Mediators Of Immediate Hypersensitivity Research Articles

Bronchial asthma: the possible role of the chemical mediators of immediate hypersensitivity in the pathogenesis of subacute chronic disease.

Bronchial asthma: the possible role of the chemical mediators of immediate hypersensitivity in the pathogenesis of subacute chronic disease.

Augmentation of antigen receptor-mediated responses by histamine H1 receptor signaling.

Histamine is considered one of the important mediators of immediate hypersensitivity and inflammation, and acts via G protein-coupled receptors. Here, we report that histamine may affect antigen receptor-mediated immune responses of T and B cells via a signal(s) from histamine H1 receptors (H1Rs). Histamine exhibited enhancing effects on the in vitro proliferative responses of anti-CD3epsilon- or anti-IgM-stimulated spleen T and B cells, respectively, at the culture condition that the fetal calf serum was dialyzed before culture and c-kit-positive cells were depleted from the spleen cells. In studies of histamine H1R knockout mice, H1R-deficient T cells had low proliferative responses to anti-CD3epsilon cross-linking or antigen stimulation in vitro. B cells from H1R-deficient mice were also affected, demonstrating low proliferative responses to B cell receptor cross-linking. Antibody production against trinitrophenyl-Ficoll was reduced in H1R-deficient mice. Other aspects of T and B cell function were normal in the H1R knockout mice. H1R-deficient T and B cells showed normal responses upon stimulation with interleukin (IL)-2, IL-4, CD40 ligand, CD40 ligand plus IL-4, and lipopolysaccharide. Collectively, these results imply that the signal generated by histamine through H1R augments antigen receptor-mediated immune responses, suggesting cross-talk between G protein-coupled receptors and antigen receptor-mediated signaling.

The phenotype of human eosinophils, basophils, and mast cells

Basophils, eosinophils, and mast cells (MCs) are specialized effector cells of the immune system. They are involved in inflammatory and allergic reactions and store and release multifunctional mediator molecules including vasoactive substances, lipid mediators, or cytokinesJ -3 Several different agonists, such as immunoglobulin, complement components, peptides, or cytokines and their specific receptors are involved in the activation of basophils, eosinophils, and MCs for mediator secretion? -~ MCs, basophils, and eosinophils originate from uncommitted multipotent progenitor cells. 5 Precursor cells giving rise to eosinophils and basophils (CFU eo/ba) are responsive to T cell-derived factors,6, 7 whereas MC precursor cells (CFUMAST) are responsive to stroma-cell-derived cytokines. 8 Basophils, eosinophils, and MCs form separate cell lineages and the committed precursor cells (giving rise to either MCs, basophils, or eosinophils) clearly are different cells?' 9 Basophils and eosinophils usually complete their differentiation in the bone marrow. After maturation both cells leave the marrow and are circulating cells. Under certain circumstances, and in particular on cell activation, basophils and eosinophils may leave the bloodstream to enter extravascular (inflamed) tissues. 3 In contrast, MCs derive from circulating multipotent progenitor cells (CFU-MIX), and after extravasation/homing of progenitors, undergo and complete their differentiation in extramedullary organs. 1° However, MCs may also migrate in the tissues and appear at sites of inflammation.

Nasal flow-resistive responses to challenge with cold dry air.

Recent studies have suggested that the inhalation of cold air through the nose is associated with the subsequent release of mediators of immediate hypersensitivity. To determine if mucosal surface heat and water loss influence the nasal functional response to cold air, we measured nasal resistance by posterior rhinomanometry before and 1, 5, and 10 min after a 4-min period of isocapnic hyperventilation (30 l/min) through the nose in nine healthy subjects (5 males, 4 females; aged 25-39 yr) while they inhaled air at 0 degrees C. During the challenge period, the subjects breathed either in and out of the nose or in through the nose and out through the mouth. No changes in nasal resistance developed when subjects breathed exclusively through the nose; however, when subjects breathed in through the nose and out through the mouth, nasal resistance was increased 200% at 1 min (P less than 0.01) after the challenge and returned to baseline values by 10 min after cessation of the challenge. These data indicate that nasal functional responses to cold dry air are dependent on the pattern of the ventilatory challenge. If the heat given up from the nasal mucosa to the incoming air is not recovered during expiration (as is the case with inspiration through the nose and expiration through the mouth), nasal obstruction will occur. Hyperpnea of cold air, per se, does not influence nasal resistance.

Analyses of microvascular permeability in response to mediators of immediate hypersensitivity

Mediator-induced changes in microvascular permeability were studied in rodent skin. To monitor these changes, Evan's blue dye, iodinated rat albumin and IgG, and tritiated neutral dextran molecules having different molecular radii were used. After intradermal injections of serotonin, histamine, and bradykinin, the degree of radiolabeled tracer efflux was determined by measuring the extent of blueing and the level of radioactivity in skin biopsy specimens. Although the mediators varied in potency on a molar basis (serotonin > bradykinin > histamine), the efflux resulting from each was similar. Furthermore, kinetic studies revealed that each of these vasoactive agents caused a marked but transient increase in macromolecular permeability that lasted less than 30 minutes. To determine the pore size created and the effect of charge on the transudation of macromolecules into the interstitium, fractions of neutral [ 3H]dextrans with a known molecular size (average radii, 12 and 4.4 nm, respectively) were infused either singly or in combination with 125I-labeled rat albumin and/or IgG before intradermal injection of serotonin, histamine, bradykinin, or compound 48 80 . Regardless of the mediator used, no differences could be demonstrated in macromolecular efflux, as indicated by either the molecular size of the charge of the tracer used. Thus, all mediators of immediate hypersensitivity reactions that were studied produce venular gaps >12 nm in addition to displaying similar vasopermeable characteristics.

Antioxidant-based inhibitors of leukotriene biosynthesis. The discovery of 6-[1-[2-(hydroxymethyl)phenyl]-1-propen-3-yl]-2,3-dihydro-5-benzofuranol, a potent topical antiinflammatory agent

The leukotrienes, metabolites of arachidonic acid produced through the action of the enzyme 5-lipoxygenase, are important mediators of immediate hypersensitivity and inflammation. Among the variety of diseases in which the leukotrienes may play a symptomatic or causative role is the dermatological condition psoriasis, a chronic proliferative disease of the skin. This study reports the synthesis and comparative biological activities of various ortho-substituted phenols including 4-methoxyphenols, 6-hydroxy-1,2,3,4-tetrahydrobenzopyrans, 2,3-dihydro-5-benzofuranols, and 5-benzofuranols. The phenols prepared in this study were evaluated for their ability to inhibit the production of leukotriene B4(LTB4) in isolated human polymorphonuclear leukocytes (PMNs) and to inhibit a topical inflammatory response in the topical mouse ear (TME) model. In the former case, when the log IC50 was plotted versus the log of the octanol/water partition coefficient (log P), to eliminate the effect of lipophilicity, the 2,3-dihydro-5-benzofuranol ring system was shown to be more potent than the other ring systems examined throughout the range of partition coefficients studied. The ability to inhibit leukotriene production in vitro in human PMNs can be rationalized on the basis of a model that suggests that the observed inhibition is dependent on the kinetic ability of the inhibitor to reduce a radical species and on the fraction of inhibitor that is partitioned into the cell membrane. While the in vivo antiinflammatory activity as measured by the TME did not correlate with the in vitro data, it was felt that the TME represented a valuable measure of the ability of a compound to penetrate the skin to the site of an ongoing inflammatory response. Of the compounds synthesized in this study, 6-[1-[2-(hydroxymethyl)phenyl]-1-propen-3-yl]-2,3-dihydro-5-benzof uranol (1, L-651896) was chosen for further development.

Are the Mast Cells Antigen Presenting Cells?

Mast cells have an important role in allergic reactions secreting histamine and other mediators of immediate hypersensitivity. In the present study we evaluated major histocompatibility complex (MHC) class II antigen expression in mast cells and their possible role in antigen presentation. In rats, 10% of mast cells isolated from the pleural cavity expressed MHC class II antigen; after incubation with gamma interferon (INF) 80% of the cells were positive. These findings suggest that mast cells, in addition to their secretory function in allergic reactions, may also function as antigen presenting cells.

Imaging asynchronous changes in intracellular Ca2+ in individual stimulated tumor mast cells.

Changes in the level of intracellular free calcium ([Ca2+]i) are associated with the secretion of mediators of immediate hypersensitivity by rat basophilic leukemia (RBL) cells, a mast cell line. Digital fluorescence ratio imaging of fura-2 was used to measure [Ca2+]i in individual RBL cells. Changes in [Ca2+]i that occurred in response to crosslinking of IgE receptors on the cell surface or to application of the Ca2+ ionophore ionomycin were studied. Stimulation of RBL cells with antigen resulted in rapid increases in [Ca2+]i following lag times that varied widely from cell to cell. Simple averaging of the Ca2+ responses of many cells yielded a gradual response profile that closely resembled that of suspensions of cells measured in the fluorometer. The results show that single cells can respond much more rapidly to antigen than has previously been suggested by studies on populations of cells. The lag time between addition of antigen and initiation of the increase in [Ca2+]i varied considerably between cells in the same field of view. Both the rise time and the variability and average duration of the lag time increased with decreasing antigen concentration.

Diagnosis of Allergy: In Vitro Testing

Relatively few laboratory tests are of proven value in the differential diagnosis and management of allergic diseases. Immunoassays for IgE and for IgE antibodies are the mainstays. Measurement of IgE in serum is advocated as a first-order laboratory test in the differential diagnosis of allergic disease in children and adults. The usefulness of laboratory tests for IgE antibodies in serum, once a subject of debate in the clinical allergy literature, is now firmly established. Confusion, in respect to the use of these tests, is most evident in clinical situations which have been the subject of limited clinical investigation, e.g., the use of tests for IgE antibodies to screen for allergic disease, the indications for their use in patients treated with allergen immunotherapy, and the diagnostic specificity of IgE antibodies to foods as an indicator of food-induced allergic symptoms. Confusion is also apparent in the interpretation of borderline test results, i.e., results which may indicate the presence of low titers of IgE antibodies, and in defining the optimum format for reporting results to maximize the analytical sensitivity of the test method. This review addresses the ambiguities noted above in the interpretation of results. The paragraphs that follow also consider the possible uses of laboratory tests for inflammatory mediators of immediate hypersensitivity, for IgG antibodies to allergens, and of tests designed to evaluate the in vitro functions of lymphocytes in patients with allergic disease.

Leukotrienes as mediators of immediate hypersensitivity

Leukotrienes as mediators of immediate hypersensitivity

Leukotrienes as mediators of immediate hypersensitivity

Leukotrienes as mediators of immediate hypersensitivity

Current Perspectives in Allergy

British physicians coined the term hay fever, pioneered the original concepts of allergy, and forged the foundations of treatment. Comparatively recently, their American counterparts rivaled these achievements, especially in the laboratory and field of technology. This book, the collaborative effort of British and American scientists, encompasses the best of both worlds—tradition, theory, and practice—each complementing the other. In clear, explicit, and easily read prose, the authors describe and explain the interactions of the various components of immediate and delayed hypersensitivity responses, the role of hypersensitivity reactions in the pathogenesis of allergic diseases, and the pharmacophysiology of β-adrenergic agents and methylaxanthines. The Americans concentrate on the discovery of IgE, the elucidation of the genetic determinants of IgE immune responses, and the identification of new classes of lipid and peptide mediators of immediate hypersensitivity. The British, who have not labored under Food and Drug Administration constraints, record their experiences and clinical trials

Can dietary selenium reduce leukotriene production?

The leukotrienes, prominent mediators of immediate hypersensitivity and inflammation, are derived from the major product of leukocyte lipoxygenase activity, 5-HPETE. An alternative pathway for 5-HPETE metabolism is reduction to 5-HETE. I hypothesize that, in analogy to its established role in platelet lipoxygenase metabolism, the selenium-dependent glutathione peroxidase mediates this reduction. If so, supplementary selenium may decrease leukotriene production, and thus have value as a nutritional adjuvant in the management of asthma and various other inflammatory disorders.

Mediators of immediate hypersensitivity in nasal secretions during natural colds and rhinovirus infection.

To test the hypothesis that viral respiratory infections cause symptoms by activating mucosal mast cells to release mediators active on vasculature and mucosal glands, the presence of histamine in nasal secretions was assessed during natural colds and rhinovirus infections. Secretions were collected either with saline washes of the nasal cavity or by forcibly blowing into a beaker, and histamine was assayed spectrofluorometrically. In blown secretions from uninfected subjects, large variations were seen between individuals (ranging from 3 +/- 2 to 59 +/- 32 ng/ml), and equally large variations were seen from day to day in given subjects. Infection with rhinovirus and with influenza A did not change these concentrations significantly. In general, both with blown nasal secretions and with nasal washes, histamine concentrations tended to be lower during infection. Concentration of another preformed mast cell mediator, TAME-esterase, also was not elevated during infection. Thus, these data do not support an hypothesis that mast cell activation occurs during rhinovirus infections.

Mediators of immediate hypersensitivity

Mediators of immediate hypersensitivity

Allergy and immunology: an annotated bibliography of recent literature. Allergy and Immunology Committee, American College of Physicians.

Allergy and immunology: an annotated bibliography of recent literature. Allergy and Immunology Committee, American College of Physicians.

Tissue mast cells in immediate hypersensitivity.

It is now known that in addition to secreting such primary mediators of immediate hypersensitivity as histamine, tissue mast cells actively metabolize arachidonic acid with resultant synthesis of potent leukotriene secondary mediators. New investigative attention is also being devoted to the “sentinel” role of the mast cells suggested by their localization at interfaces with the external environment.

Histamine content of sputum from patients with asthma and chronic bronchitis.

Studies using the guinea pig ileum bioassay technique have previously shown that patients with either asthma or chronic bronchitis have increased amounts of histamine in their sputum. Because of the limitations of this assay technique, a spectrofluorometric method for measuring the histamine content of sputum was developed. Using this technique it was found that the mean histamine concentration of sputum from patients with bronchogenic carcinoma or pneumonia was not significantly different from the mean value for sputum collected during a remission phase from patients with either chronic bronchitis or asthma. However, the mean values in patients with asthma or chronic bronchitis during an exacerbation were significantly higher and returned to basal values as the airways obstruction improved. There was no significant difference in sputum histamine concentration between those patients with extrinsic atopic asthma and those with late onset cryptogenic asthma during as exacerbation although the value in patients with an exacerbation of chronic bronchitis was significantly less. These results indicate that mediators of immediate hypersensitivity may be implicated in the pathogenesis of airways obstruction in disorders other than extrinsic atopic asthma and suggest that histamine release may occur in non-atropic subjects in response to non-antigenic stimuli.

Mediation of local homeostasis and inflammation by leukotrienes and other mast cell-dependent compounds.

The oxidative products of arachidonic acid and other mediators of immediate hypersensitivity are released by mast cells and other cells in response to the presence of noxious substances. In a normal response these chemicals produce the local inflammatory reactions that accompany destruction of the noxious substance. When the host response is misdirected or excessive, the concerted action of the same chemical mediators may produce allergic or inflammatory disease.

Mediators of immediate hypersensitivity derived from arachidonic acid.

Recent progress in the elucidation of the chemical structures and biologic properties of the lipid mediators derived from arachidonic acid promises to lead to a much greater understanding of human immunopathology and allergic diseases. Although most studies of the metabolism of arachidonic acid over the past two decades have been directed toward the cyclooxygenase pathway, which yields diverse prostaglandins and thromboxanes, substantial evidence now indicates that some of the products of the lipoxygenation of arachidonic acid termed hydroxy-eicosatetraenoic acids (HETE's) are potent mediators of more fundamental importance than the cyclooxygenase products in numerous allergic and inflammatory states.Through early bioassay . . .