The late phase of the immunoglobulin E-mediated reaction: a link between anaphylaxis and common allergic disease?

The late phase of the immunoglobulin E-mediated reaction: a link between anaphylaxis and common allergic disease? Gerald

J. Gleich,

M.D. Rochester, Minn.

Early workers observed that exposure of allergic patients to allergens provoked not only an immediate response but also a more prolonged (late) reaction. In 1873, Blackley,’ who was allergic to grass pollen, experienced sneezing and coryza lasting 6 to 8 hr after pollen inhalation. On another occasion he accidentally inhaled a large quantity of pollen and developed nasal, chest, and systemic symptoms that lasted for many hours and prevented him from working for 2 days. Prausnitz and Kustner* noted that the cutaneous inflammation associated with passive transfer of sensitivity lasted at least a day. In 1922, Cooke3 described his prolonged skin reaction to horse dander allergen; the lesion began with the typical wheal and flare but developed edema and erythema that was still evident the next day. In 1924, Vaughan4 called attention to the inflammation presenting at the site of skin tests. In 1952, Herxheimerj pointed out that the “late bronchial reaction” was “of great practical importance” and was associated with more severe asthma than the asthma in patients without late reactions. Nonetheless, it was not until Pepys et a1.6 called attention to dual skin reactions in patients with allergic bronchopulmonary aspergillosis that interest in late reactions was rekindled. The dual skin reactions in these patients showed deposition of IgG, IgM, and C3 as well as marked tissue infiltration by neutrophils, pointing to an Arthus reaction (type III) as the mechanism for the continuing inflammation. In keeping with that interpretation was the presence of precipitating antibody of both IgG and IgM isotypes. These observations suggested that the complement system is

From the Departments of Immunology and Medicine, Allergic Diseases Research Laboratory, Mayo Medical School, Mayo Clinic and Mayo Foundation, Rochester, Minn. Supported by grants from the National Institutes of Health AI11483, AI-9728 and AI-15231 and the Mayo Foundation. Received for publication May 28, 1982. Accepted for publication June 1, 1982. Reprint requests to: Gerald J. Gleich, M.D., 401 Guggenheim Bldg., Mayo Clinic, 200 First St. S.W., Rochester MN 55905. Vol.

70, No. 3, pp.

160-169

activated as a consequence of skin testing. However, cutaneous late reactions also occurred after skin testing with grass pollen extract,7 where precipitating antibody is less common. Studies of late cutaneous reactions by Dolovich et al. showed that they also occurred after injection of Bacillus subtilis enzymes* and more significantly after injection of anti-IgE.s The latter finding suggested that a late reaction might be a property of IgE-allergen interaction and that complement activation was not essential. Subsequently, Solley et al.1° presented strong evidence that IgE antibodies can induce both an immediate reaction and an LPR after skin testing. IgE-MEDIATED Characteristics

CUTANEOUS

LPR

Observations by several groups indicate that the LPR develops in a characteristic manner.8-11 After the peak of the wheal and flare reaction at 15 to 30 min, the wheal becomes less distinct and gradually merges with the flare zone. By 90 min the lesion is diffuse, edematous, and erythematous but asymptomatic. Over the next 2 to 3 hr the lesion does not change greatly, and in none of the patients we studied1° was there a disappearance of the lesion during this time. By 4 to 5 hr mild pruritus heralds an increase of inflammation, which peaks at 6 to 12 hr. At the height of the response the LPR is characterized by erythema, warmth, edema, pruritus, and tenderness; the area of involvement is much more extensive than the initial wheal and flare response. In contrast to the sharp delineation of the wheal at 15 min, the border of the LPR is ill defined. In some patients a “target lesion” remarkably similar to that seen in erythema multiforme is observed at the peak of the LPR. After the peak at 6 to 12 hr the lesion begins to subside, and by 24 to 48 hr it has disappeared except for residual petechiae, which may persist for several days. Fig. 1 shows that the size of the LPR is directly proportional to the size of the initial wheal and flare reaction.‘* Although most LPRs have followed intracutaneous injection of allergen, they can also be stimulated by

0091-6749/82/090160+10$01.0010

0 1982 The

C. V. Mosby

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reaction

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LPR: PMN:

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Late-phase reaction Polymorphonuclear

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prick test. I2 Of interest is the finding that the induction of the LPR is independent of sensory innervation; injection of anti-IgE into denervated and normal skin of the same subject gave rise to LPR lesions of comparable intensity even though the early reaction in the denervated site failed to show an immediate flare.” Attempts to repetitively induce LPRs at the same site showed that subsequent lesions were smaller, indicating a relative refractory state.13 This was the case regardless of whether the LPR was induced by anti1gE in a nonatopic patient or by allergen in an atopic patient,‘” and we confirmed this finding using passive sensitization (Gleich GJ, Solley GO, unpublished observations). Although the size of the LPR was measured in most studies simply with a ruler, Jan et al.i4 showed that the degree of local exudation associated with the LPR could be measured by an isotopic method. Occurrence As noted above, the size of the cutaneous LPR is directly related to size of the immediate wheal and flare reaction. Dolovich et al.” found that an LPR was not seen unless the immediate wheal was about 8 mm or more, and Solley et al. lo found that a wheal of 15 to 20 mm was required to regularly induce the LPR. deShazo et al.‘” determined the relationship between the sizes of the immediate wheal and the LPR by extinction dilution and found that an LPR was seen after wheal and flare reactions as small as 9.5 + 1.O mm. Thus patients showing marked immediate wheal and flare reactions should be warned that they may experience an LPR. Usually the LPR is without consequence and the best treatment is benign neglect. This is also true even for most insect stings.“j However. in the exceptional case an insect sting may be followed by the serious LPR; Giannini (personal communication) has observed a child who, after a sting, had a very marked local reaction with swelling of the forearm to the point where nerves and blood vessels were compressed. The patient required several fasciotomies to relieve pressure on the nerves and blood vessels and prevent irreversible damage. Subsequent tests of the patient’s serum showed IgE antibodies to honeybee, yellow jacket, and wasp venoms, whereas IgG antibody to honeybee venom phospholipase was not detected. Although one cannot conclude that this reaction was induced solely by IgE antibody,

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LATE REIPO1IMIE: MEAN DtkW#TER IN mm. FIG. 1. Comparison of prick tests and intracutaneous test. Allergic patients were tested with a variety of allergens, including house dust, ragweed antigen E. and whole mixed grass pollen extract. q , Reactions induced by intracutaneous testing; l , reactions induced by prick testing. For these 41 observations the correlation between the size of the immediate and late reaction was: r =. t 0.647; p c 0.001. (From J ALLERGY CLIN IMMUNOL 6660. 1976.)

the inference is clear: if an LPR occurs in a closed space, the resulting edema can cause serious consequences. It appears that any substance able to provoke a wheal and flare reaction can also cause an LPR. The materials reported to provoke the LPR include ragweed,“. “’ grass,:, ‘“Alternaria, “‘Bacillus subrilis enzymes,# Aspergillus, ‘I. I7 and soya. I” Although it has not been proven that IgE mediates the late asthmatic reaction, several considerations suggest that it does (vide infra). If so, then one can add Dermatophagoidrs, “’ cat dander, penicillin,‘” grain dust,” papain ,2’1 animal danders,‘” Candida, 2J cockroach.29 and foods including soy and presumably peas, lentils, and beans.‘” Indeed, it seems highly likely that any allergen able to provoke an immediate wheal and flare reaction can also provoke an LPR. Dependence

on IgE

The burden of evidence indicates that only IgE antibody is needed to produce the LPR. The initial observation by Dolovich and Little8 that late cutaneous reactions were not strictly related to the presence of

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*Glycine-HCL PI-I 2.2

Sepharose anti-IgE

0 0

FIG. 2. Dependence sensitive

0

Eluate

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0 0 0 0 0

of cutaneous on solid-phase

LPR on IgE antibody. anti-IgE.

IgG antibody suggested that not all late reactions were due to the formation of immune complexes with subsequent complement fixation.6 Moreover, the late reactions could be passively transferred. The subsequent demonstration that the cutaneous LPR was stimulated by injection of both intact sheep anti-IgE as well as its (Fab’), fragment but not by normal sheep serum or by the (Fab’), produced from normal sheep IgG, was strong evidence that IgE was responsible for the lesion.g Additional support came from the work of Solley et al.‘O using passive transfer. Although the LPRs produced by passive transfer were less intense and subsided more rapidly than those produced in actively sensitized patients, the ability to transfer the LPR passively provided the opportunity to test whether IgE was responsible for the LPR. Heating of the serum used in passive transfer for 4 hr at 56” C to denature IgE (97% to 99% loss as measured by radioimmunoassay) largely removed its capacity to transfer both the immediate response and LPR. Similarly, Fig. 2 shows that removal of IgE by passage of the serum over an anti-IgE solid-phase immunosorbent (99.7% loss of IgE and complete loss of reactivity in the radioallergosorbent test) abolished the capacity of serum to transfer passively both the immediate reaction and the LPR. When IgE was recovered from the anti-@ solid-phase immunosorbent by acid elution, the eluate passively transferred both the immediate reaction and the LPR. Additional evidence that IgE was responsible for the LPR came from experiments with myeloma IgE. When serum from a ragweed-sensitive subject was mixed with myeloma IgE in proportions such that the myeloma IgE was in excess of

Fractionation

Eluate

of serum

from

a ragweed-

serum IgE by lOO- and lOOO-fold, both the immediate response and the LPR were completely blocked.‘O Because IgE binds to the mast cell, the latter experiment points to the possibility that the mast cell plays a pivotal role in the LPR. The possibility that IgG antibody may also produce an LPR seems unlikely in view of the early experiments of Dolovich and Little* as well as those of Zetterstrom. l1 Dolovich and Little injected antigen plus histamine in patients with IgG antibody to Bacillus subtilis enzymes. The patients showed the expected histamine-induced immediate responses but not the LPR.* Zetterstrom” showed that passive transfer of IgE antibody, but not IgG antibody, produced late reactions that were triggered by testing with Aspergillus antigen; the possibility that IgG enhanced the IgE-mediated LPR seemed unlikely in that admixture of IgE and IgG antibodies gave smaller LPRs in three of four tests. Thus it does not appear that IgG antibody is critical for the LPR, either for its initiation or for its full expression. Rather, these findings suggest that IgG antibody might lessen both the immediate reaction and the LPR by competing with IgE antibody for antigen. Dependence on mediator-containing

cells

The critical importance of IgE in the induction of the LPR and the constant association of the wheal and flare reaction with the LPR points to the possibility that mediator-containing cells, i.e., mast cells or basophils, are needed for the expression of the LPR. Injection of compound 48/80, a chemical substance known to trigger mast cell degranulation,27 produced

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reacttons very similar to the typical LPR induced by lgE-containing serum and antigen in two of five subjects tested. ” In contrast, injection of histamine, bradykinin, or a mixture of the two did not induce the LPR. deShazo et al.‘” also found that compound 48180 could induce an LPR-like lesion. Investigation of the factors responsible for the LPR have been conducted in humans and rats. In humans, induction of blisters over skin reactions allowed aspiration of 300 to 500 ~1 of fluid, which on reinjection into normal skin produced LPRs quite similar to those induced by allergen; the possibility that allergen itself was carried over and caused these reactions was unlikely because it could not be found by passive cutaneous anaphylaxis in monkeys.‘” This model seems promising because characterization of these blister fluids could give information about the factor(s) mediating the LPR. Another possible pathway for LPR mediation is through the complement cascade, and complement fixation by IgE complexes has been suggested as a possible vehicle for late reactions.2” This possibility seems unlikely in view of the immunopathology of the LPR (vide infra). On the other hand, Stalenheim and Zetterstrom”” reported that injection of either anti-IgG, staphylococcal protein A, or anaphylatoxins produced a long-lasting local inflammatory lesion similar to the LPR. These stimuli clearly could activate mast cells, directly in the case of anaphylatoxin, or indirectly in the case of protein A”’ and anti-IgG, by forming complement-fixing immune complexes, resulting in release of anaphylatoxin. In rats intracutaneous injection of either anti-IgE or compound 48/80 increased vascular permeability and caused an infiltration of PMN cells by 1 to 2 hr and an infiltration of mononuclear cells, predominantly macrophages. at 24 hr.:” Similarly, injection of rat peritoneal mast cell granules with intact membranes yielded the same responses. In contrast, mast cell granules treated with distilled water to disrupt their membranes (and shown to be devoid of perigranular membranes) failed to increase vasopermeability but did cause the LPR, as judged by PMN and mononuclear cell infiltration. Such membrane-free granules could be solubilized in 0.5M to l.OM NaCl, and after dialysis against phosphate-buffered saline they caused PMN infiltration at 8 hr and mononuclear cell infiltration at 24 hr. Subsequently, solubilized mast cell granules were fractionated by ultrafiltration, gel filtration, and ion-exchange chromatography, and a polypeptide of molecular weight around 1400 containing 12 amino acids was isolated.33 On injection, this substance(s), termed the inflammatory factor(s) of anaphylaxis, produced both early PMN and late mononuclear cell infiltration, and it appears to differ

Late phase

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from previously described mast cell me&ators. Thus investigation of the LPR has led to the :.iirco\ery of novel mediators derived from mast ce!ih Pathology

of the cutaneous

LPR

Initially, Dolovich et al.” investigated the pathologic characteristics of 6 hr cutaneous LPR lesions and found edema, mast cell degranulatwn, and intiltration of eosinophils, neutrophils, and fnononuclear cells. lmmunofluorescence failed to show deposition of IgG. IgM, IgA. or C3. Subsequently. Solley et al.‘” analyzed the LPR lesions qualitatively and quantitatively. Biopsy specimens taken from 1 to 8 hr showed increasing edema and cellular intiltration as well as vessel abnormalities consisting of p&vascular infiltration, hyalinization, and even frank hemorrhage and necrosis in a few patients. Initially. the ce6lular infiltrate was entirely mononuclear and 1:mited to the perivascular tissues, but with time eosmophils, neutrophils, and mononuclear cells increased. Comparable results were seen in actively sensitvzrd allergic patients and in subjects passively sensitszed. although the number of infiltrating cells was greater in allergic patients than in passively sensitized sub,jects. In seven of eight lesions mononuclear cells were most prevalent, and one lesion showed a predominance of neutrophils. Overall, infiltrating cell populations were as follows: mononuclear cells, 41.6% I? Y.:)% (mean ? SD); neutrophils, 32.4% t 19.2%: eosinophils, 23.0% 2 13.0%: and basophils and mast cells, 3.0% F 1.6%. In one patient analysis of infiltrating cells by skin window showed increased numbers of basophils and eosinophils from 6 to 12 hr. suggesting that these cells are recruited into the lesnons in concert with the development of the LPR. Biopsy of a 24 hr lesion induced in a ragweed-sensitive patient showed a marked cellular infiltration that was almost entirely mononuclear. Electron microscopic exarnmation of 8 hr lesions in four specimens to define the nature of the mononuclear cells showed that of 250 cells 119 (48%) were lymphocytes. 18 (7%) monocytes or macrophages, 67 (27%) eosinophils, 33 (9%:i neutrophils, seven (3%) basophils (one mast cell was also noted), three (1%) plasma cells, and 13 (5/X i a.lable but degranulated cells. Of interest was the presence of free eosinophil granules throughout the tiss:le. Immunofluorescence failed to demonstrate consistently IgG, IgM, IgA, C3. lgE, or fibrin. Studies by Letterstrom” showed comparable findings. Subsequent investigations of the pathologic mechanisms of the LPR have shown that ceilular intiitration of the skin may occur in the absence of a olinitally evident lesion. deShazo et al i’, compared histologically the LPR with the site oP *1 prior 16 hr)

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Induration,

Wheal, cm2

CLIN. IMMUNOL. SEPTEMBER 1982

cm2

80 70 60 50 40 30 20 10 0

Baseline

Ii I

H2

Baseline

“1+“2

FIG. 3. Effect of H,, HP, and H, plus H2 blockers

on the from eight patients who received (1) no medications A.M., 12 noon, 6 P.M., and at bedtime the day before (H, blocker), (3) chlorpheniramine 8 mg at the same cimetidine and chlorpheniramine taken in combination blocker). t, p < 0.05; $, p < 0.01. (Modified from J

wheal and flare reaction that did not show a late reaction. They noted that both manifested a qualitatively similar infiltrate composed of lymphocytes, neutrophils, and less frequently eosinophils. By immunofluorescence they noted fibrin deposition and postulated that this accounted for the induration of the LPR. It is worthy of mention that the LPR is quite indurated and can be confused with delayed-type hypersensitivity reactions (type IV) if one is not aware of the preceding wheal and flare reaction. Richerson et al .34also performed biopsieson LPR sitesand sites of a prior wheal and flare reaction that were not followed by the LPR. The biopsieswere performed at 24 hr and failed to show a difference between the lesions. However, these specimenswere obtained during the subsidencephaseof the LPR and may not be a fair test of the differences when the lesion is maximal. Clearly, additional studies of the persistenceof the cellular infiltration are needed. In contrast to the findings of deShazo et al. ,I5 Richerson et a1.34did not find fibrin deposition in the LPR. Finally, deShazo et al.‘” concluded that the LPR is not a manifestation of cutaneousbasophil hypersensitivity in that the basophil was never the predominant cell in any biopsy.

PHARMACOLOGIC OF THE LPR

MODULATION

Becauseof the possibility that the cutaneous LPR may have its respiratory counterpart in the late asthmatic reaction, there hasbeen considerableinterest in

HI

HP

“1+H2

immediate reaction and LPR. The results are (baseline), (2) cimetidine 300 mg taken at 8 testing and at 7:30 A.M. on the day of testing times as indicated in (2) (H, blocker), and (4) at the times indicated in (2) (H, plus H, ALLERGY CLIN IMMUNOL 65: 118, 1980.)

the action of various drugs on the LPR. These studies can be arbitrarily divided into those employing drugs such as antihistamines, which affect the immediate wheal and flare reaction, and glucocorticoids, which do not affect the wheal and flare reaction. The effect of H, and H, antihistamines on the wheal and flare reaction and the LPR was tested by administration of chlorpheniramine or cimetidine or both to patients with strongly positive skin tests to grassand ragweed pollen. 35As shown in Fig. 3, the immediate wheal and flare reaction was significantly reduced by the H1 antagonist chlorpheniramine, whereas the H, antagonist cimetidine had no effect; the combination was more active than the drugs given separately. Neither drug affected the LPR when administered separately, whereas when given together the drugs produced a dramatic reduction in the intensity of the lesion and in many patients the LPR failed to develop. This important finding has yet to be confirmed; it has obvious implications for therapy of IgE-mediated allergic diseases.Another seriesof experiments tested the effect of clemastine, an antihistamine, and ketotifen, consideredto resemblecromolyn sodiumin action; both drugs had a moderateeffect on the LPR,36but not nearly so marked as the combination of H, and H2 antihistaminesnoted above. In another study, mepyramine, when injected with antiIgE at a doseof 30 pg, modestly suppressedboth the immediate reactionsand the LPRs.~’ The effect of the & agonist terbutaline was also tested on the immedi-

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ate responses and the LPRs at doses up to 1000 pg.:” Surprisingly, no effect was seen on either reaction. Another test of the effect of terbutaline showed a significant but modest effect.:%i Topical application of 5% indomethacin cream did not inhibit either the immediate reaction or the LPR, although the degree of erythema after the immediate reaction was reduced.“” The effect of glucocorticoids on the LPR has been tested by several groups.’ ‘ji. an.-11Ingestion of 25 mg of prednisone 12 hr and immediately before skin testing had no effect on the immediate reaction but reduced the LPR by about 50% (p < O.Ol).-‘O A more striking illustration of the effect of glucocorticoids was shown by injection of betamethasone with anti-IgE; Fig. 4 shows that the wheal and flare reaction was not altered. while the LPR was almost completely abolished.” In rats, pretreatment with methylprednisolone in a dose-related manner depressed the LPR at both 8 and 24 hr, as judged by the degree of infiltrate.” In these experiments the LPR was induced with mast cell granules and their high- and low-molecular-weight constituents. In parallel experiments the effect of hydrocortisone on the LPR was tested; interestingly, the mononuclear cell infiltrate at 24 hr induced by the low-molecular-weight fraction of mast cell granules was not affected by up to five injections of 400 pg of hydrocortisone, whereas in the same experiments the reactions stimulated by anti-IgE, intact mast cell granules, and the high-molecular-weight fraction were considerably reduced. Thus the LPR induced by the low-molecular-weight mast cell fractions was quite resistant to modulation by glucocorticoids.

RELATIONSHIP OF THE IgE-MEDIATED LATE REACTION TO COMMON ALLERGIC DISEASES Atopic dermatitis The possibility that the LPR contributes to the pathophysiology of atopic dermatitis has recently been raised.-‘2 IgE protein is usually elevated, often spectacularly so, in atopic dermatitis, and the degree of elevation is related to the extent of the disease (reviewed in ref. 43). Mitchell et al.42 have reported that patch testing on superficially abraded skin for 48 hr can induce eczematous changes in patients with atopic dermatitis, but only in those patients who have a positive immediate skin reaction to the same allergen. The lesions induced showed dermal inflammatory infiltrates most pronounced about blood vessels. Epidermal abnormalities, including focal spongiosis and microvesiculation, were present at 72 hr after challenge. Mononuclear cells, eosinophils, basophils, and neutrophils infiltrated the allergen test sites. The

Late

phase

of igE-media&o

XN!~OI’

165

W-0

FIG. 4. Effect of glucocorticoids on the LPR. Immediate reactions and LPRs were induced by injection of anti-lgE, and in this experiment betamethasone 50 N was injected together with anti-IgE. (From Allergy 99:201, 1981, Munksgaard International Publishers Ltd., Copenhagen, Denmark.)

‘;; kl r J

1.5~~~~~--l 0

4

TIME

6

8

10

(Hours)

FIG. 5. Immediate and late asthmatic reactions induced by ragweed pollen extract in one subject on 2 separate days. This particular patient had received immunotherapy and his serum contained IgG antibodies to ragweed antigen E. (From J ALLERGY CLIN IMMUNOL 54:244, 1974.1

percentages of infiltrating cells (calculated from the authors’ data by subtracting the numbers of cells present in tissues not challenged with allergen from the numbers present in tissues challenged with allergen) were as follows: mononuclear, 48%; eosinophils, 26%; basophils, 6%; and neutrophils, 5%. This pattern of infiltration is comparable to that seen in the LPR, with the exception that the number of neutrophils was decreased and the number of basophils was increased in the tissue from the patienrs with atopic dermatitis. Mitchell et al.?” suggest that inhalant allergen sensitivity should be considered as a factor in the pathogenesis of atopic dermatitis. They further point out the parallel between these results in atopic dermatitis and the findings in cutaneous basophil hypersensitivity in guinea pigs.4-’

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Allergic asthma The assumption that the cutaneous LPR has its counterpart in the late reactions occurring in the respiratory tract is an attractive but as yet unproven hypothesis. Presently, we do not know whether IgE antibody can trigger late asthmatic or late nasal reactions. Neither do we have proper information about the pathology of these diseases, especially during their chronic phases. In asthma there is a significant sampling problem due to the irregular involvement in the bronchial tree. Nonetheless, there is considerable interest in late respiratory reactions because they approach the question of the pathophysiology of chronic bronchial asthma. In bronchial asthma it is clear that bronchial challenge with a variety of common allergens can provoke an initial increase as well as a more prolonged increase in airway resistance, which lasts for 12 to 24 hr.‘7-25 The observation that pollen allergens such as ragweed (Fig. 5) can provoke such late asthmatic reactions speaks for the importance of IgE antibodies in the pathogenesis and against a primary role for IgG antibodies, which ordinarily are not present in large quantity in such patients.45 Pepys et a1.46have shown that patients may have immediate only, late only, dual (i.e., immediate and late), and intermediate asthmatic reactions after bronchial challenge with implicated substances. Even the terminology to describe these varied patterns of reactivity is difficult. Furthermore, after testing, the patient may experience a recurrence of asthma, often nocturnal, for several days. The pathogenesis of these varied reactions is obscure; although one can make correlations between seturn antibodies and reaction patterns, the inaccessibility of the airway, especially during an asthmatic attack, makes investigation of the pathophysiology exceedingly difficult. Recently Nagy et a1.47 have reported that there are two peaks of neutrophil chemotactic activity in the sera of patients undergoing allergeninduced asthma coinciding with the early and late allergen-induced reactions. This observation suggests that mast cells participate in both the immediate and late asthmatic reactions. The effects of glucocorticoids on the late asthmatic reactions induced by allergens parallel their effects on the cutaneous LPR. The immediate reaction is not altered, whereas the late asthmatic reaction is abolished by administration of glucocorticoids. Both immediate and late reactions are prevented by cromolyn sodium.46 The latter finding is in keeping with a central role for the mast cell in the pathogenesis of the late asthmatic reaction. The possibility that the late asthmatic reaction after bronchial challenge alters bronchial irritability has been pursued by Hargreave et a1.48They found that bronchial irritability as judged by sensitivity to in-

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CLIN. IMMUNOL. SEPTEMBER 1982

haled histamine was increased after allergen challenge in patients experiencing late asthmatic reactions. The increase in bronchial irritability lasted for days or weeks in certain patients. This finding suggests that the presumed inflammatory reaction occurring after allergen challenge increases the sensitivity of the airway to irritants. However, the mechanism of this increased sensitivity is not understood. Finally the investigation of the pathogenesis of the late asthmatic reactions may be considerably accelerated by the discovery of an animal model by Shampain et al.4g They immunized neonatal rabbits with Alternaria tenuis and these animals produced only IgE antibodes to the antigen. After aerosol challenge, the rabbits developed biphasic changes in lung function as determined by measurement of pulmonary resistance and dynamic compliance. Other rabbits were immunized at 7 days of age and made precipitating antibody of several isotypes. These animals also developed biphasic changes in lung function, but they were blunted when compared with the animals producing IgE only. Transfusion of rabbits producing IgE only with sera from rabbits producing IgG caused a significant reduction in the biphasic changes of pulmonary function; in contrast, transfusion with nonimmune serum had no effect. Therefore, in the rabbit, IgE antibodies cause both the immediate and late reactions. Clearly, further study of this model could yield considerable new information about the pathogenesis and the effects of late asthmatic reactions. Allergic rhinitis Comparatively fewer studies have been conducted on late reactions occurring in the nose.‘? 5o--52The most extensive study of these reactions was conducted by Pelikan,50 who tested 600 patients and found that 497 showed an immediate increase in airway resistance. Of the 497, 16 patients (3%) gave a history of continuing nasal symptoms between 4 and 48 hr and when studied carefully showed an immediate reaction after nasal challenge at 10 to 30 min and a late reaction at 6 to 13 hr. An earlier study by Taylor and Shivalker’ in patients allergic to grass pollen extracts showed a considerably higher frequency (37%) of late nasal reactions. In another study on patients allergic to grass pollen, late reactions occurred in four of 24 patients,j’ and in a study of nasal challenge with ragweed pollen extract, only seven of 47 patients complained of nocturnal nasal stuffiness.34 Analysis of late nasal reactions by rhinomanometry showed that late nasal reactions, defined as a 25% drop in nasal airway conductance at 4 hr, occurred eight times in 17 tests and were associated with symptoms such as nasal congestion, sneezing, and rhinorrhea.46 Thus the fre-

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Late phase

Percent of infiltrating cells

of IgE-mediated

~actmn

167

80

Cutaneous

MNC

LPR (5)

PMN

EOS

Mast

cetls

Bas&tils flG. 6. Infiltrating clear cells; EOS,

ceils in the cutaneous eosinophils.

LPR contrasted

quency of late nasal reactions has varied markedly in these studies. Id& ic asthma and eosinophilic nonallergii rhinitis From the considerations presented above, one can speculate that the LPR has its counterpart in the skin in atopic dermatitis and in the respiratory tract in the late allergic asthmatic and nasal reactions. The role of the mast cell is suggested by the ability of cromolyn sodium to prevent the immediate and late asthmatic reactions.“” We obviously need more information about the kinds and quantities of mediators associated with the respiratory late reactions and also about the types and numbers of infiltrating cells. Evidence from the literature suggests that the eosinophil is the predominant infiltrating cell in asthma,j3 but as noted above, eosinophils, although present. in the cutaneous LPR, are less numerous than neutrophils (although the findings of Mitchell et al.,12 where allergen was applied as a patch test, showed just the reverse). Finally, the increase in bronchial irritability after the late asthmatic reaction needs further study. Clearly, further investigation of the LPR in the respiratory tract may yield many insights into the mechanisms of chronic asthma. However, at our institution most patients hospitalized for treatment of asthma have the idiopathic (intrinsic) form of the disease.j4 The studies of Mullarky et al.j5 have provided evidence for an apparently analogous form of nasal disease, termed eosinophilic nonallergic rhinitis, in which IgE and allergens are not implicated. What relationship does the LPR have to these conditions? In both idiopathic asthma and eosinophilic nonallergic rhinitis there is no convincing evidence for an IgE-

to those

in nasal

polyps.

MNC,

Monont~

allergen interaction. Thus the hypothesis that they are related to the mechanisms responsible for the cutaneous LPR lacks the cornerstone of the IgE-allergen trigger. Understanding of idiopathic asthma and eosinophil-associated rhinitis might be furthered if the pathologic characteristics of these lesions were known in detail. We have examined the pathologic mechanisms of nasal polyps and have enumerated the numbers and types of the infiltrating cells.“” Here I am taking the nasal polyp as an example of the inflammation associated with idiopathic asthma and eosinophilic nonallergic rhinitis. Preliminary results from the study are presented in Fig. 6 and are compared with the percentages of infiltrating cells in the cutaneous LPR.‘O The most remarkable difference between the two is the percent of eosinophiis in the nasal polyps. Presently we do not understand the mechanisms of this pronounced eosinophilia. As noted above, the lesions of the cutaneous LPR show more neutrophils than eosinophils, and both are replaced by mononuclear cells by 24 hr. The mast cell contains a variety of mediators including eosinophil and neutrophil chemotactic factors.“‘, 58 Release of these would be expected to yield a lesion with the types of cells seen in the cutaneous LPR. Thus the pronounced tissue eosinophilia of the nasal polyps remains unexplained and may point to pathogenetic mechanisms not involving mast cells. ROLE OF THE LPR IN HU§T f?W?&TA@4CE In conclusion, one must ask whether the LPR has any relationship to host resistance. A series of observations discussed more fully elsewhere”” suggests the possibility that homocytotropic antibodies, mediatorcontaining cells such as mast cells and basophils, and

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eosinophils function in host defense to ward off against parasites. The evidence that eosinophils are able to kill parasites is reviewed elsewhere.60Concerning IgE, Dessein et al.61 showed that specific suppressionof IgE production in the rat prevented sensitizationof mast cells to Trichinella spiralis antigens, reduced the magnitude of the eosinophil responseto the T. spiralis both in the peripheral blood and in the infected tissues,and decreasedresistanceto the parasite. Concerning the basophil, Brown et a1.62 showed in guinea pigs that antiserum to the basophil abolishedimmunity to ticks and reduced the numbers of both basophilsand eosinophilsin the tick-infected tissues. Antiserum to the eosinophil reduced immunity to the tick, although less dramatically so than antiserum to the basophil, but it did not lessen the numbersof basophils in blood and tissues. These resultspoint to a role for the basophil in host immunity and to a cooperation between the basophil and the eosinophil. Thus one can postulate the existence of an interactive system consisting of homocytotropic antibody, mediator-containing cells such asbasophilsand mast cells, and eosinophils, which functions in resistance to parasitesand contributes to hypersensitivity reactions. Viewed from this perspective the LPR is the clinical expressionof the inflammation neededto deal with parasites;in allergic diseasesthe inflammatory responseis directed against the host. I thank Ms. Linda manuscript.

Ms. Cheryl Adolphson, Callister for assistance

Ms. Theresa Lee, and in the preparation of this

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