Immediate-type Hypersensitivity Research Articles

Ｉ型アレルギー反応と炎症

Ｉ型アレルギー反応と炎症

The molecular pathology of IgG4 in allergic conditions.

In the time available, I have built up a picture of the molecular pathology of IgE antibodies; and considered that of IgG4 antibodies in comparison. As will have become apparent, much less direct evidence is available on the latter; partly because of lack of reliable and relevant in vitro functional assays. Nevertheless, I hope that in speculating on the possible molecular pathology of IgG4 antibodies, I have said enough to convince you that their likely mode of action in immediate-type hypersensitivity reactions will prove to be fundamentally different to that of IgE antibodies. It is important to bear this in mind in attempts to devise suitable assays of use in clinical diagnosis; and in considering their unique contributions to allergic reactions.

Suppressive substance produced by T cells from mice chronically infected with Trypanosoma cruzi. I. Preferential inhibition of the induction of delayed-type hypersensitivity.

Culture supernatants of spleen cells from susceptible CBA mice chronically infected with Trypanosoma cruzi were able to inhibit the induction of delayed-type hypersensitivity (DTH) to a wide range of antigens as measured by 24-hr footpad swelling, bone marrow homing, and radioactivity accumulation assays. The suppressive activity, which was also present in the serum of these chronically infected mice, appears to be specific for the induction of DTH and had no effect on the 3-hr immediate-type hypersensitivity. It also failed to modify the expression of DTH in presensitized mice. Furthermore, it did not affect the synthesis in normal recipients of specific antibody or the induction of helper T cells or cytotoxic T cells. It also failed to induce DTH tolerance as recipient mice with markedly reduced DTH were able to develop a normal DTH response after secondary immunization. The suppressive activity was produced by an Ig- macrophage-depleted splenic T cell population, whose capacity to secrete the suppressive substance was completely abrogated by treatment in vitro with anti-L3T4 antibody and complement, but not with anti-Lyt-2 antibody and complement. These results therefore demonstrate that L3T4+ T cells from mice chronically infected with T. cruzi can produce substances which interfere with the induction of DTH. This finding may help to identify the differential antigenic stimulatory requirement for the activation of the various subsets of T cells.

Cysteinyl leukotrienes as mediators of staphylococcal enterotoxin B in the monkey.

The role of cysteinyl leukotrienes (LTs) in the action of staphylococcal enterotoxin B (SEB) was investigated in unsensitized monkeys using inhibitors of prostanoid synthesis and LT action and by measuring generation of LT in vivo. LY 171883, a selective LTD4/LTE4 receptor antagonist, proved highly efficient in inhibiting immediate-type hypersensitivity reactions in the skin and protecting against the emetic response provoked by SEB in a concentration-dependent manner. Inhibition of prostanoid formation by pretreatment of monkeys with indomethacin or aspirin did not influence SEB responses. Based on chromatographic and radioimmunologic analysis, the generation of endogenous cysteinyl LTs was demonstrated in vivo. The concentration of LTE4, the major biliary cysteinyl LT detected, increased ten-fold and a novel cysteinyl LT metabolite in urine indicated strongly enhanced LT generation upon challenge with SEB. Cysteinyl LTs are important mediators in the pathophysiology of SEB-induced enteric intoxication. Therefore, cysteinyl LT antagonists may be of therapeutic value in the treatment of this intestinal disorder.

Immediate type reactions in pathogenesis of infectious allergy

The bacterial allergens available in our country are designed to detect only delayed-type hypersensitivity. However, it is known that both delayed- and immediate-type hypersensitivity reactions may be involved in the pathogenesis of infectious-allergic diseases. A number of authors have shown the presence of specific reactive antibodies of the IgE class to bacteria in patients with infectious allergies. There is evidence of elevated levels of IgE in patients with infectious-allergic bronchial asthma, pyoderma and microbial eczema. Immediate reactions in infectious allergies may occur with the formation of circulating immune complexes.

Protection against experimental salmonellosis in mice and sheep by immunisation with aromatic-dependent Salmonella typhimurium

Mice immunised by the oral or intraperitoneal route with a live aromatic-dependent strain of Salmonella typhimurium exhibited significantly less protection against oral challenge with 50 LD50 of an ovine isolate of S. typhimurium (12313) than when a bovine isolate with the same O antigens and phage-type as strain 12313 was used as the challenge organism. When challenged with 10 LD50, however, protection against both strains was significantly better than that obtained when mice were vaccinated with killed vaccines (heat-killed, acetone-killed or irradiated) even when the antigenic mass of the killed vaccine was increased by up to 500-fold in an attempt to compensate for the expected limited multiplication of the mutant organism. Sheep immunised with the live mutant strain by either the intramuscular or oral route were protected against oral challenge with the virulent ovine isolate of S. typhimurium; unimmunised sheep died of acute enteritis within 7 days, although there was no evidence of systemic invasion by the challenge organism. After challenge, immunised animals ate more food than the unimmunised controls and suffered only transient, mild diarrhoea. Serum antibody titres against O and H antigens measured by direct or antiglobulin tests were significantly higher in sheep immunised by the intramuscular route than in those immunised orally. Sheep in both immunised groups developed skin swellings within 30 min after intradermal inoculation with purified homologous lipopolysaccharide indicating development of immediate-type hypersensitivity, but only those immunised by the intramuscular route showed significant indurated skin swellings characteristic of delayed-type hypersensitivity 48 and 72 h post-inoculation.(ABSTRACT TRUNCATED AT 250 WORDS)

Loss of the activity of human coagulation factor xii by a chymotrypsin-like protease activated in rat mast cells during degranulation with compound 48/80.

Mediator release from mast cells is an initial step in the immediate-type hypersensitivity. Thus, the interaction of neutral proteases released from mast cells with plasma kallikrein-kinin system was investigated. Two proteases, chymotrypsin-like (CHY) and trypsin-like (TRY) proteases, were activated in purified rat mast cells after degranulation with compound 48/80. Three fourths of the CHY activity remained in the cell residue, and the activity was inhibited by chymostatin, whereas most of the TRY activity was released in the medium and was inhibited by leupeptin. The incubation of rat or human plasma with degranulated mast cell (DMC) suspension did not cause the activation of plasma prekallikrein, but did cause a loss in the activity of coagulation factor XII, as ascertained by the lack of activation of prekallikrein in either the DMC-treated plasma by glass powder or in the incubation of DMC-treated human plasma with factor XII deficient plasma activated by kaolin. The prekallikrein and high-molecular-weight kininogen levels were sufficient for activation of factor XII.

Effect of Thromboxane A<sub>2</sub> Synthetase Inhibitor on Immediate-Type Hypersensitivity Reactions

The effect of the thromboxane (TX) A2 synthetase inhibitor, OKY-046, on human leukocyte histamine release and bronchial hypersensitivity in asthmatic subjects was evaluated. It was found that OKY-046 inhibited IgE- and Ca2+ ionophore A23187-mediated leukocyte histamine release in a dose-dependent fashion (IC50: 1.0 and 3.0 X 10(-3) M, respectively) and that OKY-046 could diminish bronchial hypersensitivity, determined by leukotriene D4 inhalation, following a 2-week oral medication. These data suggest that the TXA2 synthetase inhibitor can produce favorable effects upon the course of immediate-type hypersensitivity reactions.

Allergic Reactions in Healthy Platelet-Pheresis Donors Caused by Sensitization to Ethylene Oxide Gas

We observed immediate-type hypersensitivity reactions in 6 of 600 donors who underwent automated plateletpheresis procedures. Ethylene oxide gas, which was used to sterilize plastic components in the disposable apheresis kits, represented a possible source of sensitization. In skin-prick testing, 4 of the 6 donors who had had a hypersensitivity reaction and none of 40 controls who had not had such a reaction had positive tests when an ethylene oxide-human serum albumin reagent was used (P less than 0.001). Radioallergosorbent testing revealed that serum from 4 of the 6 donors who had reactions, but from only 1 of 145 controls, contained IgE antibodies to ethylene oxide-albumin (P less than 0.001). All six of the donors who had reactions had specific ethylene oxide-induced basophil histamine release (mean release [+/- SE], 34.2 +/- 5.6 percent), whereas none of four controls had specific histamine release in response to ethylene oxide (mean release, 5.7 +/- 1.2 percent; P less than 0.005). Repeat plateletpheresis in five of the donors who reacted was accompanied by a recurrence of mild allergic symptoms. These studies demonstrate that sensitization to ethylene oxide gas can occur in healthy plateletpheresis donors and that it may result in immediate hypersensitivity reactions during the donation. The prevalence of such reactions was 1.0 percent in our apheresis donor population.

Structure, Antigenic Determinants of Some Clinically Important Insect Allergens: Chironomid Hemoglobins

Determination of the molecular structure and properties of allergens that elicit severe immediate-type hypersensitivity diseases in humans and a knowledge of the structure of their antibody-binding sites should provide new insight into the pathogenetic mechanisms of allergic diseases. Monomeric and homodimeric hemoglobins (CTT I to X) have been identified as potent allergenic components of Chironomidae, a family of Diptera. Immunologic investigations of peptides of three of these hemoglobins (CTT IV, CTT VI, and CTT VIII) showed that human antibodies of the E and G classes recognize at least two different sites within each molecule. Individual hemoglobin peptides were aligned with homologous regions of chironomid hemoglobin CTT III, whose tertiary structure has been determined by x-ray analysis at a resolution of 1.4 angstroms. The antigenic site CTT IV(91 to 101) showed the following characteristics: (i) seven polar or hydroxylated amino acids, from a total of eleven, occupying predominantly superficial regions; (ii) the property of linkage to other molecules by hydrogen bonds or solvent clusters; and (iii) high thermal mobility factors. In contrast, peptide CTT IV(102 to 108), which does not bind human antibodies, contained no polar amino acids and had low thermal mobility factors. These results support the idea that the antigenicity of clinically relevant proteins is related to regions with a predominance of polar amino acids and with low energy barriers between different conformations, which allow high flexibility, including site-specific adaptation in antibody binding.

Anaphylactic shock caused by formaldehyde in a patient undergoing long-term hemodialysis

Formaldehyde (F) elicits contact dermatitis and asthma in subjects who are exposed to this chemical when it is applied on the skin or inhaled. An immediate-type hypersensitivity reaction was never confirmed in these reactions. F is widely used in hemodialysis to sterilize adhesives, surgical devices, or reconditioned dialyzers. A 20-year-old woman who was subjected to hemodialysis for the past 4 years had a contact dermatitis to F. When hemodialysis was performed with a new dialyzer not sterilized with F, there were no symptoms. She had minor symptoms of anaphylaxis characterized by rhinitis, wheezing, and headache on the first use of a reconditioned dialyzer. Two days later, she was dialyzed with the same reconditioned dialyzer and developed within minutes a severe anaphylactic shock requiring resuscitation. The patient had no personal or family history of atopy. Prick tests and RAST to common food and inhlant allergens were negative. Prick tests performed with 0.1% and 1% F were positive in the patient, whereas they were negative in control subjects. RAST to F was performed with discs specially prepared and coated with human serum albumin. RAST was strongly positive. RAST to ethylene oxide was negative. A patch test with F was performed and induced an anaphylactic shock 26 hours after the skin application of F. The patient did not present any anaphylactic symptoms with the use of nonreconditioned dialyzers. An immediate-type allergy to F mediated by IgE may be envisaged in this patient.

Anaphylaxis: Clinical presentation, immunologic mechanisms, and treatment

Anaphylaxis is a devastating allergic catastrophe. It is described as a systemic, immediate-type hypersensitivity reaction induced by exposure to a specific antigen and is immunologically based. The clinical manifestations may be mild but are often rapidly progressive, leading to respiratory distress and cardiovascular collapse. In addition to avoiding exposure to the antigen, treatment includes general supportive measures and specific therapeutic modalities. The purpose of this article is to review the current concepts of anaphylaxis and discuss the etiologic agents, immunologic mechanisms, clinical presentation, and treatment of this true allergic emergency.

Immunologic responses to intravenous streptokinase in dogs.

Streptokinase is used worldwide as a thrombolytic agent. Allergic reactions to streptokinase have been reported, but the immunologic mechanisms have not been well characterized. To develop a canine model of streptokinase immune responses analogous to human responses, four dogs received intravenous streptokinase infusions. Significant rises in IgG, IgA and IgM antibody levels occurred after streptokinase administration in three of four dogs; a fourth dog developed significant increases in IgG and IgA antibody levels. Two dogs developed immediate-type cutaneous hypersensitivity to streptokinase. One dog developed subacute dermatitis with eosinophilic infiltrates which was possibly a manifestation of an allergic reaction to streptokinase.

Hapten-modified basophils: a model of human immediate hypersensitivity that can be elicited by IgG antibody.

Trimellitic anhydride (TMA) was incubated with human leukocytes to produce leukocytes with trimellityl (TM) haptenic determinants. The basophils in these TM leukocytes released histamine when challenged with human serum containing IgG but no IgE antibodies against TM determinants. Controls of TMA-treated cells exposed to normal human sera or untreated cells exposed to anti-TM sera released no histamine. The most relevant site of TMA modification of the basophil was receptor-bound IgE. This was demonstrated by the marked reduction in histamine release if IgE was removed from the leukocytes before TMA treatment and challenge and also by activation of release from untreated cells by passive sensitization with TM-IgE before challenge. Affinity-purified IgG from an anti-TM serum released much more histamine from TMA-treated cells than did the IgG-poor effluent at similar protein concentrations. These observations suggest a new model of hypersensitivity resulting from human exposure to chemicals capable of combining with autologous proteins. In some individuals this could result in both an immune response to the new determinants without the production of significant quantities of IgE antibodies and hapten modification of receptor-bound IgE on mast cells and basophils. After sufficient antibody was produced, reexposure to the chemical with hapten modification of mast cells or basophils or both could result in mediator release and clinical symptoms. This mechanism may be relevant to immediate-type chemical hypersensitivity reactions in which IgE antibody has not been demonstrated.

Induction of intradermal skin reactions in the bovine by fractionated proteins of Hypoderma lineatum

Protein species found in crude extracts of Hypoderma lineatum (Villers) 1st-instar gullet-stage larval homogenates were fractionated by chromatography and further identified by conventional polyacrylamide gel electrophoresis (PAGE) and SDS/PAGE techniques. Seven major fractions were resolved by ion exchange chromatography. Conventional PAGE of the crude antigen preparation revealed a minimum of 14 protein species, while SDS/PAGE revealed 3 major protein species. The ability to elicit cutaneous reactivity by isolated proteins was determined by the intradermal skin test. An immediate-type hypersensitivity reaction was elicited in the skin of vaccinated and previously infested animals by the components of the 4 protein fractions tested. Only one protein fraction, fraction 4, elicited an apparent delayed reaction at 48 h in vaccinated and previously infested animals. A non-specific background reaction was elicited in control animals by the fractionated proteins and was most notable between 1- and 4-h post-injection.

Anaphylactic Reactivity to Streptokinase

Streptokinase is used worldwide as a thrombolytic agent. Allergic reactions have been observed to streptokinase; however, the immunologic mechanisms have not been described. In a case of an anaphylactic reaction to intravenously administered streptokinase during the evolution of a myocardial infarction, the patient had elevated specific IgE and IgG levels to this agent demonstrated by in vitro methods. In vivo testing demonstrated cutaneous immediate-type hypersensitivity with a typical wheal and flare reaction. Critically ill patients receive short-term treatment with streptokinase. Because of the potential danger of anaphylaxis in these patients, we provide an approach that may identify those at risk. The urgency of the requirement for immediate administration of streptokinase is such that an in vitro test cannot be used; thus, results of appropriate skin testing must be evaluated.

Subcorneal pustular dermatosis--an unusual course

In a patient with subcorneal pustular dermatosis (SPD) the appearance of new pustular lesions characteristic of the disease was triggered by two episodes of drug eruption (induced by dapsone and quinidine sulphate respectively) and by the intra-dermal injection of the recall antigens Candida and streptokinase-streptodornase, performed for evaluation of delayed hypersensitivity. Both episodes of drug eruption were probably the result of an immediate-type hypersensitivity reaction towards the offending drugs, as indicated by positive mast cell degranulation tests.

Mechanisms of protective immunity against Schistosoma mansoni infection in mice vaccinated with irradiated cercariae. IV. Analysis of the role of IgE antibodies and mast cells.

Mice resistant to challenge infection with Schistosoma mansoni by vaccination with highly irradiated cercariae were examined for the presence of circulating IgE antibodies and peritoneal mast cells sensitized against schistosome antigens. Significant levels of SWAP- or CAP-specific IgE antibodies could not be detected by solid phase radioimmunoassay in the sera of C57BL/6 mice during the first 6 wk after vaccination. Similarly, heatlabile antibodies capable of passively sensitizing normal mast cells for degranulation in response to SWAP could not be identified in the same sera. In contrast, peritoneal mast cells harvested from C57BL/6 mice 2 wk or later after vaccination gave strong degranulation responses when challenged with SWAP or CAP. Thus, vaccination with irradiated cercariae induces an unusual form of immediate-type hypersensitivity in which mast cells become sensitized in the absence of detectable circulating IgE antibodies. Mice deficient in mast cells (W/Wv mutant strain) were observed to develop the same resistance to challenge infection after vaccination with irradiated cercariae as nondeficient littermates. Similarly, vaccinated SJL/J mice were found to mount an extremely weak IgE response as measured by mast cell degranulation yet displayed the same level of resistance to challenge infection as other inbred mice developing potent mast cell responses. These findings argue that IgE antibodies and mast cells are not essential components in the effector mechanism of irradiated vaccine-induced immunity against schistosome infection.

Antigen induced histamine release from mucosa in nasal polyposis.

This study was designed to detect local immediate-type hypersensitivity in patients with nasal polyposis. For this purpose, 20 patients were tested for antigen-induced histamine release from biopsies of nasal mucosa and nasal polyps. Compared with controls, histamine-release was increased after incubation with bacterial but not synthetic antigens. Fourteen patients allergic to pollen were studied; biopsy specimens of their nasal mucosa released more histamine on incubation with pollen than with synthetic antigens. These findings suggest that, like pollen allergy, nasal polyposis is a manifestation of immediate type hypersensitivity, possibly to bacterial antigens.

Immune responses of patients with tinea imbricata.

Tinea imbricata is a chronic dermatophyte infection caused by Trichophyton concentricum affecting large areas of the skin surface. Spontaneous improvement is unusual and relapse after apparently successful treatment is common. In this study in Papua New Guinea it was found that a high proportion of infected patients had immediate-type hypersensitivity (52%) or negative responses (46%) to intradermal trichophytin. The majority of patients failed to develop delayed-type hypersensitivity on skin testing or as assessed in vitro by leucocyte migration inhibition. However, 78% of patients investigated had antibody to T. concentricum. The relevance of T-lymphocyte hyporeactivity to persistence of the infection is discussed.