESULTS: In immunocompetent rats, rodent IgE restricted growth of syngeneic tumours in the absence of clinical, histopathological or metabolic signs associated with obvious toxicity. No physiological or immunological evidence of a "cytokine storm" or allergic response was seen, even at 50 mg/kg weekly doses. IgE treatment was associated with elevated serum concentrations of TNFα, a mediator previously linked with IgE-mediated antitumour and antiparasitic functions, alongside evidence of substantially elevated tumoural immune cell infiltration and immunological pathway activation in tumour-bearing lungs. CONCLUSION: Our findings indicate safety of MOv18 IgE, in conjunction with efficacy and immune activation, supporting the translation of this therapeutic approach to the clinical arena.

Tolerability and immunological effect of short up-dosing immunotherapy with 2 standardized native allergen extracts derived from the pollen of Salsola kali and Cupressus arizonica

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Protein contact dermatitis to chrysanthemum

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Neuropeptide-Induced Mast Cell Degranulation and Characterization of Signaling Modulation in Response to IgE Conditioning.

As tissue-resident immune cells, mast cells are frequently found in close proximity to afferent neurons and are subjected to immunoactive mediators secreted by these neurons, including substance P (SP) and calcitonin gene-related peptide (CGRP). Neurogenic inflammation is thought to play an important role in the pathophysiology of many diseases. Unraveling the cellular mechanisms at the interface between the immune response and the peripheral nervous system is important for understanding how these diseases arise and progress. In this work, mast cell degranulation following direct exposure to CGRP and SP was studied both at the bulk and single-cell levels to characterize the mouse peritoneal mast cell response to neuropeptides and compare this response to well-studied mast cell activation pathways. Results show that mast cells secrete fewer chemical messenger-filled granules with increased IgE preincubation concentrations. The biophysical characteristics of mast cell degranulation in response to SP and CGRP is in many ways similar to calcium ionophore-induced mast cell degranulation; however, neuropeptide-stimulated mast cells secrete reduced chemical messenger content per secretion event, resulting in an overall relative decrease in secreted chemical messengers.

[Sensitivity and specificity of prick skin test with two concentrations of standardized extract of Culex quinquefasciatus in allergic children]. / Sensibilidad y especificidad de la prueba cutánea por punción con dos concentraciones del extracto estandarizado de Culex quinquefasciatus en niños alérgicos.

BACKGROUND: Diagnostic options for immune reactions to mosquito bites are limited. In Cuba, IgE-mediated reactions are frequently related to Culex quinquefasciatus bite. OBJECTIVE: To determine the sensitivity and specificity of skin prick test with two doses of standardized extract in nitrogen protein units (PNU of Culex quinquefasciatus (BIOCEN, Cuba). MATERIAL AND METHOD: An analytical study was conducted on 100 children between 2 and 15 years old. Fifty atopic patients with a history of allergy to mosquito bite and positive specific serum IgE Culex quinquefasciatus and fifty atopic patients without a history of allergy to mosquito bite and negative specific serum IgE to Culex quinquefasciatus. Skin prick tests (SPT) were performed by duplicates on the forearms of the patients. Investigated doses were 100 PNU/mL and 10 PNU/mL. RESULTS: SPT with the highest concentration obtained a mean wheal size of 22.09 mm2 and for lower doses of 8.09 mm2, a statistically significant difference (p=0.001, Student's t test). Positive skin test correlated in 100% of patients with the presence of specific IgE. Testing with both doses showed a 94% of specificity and 88% of sensitivity. CONCLUSION: The diagnostic accuracy of SPT using both doses of standardized extract was similar, which justifies its use for diagnosis of sensitization to Culex quinquefasciatus in patients with symptoms of allergy to mosquito bite.

Antecedentes: las opciones diagnósticas de las reacciones inmunológicas a la picadura del mosquito son limitadas. En Cuba, las reacciones mediadas por IgE más frecuentes son por picadura de Culex quinquefasciatus. Objetivo: determinar la sensibilidad y especificidad de la prueba cutánea por punción con dos dosis del extracto estandarizado en unidades de nitrógeno proteico (UNP) de Culex quinquefasciatus (BIOCEN, Cuba). Material y método: estudio analítico efectuado en 100 niños entre 2 y 15 años de edad: 50 pacientes atópicos con antecedentes de alergia a la picadura de mosquito e IgE sérica específica positiva a Culex quinquefasciatus y 50 pacientes atópicos sin antecedentes de alergia a la picadura de mosquito e IgE sérica específica negativa a Culex quinquefasciatus. La prueba cutánea por punción se realizó por duplicado en los antebrazos de los pacientes. Las dosis investigadas fueron 100 y 10 UNP/mL. Resultados: en la prueba cutánea por punción con el extracto de mayor concentración se obtuvo un tamaño del área del habón de 22.09 mm2 y con la menor concentración de 8.19 mm2; una diferencia estadísticamente significativa (p=0.001, prueba t de Student). La prueba cutánea positiva se correlacionó en el 100% de los pacientes con la existencia de IgE específica. La prueba con ambas dosis mostró 94% de especificidad y 88% de sensibilidad. Conclusión: la alta coincidencia en el resultado de la prueba cutánea nos muestra que puede sustituirse la concentración del extracto a 100 UNP/mL por la de menor concentración, sin perder confiabilidad en el diagnóstico de sensibilización al mosquito Culex quinquefasciatus, utilizando ese método in vivo.

A new, rapid in vivo method to evaluate allergic responses through distinctive distribution of a fluorescent-labeled immune complex: Potential to investigate anti-allergic effects of compounds administered either systemically or topically to the skin.

We herein established a new method to evaluate allergic responses in mice rapidly and easily with ethical improvement by reducing the number of animals used. A single intravenous injection of a mixture of anti-OVA monoclonal IgE and fluorescein-ovalbumin (FITC-OVA) induced the distinctive spotted distribution of FITC-OVA in skin, named "ASDIS (Anaphylaxis-dependent Spotted Distribution of a fluorescent-labeled Immune complex in Skin)", and this was easily detected by in vivo imaging. The parallel induction of hypothermia, scratching, serum histamine increases, and ASDIS as well as the inhibition of ASDIS by either the systemic administration of a histamine H1 receptor antagonist or mast cell-depleting antibody suggested that our method, which only required 15 min, induced these allergic responses including ASDIS. Relatively mild but significant ASDIS was induced also in mice with passive systemic anaphylaxis by the method, requiring 2 separate days. The painting of anti-histamines on the skin markedly reduced ASDIS in the painted area only, suggesting the potential of this model to simultaneously compare the anti-allergic effects of several candidate compounds with control drugs in the same mice. ASDIS was suggested to originate from extravasated FITC-OVA/OE-1 immune complexes from blood to skin tissues other than mast cells. Our new method has the advantages of rapidity, easy method, and lower animal numbers to evaluate anti-allergic compounds as well as the characteristics of the used antibody, antigen, labeling molecules, additives, and other formulations. Our model for inducing ASDIS may contribute to the development of anti-allergic drugs, especially those intended for application to the skin.

Mast cells mediate neutrophil recruitment during atherosclerotic plaque progression.

AIMS: Activated mast cells have been identified in the intima and perivascular tissue of human atherosclerotic plaques. As mast cells have been described to release a number of chemokines that mediate leukocyte fluxes, we propose that activated mast cells may play a pivotal role in leukocyte recruitment during atherosclerotic plaque progression. METHODS AND RESULTS: Systemic IgE-mediated mast cell activation in apoE(-/-)µMT mice resulted in an increase in atherosclerotic lesion size as compared to control mice, and interestingly, the number of neutrophils was highly increased in these lesions. In addition, peritoneal mast cell activation led to a massive neutrophil influx into the peritoneal cavity in C57Bl6 mice, whereas neutrophil numbers in mast cell deficient Kit(W(-sh)/W(-sh)) mice were not affected. Within the newly recruited neutrophil population, increased levels of CXCR2(+) and CXCR4(+) neutrophils were observed after mast cell activation. Indeed, mast cells were seen to contain and release CXCL1 and CXCL12, the ligands for CXCR2 and CXCR4. Intriguingly, peritoneal mast cell activation in combination with anti-CXCR2 receptor antagonist resulted in decreased neutrophil recruitment, thus establishing a prominent role for the CXCL1/CXCR2 axis in mast cell-mediated neutrophil recruitment. CONCLUSIONS: Our data suggest that chemokines, and in particular CXCL1, released from activated mast cells induce neutrophil recruitment to the site of inflammation, thereby aggravating the ongoing inflammatory response and thus affecting plaque progression and destabilization.

Cutting Edge: Drebrin-Regulated Actin Dynamics Regulate IgE-Dependent Mast Cell Activation and Allergic Responses.

Mast cells play critical roles in allergic responses. Calcium signaling controls the function of these cells, and a role for actin in regulating calcium influx into cells has been suggested. We have previously identified the actin reorganizing protein Drebrin as a target of the immunosuppressant 3,5-bistrifluoromethyl pyrazole, which inhibits calcium influx into cells. In this study, we show that Drebrin(-/-) mice exhibit reduced IgE-mediated histamine release and passive systemic anaphylaxis, and Drebrin(-/-) mast cells also exhibit defects in FcεRI-mediated degranulation. Drebrin(-/-) mast cells exhibit defects in actin cytoskeleton organization and calcium responses downstream of the FcεRI, and agents that relieve actin reorganization rescue mast cell FcεRI-induced degranulation. Our results indicate that Drebrin regulates the actin cytoskeleton and calcium responses in mast cells, thus regulating mast cell function in vivo.

SG-HQ2 inhibits mast cell-mediated allergic inflammation through suppression of histamine release and pro-inflammatory cytokines.

In this study, we investigated the effect of 3,4,5-trihydroxy-N-(8-hydroxyquinolin-2-yl)benzamide) (SG-HQ2), a synthetic analogue of gallic acid (3,4,5-trihydroxybenzoic acid), on the mast cell-mediated allergic inflammation and the possible mechanism of action. Mast cells play major roles in immunoglobulin E-mediated allergic responses by the release of histamine, lipid-derived mediators, and pro-inflammatory cytokines. We previously reported the potential effects of gallic acid using allergic inflammation models. For incremental research, we synthesized the SG-HQ2 by the modification of functional groups from gallic acid. SG-HQ2 attenuated histamine release by the reduction of intracellular calcium in human mast cells and primary peritoneal mast cells. The inhibitory efficacy of SG-HQ2 was similar with gallic acid. Enhanced expression of pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1ß, interleukin-4, and interleukin-6 in activated mast cells was significantly diminished by SG-HQ2 100 times lower concentration of gallic acid. This inhibitory effect was mediated by the reduction of nuclear factor-κB. In animal models, SG-HQ2 inhibited compound 48/80-induced serum histamine release and immunoglobulin E-mediated local allergic reaction, passive cutaneous anaphylaxis. Our results indicate that SG-HQ2, an analogue of gallic acid, might be a possible therapeutic candidate for mast cell-mediated allergic inflammatory diseases through suppression of histamine release and pro-inflammatory cytokines.

Practical interest of both skin prick test and specific IgE in the evaluation of tolerance acquisition in IgE mediated cow's milk allergy (CMA). A clinical retrospective study in a cohort of 184 children

BACKGROUND: Cow's milk protein allergy (CMPA) represents one of the leading causes of food allergy in infants and young children. The immune reaction may be IgE mediated, non-IgE mediated, or mixed. IgE-mediated cow's milk protein allergy is revealed by immediate and acute symptoms which can be severe. The aim of this study is to report a one centre experience in the real life of testing children with IgE-mediated CMPA and try to identify predictive factor for follow-up challenges. METHOD: Retrospective and monocentric study between September 1997 and February 2008. 178 infants diagnosed with IgE-mediated CMPA during breastfeeding weaning were included. Initial factors such as age, sex, skin prick tests (SPTs), specific IgE (sIgE), atopic dermatitis and types of reaction were noted. Between 12 and 24 months all infants have undergone at least one evaluation including SPT. RESULTS: At the food challenge, 138 (75.8%) infants were found tolerant. Results of the skin prick test (SPT) were statistically different according to the food challenge result (2.2 mm vs. 5.1 mm, p < 0.0001). It was the same result for sIgE for CM 2.0 ku/l vs. 11.5 ku/l - p < 0.0001 and for casein 1.0 ku/l vs. 16.0 ku/l - p = 0.0014. CONCLUSION: This study confirms the practical interest of both SPT and sIgE in the evaluation of tolerance induction in IgE-mediated CMPA, but with no corresponding results. Sensitivity, specificity and probability curves of success for cow's milk challenge can be determined and have clinical utility

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Identification of plantago lanceolata pollen allergens using an immunoproteomic approach

Background: Airborne Plantago pollen triggers respiratory allergies in Mediterranean countries. Objectives: We aimed to study sensitization in patients with seasonal respiratory allergy and identify proteins of Plantago lanceolata pollen that could be responsible for hypersensitivity reactions in sensitized patients. We also determined the airborne pollen concentration of Plantago species from 2004 to 2011. Methods: IgE-binding proteins were analyzed and characterized using 1D and 2D gel electrophoresis and immunoblotting with sera from individuals sensitized to P lanceolata pollen extracts, mass spectrometry analysis, and protein data mining. We used aerobiological methods to study airborne pollen. Results: P lanceolata pollen accounts for 3% of the annual pollen spectrum in the air of Porto. Of a total of 372 patients, 115 (31%) showed specific IgE levels to P lanceolata pollen extracts. All sera from P lanceolata –allergic patients recognized 8 prominent groups of IgE-reactive allergens. Separation of proteins using 2D gel electrophoresis followed by identification with mass spectrometry revealed the presence of other IgE-reactive components that could be involved in sensitization. Conclusions: We detected proteins in P lanceolata pollen extracts that, to our knowledge, have not yet been studied and could worsen sensitization to this weed pollen species. The proteins identified were involved in a variety of cellular functions. By applying 2D electrophoresis and immunoblotting with a pool of 2 sera from different P lanceolata -allergic patients, we obtained a more detailed characterization of the P lanceolata allergen profile (AU)

Antecedentes: El polen de Plantago provoca alergia respiratoria en los países mediterráneos. Objetivos: El objetivo de este estudio fue analizar las sensibilizaciones de pacientes con alergia estacional e identificar las proteínas de polen de Plantago lanceolata que puedan ser responsables de las reacciones de hipersensibilidad en pacientes sensibles. Adicionalmente determinamos la concentración de polen de Plantago spp en el aire, en los años 2004-2011. Métodos: Las proteínas que se unen a la IgE fueron analizadas y caracterizadas a través de electroforesis en gel 1-D y 2-D e inmunobloting con suero de pacientes sensibilizados al polen de P. lanceolata . Se analizó mediante espectrometría de masas el contenido en las proteínas y se aplicaron métodos aerobiológicos para estudiar el espectro de polen en el ambiente. Resultados: En cuanto a los resultados obtenidos, el polen de P. lanceolata representa el 3% del espectro de polen anual en la atmósfera de Oporto. De los 372 pacientes, el 31% presentaban IgE específica frente al polen de P. lanceolata. Todos los sueros de los pacientes alérgicos a P. Lanceolata reconocían los ocho grupos prominentes de alérgenos reactivos a IgE. La separación de proteínas mediante electroforesis en gel 2-D, seguida de la espectrofotometría de masas permitieron identificar en el polen la presencia de otros componentes IgE reactivos que podrían estar implicados en la sensibilización de estos pacientes. Conclusiones: En conclusión, este estudio muestra la presencia de proteínas en el polen de P. Lanceolata que hasta ahora no habían sido estudiadas y que pueden intervenir en la sensibilización a éste polen. Se detectaron proteínas involucradas en una gran variedad de funciones celulares. Mediante las técnicas aplicadas en este estudio, entre ellas el inmunobloting, nos permite realizar una detallada caracterización del perfil alergénico del polen de P. lanceolata (AU)

Anaphylactic responses to histamine in mice utilize both histamine receptors 1 and 2.

BACKGROUND: Anaphylaxis is a severe, potentially life-threatening reaction that can occur in response to common triggers, including food allergens (e.g., peanut), insect stings, and several medications. Activation of mast cells and basophils to release preformed mediators, such as histamine, is thought to be an important process that underlies reactions. Histamine can exert effects through four different receptors, termed H1R-H4R. Despite clinical use of both H1R and H2R blockers in the therapy for acute allergic reactions, there is little mechanistic evidence to support the necessity for blocking H2R, a receptor best characterized for its role in stomach acid production. METHODS: Here, we sought to define the necessity for histamine receptors in the pathology of anaphylaxis using H1R and H2R knockout (KO) mice, as well as a H1R/H2R double KO strain. RESULTS: In response to IgE-mediated systemic anaphylaxis, the symptoms and decreases in core body temperature observed in wild-type mice were reduced but not ablated in either H1R or H2R KO. In contrast, H1R/H2R KO were significantly protected and were indistinguishable from histamine-deficient mice. Intravenous injection of histamine was sufficient to elicit these responses, and similar to IgE-mediated anaphylaxis, loss of both H1R and H2R was necessary for complete protection. CONCLUSION: Our data demonstrate definitively that both H1R and H2R participate in the immediate systemic responses during histamine-associated pathophysiology and mechanistically support the utility of H2R-blocking therapeutics in alleviating symptoms of anaphylaxis.

IgG and IgE collaboratively accelerate expulsion of Strongyloides venezuelensis in a primary infection.

The host deploys a subset of immune responses to expel helminths, which differs depending on the nature of the helminth. Strongyloides venezuelensis, a counterpart of the human pathogen S. stercoralis, naturally infects rodents and has been used as an experimental model. Here we show that induction of immunoglobulin G (IgG) and IgE is a prerequisite for rapid expulsion of S. venezuelensis during a primary infection. Activation-induced cytidine deaminase-deficient (AID(-/-)) mice, which lack the ability to switch IgM to other isotypes, normally developed T-helper 2 (Th2) cells and intestinal mastocytosis after infection with S. venezuelensis. Although AID(-/-) mice expelled Nippostrongylus brasiliensis normally, they required a much longer period to expel S. venezuelensis than wild-type (WT) mice. Adoptive transfers of immune sera from S. venezuelensis-infected but not N. brasiliensis-infected mice restored the ability of AID(-/-) mice to promptly expel S. venezuelensis. Immune serum-derived IgG and IgE induced worm expulsion via Fc γ receptor III (FcγRIII) and Fc ε receptor I (FcεRI), respectively, and a mixture of IgG and IgE showed collaborative effects. Whereas FcγRIII(-/-) mice or FcεRIα(-/-) mice normally could expel S. venezuelensis, FcγRIII(-/-) mice, when their IgE was neutralized by anti-IgE, or FcεRIα(-/-) mice, when their IgG binding to FcγRIII was blocked by anti-FcγRIII, showed a markedly reduced ability to expel S. venezuelensis. These data reveal that IgG and IgE play redundant roles but act in concert to accelerate S. venezuelensis expulsion. Mast cell-deficient mice, even those equipped with immune serum-derived IgG or IgE, failed to expel S. venezuelensis promptly, suggesting that mast cells are cellular targets of IgG and IgE.