Postgraduate Medical Journal (March 1971) 47, 166-170.

Immunological aspects of asthma

H. E. AMOSM.B., B.S., Ph.D.

Department of Pathology, University of Cambridge

PROFESSOR SCADDING's definition of asthma (Scad-ding, 1969) i.e. 'a condition characterized by variabledyspnoea with wheezing and prolonged expirationwholly or partially reversed by bronchodilators', isa clinical definition. It would be premature at thisstage to attempt to define asthma in relation to itspathogenesis as this is still not understood. For thepurpose of this symposium, however, I would liketo present firstly asthma as an immunological diseaseand secondly, as a condition in which the intrinsicand extrinsic types have the same underlying abnor-mality.

Evidence for immunological involvement in asthmaThe tissue damage seen in the lungs during a

paroxysm of dyspnoea are shown at the microscopiclevel in Fig. 1. It can be seen that the lumen of thesmall 2-5 mm bronchus is filled with mucus and celldebris. The cellular infiltration consists mainly ofeosinophils. Neutrophils are also present and thesemay be particularly dense if there is a concurrent in-fection. Goblet cells in the submucosa are increasedin number and there are islands of epithelial re-generation. If the disease is long-standing the base-ment membrane becomes thickened and the smooth

muscle surrounding the bronchi increases in thick-ness. Oedema and vessel dilatation are also present.Thus there is suggestive evidence in the histopatho-logy of an allergic element to the disease.

Other evidence in favour of an immunologicalinvolvement includes the relationship between theinduction of an asthmatic attack and unusual en-vironmental antigens like castor bean (Figley &Elrod, 1928), the close seasonal correlation with grasspollens and the evidence afforded by provocationtest with aerosol extracts (Lowell & Schiller, 1948).

The hypersensitivity reaction in asthmaThe incrimination of immunological mechanisms

in asthma implies that in the first instance the patientmust become sensitized to the allergen: this phasedoes not manifest as a clinical disease. Further con-tact with the allergen produces a hypersensitivityreaction which leads to tissue damage and clinicalsymptoms. Coombs & Gell (1963) classified theclinical results of hypersensitivity reactions into fourtypes of allergic mechanism. These are illustrated inFig. 2. Historically asthma has been linked with Type1. In this reaction a specialized class of antibody isproduced which has affinity for certain target cells.

.......AWl

FIG. 1. Histology section of the lung from patient dyingin status asthmaticus.

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Immunological aspects of asthma 167

A IAY

44

TYPE I TYE4

CONPLEMEITACTIVATED

* E~~~~~~~~~~

ANTIOIW TYPE. III TYPE. IVKEY.

*A*ANTIGENS

-+ UIEMION OF HIAMIE AND OTHER

PHARACLOICALY ACTiV USTNEX> k ANTEKX)w SITE OF INVOLVEMENT OF COMPLEMENT

)> MECHANISMS IN MOONCLA-R. CELLS DIRECTEDMAU ACTWSOMCINiC-TE

FIG. 2. Types of allergic mechanisms underlying hyper-sensitivity tissue damage. (Reproduced with permission,from Clinical Aspects of Immunology, edited by P. G. N;Gell & R. R. A. Coombs, Blackwell Scientific Publica-tions, Oxford.)

The antibodies are termed reagins. When antigen/antibody combination takes place on the surface ofthe passively sensitized cell, a biochemical sequenceis started which leads eventually to the release ofhistamine and other mediators. Although substancessuch as histamine, 5-hydroxytryptamine (5-HT),slow reacting substance-A (SRS-A), kinins and pros-taglandins can be shown in in vitro systems to bereleased by antigen/antibody interactions, con-clusive evidence of their role in atopic diseases islacking.

Perhaps the most significant advance in relationto Type 1 hypersensitivity is the identification of thereaginic antibody. A serum protein was isolated fromthe sera of atopic patients and shown to carryreaginic activity (Ishizaka, Ishizaka & Hornbrook,1966). It was later shown to be an immunoglobulindistinct from the already known classes and desig-nated IgE (Ishizaka, Ishizaka & Terry, 1967). Thefinding of a myeloma protein (Johansson & Bennich,1967) which cross-reacted with IgE greatly acceler-ated the work on its structure and properties. The

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H. E. Amos

molecule was shown to be susceptible to cleavage bythe enzymes papain and pepsin and thus to consistof two light and two heavy polypeptide chains(Bennich & Johansson, 1967). PhysicochemicallyIgE has a molecular weight of about 200,000 and asedimentation coefficient of 8 2S. Metabolic studiesby Waldman & Terry (1970) indicate that the anti-body has a half-life of 2 days. This would be com-patible with the continuous production of antibodywhich probably occurs in allergic conditions. Theserum concentration of IgE in normal individuals isvery low. The range has been reported as 0-1-0-7 [g/ml (Johansson, Bennich & Wide, 1968). A recentsurvey by Rowe & Woods (1970) in which IgE serumlevels were measured in asthmatic and normalchildren did not arrive at a definite correlation be-tween raised IgE levels and the disease state. Manyatopic patients had levels of antibody well within thenormal range. However, plasma cells producing IgEhave been demonstrated in the upper and lowerrespiratory tract (Ishizaka & Newcomb, 1970) whichsuggests that the local production of IgE might be afactor in the pathogenesis of allergic hay fever andasthma.One of the properties of yE antibodies is that they

can sensitize homologous species which is a reflectionof the affinity of the IgE molecules for the specializedtarget cells. Such passive sensitization can be blockedby non-antibody yE (Ishizaka, Ishizaka & Borsos,1961) and by E myeloma proteins (Stanworth et al.,1967). The Fc fragment of the molecule was shownto be responsible for this effect (Stanworth et al.,1968) which means that the structures necessary forskin fixation reside in the Fc piece of the antibody.In vitro experiments using an isolated monkey-lungpreparation passively sensitized with antibody,showed that anti-yE and its F(ab')2 dimerbrought about the release of histamine and SRS-A.The monomer fragment Fab' did not (Ishizaka et al.,1970). The conclusion drawn from these experimentswas that complement is not essential for the reaction,as F(ab')2 has no complement-fixing activity andthat yE antibody is needed to bridge two IgE mole-cules on the target cells for the induction of thereaction. In other words IgE is divalent. A furtherimportant finding which may be very relevant inasthma is that circulating basophils from atopicsubjects have IgE on their membranes (Ishizaka,Tomioka & Ishizaka, 1970). The role of basophils inasthma is not clear but it is conceivable that a con-tinuous supply of the cells from the circulationmigrating into the local site of action, could poten-tiate and prolong the atopic symptoms.

Until recently, delayed hypersensitivity was be-lieved to play no part in atopic disease. Reference toFig. 2 shows that delayed hypersensitivity does notinvolve serum antibodies. Instead, the tissue damage

is caused by specifically allergized cells reacting withantigen. The usual way to demonstrate the state ofdelayed hypersensitivity is by a reaction induced inthe skin to an intradermal challenge of the antigen.The reaction has a characteristic time-course andwell-defined histological features (Boughton &Spector, 1963). Intradermal injection of the antigenin atopic individuals produces the very differentwheal and flair which is seen almost immediatelyupon injection. Thus it appeared that delayed andimmediate hypersensitivities could not co-exist tothe same allergen in the same individual. The de-velopment of in vitro techniques for cell-mediatedhypersensitivity has led to a reappraisal of this inter-relationship. Brostoff & Roitt (1969) using thelymphocyte-transformation test (Oppenheim, Wol-stencroft & Gell, 1967) and macrophage-migrationinhibition (David Al-Askari & Lawrence, 1964) wereable to demonstrate the immunologically specificallergized cells which mediate delayed hypersensiti-vity in patients with summer hay fever. Furthermorethey were able to reproduce a Type 4 skin reactionby injecting the allergen along with an antihistamine.The existence in hay fever and asthma of cells capableof producing Type 4 tissue damage is not reflected inthe pathological findings. Histologically the featuresshown in Fig. 1 do not resemble the granulomatousreaction associated with the delayed hypersensitivity.Brostoff & Roitt (1969) therefore interpreted thepresence of the allergized cells in the light of thecurrent concept of cell-cooperation. The lympho-cytes involved in delayed hypersensitivity and thelymphocytes involved in antibody production botharise from a common bone-marrow precursor cellbut they can be immunologically separated. Theformer develop an antigenic marker by passagethrough the thymus and are called T lymphocytes(Reif & Allen, 1964). The B lymphocytes whicheventually produce antibody do not pass throughthe thymus. There is evidence to suggest that incertain circumstances before the B lymphocytes canproduce antibody, cooperation from the T lympho-cytes is necessary (Miller & Mitchell, 1968). Thus thepresence of T lymphocytes in conditions mediatedby IgE is not mutually exclusive. Much of the workon cell cooperation is still to be confirmed, butnevertheless it seems that in atopic diseases morethan one allergic mechanism is probably involved.

In order to keep a perspective I would like now tobroaden my brief slightly and consider asthma as apattern of bronchial hyperreactivity which can betriggered by a wide range of stimuli. The knownfindings which need an explanation are the following:

(a) the pathology and physiology of bronchial con-striction and the hyperreactivity of the bronchialtissue in asthmatic subjects to the action ofhistamine,

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Immunological aspects of asthma 169

(b) immunologically why a specialized class ofantibody is produced,

(c) eosinophilia and the concept of the 'shockorgan',

(d) the close association of asthmatic attacks withrespiratory infection,

(e) adrenalin tolerance and the effectiveness ofbronchodilator drugs.The anaphylactic guinea pig upon which the sympto-matology of asthma was previously interpreted doesnot explain many of the above points and is thereforenot a good experimental model. A better one is thatproposed by Szentivanyi, Fishel & Talmage (1963)i.e. the response in animals to the infection withBordetella pertussis. It has been shown that in suchanimals the tissues are hyperreactive to histamine(Kind, 1958) and that the hyperreactivity extends toless specific stimuli like temperature (Munoz &Schuchardt, 1957) and respiratory irritants (Fair-child, Bobb & Thompson, 1966). Immunologically,Bordetella pertussis has a marked adjuvant effect(Munoz, 1964) and the antibody response includesantibodies of the reaginic type (Mota, 1958). Thereis also an increase in circulating eosinophils (Tjabbes& De Wied, 1962). In contrast to the hyperreactivityto pharmacological mediators, the animals showedreduced susceptibility to catecholamines (Szenti-vanyi et al., 1963). It was claimed (Szentivanyi et al.,1963) that the pharmacological hyperreactivity is dueto an imbalance of the two adrenergic receptorsystems. They showed that if the uptake of peripheralglucose is inhibited by deprivation of normal f3-adrenergic activity, then thetissues aremorereactive tohistamine. On the evidence afforded by the Bordetellapertussis mouse, Szentivanyi (1968) proposed that asimilar adrenergic imbalance might account for theclinical manifestations of asthma. The main tenetsof his hypothesis are that histamine and othermediators, if considered in their physiological role,are the natural chemical organizers of autonomicaction. Consequently, non-immunological triggers ofasthma would probably still act by utilizing the samemediators. Adjustment to their action requires acti-vation of their natural antagonists-the catechol-amines-and the balanced expression of the aminesthrough the two adrenergic effector systems. If asSzentivanyi proposes, a genetic or an acquired blockexists on the 3 side, then a stimulation would be un-opposed. In the context of asthma therefore, thebronchial tissue deprived of f3-adrenergic stimulationwould respond to unopposed a activity by constrict-ing. Fig. 3 shows diagrammatically the major path-ways postulated. Current thinking on the P3 receptorassociates it with an enzyme adenyl cyclase (Szenti-vanyi, 1968). In the presence of magnesium ionsadenyl cyclase is activated by the catecholamines andcatalyses the formation of 3'5'AMP and pyro-

Trigger mechanism

Infection Immunological Psychological

Mediatorsof

homeostatic controlHistamine5-HTSRSKinins

_Prosta landins

Adrenergic effectorsystems

Adenylcyc ase~ x

Phosphodiesterase

5'AMP I 3 5'AMPMethyxonthines

FIG. 3. Scheme outlining the Il-adrenergic block hypo-thesis of the atopic abnormality. The jagged line repre-sents the site of postulated blockage.

phosphate from ATP (Sutherland Robison, 1966;Belleau, 1966). The cyclic nucleotide then functionsas an intracellular organizer of amine action. Theinactivation of 3 '5'AMP is brought about by asecond enzyme phosphodiesterase, which can beinhibited by the methylxanthines. Thus these drugsexert their beneficial effect in asthma, by inducingadrenergic action distal to the hypothetical blockage.Time does not permit a more full analysis, but allthe points listed earlier are explicable wholly orpartially in terms of P-adrenergic blockade There isalso experimental evidence to show that the immuno-logical trigger, that is IgE/antigen interaction pro-ducing the release of histamine, works through theaccumulation of intracellular cyclic AMP. Lichten-stein & Margolis, 1968 demonstrated that the releaseof histamine from sensitized leucocytes could beprevented by the catecholamines and indeed by 3'5'AMP itself (Ishizaka & Ishizaka, 1970).

In conclusion therefore it is possible that both theintrinsic and extrinsic types of asthma have the samebasic atopic abnormality. By differing in respect totheir triggering mechanisms it appears clinically thateach has a distinct aetiology.

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