The role of histamine in allergic diseases Martha V. White, MD Bethesda, Md Histamine, which is stored mainly in mast cells and basophils, is a prominent contributor to allergic disease. Elevations in plasma or tissue histamine levels have been noted during anaphylaxis and experimental allergic responses of the skin, nose, and airways. Of the four cardinal signs of asthma (bronchospasm, edema, inflammation, and mucus secretion), histamine is capable of mediating the first two through its H1 receptor and mucus secretion through its 1-12 receptor. Of the five cardinal signs of allergic rhinitis (pruritus, mucosal edema, sneezing, mucus secretion, and late-phase inflammatory reactions), histamine is capable of mediating the first three through its HI receptor. In the nose, mucus secretion can be reflexively mediated by H~ and possibly also by 1-12receptors. In the skin the cardinal features of urticaria (vasodilation, vascular permeability, and pruritus) can be mediated by stimulation of the 1-11receptor. In anaphylaxis histamine Hx-receptor stimulation can mediate vascular permeability, smooth muscle contraction, and tachycardia, whereas H2-receptor stimulation can mediate mucus secretion. Stimulation of both receptors can mediate vasodilation and reduce peripheral vascular resistance. Thus although histamine is only one of many mediators of allergic disease, it plays a primary role in allergic rhinitis, urticaria, anaphylaxis, and to a lesser degree, asthma. (J ALLERGY CLIN IMMUNOL 1990;86:599-605.)
The clinical expression of allergic diseases, which is mediated in part by IgE, actually depends on the actions of multiple mediators, many of which are derived from mast cells; histamine (one of the earliest recognized mediators of allergy) is prominent among them. Histamine has been studied extensively since 1911, when Dale and Laidlaw ~discovered that it was a potent vasoactive substance. In the past decade the actions of histamine, through its H1 and H2 receptors, have been clarified. This review focuses on the biosynthesis and biodegradation of histamine, the physiology of its release from mast cells and basophils, and its actions on target tissues. The pathophysiology of the allergic response is also discussed, with emphasis on the role of histamine in asthma, allergic rhinitis, urticaria, and anaphylaxis.
HISTAMINE SYNTHESIS AND METABOLISM Histamine is formed during decarboxylation of histidine by the pyridoxal phosphate-dependent enzyme L-histidine decarboxylase (Fig. 1). 2 Most histamine is stored preformed in cytoplasmic granules of mast cells and basophils, which are bound to the anionic
From the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Reprint requests: Martha V. White, MD, Rm. 11C207, Bldg. 10, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. 1/0/23306
Abbreviation used
IL: Interleukin
side-chains of the proteoglycans that make up the granule matrix. In humans mast cells are found in the loose connective tissue of all organs, especially around blood and lymphatic vessels and nerves. These cells are most abundant in the organs expressing allergic diseases: the skin, upper and lower respiratory tracts, and gastrointestinal tract, as well as the reproductive mucosa. Antigen cross-linked IgE is the classic mast cell secretagogue in allergic diseases, but other physiologic mediators may also be involved (Table I). Opioids, such as morphine, cause cutaneous mast cell degranulation through a naloxone-sensitive receptor, and endogenous opioids, or endorphins, may cause a similar reaction. Some of the neuropeptides are also mast cell secretagogues. The best studied, substance P, induces human cutaneous mast cell degranulation at micromolar concentrations. Injected intradermally, substance P induces a wheal-and-flare response that can be inhibited by mast cell stabilization, histamine H~-receptor antagonism, or histamine depletion with compound 4 8 / 8 0 . 3 Depletion of neuropeptides from C fibers with capsaicin causes loss of the histaminemediated flare, but not the whealing response. Collectively, these data suggest that substance P causes
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J. ALLERGYCLIN.IMMUNOL.
OCTOBER1990
NH2 I
Histidine
I~'--5--CH2-CH-COOH 3 1
HN~N I
L-Histidine Decarboxylase Histamine
Smallintestine,"~ Liver,MonocytesKid//~ ney,
3
1
1 -- CH2CH2NH2
HN ~ N
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l
~
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Diamine ~, Oxidase
I
T CH2CH2NH2
] -CH200OH
HN
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CH3
~'Mastcells,~ ~ BasophilsI
.,,,,~ N
/
Monoamine Oxidase i
I--~CH~COOH
N
Conjugate with
__ H
Ribose
CH3 "~"" "~ N-Methyl Imidazole AceticAcid 42-47%
1 l
N-Methyl Histamine 4-8%
Histamine 2-3%
Imidazole AceticAcid 9-11%
Imidazole AceticAcid Riboside
16-23%
FIG. 1. Synthesis and catabolism of histamine. Percentage recovery of histamine and its metabolites in the urine in the 12 hours after intradermal [14C]histamine in human males. (Modified from Douglas WW. Histamine and 5-hydroxytrystamine [serotonin] and their autocords. In: Gilman AG, Goodman LS, Gilman A, eds. Toodman and Gilman's The pharmacologic basis of therapeutics. 6th ed. New York: Macmillan Publishing, 1980:618.)
the release of histamine from human mast cells, that histamine can cause the release of substance P from sensory nerve fibers, and that both histamine and substance P contribute to histamine-induced vasodilation. Histamine release in physical urticaria and angloedema caused by cold, vibration, or pressure has been well described, but the mechanism by Which these stimuli cause mast cell degranulati0:h is not clear. Most inflammatory cells, including tymphocytes, neutrophils, platelets, macrophages,and eosinophils, as well as endothelial cells and nasal lavage fluid, produce or contain histamine-releasing factors. This heterogeneous group o f factors cause basophil degranulation. Several of the cytokines IL-1, IL-3. IL-8, and granulocyte macrophage-colony stimulating factor also cause basophil degranulation, although IL-1 is active only at high concentrations. In addition, the neutrophil-derived histamine-releasing activity is active on human skin mast ceils, whereas the nasal lavage and mononuclear cell factors have been shown
to be active on mast cells in bronchoalveolar lavage fluid. Cross-desensitization and IgE stripping and reconstitution experiments support the hypothesis that some, but not all, of these histamine-releasing factors work through IgE. 4 All these histamine-releasing factors may also recruit mast cell or basophil participation in late-phase allergic reactions and possibly other chronic inflammatory conditions. Hypoxia can also cause mast cell degranulation, perhaps by inducing mast cell participation in hypoxic conditions (e.g., adult respiratory distress syndrome). Finally, various inflammatory products, such as C5a. C4a, and C3a, cause receptor-mediated mast cell degranulation and may therefore be capable of inducing mast cell participation in immune complex diseases. Morphologic changes accompanying mast cell degranulation vary, depending on the type of mast cell involved. Human skin mast cells release intact granules into the extracellular milieu, and some of these granules can subsequently be phagocytosed by con-
VOLUME 86 NUMBER 4, PART 2
TABLE I. Mast cell secretagogues
IgE C3a, C4a, C5a Substance P Opioids, endorphins Physical stimuli: vibration, cold, pressure Histamine-releasing activities from lymphocytes, neutrophils, platelets, endothelial cells, human lung macrophages, eosinophils, and human nasal washings 9 Cytokines: IL-1, IL-3, IL-8; granutocyte macrophage-colony stimulating factor, connective tissue activating peptide lII
H i s t a m i n e in allergic diseases
TABLE II. Nonleukocyte activities mediated through histamine H1 and H2 receptors in humans Receptor
H1
H2 nective tissue fibroblasts. In contrast, degranulation of human lung and nasal mucosal mast cells is characterized by intracellular solubilization of granule contents and fusion of granular membranes with each other and with the cell membrane to form channels to the outside, through which the solubilized granule contents are extruded? After its release, histamine diffuses rapidly into the surrounding tissues: it appears in blood within 21/2 minutes, peaks at 5 minutes, and returns to baseline levels by 15 to 30 minutes. 3 Urinary histamine elevations are more prolonged than plasma elevations. Consequently, abnormalities are more easily detected with the urinary histamine assay. Three methods are commonly used to measure histamine; the radioenzymatic and fluorometric assays are sensitive at 100 pg/ml (normal, 200 to 300 pg/ml) and 1 to 5 ng/ml, respectively. A radioimmunoassay has recently been developed in which histamine, acetylated to a carrier molecule, competes with iodinated, chemically modified histamine for recognition by a monoclonal antibody directed against the modified histamine. This assay is sensitive at 15 pg/ml and is easier to use than the two former methods. 4 Elevations in plasma or tissue histamine have been found after experimental provocation with physical stimuli in various physical urticarias, in antigen- and exercise-induced anaphylaxis, in natural and provoked bronchospasm, after intradermal skin testing, and in patients with mastocytosis. Urinary histamine is increased in mastocytosis, in idiopathic hypereosinophilic syndrome with concomitant allergic disease, in some cases of Zollinger-Ellison syndrome, and occasionally in pregnant women.6 Only 2% to 3% of histamine is excreted unchanged in the urine. The rest is metabolized by two major enzymatic pathways (Fig. 1). Most (50% to 70%) histamine is metabolized to N-methylhistamine by Nmethyltransferase, and some is metabolized further by monoamine oxidase to N-methylimidazoleacetic acid
601
H1 and H2
Action
Smooth muscle contraction Increased vascular permeability Increased cyclic guanosine monophosphate Pruritus Prostaglandin generation Decreased atrioventxicular node conduction time Airway vagal afferent nerve activation Gastric acid secrection Increased lower airway mucus secretion Increased cyclic adenosine monophosphate Esohpageal contraction Basophil histamine release inhibition Neutrophil chemotaxis and enzyme release inhibition Suppressor T cell stimulation Hypotension Flushing Headache
and excreted in the urine. The remaining 30% to 40% of histamine is metabolized to imidazoleacetic acid by diamine oxidase, which is also called histaminase. HISTAMINE EFFECTS
The actions of histamine are mediated through three distinct receptors defined pharmacologically by the actions of their respective agonists and antagonists (Table II). Most of the important histamine effects in allergic diseases are mediated through the Ht receptor. These include smooth muscle contraction, increased vascular permeability, pruritus, prostaglandin generation, decreased atrioventficular node conduction time, with resultant tachycardia, activation of vagal reflexes, and increased cyclic guanosine monophosphate. The H2-mediated effects include gastric acid secretion, increased lower airway mucus secretion (in the nose, mucus secretion is the result of a histamine Hi-mediated muscarinic reflex), increased cyclic adenosine monophosphate, esophageal contraction, inhibition of basophil, but not mast cell, histamine release, inhibition of neutrophil activation, and induction of suppressor T cells. Several effects are mediated through combined H~/H2-receptor stimulation: vasodilation-related symptoms (e.g., hypotenSion, flushing, and headache), as well as tachycardia stimulated indirectly through vasodilation and catecholamine secretion. 3 A third histamine receptor, thought
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White
J. ALLERGY CLIN. IMMUNOL. OCTOBER 1990
TABLE III. Pathologic features of asthma and proposed mediators Pathologic feature
Bronchospasm
Mucosal edema
Airway inflammation
MHCllS secretion
Proposed mediator
Histamine (H,) Leukotriene C4, D4, and E4 Prostaglandins and thromboxane A2 Bradykinin Platelet-activating factor Histamine (H,) Leukotriene C4, D4, and E4 Prostaglandin E Bradykinin Platelet-activating factor Eosinophil chemotactic factor Neutrophil chemotactic factor Leukotriene B4 Platelet-activating factor Leukotriene C4, D4, and E4 Prostaglandin-generating factor 5- and 15-HETE
Modified from Kaliner M. Chest 1985;87S:2S-5S.
to mediate a negative feedback action on histamine synthesis, has recently been described in neural tissue. 4 Histamine-induced vascular permeability is an H~mediated effect that is caused by contraction of actomyosin fibers in endothelial cells of the postcapillary venules. 3 Increased permeability occurs in all allergic diseases and therefore is a feature o f allergic rhinitis, asthma, urticaria, and anaphylaxis. Histamine's ability to induce smooth muscle contraction forms the basis for the histamine bioassay. Diseases that feature smooth muscle contraction include asthma and food allergy. Histamine is also the only proved mediator of pruritus; it is prominent in urticaria, eczema, and allergic rhinitis. The mechanism by which histamine mediates pruritus is indirect and involves stimulation of sensory nerve endings. Neurohormones probably partially mediate histamine-induced cutaneous vasodilation and flushing because capsaicin treatment inhibits the histamine-induced flare but not the wheal. Vasodilation is a prominent component of urticaria and anaphylaxis. Increased mucus production from both vascular and glandular sources is prominent in asthma, allergic rhinitis, and food allergy. In the nose the glandular component is indirectly mediated by histamine through a vagal reflex; unilateral nasal histamine challenge resuits in contralateral glandular secretion that is inhib-
ited by atropine. 7, 8 In addition, hypotension and shock in anaphylaxis are secondary to increased vascular permeability and vasodilation. Tachycardia, which is also prominent in anaphylaxis, can be caused by decreased atrioventricular node conduction time and indirectly by histamine-induced vasodilation and resultant catecholamine secretion. Finally, histamine induces prostaglandin formation, possibly contributing to both asthma and allergic rhinitis. 3 Although histamine is a primary mediator in allergic disease, effects known to be mediated by histamine can also be caused by other mediators derived from mast cells. A systematic review of the pathophysiology of individual allergic diseases, including potential contributing mediators, will facilitate an assessment of the importance of histamine in the pathophysiology of allergic diseases. Asthma
The cardinal features of asthma include smooth muscle spasm, mucosal edema, inflammation, and mucus secretion, which can be the result of both glandular secretion of mucus glycoproteins and increased movement of interstitial fluid into the airway lumen. Examination of the mediators potentially responsible for causing these pathologic features of asthma reveals that bronchospasm and mucosal edema can be caused by H~-receptor stimulation, whereas H2 and possibly H1 activation may be minor causes of mucus secretion (Table 1II). 9 Other mediators may also be significant contributors. Leukotrienes, prostaglandins, bradykinin, and platelet-activating factor can stimulate both bronchospasm and mucosal edema. Airway inflammation is not stimulated by histamine but can be caused by inflammatory factors, such as neutrophil and eosinophil chemotactic factors, leukotriene B4, and platelet-activating factor. Mucus glycoprotein secretion can be induced by H2-receptor activation, whereas increased movement of interstitial fluid into the airway lumen can be mediated by H] receptors. In addition, leukotrienes, prostaglandin-generating factor, and 5- and 15-hydroxy-eicosatetranoic acid (HETE) can mediate increased mucus secretion. Clinical trials with classic H] antagonists for the treatment of asthma have yielded disappointing results. On the other hand, experiments with high doses of the newer, nonsedating H] antagonists have demonstrated complete protection agaisnt histamine and partial protection (10% to 20%) against exercise- and antigen-induced asthma. 4 Although histamine is probably not a major mediator in asthma, it contributes to the pathogenesis of the disease. Consequently, highdose nonsedating H~ antagonists deserve further study as potential agents in the treatment of asthma.
Histamine in allergic diseases 603
VOLUME86 NUMBER 4, PART 2
TABLE IV. Symptoms and pathologic features of allergic rhinitis and proposed mediators Symptom
Pathologic feature
Proposed mediator
Pruritus
Sensory nerve stimulation
Nasal obstruction
Mucosal edema
Sneezing
Sensory nerve stimulation
Rhinorrhea
Increased mucus secretion
Hyperirritability and congestion
Late-phase reaction
Histamine (H1) Prostaglandins Histamine (HI) Kinins Leukotriene (24, 94, and E4 Histamine (H0 Leukotriene C4, D4, and E4 Histamine; indirect (muscarinic discharge) Leukotriene C4, D4, and E4 Inflammatory factors Eicosanoids Chemotactic factors: Neutrophil and eosinophil
Modified from Druce HM, Kaliner MA. JAMA 1988;259:260-3, copyright 1988, American Medical Association.
Allergic rhinitis
The symptom complex of seasonal allergic rhinitis consists of paroxysms of sneezing, nasal and palatal pruritus, nasal congestion, and clear rhinorrhea. In severe cases contiguous or adjacent mucous membranes of the eye, middle ear, or paranasal sinuses may be involved. This involvement can lead to mucosal swelling, followed by occlusion of the eustachian tubes and sinus ostia, with resultant serous or purulent otitis media or sinusitis, respectively. Approximately 10% to 15% of the general U.S. population has allergic rhinitis. The peak incidence occurs during adolescence, and approximately two thirds of the cases occur before age of 30 years. 6 Insufflation of specific allergen into the nose of a person with allergic rhinitis induces congestion, pruritus, sneezing, and increased secretion. Congestion is caused by vasodilation and increased vascular permeability, whereas both pruritus and sneezing are caused by sensory nerve stimulation. Approximately 80% of increased secretions are derived from the vasculature and 20% from the blands. 8 Examination of the putative mediators reveals that histamine can cause all the pathologic features of allergic rhinitis, with the exception of late-phase inflammatory reactions (Table IV). 6 Pruritus, which is responsible for the palatal clicking so characteristic of allergic rhinitis, is caused by stimulation of HI receptors on sensory nerve endings; prostaglandins may also contribute. Mucosal edema, which manifests as nasal obstruction, can be caused by H~ stimulation as well as eicosanoids and kinins. Sneezing, like prutitus, is an Hi-mediated neural reflex and can also be mediatedby eicosanoids. Nasal mucus secretion can be mediated by histamine both directly and indirectly through muscarinic discharge and by eicosanoids.
Late-phase reactions, which manifest as nasal congestion and hyperirritability, are mediated not by histamine, but rather by inflammatory and chemotactic factors and eicosanoids. Therefore, overall histamine can cause four of the five pathologic components of allergic rhinitis. In view of the excellent response to H1 antagonists experienced by most patients with allergic rhinitis, histamine is a likely primary mediator of this disease. Urticaria
The hallmark of urticaria is a pruritic, erythematous raised lesion that blanches with pressure; this sign is indicative of venous dilation and edema. Therefore the three cardinal features of urticaria are pruritus, vasodilation, and increased vascular permeability involving the superficial dermis. Histamine, acting through its H1 receptor, can mediate all three pathologic components of urticaria: it is the only proved mediator of pruritus and can mediate vascular permeability and vasodilation. Other vasoactive mediators that might contribute to vasodilation and edema include prostaglandin D2, leukotrienes C4 and D4, platelet-activating factor, and bradykinin (Table V). prostaglandin D2 is a vasodilator, whereas leukotrienes C4 and C4 mediate increased vascular permeability. ~0 These eicosanoids may act synergistically in the skin." Release of platelet-activating factor, which can mediate increased vascular permeability, has been measured during experimentally induced cold urticaria. 12 Bradykinin, which is generated in the tissues after mast cell degranulation, is also a potent vastactive substance that induces a burning pain. Bradykinin may be a more prominent mediator in angloedema, which is characterized by deep dermal vastdilation and edema concomitant with burning pain.
604 White
J. ALLERGYCLIN.IMMUNOL. OCTOBER 1990
TABLE V. Symptoms and pathologic features of urticaria and proposed mediators Symptom
Pathologic feature
Proposed mediator
Wheal
Vascular permeability
Flare
Vasodilation
Pruritus
Sensory nerve stimulation
Histamine (H~) Prostaglandin D2 Platelet-activating factor Bradykinin Leukotriene C4, D4, and E4 Histamine (H,) Prostaglandins Platelet-activating factor Bradykinin Leukotriene C4, D4, and E4 Histamine (H~)
TABLE Vl. Symptoms and pathologic features of anaphylaxis and proposed mediators
Symptom
Pathologic feature
Proposed mediator
Urticaria, angioedema, laryngeal and intestinal edema
Vascular permeability
Flushing, headache, and hypotension
Vasodilation
Palpitations Rhinorrhea and bronchorrhea
Arrhythmias Mucus secretion
Histamine (HI) Eicosanoids Histamine (H~ and H2) Eicosanoids Histamine (H0 Histamine (H~ and H2) Eicosanoids
Modified from Kaliner MA. In: Lockey RE, Bukantz SC, eds. Fundamentals of immunology and allergy. Philadelphia: WB Saunders, 1987: 203-16.
H1 antihistamines are the primary therapy for urticaria; many patients' symptoms can be controlled with these agents alone. Anaphylaxis
Anaphylaxis is a mast cell-mediated, lifethreatening multiorgan disorder. The major organs involved include the skin (where symptoms including flushing, urticaria, and angioedema), the cardiovascular system (tachycardia, hypotension, shock, syncope, and arrhythmias), the gastrointestinal tract (abdominal bloating, diarrhea, and vomiting), and the respiratory tract (rhinorrhea, laryngeal edema, wheezing, bronchorrhea, and asphyxiation). Other effects include diaphoresis and fecal or urinary incontinence. Patients complain of pruritus (especially around the face, neck, and back), weakness, palpitations, bloating, crampy diarrhea, congestion, and dyspnea. In addition, these persons frequently have a peculiar metallic taste in their mouths and a feeling of impending doom. When anaphylaxis is separated into its pathologic components, the pattern mirrors the pathology inherent to other mast cell-mediated processes. In fact, all the symptoms of anaphylaxis can be reproduced
by histamine. Vascular permeability manifests as urticaria, angioedema, and laryngeal and intestinal edema; vasodilation leads to flushing and headache; and smooth muscle contraction results in wheezing, abdominal cramping,, and diarrhea. Tachycardia resuits in palpitations; reduced peripheral vascular resistance is responsible for syncope; and mucus secretion manifests as rhinorrhea and bronchorrhea. Histamine, either alone or in conjunction with eicosanoids, can mediate all the features of anaphylaxis (Table VI). 13 Mild anaphylaxis restricted to pruritus, or hives may be effectively treated with H1 antagonists alone, but systemic reactions with cardiovascular involvement require combination therapy with HI and H2 antagonists, with or without volume expansion, pressors, and corticosteroids. CONCLUSION
Mast cell degranulation results in the release of preformed mediators, such as histamine and chemotactic factors, and in the generation of mediators, such as eicosanoids and platelet-activating factor from membrane lipids, and kinins by the action of mast cell enzymes on tissue precursors. These mediators share responsibility for the pathologic processes in-
VOLUME86
Histamine in allergic diseases
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NUMBER 4, PART 2
herent in allergic disorders. H i s t a m i n e can elicit all or m o s t o f the pathologic processes i n v o l v e d in allergic rhinitis, urticaria, anaphylaxis, and asthma. Furtherm o r e , H1 antagonists, alone or in c o m b i n a t i o n with H2 antagonists, are h i g h l y e f f e c t i v e in the treatment of allergic rhinitis, urticaria, and anaphylaxis; H1 antihistamines offer partial protection in asthma. C o n sequently, even t h o u g h histamine is only one o f m a n y mediators o f allergic disease, it should be strongly c o n s i d e r e d w h e n analyzing the cause and treatment o f any m a s t c e l l - r e l a t e d disease. REFERENCES
1. Dale HH, Laidlaw PP. The physiologic action of 13imidazolylethylamine. J Physiol 1911;41:318-44. 2. Douglas WW. Histamine and 5-hydroxytryptamine (serotonin) and their antagonists. In: Gilman AG, Goodman LS, Gilman A, eds. The pharmacologic basis of therapeutics, 6th ed. New York: Macmillan, 1980:609-46. 3. White MV, Slater JE, Kaliner MA. Histamine and asthma. Am Rev Respir Dis 1987;135:1165-76. 4. White MV, Kaliner MA. Histamine. In: Barnes PJ, Chemiack NS, Weibel ER, eds. The lung: scientific foundations. New York: Raven Press [in press]. 5. White MV, Kowalski ML, Katiner MA. Mast cell secretagogues. In: Wintraub B, Tauber F, Simon AS, eds. Biochemistry of the acute allergic reaction, Fifth International Symposium. New York: Alan R Liss, 1989:83-101. 6. Druce HM, Kaliner MA. Allergic rhinitis. JAMA 1988; 259:260-3. 7. Raphael GD, Meredith SC. Baraniuk JN, Druce HM, Banks SM, Kaliner MA. The pathophysiology of rhinitis. II. Assessment of the sources of protein in histamine-induced nasal secretions. Am Rev Respir Dis 1989;139:791-800. 8. Mullol J, Raphael GD, Baraniuk JN, et al. Neurohormonal glandular secretion from human nasal mucosa in vivo and in vitro [Abstract]. J ALLERGYCLrN IMMUNOL1990;85:224. 9. Kaliner M. Mast cell mediators and asthma. Chest 1985; 87(suppl):2S-5S. 10. Orange RP, Austen KF. Immunologic and pharmacologic receptor control of the release of chemical mediators from human lung. In: lshizaka K, Dayton DH Jr, eds. The biological role of the immunoglobulin E system. Bethesda, Md.: National Institutes of Health, U.S. Department of Health, Education, and Welfare, 1972. 11. Soter NA, Lewis R_A, Corey EJ, Austen KF. Local effects of synthetic leukotrienes (LTC4, LTD4, LTE4 and LTB4) in human skin. J Invest Dermatol 1983;80:115-20. 12. Kaplan AP. Urticaria and angioedema. In: Middleton E, Reed CE, Ellis EF, eds. Allergy; principles and practice. 3rd ed. St. Louis: The CV Mosby Co, 1988:1377-401.
13. Kaliner MA. Anaphylaxis. In: Lockey RE, Bukantz SC, eds. Fundamentals of immunology and allergy. Philadelphia: WB Saunders, 1987:203-16. DISCUSSION
Question. What do you believe is the role of the H3 receptor, which has recently been identified? Dr. White. To the best of my knowledge, the H3 receptor is primarily responsible for turning off histamine secretion. This receptor is found in the brain, but some data suggest that it may also be present in the lungs and other tissues. Furthermore, the ability of the H2 receptor to turn off histamine secretion in the basophil may be mediated by the H3 receptor. Question. In patients who experience anaphylaxis, the severity of the response often varies, even within the same person and with exposure to the same gross quantity of allergen. Can you explain these differences? Dr. White. Several explanations can be considered. First, the amount of mediators released, or the susceptibility of the target organs to these mediators, may vary. Alternatively, the presence of the H3 or H2 receptor might alter susceptibility to H1 effects. Another possibility is that these variations are linked to the distribution of mast cells. Question, How do you interpret the recently postulated phenomenon of spontaneous histamine release? Dr. White. We have observed increased spontaneous histamine release in some patients with food allergies, as well as in persons without food allergies. Some information is available that suggests the involvement of circulating histamine-releasing factors that may work through the IgE receptor. Despite recently published data, however, I am not convinced that increased spontaneous release is caused by mononuclear cell-derived histamine-releasing factor. Question. How certain are we that histamine comes only from mast cells or basophils? Are any good immunohistochemical data available to show that epithelial or glandular cells do not contain histamine? Could spontaneous release of histamine be the result of involvement of another cell type? Dr. White, Histamine has not been shown to be released from other cell types, although there is a non-mast c e l l basophil source in the brain. It may also exist in other parts of the body that have not yet been identified. Question. Is there a difference between acute and chronic urticaria with regard to the roles of H1 and I-I2 receptors? Dr. White. There is no clearcut difference between acute and chronic urticaria in terms of either antihistamine responsiveness or histology.
The clinical expression of allergic diseases, which is mediated in part by IgE, actually depends on the actions of multiple mediators, many of which are derived from mast cells; histamine (one of the earliest recognized mediators of allergy) is prominent among them. Histamine has been studied extensively since 1911, when Dale and Laidlaw ~discovered that it was a potent vasoactive substance. In the past decade the actions of histamine, through its H1 and H2 receptors, have been clarified. This review focuses on the biosynthesis and biodegradation of histamine, the physiology of its release from mast cells and basophils, and its actions on target tissues. The pathophysiology of the allergic response is also discussed, with emphasis on the role of histamine in asthma, allergic rhinitis, urticaria, and anaphylaxis.
HISTAMINE SYNTHESIS AND METABOLISM Histamine is formed during decarboxylation of histidine by the pyridoxal phosphate-dependent enzyme L-histidine decarboxylase (Fig. 1). 2 Most histamine is stored preformed in cytoplasmic granules of mast cells and basophils, which are bound to the anionic
From the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Reprint requests: Martha V. White, MD, Rm. 11C207, Bldg. 10, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. 1/0/23306
Abbreviation used
IL: Interleukin
side-chains of the proteoglycans that make up the granule matrix. In humans mast cells are found in the loose connective tissue of all organs, especially around blood and lymphatic vessels and nerves. These cells are most abundant in the organs expressing allergic diseases: the skin, upper and lower respiratory tracts, and gastrointestinal tract, as well as the reproductive mucosa. Antigen cross-linked IgE is the classic mast cell secretagogue in allergic diseases, but other physiologic mediators may also be involved (Table I). Opioids, such as morphine, cause cutaneous mast cell degranulation through a naloxone-sensitive receptor, and endogenous opioids, or endorphins, may cause a similar reaction. Some of the neuropeptides are also mast cell secretagogues. The best studied, substance P, induces human cutaneous mast cell degranulation at micromolar concentrations. Injected intradermally, substance P induces a wheal-and-flare response that can be inhibited by mast cell stabilization, histamine H~-receptor antagonism, or histamine depletion with compound 4 8 / 8 0 . 3 Depletion of neuropeptides from C fibers with capsaicin causes loss of the histaminemediated flare, but not the whealing response. Collectively, these data suggest that substance P causes
599
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White
J. ALLERGYCLIN.IMMUNOL.
OCTOBER1990
NH2 I
Histidine
I~'--5--CH2-CH-COOH 3 1
HN~N I
L-Histidine Decarboxylase Histamine
Smallintestine,"~ Liver,MonocytesKid//~ ney,
3
1
1 -- CH2CH2NH2
HN ~ N
N-Meth ,~nsferase I
l
~
Placenta,Liver, / Skin, Kidney, Thymus, / Eosinophil, Neutrophil
Diamine ~, Oxidase
I
T CH2CH2NH2
] -CH200OH
HN
t N-.....~ N
CH3
~'Mastcells,~ ~ BasophilsI
.,,,,~ N
/
Monoamine Oxidase i
I--~CH~COOH
N
Conjugate with
__ H
Ribose
CH3 "~"" "~ N-Methyl Imidazole AceticAcid 42-47%
1 l
N-Methyl Histamine 4-8%
Histamine 2-3%
Imidazole AceticAcid 9-11%
Imidazole AceticAcid Riboside
16-23%
FIG. 1. Synthesis and catabolism of histamine. Percentage recovery of histamine and its metabolites in the urine in the 12 hours after intradermal [14C]histamine in human males. (Modified from Douglas WW. Histamine and 5-hydroxytrystamine [serotonin] and their autocords. In: Gilman AG, Goodman LS, Gilman A, eds. Toodman and Gilman's The pharmacologic basis of therapeutics. 6th ed. New York: Macmillan Publishing, 1980:618.)
the release of histamine from human mast cells, that histamine can cause the release of substance P from sensory nerve fibers, and that both histamine and substance P contribute to histamine-induced vasodilation. Histamine release in physical urticaria and angloedema caused by cold, vibration, or pressure has been well described, but the mechanism by Which these stimuli cause mast cell degranulati0:h is not clear. Most inflammatory cells, including tymphocytes, neutrophils, platelets, macrophages,and eosinophils, as well as endothelial cells and nasal lavage fluid, produce or contain histamine-releasing factors. This heterogeneous group o f factors cause basophil degranulation. Several of the cytokines IL-1, IL-3. IL-8, and granulocyte macrophage-colony stimulating factor also cause basophil degranulation, although IL-1 is active only at high concentrations. In addition, the neutrophil-derived histamine-releasing activity is active on human skin mast ceils, whereas the nasal lavage and mononuclear cell factors have been shown
to be active on mast cells in bronchoalveolar lavage fluid. Cross-desensitization and IgE stripping and reconstitution experiments support the hypothesis that some, but not all, of these histamine-releasing factors work through IgE. 4 All these histamine-releasing factors may also recruit mast cell or basophil participation in late-phase allergic reactions and possibly other chronic inflammatory conditions. Hypoxia can also cause mast cell degranulation, perhaps by inducing mast cell participation in hypoxic conditions (e.g., adult respiratory distress syndrome). Finally, various inflammatory products, such as C5a. C4a, and C3a, cause receptor-mediated mast cell degranulation and may therefore be capable of inducing mast cell participation in immune complex diseases. Morphologic changes accompanying mast cell degranulation vary, depending on the type of mast cell involved. Human skin mast cells release intact granules into the extracellular milieu, and some of these granules can subsequently be phagocytosed by con-
VOLUME 86 NUMBER 4, PART 2
TABLE I. Mast cell secretagogues
IgE C3a, C4a, C5a Substance P Opioids, endorphins Physical stimuli: vibration, cold, pressure Histamine-releasing activities from lymphocytes, neutrophils, platelets, endothelial cells, human lung macrophages, eosinophils, and human nasal washings 9 Cytokines: IL-1, IL-3, IL-8; granutocyte macrophage-colony stimulating factor, connective tissue activating peptide lII
H i s t a m i n e in allergic diseases
TABLE II. Nonleukocyte activities mediated through histamine H1 and H2 receptors in humans Receptor
H1
H2 nective tissue fibroblasts. In contrast, degranulation of human lung and nasal mucosal mast cells is characterized by intracellular solubilization of granule contents and fusion of granular membranes with each other and with the cell membrane to form channels to the outside, through which the solubilized granule contents are extruded? After its release, histamine diffuses rapidly into the surrounding tissues: it appears in blood within 21/2 minutes, peaks at 5 minutes, and returns to baseline levels by 15 to 30 minutes. 3 Urinary histamine elevations are more prolonged than plasma elevations. Consequently, abnormalities are more easily detected with the urinary histamine assay. Three methods are commonly used to measure histamine; the radioenzymatic and fluorometric assays are sensitive at 100 pg/ml (normal, 200 to 300 pg/ml) and 1 to 5 ng/ml, respectively. A radioimmunoassay has recently been developed in which histamine, acetylated to a carrier molecule, competes with iodinated, chemically modified histamine for recognition by a monoclonal antibody directed against the modified histamine. This assay is sensitive at 15 pg/ml and is easier to use than the two former methods. 4 Elevations in plasma or tissue histamine have been found after experimental provocation with physical stimuli in various physical urticarias, in antigen- and exercise-induced anaphylaxis, in natural and provoked bronchospasm, after intradermal skin testing, and in patients with mastocytosis. Urinary histamine is increased in mastocytosis, in idiopathic hypereosinophilic syndrome with concomitant allergic disease, in some cases of Zollinger-Ellison syndrome, and occasionally in pregnant women.6 Only 2% to 3% of histamine is excreted unchanged in the urine. The rest is metabolized by two major enzymatic pathways (Fig. 1). Most (50% to 70%) histamine is metabolized to N-methylhistamine by Nmethyltransferase, and some is metabolized further by monoamine oxidase to N-methylimidazoleacetic acid
601
H1 and H2
Action
Smooth muscle contraction Increased vascular permeability Increased cyclic guanosine monophosphate Pruritus Prostaglandin generation Decreased atrioventxicular node conduction time Airway vagal afferent nerve activation Gastric acid secrection Increased lower airway mucus secretion Increased cyclic adenosine monophosphate Esohpageal contraction Basophil histamine release inhibition Neutrophil chemotaxis and enzyme release inhibition Suppressor T cell stimulation Hypotension Flushing Headache
and excreted in the urine. The remaining 30% to 40% of histamine is metabolized to imidazoleacetic acid by diamine oxidase, which is also called histaminase. HISTAMINE EFFECTS
The actions of histamine are mediated through three distinct receptors defined pharmacologically by the actions of their respective agonists and antagonists (Table II). Most of the important histamine effects in allergic diseases are mediated through the Ht receptor. These include smooth muscle contraction, increased vascular permeability, pruritus, prostaglandin generation, decreased atrioventficular node conduction time, with resultant tachycardia, activation of vagal reflexes, and increased cyclic guanosine monophosphate. The H2-mediated effects include gastric acid secretion, increased lower airway mucus secretion (in the nose, mucus secretion is the result of a histamine Hi-mediated muscarinic reflex), increased cyclic adenosine monophosphate, esophageal contraction, inhibition of basophil, but not mast cell, histamine release, inhibition of neutrophil activation, and induction of suppressor T cells. Several effects are mediated through combined H~/H2-receptor stimulation: vasodilation-related symptoms (e.g., hypotenSion, flushing, and headache), as well as tachycardia stimulated indirectly through vasodilation and catecholamine secretion. 3 A third histamine receptor, thought
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J. ALLERGY CLIN. IMMUNOL. OCTOBER 1990
TABLE III. Pathologic features of asthma and proposed mediators Pathologic feature
Bronchospasm
Mucosal edema
Airway inflammation
MHCllS secretion
Proposed mediator
Histamine (H,) Leukotriene C4, D4, and E4 Prostaglandins and thromboxane A2 Bradykinin Platelet-activating factor Histamine (H,) Leukotriene C4, D4, and E4 Prostaglandin E Bradykinin Platelet-activating factor Eosinophil chemotactic factor Neutrophil chemotactic factor Leukotriene B4 Platelet-activating factor Leukotriene C4, D4, and E4 Prostaglandin-generating factor 5- and 15-HETE
Modified from Kaliner M. Chest 1985;87S:2S-5S.
to mediate a negative feedback action on histamine synthesis, has recently been described in neural tissue. 4 Histamine-induced vascular permeability is an H~mediated effect that is caused by contraction of actomyosin fibers in endothelial cells of the postcapillary venules. 3 Increased permeability occurs in all allergic diseases and therefore is a feature o f allergic rhinitis, asthma, urticaria, and anaphylaxis. Histamine's ability to induce smooth muscle contraction forms the basis for the histamine bioassay. Diseases that feature smooth muscle contraction include asthma and food allergy. Histamine is also the only proved mediator of pruritus; it is prominent in urticaria, eczema, and allergic rhinitis. The mechanism by which histamine mediates pruritus is indirect and involves stimulation of sensory nerve endings. Neurohormones probably partially mediate histamine-induced cutaneous vasodilation and flushing because capsaicin treatment inhibits the histamine-induced flare but not the wheal. Vasodilation is a prominent component of urticaria and anaphylaxis. Increased mucus production from both vascular and glandular sources is prominent in asthma, allergic rhinitis, and food allergy. In the nose the glandular component is indirectly mediated by histamine through a vagal reflex; unilateral nasal histamine challenge resuits in contralateral glandular secretion that is inhib-
ited by atropine. 7, 8 In addition, hypotension and shock in anaphylaxis are secondary to increased vascular permeability and vasodilation. Tachycardia, which is also prominent in anaphylaxis, can be caused by decreased atrioventricular node conduction time and indirectly by histamine-induced vasodilation and resultant catecholamine secretion. Finally, histamine induces prostaglandin formation, possibly contributing to both asthma and allergic rhinitis. 3 Although histamine is a primary mediator in allergic disease, effects known to be mediated by histamine can also be caused by other mediators derived from mast cells. A systematic review of the pathophysiology of individual allergic diseases, including potential contributing mediators, will facilitate an assessment of the importance of histamine in the pathophysiology of allergic diseases. Asthma
The cardinal features of asthma include smooth muscle spasm, mucosal edema, inflammation, and mucus secretion, which can be the result of both glandular secretion of mucus glycoproteins and increased movement of interstitial fluid into the airway lumen. Examination of the mediators potentially responsible for causing these pathologic features of asthma reveals that bronchospasm and mucosal edema can be caused by H~-receptor stimulation, whereas H2 and possibly H1 activation may be minor causes of mucus secretion (Table 1II). 9 Other mediators may also be significant contributors. Leukotrienes, prostaglandins, bradykinin, and platelet-activating factor can stimulate both bronchospasm and mucosal edema. Airway inflammation is not stimulated by histamine but can be caused by inflammatory factors, such as neutrophil and eosinophil chemotactic factors, leukotriene B4, and platelet-activating factor. Mucus glycoprotein secretion can be induced by H2-receptor activation, whereas increased movement of interstitial fluid into the airway lumen can be mediated by H] receptors. In addition, leukotrienes, prostaglandin-generating factor, and 5- and 15-hydroxy-eicosatetranoic acid (HETE) can mediate increased mucus secretion. Clinical trials with classic H] antagonists for the treatment of asthma have yielded disappointing results. On the other hand, experiments with high doses of the newer, nonsedating H] antagonists have demonstrated complete protection agaisnt histamine and partial protection (10% to 20%) against exercise- and antigen-induced asthma. 4 Although histamine is probably not a major mediator in asthma, it contributes to the pathogenesis of the disease. Consequently, highdose nonsedating H~ antagonists deserve further study as potential agents in the treatment of asthma.
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TABLE IV. Symptoms and pathologic features of allergic rhinitis and proposed mediators Symptom
Pathologic feature
Proposed mediator
Pruritus
Sensory nerve stimulation
Nasal obstruction
Mucosal edema
Sneezing
Sensory nerve stimulation
Rhinorrhea
Increased mucus secretion
Hyperirritability and congestion
Late-phase reaction
Histamine (H1) Prostaglandins Histamine (HI) Kinins Leukotriene (24, 94, and E4 Histamine (H0 Leukotriene C4, D4, and E4 Histamine; indirect (muscarinic discharge) Leukotriene C4, D4, and E4 Inflammatory factors Eicosanoids Chemotactic factors: Neutrophil and eosinophil
Modified from Druce HM, Kaliner MA. JAMA 1988;259:260-3, copyright 1988, American Medical Association.
Allergic rhinitis
The symptom complex of seasonal allergic rhinitis consists of paroxysms of sneezing, nasal and palatal pruritus, nasal congestion, and clear rhinorrhea. In severe cases contiguous or adjacent mucous membranes of the eye, middle ear, or paranasal sinuses may be involved. This involvement can lead to mucosal swelling, followed by occlusion of the eustachian tubes and sinus ostia, with resultant serous or purulent otitis media or sinusitis, respectively. Approximately 10% to 15% of the general U.S. population has allergic rhinitis. The peak incidence occurs during adolescence, and approximately two thirds of the cases occur before age of 30 years. 6 Insufflation of specific allergen into the nose of a person with allergic rhinitis induces congestion, pruritus, sneezing, and increased secretion. Congestion is caused by vasodilation and increased vascular permeability, whereas both pruritus and sneezing are caused by sensory nerve stimulation. Approximately 80% of increased secretions are derived from the vasculature and 20% from the blands. 8 Examination of the putative mediators reveals that histamine can cause all the pathologic features of allergic rhinitis, with the exception of late-phase inflammatory reactions (Table IV). 6 Pruritus, which is responsible for the palatal clicking so characteristic of allergic rhinitis, is caused by stimulation of HI receptors on sensory nerve endings; prostaglandins may also contribute. Mucosal edema, which manifests as nasal obstruction, can be caused by H~ stimulation as well as eicosanoids and kinins. Sneezing, like prutitus, is an Hi-mediated neural reflex and can also be mediatedby eicosanoids. Nasal mucus secretion can be mediated by histamine both directly and indirectly through muscarinic discharge and by eicosanoids.
Late-phase reactions, which manifest as nasal congestion and hyperirritability, are mediated not by histamine, but rather by inflammatory and chemotactic factors and eicosanoids. Therefore, overall histamine can cause four of the five pathologic components of allergic rhinitis. In view of the excellent response to H1 antagonists experienced by most patients with allergic rhinitis, histamine is a likely primary mediator of this disease. Urticaria
The hallmark of urticaria is a pruritic, erythematous raised lesion that blanches with pressure; this sign is indicative of venous dilation and edema. Therefore the three cardinal features of urticaria are pruritus, vasodilation, and increased vascular permeability involving the superficial dermis. Histamine, acting through its H1 receptor, can mediate all three pathologic components of urticaria: it is the only proved mediator of pruritus and can mediate vascular permeability and vasodilation. Other vasoactive mediators that might contribute to vasodilation and edema include prostaglandin D2, leukotrienes C4 and D4, platelet-activating factor, and bradykinin (Table V). prostaglandin D2 is a vasodilator, whereas leukotrienes C4 and C4 mediate increased vascular permeability. ~0 These eicosanoids may act synergistically in the skin." Release of platelet-activating factor, which can mediate increased vascular permeability, has been measured during experimentally induced cold urticaria. 12 Bradykinin, which is generated in the tissues after mast cell degranulation, is also a potent vastactive substance that induces a burning pain. Bradykinin may be a more prominent mediator in angloedema, which is characterized by deep dermal vastdilation and edema concomitant with burning pain.
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J. ALLERGYCLIN.IMMUNOL. OCTOBER 1990
TABLE V. Symptoms and pathologic features of urticaria and proposed mediators Symptom
Pathologic feature
Proposed mediator
Wheal
Vascular permeability
Flare
Vasodilation
Pruritus
Sensory nerve stimulation
Histamine (H~) Prostaglandin D2 Platelet-activating factor Bradykinin Leukotriene C4, D4, and E4 Histamine (H,) Prostaglandins Platelet-activating factor Bradykinin Leukotriene C4, D4, and E4 Histamine (H~)
TABLE Vl. Symptoms and pathologic features of anaphylaxis and proposed mediators
Symptom
Pathologic feature
Proposed mediator
Urticaria, angioedema, laryngeal and intestinal edema
Vascular permeability
Flushing, headache, and hypotension
Vasodilation
Palpitations Rhinorrhea and bronchorrhea
Arrhythmias Mucus secretion
Histamine (HI) Eicosanoids Histamine (H~ and H2) Eicosanoids Histamine (H0 Histamine (H~ and H2) Eicosanoids
Modified from Kaliner MA. In: Lockey RE, Bukantz SC, eds. Fundamentals of immunology and allergy. Philadelphia: WB Saunders, 1987: 203-16.
H1 antihistamines are the primary therapy for urticaria; many patients' symptoms can be controlled with these agents alone. Anaphylaxis
Anaphylaxis is a mast cell-mediated, lifethreatening multiorgan disorder. The major organs involved include the skin (where symptoms including flushing, urticaria, and angioedema), the cardiovascular system (tachycardia, hypotension, shock, syncope, and arrhythmias), the gastrointestinal tract (abdominal bloating, diarrhea, and vomiting), and the respiratory tract (rhinorrhea, laryngeal edema, wheezing, bronchorrhea, and asphyxiation). Other effects include diaphoresis and fecal or urinary incontinence. Patients complain of pruritus (especially around the face, neck, and back), weakness, palpitations, bloating, crampy diarrhea, congestion, and dyspnea. In addition, these persons frequently have a peculiar metallic taste in their mouths and a feeling of impending doom. When anaphylaxis is separated into its pathologic components, the pattern mirrors the pathology inherent to other mast cell-mediated processes. In fact, all the symptoms of anaphylaxis can be reproduced
by histamine. Vascular permeability manifests as urticaria, angioedema, and laryngeal and intestinal edema; vasodilation leads to flushing and headache; and smooth muscle contraction results in wheezing, abdominal cramping,, and diarrhea. Tachycardia resuits in palpitations; reduced peripheral vascular resistance is responsible for syncope; and mucus secretion manifests as rhinorrhea and bronchorrhea. Histamine, either alone or in conjunction with eicosanoids, can mediate all the features of anaphylaxis (Table VI). 13 Mild anaphylaxis restricted to pruritus, or hives may be effectively treated with H1 antagonists alone, but systemic reactions with cardiovascular involvement require combination therapy with HI and H2 antagonists, with or without volume expansion, pressors, and corticosteroids. CONCLUSION
Mast cell degranulation results in the release of preformed mediators, such as histamine and chemotactic factors, and in the generation of mediators, such as eicosanoids and platelet-activating factor from membrane lipids, and kinins by the action of mast cell enzymes on tissue precursors. These mediators share responsibility for the pathologic processes in-
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herent in allergic disorders. H i s t a m i n e can elicit all or m o s t o f the pathologic processes i n v o l v e d in allergic rhinitis, urticaria, anaphylaxis, and asthma. Furtherm o r e , H1 antagonists, alone or in c o m b i n a t i o n with H2 antagonists, are h i g h l y e f f e c t i v e in the treatment of allergic rhinitis, urticaria, and anaphylaxis; H1 antihistamines offer partial protection in asthma. C o n sequently, even t h o u g h histamine is only one o f m a n y mediators o f allergic disease, it should be strongly c o n s i d e r e d w h e n analyzing the cause and treatment o f any m a s t c e l l - r e l a t e d disease. REFERENCES
1. Dale HH, Laidlaw PP. The physiologic action of 13imidazolylethylamine. J Physiol 1911;41:318-44. 2. Douglas WW. Histamine and 5-hydroxytryptamine (serotonin) and their antagonists. In: Gilman AG, Goodman LS, Gilman A, eds. The pharmacologic basis of therapeutics, 6th ed. New York: Macmillan, 1980:609-46. 3. White MV, Slater JE, Kaliner MA. Histamine and asthma. Am Rev Respir Dis 1987;135:1165-76. 4. White MV, Kaliner MA. Histamine. In: Barnes PJ, Chemiack NS, Weibel ER, eds. The lung: scientific foundations. New York: Raven Press [in press]. 5. White MV, Kowalski ML, Katiner MA. Mast cell secretagogues. In: Wintraub B, Tauber F, Simon AS, eds. Biochemistry of the acute allergic reaction, Fifth International Symposium. New York: Alan R Liss, 1989:83-101. 6. Druce HM, Kaliner MA. Allergic rhinitis. JAMA 1988; 259:260-3. 7. Raphael GD, Meredith SC. Baraniuk JN, Druce HM, Banks SM, Kaliner MA. The pathophysiology of rhinitis. II. Assessment of the sources of protein in histamine-induced nasal secretions. Am Rev Respir Dis 1989;139:791-800. 8. Mullol J, Raphael GD, Baraniuk JN, et al. Neurohormonal glandular secretion from human nasal mucosa in vivo and in vitro [Abstract]. J ALLERGYCLrN IMMUNOL1990;85:224. 9. Kaliner M. Mast cell mediators and asthma. Chest 1985; 87(suppl):2S-5S. 10. Orange RP, Austen KF. Immunologic and pharmacologic receptor control of the release of chemical mediators from human lung. In: lshizaka K, Dayton DH Jr, eds. The biological role of the immunoglobulin E system. Bethesda, Md.: National Institutes of Health, U.S. Department of Health, Education, and Welfare, 1972. 11. Soter NA, Lewis R_A, Corey EJ, Austen KF. Local effects of synthetic leukotrienes (LTC4, LTD4, LTE4 and LTB4) in human skin. J Invest Dermatol 1983;80:115-20. 12. Kaplan AP. Urticaria and angioedema. In: Middleton E, Reed CE, Ellis EF, eds. Allergy; principles and practice. 3rd ed. St. Louis: The CV Mosby Co, 1988:1377-401.
13. Kaliner MA. Anaphylaxis. In: Lockey RE, Bukantz SC, eds. Fundamentals of immunology and allergy. Philadelphia: WB Saunders, 1987:203-16. DISCUSSION
Question. What do you believe is the role of the H3 receptor, which has recently been identified? Dr. White. To the best of my knowledge, the H3 receptor is primarily responsible for turning off histamine secretion. This receptor is found in the brain, but some data suggest that it may also be present in the lungs and other tissues. Furthermore, the ability of the H2 receptor to turn off histamine secretion in the basophil may be mediated by the H3 receptor. Question. In patients who experience anaphylaxis, the severity of the response often varies, even within the same person and with exposure to the same gross quantity of allergen. Can you explain these differences? Dr. White. Several explanations can be considered. First, the amount of mediators released, or the susceptibility of the target organs to these mediators, may vary. Alternatively, the presence of the H3 or H2 receptor might alter susceptibility to H1 effects. Another possibility is that these variations are linked to the distribution of mast cells. Question, How do you interpret the recently postulated phenomenon of spontaneous histamine release? Dr. White. We have observed increased spontaneous histamine release in some patients with food allergies, as well as in persons without food allergies. Some information is available that suggests the involvement of circulating histamine-releasing factors that may work through the IgE receptor. Despite recently published data, however, I am not convinced that increased spontaneous release is caused by mononuclear cell-derived histamine-releasing factor. Question. How certain are we that histamine comes only from mast cells or basophils? Are any good immunohistochemical data available to show that epithelial or glandular cells do not contain histamine? Could spontaneous release of histamine be the result of involvement of another cell type? Dr. White, Histamine has not been shown to be released from other cell types, although there is a non-mast c e l l basophil source in the brain. It may also exist in other parts of the body that have not yet been identified. Question. Is there a difference between acute and chronic urticaria with regard to the roles of H1 and I-I2 receptors? Dr. White. There is no clearcut difference between acute and chronic urticaria in terms of either antihistamine responsiveness or histology.
