The pathophysiology of anaphylaxis Reber, Laurent L.; Hernandez, Joseph D.; Galli, Stephen J.
Journal of allergy and clinical immunology,
August 2017, 2017-Aug, 2017-08-00, 20170801, 2017-08, Letnik:
140, Številka:
2
Journal Article
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Anaphylaxis is a severe systemic hypersensitivity reaction that is rapid in onset; characterized by life-threatening airway, breathing, and/or circulatory problems; and usually associated with skin ...and mucosal changes. Because it can be triggered in some persons by minute amounts of antigen (eg, certain foods or single insect stings), anaphylaxis can be considered the most aberrant example of an imbalance between the cost and benefit of an immune response. This review will describe current understanding of the immunopathogenesis and pathophysiology of anaphylaxis, focusing on the roles of IgE and IgG antibodies, immune effector cells, and mediators thought to contribute to examples of the disorder. Evidence from studies of anaphylaxis in human subjects will be discussed, as well as insights gained from analyses of animal models, including mice genetically deficient in the antibodies, antibody receptors, effector cells, or mediators implicated in anaphylaxis and mice that have been “humanized” for some of these elements. We also review possible host factors that might influence the occurrence or severity of anaphylaxis. Finally, we will speculate about anaphylaxis from an evolutionary perspective and argue that, in the context of severe envenomation by arthropods or reptiles, anaphylaxis might even provide a survival advantage.
Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different ...activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-β during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P-dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation.
Food allergy is becoming a major public health issue, with no regulatory approved therapy to date. Food allergy symptoms range from skin rash and gastrointestinal symptoms to anaphylaxis, a ...potentially fatal systemic allergic shock reaction. IgE antibodies are thought to contribute importantly to key features of food allergy and anaphylaxis, and measurement of allergen‐specific IgE is fundamental in diagnosing food allergy. This review will discuss recent advances in the regulation of IgE production and IgE repertoires in food allergy. We will describe the current understanding of the role of IgE and its high‐affinity receptor FcεRI in food allergy and anaphylaxis, by reviewing insights gained from analyses of mouse models. Finally, we will review data derived from clinical studies of the effect of anti‐IgE therapeutic monoclonal antibodies (mAbs) in food allergy, and recent insight on the efficiency and mechanisms through which these mAbs block IgE effector functions.
Allergen‐specific IgE can be produced locally by gastrointestinal plasma cells from food allergic subjects, and bind the high‐affinity receptor FcεRI on mast cells. Re‐exposure to the allergen induces mast cell degranulation, driving food allergic symptoms. Clinical evidence indicate that anti‐IgE mAbs could have beneficial effects on food allergy.
Asthma is the most common chronic lung disease, affecting more than 250 million people worldwide. The heterogeneity of asthma phenotypes represents a challenge for adequate assessment and treatment ...of the disease. However, approximately 50% of asthma patients present with chronic type 2 inflammation initiated by alarmins, such as IL-33 and thymic stromal lymphopoietin (TSLP), and driven by the TH2 interleukins IL-4, IL-5 and IL-13. These cytokines have therefore become important therapeutic targets in asthma. Here, we discuss current knowledge on the structure and functions of these cytokines in asthma. We review preclinical and clinical data obtained with monoclonal antibodies (mAbs) targeting these cytokines or their receptors, as well as novel strategies under development, including bispecific mAbs, designed ankyrin repeat proteins (DARPins), small molecule inhibitors and vaccines targeting type 2 cytokines.
Allergies are widely considered to be misdirected type 2 immune responses, in which immunoglobulin E (IgE) antibodies are produced against any of a broad range of seemingly harmless antigens. ...However, components of insect venoms also can sensitize individuals to develop severe IgE-associated allergic reactions, including fatal anaphylaxis, upon subsequent venom exposure. We found that mice injected with amounts of honeybee venom similar to that which could be delivered in one or two stings developed a specific type 2 immune response that increased their resistance to subsequent challenge with potentially lethal amounts of the venom. Our data indicate that IgE antibodies and the high affinity IgE receptor, FcεRI, were essential for such acquired resistance to honeybee venom. The evidence that IgE-dependent immune responses against venom can enhance survival in mice supports the hypothesis that IgE, which also contributes to allergic disorders, has an important function in protection of the host against noxious substances.
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•Th2 cell immunity can enhance mouse resistance to honeybee or Russell’s viper venoms•IgE and FcεRI contribute to such acquired increased resistance to honeybee venom•IgE-associated immune responses can protect the host against noxious substances
Neutrophils are the most abundant leukocytes in human blood and critical actors of the immune system. Many neutrophil functions and facets of their activity
were revealed by studying genetically ...modified mice or by tracking fluorescent neutrophils in animals using imaging approaches. Assessing the roles of neutrophils can be challenging, especially when exact molecular pathways are questioned or disease states are interrogated that alter normal neutrophil homeostasis. This review discusses the main
models for the study of neutrophils, their advantages and limitations. The side-by-side comparison underlines the necessity to carefully choose the right model(s) to answer a given scientific question, and exhibit caveats that need to be taken into account when designing experimental procedures. Collectively, this review suggests that at least two models should be employed to legitimately conclude on neutrophil functions.
IgE is the antibody isotype found at the lowest concentration in the circulation. However IgE can undeniably play an important role in mediating allergic reactions; best exemplified by the clinical ...benefits of anti-IgE monoclonal antibody (omalizumab) therapy for some allergic diseases. This review will describe our current understanding of the interactions between IgE and its main receptors FcεRI and CD23 (FcεRII). We will review the known and potential functions of IgE in health and disease: in particular, its detrimental roles in allergic diseases and chronic spontaneous urticaria, and its protective functions in host defense against parasites and venoms. Finally, we will present an overview of the drugs that are in clinical development or have therapeutic potential for IgE-mediated allergic diseases.
Allergic asthma is characterized by elevated levels of IgE antibodies, type 2 cytokines such as interleukin-4 (IL-4) and IL-13, airway hyperresponsiveness (AHR), mucus hypersecretion and ...eosinophilia. Approved therapeutic monoclonal antibodies targeting IgE or IL-4/IL-13 reduce asthma symptoms but require costly lifelong administrations. Here, we develop conjugate vaccines against mouse IL-4 and IL-13, and demonstrate their prophylactic and therapeutic efficacy in reducing IgE levels, AHR, eosinophilia and mucus production in mouse models of asthma analyzed up to 15 weeks after initial vaccination. More importantly, we also test similar vaccines specific for human IL-4/IL-13 in mice expressing human IL-4/IL-13 and the related receptor, IL-4Rα, to find efficient neutralization of both cytokines and reduced IgE levels for at least 11 weeks post-vaccination. Our results imply that dual IL-4/IL-13 vaccination may represent a cost-effective, long-term therapeutic strategy for the treatment of allergic asthma as demonstrated in mouse models, although additional studies are warranted to assess its safety and feasibility.
In addition to their well-accepted role as critical effector cells in anaphylaxis and other acute IgE-mediated allergic reactions, mast cells (MCs) have been implicated in a wide variety of processes ...that contribute to disease or help to maintain health. Although some of these roles were first suggested by analyses of MC products or functions in vitro, it is critical to determine whether, and under which circumstances, such potential roles actually can be performed by MCs in vivo. This review discusses recent advances in the development and analysis of mouse models to investigate the roles of MCs and MC-associated products during biological responses in vivo, and comments on some of the similarities and differences in the results obtained with these newer versus older models of MC deficiency.
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