Phylogenetic aspects of hypersensitivity: immediate hypersensitivity reactions in flatfish.
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Immediate hypersensitivity reactions were induced in the periodontium and skin of monkeys sensitized with novo alcalase. Animals were challenged in the gingival papillae with 0.1, 1.0, and 10 micrograms of antigen for 1, 3, 5, or 7 consecutive days prior to sacrifice. At the same time, skin sites were challenged with 1 microgram of antigen. With repetitive immediate hypersensitivity reactions, the inflammatory infiltrate changed from one characterized by polymorphonuclear leukocytes to one characterized by plasma cells and lymphocytes. The repetitive gingival exposure to bacterial antigens which occur in periodontal disease could lead to repetitive immediate hypersensitivity reactions. Such reactions could play a role in the histopathology of human periodontal disease.
To evaluate immediate hypersensitivity and environmental factors, 2,187 allergic children were given intradermal skin tests (ID test) and specific IgE antibodies (RAST) at Kudanzaka Hospital for 21 years (1967-1987). The incidence of positive ID test to house dust (HD) was 23% at 1 year, 50% at 2 years, 63% at 3 years and 84% at 8 years of age. The results of average positive test obtained at an earlier age in 1975 and 1985 than in 1965. Children born recently begin to have positive test scores earlier than those born between 1965 and 1969. This could be related to the recent increase in the number of HD mites. The incidence of positive ID test to Japanese cedar pollen (sugi) was 5% at 1 year, 10% at 4 years, 16% at 8 years and 30% at 15 years of age. The positive test scores were again obtained at an earlier age in 1975 and 1985 than in 1965, in the same way as for HD mites. Children born between 1965 and 1969 showed 30-60% positive rate after 13 years of age; this level was seen after 10 years of age in children born in 1975 and 1979, and after 6 years in those born between 1980-1984. This could be due to the recent increase in the amount of sugi pollen. Only Candida showed any significant rises in positive rate 27% at 1 year of age; slow increase was observed in the case of ragweed, molds, epidermals and others. No remarkable change was seen in ragweed and Alternaria at the years of examination and the years of birth.
To evaluate the relation between immediate hypersensitivity and environmental factors, a total of 2,187 allergic children were given the intracutaneous skin tests (IC test) and specific IgE antibodies (RAST) at Kudanzaka Hospital over a period of 21 years (1967-1987). The incidence of positive IC test to house dust (HD) and Japanese cedar pollen (sugi) increased, and that to molds increased transiently in the period 1965-1975. There was no sex difference in the incidence. Asthmatic children with allergic rhinitis scored higher both in IC test and RAST than those with asthma only. The more severely asthmatic children had a higher incidence of positive IC test to HD, molds, sugi, ragweed, cat dander, silk and buckwheat (sobagara). The recent rise of in the number of allergic diseases was partly proved by higher positive IC tests to HD and sugi. The number of positive test to HD mites also increased because twice as many non-wooden houses as wooden houses, have been built since 1969, and there were 3 times as many, high-rise building in 1975 as in 1965. Pollution and the increasing area of sugi forests were also responsible for increased allergic problems.
A 63-year-old female, with type II diabetes mellitus, diagnosed in 1967, was started on combination therapy with sulphonylureas and human depot insulin in May 1989, because of inadequate blood sugar control with sulphonylureas alone. Within 3 months she began to develop nodular skin reactions at the site of injection, 12-24 hours after insulin injections. Intradermal testing demonstrated delayed (Gell and Coombs type IV) hypersensitivity to protamine. No specific IgE or IgG antibodies were demonstrable. She was changed to protamine-free human delayed action insulin. After an initial reaction-free period, red urticarial lesions, attributable to immediate (Gell and Coombs type I) hypersensitivity to human insulin, appeared at the injection sites. There were no other complications with continued insulin therapy, and after about 6 weeks no further local reactions were detectable. When an allergic reaction to an insulin preparation is suspected, careful immunological investigation should be performed, to ensure adequate treatment without risk to the patient.
Skin testing represents a direct method of assessing immune responses in vivo. Twenty-six patients with metastatic cancer of the lung, kidney, or melanoma were treated with adoptive transfers of autologous tumor-infiltrating or blood lymphocytes and continuous infusions of interleukin-2 (IL-2). Prior to therapy, cutaneous anergy to recall antigens was observed in 19 patients (73%), whereas 6 (27%) displayed normal delayed-type hypersensitivity (DTH) responses. When tested again at the end of therapy, DTH responses could not be elicited in any of the patients. Proliferative responses to skin test antigens, lectins, and IL-2 diminished progressively during therapy but returned to baseline values at 1 month. Unexpectedly, 14 of these patients (53%) developed immediate skin test responses to candida antigens and 5 (19%) to mumps antigens. These immediate responses were characterized by local erythema and induration that developed within minutes of injecting antigen. Biopsies displayed marked dermal edema and infiltration by eosinophils. Although serum IgE levels were not increased, immediate reactivity could be transferred by a heat-sensitive serum factor. The implications of this novel response are uncertain, and its development did not correlate directly with the anti-tumor effects of therapy. We conclude that adoptive immunotherapy with IL-2 produces a reduction in cutaneous DTH and diminished responses to mitogens while simultaneously promoting cutaneous allergy. We hypothesize that this may reflect diminished IL-2 production by antigen-specific helper T cells and that other lymphokines may promote these immediate hypersensitivity responses.
Cardiac immediate hypersensitivity reactions in vitro are characterized by tachycardia, arrhythmias and coronary constriction. Whereas endogenous cardiac histamine release is responsible for the generation of arrhythmias, metabolites of arachidonic acid mediate the fall in coronary flow. In the present study, we have shown that antigenic challenge of sensitized guinea-pig hearts results in the release into the coronary effluent of immunoreactive thromboxane B2, 6-keto prostaglandin (PG) F1 alpha and PGF2 alpha. Thromboxane B2 was the predominant metabolite generated. After the administration of histamine (1-100 micrograms) or a partially purified preparation of slow-reacting substance of anaphylaxis (5-100 U) to the sensitized heart there was no detectable release of thromboxane B2 into the coronary effluent. After the administration of sodium arachidonate (3 X 10(-6) M) to the sensitized heart 40 min after antigenic challenge, there was a predominant release of 6-keto PGF1 alpha into the coronary effluent. Pretreatment of sensitized hearts with aspirin (5.5 X 10(-5) M), indomethacin (1.4 X 10(-5) M) or 1-(2-isopropylphenyl)imidazole (5.4 X 10(-5) M) resulted in inhibition of antigen-induced thromboxane B2 release and coronary vasoconstriction. These results suggest that during immediate hypersensitivity reactions, the coronary vasculature may be predisposed to ischemic and thrombotic episodes as a result of thromboxane release. Thromboxane formation occurs independently of the actions of histamine and slow-reacting substance of anaphylaxis and, since it is not generated preferentially by the coronary circulation of the sensitized heart in response to arachidonate infusion, it is plausible to suggest that it is of mast cell origin.
The effects of the following parameters on the immunologic specificity of delayed and immediate hypersensitivity reactions were investigated in the guinea pig using the picryl and p-toluenesulfonyl systems: (a) the contribution of the carrier protein, (b) the effect of the number of hapten groups per molecule of the immunizing and challenging antigens, and (c) the effect of interposing a 6 carbon chain (epsilon-aminocaproic acid) between the hapten and its usual attachment to the lysine epsilon-NH(2) groups of the carrier protein. It was found that induction of delayed hypersensitivity was accomplished equally well with both lightly and heavily coupled conjugates. Sensitized animals which gave strong delayed reactions to the immunizing conjugate cross-reacted poorly or not at all to (a) conjugates of the same hapten with a different carrier protein, or (b) conjugates differing from the immunizing conjugate by having an epsilon-aminocaproyl chain interposed between hapten and its attachment onto the carrier protein. Animals sensitized with either lightly or heavily substituted conjugates exhibited strong delayed reactions to both conjugates, but more intense reactions to the immunizing conjugate were always observed. In contrast to the marker carrier specificity exhibited by the delayed hypersensitivity reactions, immediate hypersensitivity reactions, (specific precipitation, Arthus, and PCA reactions) could be elicited equally well with hapten conjugates of all carrier proteins, as well as with conjugates containing epsilon-aminocaproyl chains interposed between hapten and the carrier protein, provided the number of hapten groups per molecule conjugate was sufficiently high. Both in inducing antibody response and in provoking immediate hypersensitivity reactions, heavily substituted conjugates were considerably more effective than were lightly substituted conjugates. Alternative explanations for these observed differences in specificity between immediate and delayed hypersensitivity reactions are discussed.
A modified model of conjunctival immediate hypersensitivity in the rat is described. The advantages of this model over previously reported rat models are that it does not require invasive challenges, pre-treatment with mucolytic agents to enhance antigen penetration, or the use of haptens, and is therefore more representative of the mode of allergen challenge seen in human hay fever conjunctivitis. This model has been shown to have both early and late-phase cellular responses but only early phase clinical signs. During the early phase of the response the tarsal region accommodates a massive neutrophil infiltration and the fornix-bulbar region participates to a greater extent during the late-phase reaction, with a significant eosinophil infiltration. The development of this model has allowed us to gain a clearer insight into the mechanisms involved during conjunctival immediate hypersensitivity in the rat; and the simplicity of this model makes it attractive to use in the evaluation of new drug therapies prior to their introduction into human clinical trials.
Immediate hypersensitivity reactions to betalactams are IgE mediated and constitute the most frequent allergic reactions mediated by specific immunological mechanisms. IgE responses to benzyl penicillin (BP), the first antibiotic producing the benzyl penicilloyl structure (BPO), are characterized by a quick release of inflammatory mediators, resulting in anaphylactic shock, urticaria and angioedema. With the progressive appearance of other structures, comprising cephalosporins, carbapenems, monobactams and clavulanic acid, IgE selective responses and cross-reactivity reactions were observed. The diagnosis of betalactam hypersensitivity, classically based on skin testing with major and minor determinants of benzyl penicillin or in vitro IgE antibodies to BP, has been modified by the inclusion of different determinants generated from these compounds, for which amoxicillin (AX) is the most relevant, followed by cephalosporins. Some subjects develop positive responses to several betalactams, mostly within the same family, but others develop a selective response. These are relevant for the appropriate selection of antimicrobial drugs in patients who have immediate hypersensitivity to betalactams.
The involvement of peptidoleukotrienes (LTs) in mediating the increase in microvascular permeability associated with experimental cutaneous immediate hypersensitivity was studied by examining the effect of SK&F 104353, a potent and selective LT-antagonist, on the response evoked by graded, intradermal injections of antigen. SK&F 104353, employed at doses that profoundly blocked LTC4, LTD4 and LTE4 responses, significantly reduced the response produced by experimental cutaneous immediate hypersensitivity. The response to the lowest antigen dose (0.1 microgram) was, however, entirely insusceptible to SK&F 104353. The effect of SK&F 104353 was also examined in combination with a pyrilamine-cimetidine dosing regimen sufficient to remove the histaminergic component of cutaneous immediate hypersensitivity. The non-histaminergic component associated with higher antigen doses (10 and 100 micrograms) was significantly reduced but not abolished by SK&F 104353; the non-histaminergic component associated with low antigen doses (0.1 and 1 microgram) was not susceptible to SK&F 104353. Thus, the increase in cutaneous microvascular permeability evoked by immediate hypersensitivity appears to comprise three components: (1) A histaminergic response apparent for all antigen doses; (2) a LT-mediated component which is manifest in response to high antigen doses; (3) a third, unidentified component that is present for the entire antigen dose-range but contributes less to the overall response when high antigen doses are used. A distinct non-histaminergic, non-leukotriene mediated component was not a feature of conjunctival immediate hypersensitivity. SK&F 104353 administered in combinatio with pyrilamine-cimetidine virtually abolished the response with a small residual remaining only for the highest antigen dose. In further contrast to cutaneous immediate hypersensitivity, SK&F 104353 alone was comparatively ineffective in type 1 allergic conjunctivitis. This difference in susceptibility to SK&F 104353 appears to reflect the type of histamine-LTD4 interactive effect on microvascular permeability. Histamine and LTD4 were additive in terms of cutaneous microvascular permeability. In the conjunctiva, histamine and LTD4 appeared mutually exclusive in that the level of response produced by the combination tended not to exceed that of the single component which caused the greater effect.
Immediate hypersensitive reactions (IHR) induced by buckwheat ingestion are considered to be IgE-mediated. However we found 28 subjects without IHR to buckwheat ingestion out of 46 subjects who had positive RAST values for both buckwheat and rice antigens. The IHR-positive group showed significantly higher RAST values for buckwheat antigens (p < 0.01) but lower RAST values for rice antigens (p < 0.01) than did the IHR-negative group. RAST values for buckwheat and rice were significantly correlated with each other (p < 0.01) in the IHR-negative group, but not in the IHR-positive group. An effective dose-dependent inhibition was obtained in a RAST inhibition assay between homologous combinations of inhibitor and disc antigens such as rice and rice or buckwheat and buckwheat. The IHR-positive group showed no significant RAST inhibition between heterogeneous combinations of rice and buckwheat antigens. In contrast, the IHR-negative group showed a significant decrease in IgE binding even in the RAST inhibition assay between heterogenous combinations. These results led to the conclusion that there is cross-reactivity with IgE antibodies between buckwheat and rice and that IgE antibodies from IHR-negative subjects might recognize the epitopes on buckwheat antigens which cross react with rice antigens, whereas IgE antibodies from IHR-positive subjects might bind to buckwheat-specific epitopes.
The experiments discussed above indicate that during immediate hypersensitivity reactions, macrophages are stimulated by mast cells to synthesize PGE2 and 6-keto-PGF1 alpha but not LTC4. The arachidonic acid utilized for these products is mobilized from the macrophages itself and not shuttled from the mast cells. The stimulus for the involvement of the macrophage does not appear to be a direct cell interaction between the two cell types or a soluble factor released by the mast cells. Since the profile of eicosanoids produced by macrophages when exposed to mast cell granules is similar to that observed in the contribution of macrophages to immediate hypersensitivity reactions, mast cell granules appear to be responsible for the recruitment of macrophages to this reaction.
Six devices commonly used for immediate hypersensitivity epicutaneous skin testing were compared with regard to precision and diagnostic accuracy. Fifteen subjects were tested on the back to 10 mg/ml of histamine phosphate and 50% glycerosaline by prick technique with a smallpox needle (SN), bifurcated needle (BN), Greer "pen" (GP), and blood lancet, and by puncture with the Morrow-Brown needle (MB) and Multi-Test (MT). Five devices were tested in quintuplicate to histamine and once to glycerosaline in each subject; with MT, five histamine and three glycerosaline sites were used. Analysis of the wheal areas obtained with SN, BN, GP, and MB demonstrated comparable degrees of precision (coefficient of variation). The precision of MT was less than the other devices (p less than 0.05). The blood lancet demonstrated intermediate precision. Twenty-two of 45 (49%) of the glycerosaline skin tests performed with MT were falsely positive, significantly more than the other devices (p = 0.0001). We conclude that MB, BN, GP, and SP are comparable devices for use in immediate hypersensitivity skin testing. The low precision and reliability of MT used for testing on the back would appear to make this device less than adequate for diagnostic or research studies. Its high rate of false positive reactions requires caution in interpretation of results when it is used in the clinical diagnosis of allergy.
A patient had a chronic hand eczema, presumably as a manifestation of atopy. Treatment resistance appeared due to handling certain foods that produced burning and stinging in the chronically eczematous skin and not in otherwise normal skin. Selected tests for delayed hypersensitivity and for immediate hyper sensitivity on intact skin of the back produced negative results, but on chronically inflamed skin of the arm and back, application of the pertinent foods produced a wheal and flare response. On intact skin, scratch tests with the foods produced positive results. Intradermal tests with commercial antigens were negative. Avoidance of these foods, as contactants, led to resolution of the dermatitis. Reappraisal of the role of immediate-type hypersensitivity in chronic hand eczema is important.
Diseases in which immediate hypersensitivity (IH) reactions occur, (asthma, allergic rhinitis and eczema) are very common in Australia although their overall prevalence is unknown. Until recently the clinical investigation of IH has been undertaken almost exclusively by allergists using scratch tests. The discovery of Ige by Ishizaka et al. in 1966 resulted in a rapid increase in the understanding of the processes involved in IH reactions and, although much remains unclear, respiratory physicians,immunologists and epidemiologists are becoming increasingly involved in investigating the IH reactivity of individuals and populations. In this review the immunological basis of IH reactions is briefly presented; the role of skin tests in their assessment is evaluated and the relationship between IH and clinical allergic disease is discussed in terms of patient management.
The release of histamine and other mediators from an immediate hypersensitivity reaction is energy dependent and cyclic AMP dependent. Drugs which inhibit the active secretion of mediators, or which may change cyclic AMP are effective in inhibiting mediator release. We used a model of Type I (immediate) hypersensitivity in the conjunctiva of guinea pigs sensitized to normal rabbit serum to test the efficacy of 2-deoxy-D-glucose or a combination of isoproterenol and diethylcarbamazine in inhibiting conjunctival hypersensitivity. After topical challenge with rabbit serum, edema was evaluated in five areas of the guinea pig conjunctiva. Controls were compared to conjunctiva pretreated with 2-deoxy-D-glucose or isoproterenol and diethylcarbamazine. Pretreatment with 2-deoxy-D-glucose or a combination of isoproterenol and diethylcarbamazine was found to inhibit the immediate hypersensitivity reaction.