Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglobulin-E-mediated systemic anaphylaxis

Anaphylaxis is an acute, severe, and potentially fatal systemic allergic reaction. Immunoglobulin E (IgE), mast cells, and histamine have long been associated with anaphylaxis, but an alternative pathway mediated by IgG has been suggested to be more important in the elicitation of anaphylaxis. Here, we showed that basophils, the least common blood cells, were dispensable for IgE-mediated anaphylaxis but played a critical role in IgG-mediated, passive and active systemic anaphylaxis in mice. In vivo depletion of basophils but not macrophages, neutrophils, or NK cells ameliorated IgG-mediated passive anaphylaxis and rescued mice from death in active anaphylaxis. Upon capture of IgG-allergen complexes, basophils released platelet-activating factor (PAF), leading to increased vascular permeability. These results highlight a pivotal role for basophils in vivo and contrast two major, distinct pathways leading to allergen-induced systemic anaphylaxis: one mediated by basophils, IgG, and PAF and the other "classical" pathway mediated by mast cells, IgE, and histamine.     

IgG-mediated anaphylaxis via Fcγ receptor in CD40-deficient mice

Anaphylaxis denotes an immediate hypersensitivity reaction to allergen, exclusively mediated by IgE antibodies. However, IgE antibodies do not explain all the syndromes that are encountered. We investigated potent IgG-mediated anaphylaxis in CD40-deficient mice that lack the immunoglobulin class switching for T cell-dependent antigens. Immunization with ovalbumin did not induce either humoral responses of IgG, IgA, and IgE, or systemic anaphylaxis in CD40-deficient mice. Although systemic anaphylaxis by active immunization was not observed in CD40-deficient mice, both passive cutaneous anaphylaxis (PCA) and passive systemic anaphylaxis assessed by mouse blood pressure monitoring with cervical artery catheterization did take place when antigen-specific IgG was transferred and then antigen challenge given. Further, to investigate the inflammatory pathway of IgG-mediated immediate hypersensitivity reactions, we focused on the Fcγ receptor (FcγR) function. Pretreatment of the mice with the anti-FcγRII/FcγRIII MoAb clearly blocked the response of PCA and passive systemic anaphylaxis, suggesting that they were initiated through FcγR. In conclusion, we directly demonstrate the IgG-mediated anaphylaxis and its triggering mechanism through FcγR in in vivo conditions. In addition to IgE-mediated anaphylaxis, IgG-mediated anaphylaxis should be considered and the blocking of FcγR would provide one of the therapeutic targets for the control of IgG-mediated hypersensitivity diseases.     

Allergic reactions to streptokinase consistent with anaphylactic or antigen-antibody complex-mediated damage

Streptokinase used as a thrombolytic agent may produce immunologic drug reactions. We report a second case of IgE-mediated anaphylaxis and a late reaction to streptokinase. This late reaction was consistent with an IgG-mediated antigen-antibody disease with transient renal involvement, fever, and cutaneous lesions. The second case responded to prednisone therapy.     

An audit of reported acute transfusion reactions in Universiti Kebangsaan Malaysia Medical Centre

Transfusion is an irreversible event which carries potential benefits as well as risk to the recipient. The objective of this study was to analyse all reported transfusion reactions of the year 2008 in the Blood Bank Unit of Universiti Kebangsaan Malaysia Medical Centre (UKMMC). This is a retrospective study that was carried out by retrieving data from the laboratory information system. A total of 27842 transfusions were documented and the total reported transfusion reactions were 149. The incidence of transfusion reaction was 1 in 187 of all transfusions (0.54%); in which 69 (0.25%) were allergic in nature and 61 (0.22%) were febrile non-haemolytic transfusion reactions (FNHTR). Hypotensive reactions were identified in 6 (0.02%) patients. There were 9 (0.03%) cases reported with haemoglobinuria where no serological evidence of haemolytic transfusion reaction (HTR) was found. One HTR (0.003%) was identified and this was due to an error in patient identification in the ward. Other specified reactions like transfusion-related acute lung injury (TRALI), bacterial infections, Graft verses host disease (GVHD) were not reported. The highest frequency of the reactions occurred in the red cell transfusions which accounted for 111 cases. In conclusion, the incidences of transfusion reactions are low when compared to those reported by other centres.     

中山大学附属第一医院2017年输血不良反应调查

目的 通过对我院临床输血不良反应情况的回顾性分析,降低输血不良反应的发生,保障临床输血安全。方法 收集我院2017年1月1日~12月31日输血不良反应病例,进行分类分析。结果 共发生输血不良反应143例,发生率0.50%,其中107例为过敏反应,占比74.82%,32例为非溶血性发热反应,占比22.38%,过敏反应合并非溶血性发热反应有4例,占比2.80%。结论 我院的输血不良反应率较低,主要的不良反应类型是由于输血小板制品引起的过敏反应。临床上应对输血进行严格掌握,合理实施输血治疗措施,降低不良反应发生率,提高输血安全。     

Anaphylaxis: lessons from mouse models

Studies with mouse models demonstrate 2 pathways of systemic anaphylaxis: a classic pathway mediated by IgE, FcepsilonRI, mast cells, histamine, and platelet-activating factor (PAF) and an alternative pathway mediated by IgG, FcgammaRIII, macrophages, and PAF. The former pathway requires much less antigen and antibody than the latter. This is modified, however, by IgG antibodies that prevent IgE-mediated anaphylaxis by intercepting antigen before it binds to mast cell-associated IgE. Consequently, IgG antibodies block systemic anaphylaxis induced by small quantities of antigen but mediate systemic anaphylaxis induced by larger quantities. The importance of the alternative pathway in human subjects is unknown, but human IgG, IgG receptors, macrophages, mediators, and mediator receptors have appropriate properties to support this pathway if sufficient IgG and antigen are present. The severity of systemic anaphylaxis is increased by nitric oxide produced by the enzyme endothelial nitric oxide synthase and by the cytokines IL-4 and IL-13 and decreased by endogenous beta-adrenergic stimulation and receptors that contain ITIM that bind tyrosine phosphatases. Anaphylaxis is also suppressed by other receptors and ion channels that function through distinct mechanisms. Unlike systemic anaphylaxis, intestinal anaphylaxis (allergic diarrhea) is almost totally IgE and mast cell dependent and is mediated predominantly by PAF and serotonin. Some potent food allergens, including peanuts and tree nuts, can directly enhance anaphylaxis by stimulating an anaphylactoid response through the innate immune system. Results of these studies suggest novel prophylactic agents, including nonstimulatory anti-IgE mAbs, IL-4 receptor antagonists, PAF antagonists, and agents that cross-link FcepsilonRI or FcgammaRIII to an ITIM-containing inhibitory receptor.     

Pathways of anaphylaxis in the mouse

BACKGROUND: Although anaphylaxis is classically mediated by IgE, FcepsilonRI, mast cells, and histamine, several rodent studies suggest that an alternative pathway involving IgG, FcgammaRIII, macrophages and platelets, and platelet-activating factor (PAF) may be more important in the anaphylactic response to antigen challenge. OBJECTIVES: We sought to determine the relative roles of the classical and alternative pathways of anaphylaxis in a mouse model characterized by mastocytosis and a high level of antigen-specific IgE antibody. METHODS: Wild-type, IgE-deficient, FcepsilonRI-deficient, and mast cell-deficient mice were immunized with goat anti-mouse IgD antibody, which induces mastocytosis and a large IgE and IgG anti-goat IgG response, and then challenged 14 days later with antigen (goat IgG) or rat anti-mouse IgE mAb. Specific vasoactive mediators, cell types, Ig isotypes, or Ig receptors were blocked or eliminated before challenge in some experiments. The severity of anaphylaxis was gauged by changes in body temperature, physical activity, and mortality. RESULTS: Equal doses of antigen or anti-IgE mAb induced similar anaphylactic responses. Anti-IgE mAb-induced anaphylaxis was FcepsilonRI and mast cell dependent and mediated predominantly by histamine. In contrast, neither mast cells nor platelets appeared important for antigen-induced anaphylaxis, which was FcgammaRIII and macrophage dependent and mediated predominantly by PAF. CONCLUSIONS: Antigen-induced anaphylaxis in the mouse proceeds primarily through the IgG, FcgammaRIII, macrophage, and PAF pathway, even in an experimental model that is characterized by strong mast cell and IgE responses. The presence of FcgammaRIII on human macrophages makes it possible that the IgG, FcgammaRIII, macrophage, and PAF pathway also contributes to human anaphylaxis.     

Three cases of food-dependent exercise-induced anaphylaxis

A variety of systemic reactions associated with exercise are recognized. This article describes three cases of anaphylaxis induced by exercise within 2 hours after the ingestion of causative foods. Their symptoms were urticaria, angioedema, bronchial asthma, fall in blood pressure and syncope. Cases #1 and #3 showed exercise-induced anaphylaxis after ingestion of wheat. However, case #1 reacted only to toasted wheat. In case #2 the most likely responsible food was also wheat, although we could not definitely confirm this. Two subjects exhibited an elevation in plasma histamine level when symptoms developed. In addition, we observed inhibition of these symptoms by pretreatment with anti-allergic drugs. These observations suggest that type I allergic reaction is involved in the development of these symptoms. However, why exercise combined with ingestion of food is needed for this type of anaphylaxis still remains unknown.     

Action of 3-isobutyl-1-methylxanthine and prostaglandins D2 and E1 on histamine release from rat and guinea pig mast cells

The action of three compounds reported to elevate intracellular cyclic adenosine monophosphate (cAMP) namely 3-isobutyl-1-methylxanthine (IBMX) and prostaglandins D2 and E1 (PGD2 and PGE1), on histamine release was examined. Three test systems were used: (i) the perfused ovalbumin-sensitized guinea pig lung and (ii) isolated cells from ovalbumin-sensitized guinea pig lung, both of which are IgG-mediated models of anaphylaxis, and (iii) an IgE model of anaphylaxis, using isolated rat peritoneal mast cells from sensitized rats. Both PGD2 and PGE1 were without effect at concentrations likely to be found during anaphylaxis. In contrast, the phosphodiesterase inhibitor, IBMX, was highly active in all three test systems. The role of raised intracellular cAMP levels in the inhibition of histamine release is discussed.     

Investigations on the involvement of the lectin pathway of complement activation in anaphylaxis

BACKGROUND: Systemic anaphylaxis is the most severe form of immediate hypersensitivity reaction. The activation of the complement system occurs during anaphylactic shock. The purpose of this study was to determine in a mouse model whether the lectin pathway of complement activation is involved in anaphylaxis. METHODS: To see whether the lectin pathway is involved in anaphylactic shock, serum mannan-binding lectin (MBL) levels were measured after passive anaphylaxis. Also MBL expression and binding to potential ligands were investigated. To determine whether complement or mast cell activation is essential for hypothermia in anaphylactic shock, mouse strains deficient in MBL-A and MBL-C, C1q, factors B and C2, C5, C5aR, or mast cells were tested. RESULTS: After antigenic challenge a marked drop in body temperature as well as a rapid decrease in serum MBL levels were observed. The decrease of serum MBL levels in shock could not be attributed to MBL binding to immune complexes or tissues, but an interaction of MBL with mast cell-derived proteoglycans was seen. In contrast to mast cell-deficient mice, none of the complement-deficient mouse strains were protected from shock-associated hypothermia. CONCLUSIONS: These results indicate that neither MBL nor activation of the complement cascade is crucial for the induction of anaphylaxis. In contrast mast cell activation is associated with the development of hypothermia and possibly the observed decrease in serum MBL levels.     

A Case of Levofloxacin-Induced Anaphylaxis With Elevated Serum Tryptase Levels

Levofloxacin, a fluoroquinolone and L-isomer of the racemate ofloxacin, has been approved for the treatment of acute and chronic bacterial infections. Gastrointestinal complaints are the most frequently reported adverse drug reactions to fluoroquinolones. Other adverse events include headache, dizziness, increased liver enzyme levels, photosensitivity, tachycardia, QT prolongation, and eruptions. Anaphylaxis has been documented as a rare adverse drug reaction to levofloxacin; however, diagnostic tests are needed to evaluate whether these reactions are the result of levofloxacin treatment. While the results of skin tests are considered unreliable due to false-positive responses, the oral provocation test is currently considered to be the most reliable test. Tryptase, a neutral protease, is the dominant protein component of secretory granules in human mast cells, and an increased serum concentration of tryptase is a highly sensitive indicator of anaphylaxis. Herein, we report a case of levofloxacin-induced anaphylaxis in which the patient exhibited elevated serum tryptase levels and a positive oral levofloxacin challenge test result. As anaphylaxis is potentially life-threatening, the administration of fluoroquinolones to patients who have experienced a prior reaction to this type of agent should be avoided.     

No consumption of IgE antibody in serum during allergic drug anaphylaxis

BACKGROUND: The general understanding is that a blood sample for analysis of immunoglobulin (Ig) E antibodies to an allergen suspected to cause an anaphylaxis cannot be drawn until several weeks after the reaction. As this is most unpractical, the changes in IgE antibody levels during anaphylaxis were studied to evaluate the possibility of using samples drawn at the time of the reaction. METHODS: Immunoglobulin E antibodies to suxamethonium were quantitated with ImmunoCAP before, during and after an anaphylactic reaction occurring during anaesthesia using neuromuscular blocking agents. RESULTS: Serum IgE antibody concentrations against suxamethonium in blood samples collected up to 6 h after the reaction were not different from those in samples drawn before or days and weeks after the anaphylaxis. CONCLUSIONS: A serum sample intended to trace the drug involved in an IgE-mediated anaphylactic reaction can be drawn in direct relation to the reaction.     

Allergy to monoclonal antibodies: cutting-edge desensitization methods for cutting-edge therapies

Monoclonal antibodies are important therapeutic tools, but their usefulness is limited in patients who experience acute infusion reactions, most of which are consistent with type I hypersensitivity reactions including anaphylaxis. Patients who experience acute infusion reactions face the prospect of stopping treatment or switching to an alternative, and potentially more toxic or inferior treatment. Another option that overcomes the treatment hurdle of these reactions is rapid desensitization, a procedure in which the offending agent is re-administered in a step-wise, highly controlled fashion. While the risk of reactions is not completely eliminated, desensitization has proven to be a highly effective re-administration strategy for most patients who otherwise would not be able to tolerate their monoclonal antibody therapy owing to drug-induced anaphylaxis. This article reviews the current literature on desensitization and other readministration protocols to monoclonal antibodies with an emphasis on four agents: rituximab, infliximab, cetuximab and trastuzumab.     

Basophils are back!

In this issue of Immunity, Tsujimura et al. (2008) report that the release of platelet-activating factor by basophils stimulated with immunoglobulin G1 (IgG1)-antigen immune complexes contributes substantially to the expression of an IgG1-dependent alternative pathway of systemic anaphylaxis in mice.     

Molecular mechanisms of anaphylaxis: lessons from studies with murine models

Studies with murine models demonstrate 2 pathways of systemic anaphylaxis: one mediated by IgE, Fc epsilonRI, mast cells, histamine, and platelet-activating factor (PAF), and the other mediated by IgG, Fc gammaRIII, macrophages, and PAF. The former pathway requires much less antibody and antigen than the latter. As a result, IgG antibody can block IgE-mediated anaphylaxis induced by small quantities of antigen without mediating Fc gammaRIII-dependent anaphylaxis. The IgE pathway is most likely responsible for most human anaphylaxis, which generally involves small amounts of antibody and antigen; similarities in the murine and human immune systems suggest that the IgG pathway might mediate disease in persons repeatedly exposed to large quantities of antigen. Mice, like human subjects, can experience IgE/Fc epsilonRI/mast cell-mediated gastrointestinal and systemic anaphylaxis in response to ingested antigen. Gastrointestinal symptoms depend on serotonin and PAF; mediator dependence of systemic symptoms has not been determined. Both local and systemic anaphylaxis induced by ingested antigens might be blocked by IgA and IgG antibodies. IL-4 and IL-13 signaling through the IL-4 receptor alpha chain, in addition to promoting the mastocytosis and IgE antibody production that mediate most human anaphylaxis, exacerbates the effector phase of anaphylaxis by increasing target cell responsiveness to vasoactive mediators. As a result, IL-4 receptor alpha chain antagonists might be particularly effective suppressors of anaphylaxis.     

Evaluation of hypersensitivity reactions to cancer chemotherapeutic agents in pediatric patients

BackgroundHypersensitivity reactions (HSRs) to chemotherapeutic agents have been increasingly documented.ObjectiveThe aim of this study was to investigate HSRs due to chemotherapeutics agents in childhood.MethodsFrom January 2007 to June 2019, the patients who were treated for neoplastic diseases in our hospital were evaluated. Patients who developed a HSR to a chemotherapeutic agent were included.ResultsFifty-seven patients with 65 reactions (60% anaphylaxis) were evaluated. Escherichia coli asparaginase was responsible for 38 (58.5%) of these 65 reactions. The other agents were polyethylene glycol (PEG)–asparaginase (n = 11), etoposide (n = 7), methotrexate (n = 4), carboplatin (n = 4), and procarbazine (n = 1). Of the 38 patients who had a reaction to E coli–asparaginase, 33 patients received alternative treatment (PEG-asparaginase or Erwinia asparaginase), 3 patients continued with desensitization, and 2 patients underwent bone marrow transplantation. Five patients who had an initial reaction to PEG-asparaginase continued their treatment with Erwinia asparaginase or E coli asparaginase uneventfully. Of 7 patients who had a reaction to etoposide (4 had anaphylaxis), 3 patients continued with desensitization, and 2 patients used the drug with premedication and prolonged infusion. Two patients had anaphylaxis with methotrexate. Treatment was continued with desensitization in 1 patient and methotrexate treatment was discontinued in the other patient. Of the 4 patients with carboplatin hypersensitivity, 2 had anaphylaxis. Desensitization was performed in 2 patients. One patient had procarbazine HSR, drug was given with premedication.ConclusionAmong all chemotherapeutic agents reviewed in our study that caused HSRs, asparaginase was the most common culprit agent in children. Most of reactions are immediate type. Many of the patients can take their treatment by drug replacement or desensitization.     

Food-induced anaphylaxis

Food-induced anaphylaxis (FIA) is a serious allergic reaction that may cause death rapidly in otherwise healthy individuals. There is no universal agreement on its definition or criteria for diagnosis. Hospital admissions for FIA have more than doubled in the last decade. Food is one of the most common causes of anaphylaxis, with most surveys indicating that food-induced reactions account for 30% to 50% of cases. The most commonly implicated foods are peanut, tree nuts, milk, eggs, sesame seeds, fish, and shellfish. The only life-saving treatment for anaphylaxis is allergen avoidance, and epinephrine injection if an anaphylactic event occurs.     

Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization

Anaphylaxis is an acute and potentially lethal multi-system allergic reaction. Most consensus guidelines for the past 30 years have held that epinephrine is the drug of choice and the first drug that should be administered in acute anaphylaxis. Some state that properly administered epinephrine has no absolute contraindication in this clinical setting. A committee of anaphylaxis experts assembled by the World Allergy Organization has examined the evidence from the medical literature concerning the appropriate use of epinephrine for anaphylaxis. The Committee strongly believes that epinephrine is currently underutilized and often dosed suboptimally to treat anaphylaxis, is under-prescribed for potential future self-administration, that most of the reasons proposed to withhold its clinical use are flawed, and that the therapeutic benefits of epinephrine exceed the risk when given in appropriate i.m. doses.     

Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products

Despite yielding a definitive diagnosis in fewer than 20 percent of anaphylactic transfusion reactions, investigation for IgA deficiency and the presence of presumably pathogenic IgG anti-IgA is useful in patient management. Individuals with demonstrated anti-IgA are thereafter committed to receiving IgA-depleted cellular products or IgA-deficient plasma and derivatives to prevent recurrent severe reactions. Unfortunately, in populations of IgA-deficient individuals screened for anti-IgA, the predictive value of the test in the absence of a prior reaction is quite low. Anti-IgA testing is complex and limited to a few reference laboratories, many of which still employ a labor-intensive hemagglutination assay developed in the late 1960s. Timely decisions regarding further transfusion management of patients experiencing anaphylaxis often rely upon more rapidly obtained assays of the IgA concentration as an indicator of the likelihood of subsequent demonstration of anti-IgA. The scarcity of IgA-deficient banked plasma products and dedicated plateletpheresis donors has led to the development of American Rare Donor Program policies designed to appropriately allocate these precious resources. The test methods used to establish the diagnosis of IgA deficiency and identify the approximately one third of these individuals with anti-IgA are discussed, along with the incidence of abnormal tests in various populations. Also presented are testing recommendations for the identification of an IgA-mediated mechanism for transfusion-associated anaphylaxis and qualification of patients to receive rare IgA-deficient plasma-containing products.     

Passive Paw Anaphylaxis in the Rat Optimum

The difficulties involved in quantitating passive cutaneous anaphylaxis led us to examine the rat paw as a site for passive anaphylaxis and to define optimum conditions for passive paw anaphylaxis. Generation of homocytotropic antibodies in a number of different rat strains revealed that female Brown Norway rats were excellent producers of high titre antisera after only a single injection of antigen and Bordetella pertussis. Injection of ratpaws with diluted antisera followed by short (1-2 h) or long (72 h or more) sensitization periods showed that maximum paw swelling occurred 15 min after antigen challenge. Retention of tissue sensitizing capacity in the paw for greater than 35 days but loss of this capacity following heating of antiserum at 56 degrees C, indicated that the rat homocytotropic antibodies involved in passive paw anaphylaxis belong to the IgE class. Experiments using mepyramine, methysergide and diethylcarbamazine showed that 5-hydroxytryptamine is the most important mediator of passive paw anaphylaxis after both a short (2 h) and a long (72 h) sensitization procedure. Passive paw anaphylaxis in the rat is at least as easy to perform as passive cutaneous anaphylaxis, results can be obtained more rapidly and accurate measurement of paw thickness is not difficult. The procedure is a viable alternative to passive cutaneous anaphylaxis and may offer advantages over the latter method especially in the search for, and rapid assessment of, anti-allergic compounds.