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
Recenzirano
Odprti dostop
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.
Ingestion of innocuous antigens, including food proteins, normally results in local and systemic immune nonresponsiveness in a process termed oral tolerance. Oral tolerance to food proteins is likely ...to be intimately linked to mechanisms that are responsible for gastrointestinal tolerance to large numbers of commensal microbes. Here we review our current understanding of the immune mechanisms responsible for oral tolerance and how perturbations in these mechanisms might promote the loss of oral tolerance and development of food allergies. Roles for the commensal microbiome in promoting oral tolerance and the association of intestinal dysbiosis with food allergy are discussed. Growing evidence supports cutaneous sensitization to food antigens as one possible mechanism leading to the failure to develop or loss of oral tolerance. A goal of immunotherapy for food allergies is to induce sustained desensitization or even true long-term oral tolerance to food allergens through mechanisms that might in part overlap with those associated with the development of natural oral tolerance.
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.
Research on the gut microbiota of free-ranging mammals is offering new insights into dietary ecology. However, for free-ranging primates, little information is available for how microbiomes are ...influenced by ecological variation through time. Primates inhabiting seasonal tropical dry forests undergo seasonally specific decreases in food abundance and water availability, which have been linked to adverse health effects. Throughout the course of a seasonal transition in 2014, we collected fecal samples from three social groups of free-ranging white-faced capuchin monkeys (Cebus capucinus imitator) in Sector Santa Rosa, Área de Conservación Guanacaste, Costa Rica. 16S rRNA sequencing data reveal that unlike other primates, the white-faced capuchin monkey gut is dominated by Bifidobacterium and Streptococcus. Linear mixed effects models indicate that abundances of these genera are associated with fluctuating availability and consumption of fruit and arthropods, whereas beta diversity clusters by rainfall season. Whole shotgun metagenomics revealed that the capuchin gut is dominated by carbohydrate-binding modules associated with digestion of plant polysaccharides and chitin, matching seasonal dietary patterns. We conclude that rainfall and diet are associated with the diversity, composition, and function of the capuchin gut microbiome. Additionally, microbial fluctuations are likely contributing to nutrient uptake and the health of wild primate populations.
Key points
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Dietary supplementation with inorganic nitrate has beneficial effects on skeletal muscle responses to exercise.
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Both mitochondrial and extra‐mitochondrial explanations have been ...proposed.
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Contractile force of fast‐twitch muscles was enhanced in mice supplemented with 1 mm NaNO3 in drinking water for 7 days.
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Myoplasmic free Ca2+ during tetanic stimulation was increased in fast‐twitch muscles of nitrate‐supplemented mice and this was accompanied by increased expression of calsequestrin 1 and the dihydropyridine receptor.
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These results provide a new mechanism by which nitrate exerts beneficial effects on muscle function with applications to sports performance and a potential therapeutic role in conditions with muscle weakness.
Dietary inorganic nitrate has profound effects on health and physiological responses to exercise. Here, we examined if nitrate, in doses readily achievable via a normal diet, could improve Ca2+ handling and contractile function using fast‐ and slow‐twitch skeletal muscles from C57bl/6 male mice given 1 mm sodium nitrate in water for 7 days. Age matched controls were provided water without added nitrate. In fast‐twitch muscle fibres dissected from nitrate treated mice, myoplasmic free Ca2+ was significantly greater than in Control fibres at stimulation frequencies from 20 to 150 Hz, which resulted in a major increase in contractile force at ≤50 Hz. At 100 Hz stimulation, the rate of force development was ∼35% faster in the nitrate group. These changes in nitrate treated mice were accompanied by increased expression of the Ca2+ handling proteins calsequestrin 1 and the dihydropyridine receptor. No changes in force or calsequestrin 1 and dihydropyridine receptor expression were measured in slow‐twitch muscles. In conclusion, these results show a striking effect of nitrate supplementation on intracellular Ca2+ handling in fast‐twitch muscle resulting in increased force production. A new mechanism is revealed by which nitrate can exert effects on muscle function with applications to performance and a potential therapeutic role in conditions with muscle weakness.
Although IL-2 was first recognized as growth factor for T cells, it is now also appreciated to be a key regulator of T cells through its effects on regulatory T cells (Treg). The IL-2 receptor ...(IL-2R) subunits’ different (i) ligand affinities, (ii) dimerization or trimerization relationships with other cytokine subunits, (iii) expression across multiple cell types, and (iv) downstream signaling effects, largely dictate cellular tolerance and antimicrobial processes. Defects in IL-2Rγ result in profound and almost universally fatal immune deficiency, unless treated with hematopoietic stem cell transplantation (HSCT). Defects in IL-2Rα and IL-2Rβ result in more limited infection susceptibility, particularly to herpesviruses. However, the most prominent clinical symptomatology for IL-2Rα and IL-2Rβ defects include multi-organ autoimmunity and inflammation, consistent with the critical role of IL-2 in establishing and maintaining immune tolerance. Here, we review how we have arrived at our current understanding of the complex roles of IL-2/2R in host defense and tolerance focusing on the insights gained from human clinical immunology.
Regulated glycosylation controls T cell processes, including activation, differentiation and homing by creating or masking ligands for endogenous lectins. Here we show that stimuli promoting T helper ...type 1 (TH1), TH2 or interleukin 17-producing T helper (TH-17) differentiation can differentially regulate the glycosylation pattern of T helper cells and modulate their susceptibility to galectin-1, a glycan-binding protein with anti-inflammatory activity. Although TH1- and TH-17-differentiated cells expressed the repertoire of cell surface glycans critical for galectin-1-induced cell death, TH2 cells were protected from galectin-1 through differential sialylation of cell surface glycoproteins. Consistent with those findings, galectin-1-deficient mice developed greater TH1 and TH-17 responses and enhanced susceptibility to autoimmune neuroinflammation. Our findings identify a molecular link among differential glycosylation of T helper cells, susceptibility to cell death and termination of the inflammatory response.
Background Activation of Toll-like receptors (TLRs) induces inflammatory responses involved in immunity to pathogens and autoimmune pathogenesis, such as in patients with systemic lupus erythematosus ...(SLE). Although TLRs are differentially expressed across the immune system, a comprehensive analysis of how multiple immune cell subsets respond in a system-wide manner has not been described. Objective We sought to characterize TLR activation across multiple immune cell subsets and subjects, with the goal of establishing a reference framework against which to compare pathologic processes. Methods Peripheral whole-blood samples were stimulated with TLR ligands and analyzed by means of mass cytometry simultaneously for surface marker expression, activation states of intracellular signaling proteins, and cytokine production. We developed a novel data visualization tool to provide an integrated view of TLR signaling networks with single-cell resolution. We studied 17 healthy volunteer donors and 8 patients with newly diagnosed and untreated SLE. Results Our data revealed the diversity of TLR-induced responses within cell types, with TLR ligand specificity. Subsets of natural killer cells and T cells selectively induced nuclear factor κ light chain enhancer of activated B cells in response to TLR2 ligands. CD14hi monocytes exhibited the most polyfunctional cytokine expression patterns, with more than 80 distinct cytokine combinations. Monocytic TLR-induced cytokine patterns were shared among a group of healthy donors, with minimal intraindividual and interindividual variability. Furthermore, autoimmune disease altered baseline cytokine production; newly diagnosed untreated SLE patients shared a distinct monocytic chemokine signature, despite clinical heterogeneity. Conclusion Mass cytometry defined a systems-level reference framework for human TLR activation, which can be applied to study perturbations in patients with inflammatory diseases, such as SLE.
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