- Email: [email protected]
Atopic allergy: asthma and atopic dermatitis
Atopic
allergy:
asthma Thomas
University
of Virginia
and atopic
dermatitis
A.E. Platts-Mills
Medical
Centre,
Charlottlesville,
Virginia,
USA
During the past 2 years much progress has been made in our understanding of allergic diseases: there is now increasing evidence for a direct causal relationship between exposure to allergen and the chronic diseases, asthma and atopic dermatitis; furthermore, it seems very likely that exposure to indoor allergens is the most common cause of the inflammation of the lungs that is characteristic of asthma. Current
Opinion
in Immunology
1991, 3:874-880
studies of T-cell responses, development of monoclonal antibodies and quantitation of exposure [ 11.
Introduction
Allergy covers a wide range of symptoms or reactions to substances in our environment, many of which have not been shown to have any connection with immunology. There is now good evidence to suggest that chronic exposure of allergic individuals to foreign proteins in houses is an important cause of two major chronic diseases: asthma and atopic dermatitis (AD). Atopic allergy describes those symptoms or diseases that are epidemiologically associated with, and thought to be caused by, immediate hypersensitivity to common inhaled allergens. Because patients with atopic allergy are identied by wheal and flare skin responses, which develop within 15min, and/or serum IgE antibodies, there has been a natural tendency to expect that their symptoms have the same rapid time relationship to exposure. Although this can be true for anaphylaxis caused by insect stings or acute rhinitis caused by high level exposure to pollen or cat allergies, it is generally not true for asthma and AD. Thus, most patients with asthma or AD are not aware of an immediate relationship between their disease and exposure to house dust, pollens or other environmental factors. Indeed, many patients and physicians do not include asthma or AD as forms of ‘allergy’. A second major reason for diEculty in understanding the causal role of inhalant allergens in these diseases has been the poor knowledge of the main source of allergens, which is house dust. Since 1920, studies of asthma and AD have shown a high prevalence of wheal and flare skin responses to house-dust extracts. As long as house dust was considered as a black liquid standardized in ‘vacuum cleaner bags per liter’, it was Impossible to quant&ate exposure and difficult to make any progress in understanding the role that house dust exposure played in these chronic diseases. Over the past 10 years the major protein allergens in house dust, as well as in pollens, have been increasingly well delined. This has included purRication, cloning and sequencing of the allergens, detailed
During the past 10 years it has become accepted that asthma is an inflammatory disease of the bronchi, characterized by eosinophil, T-cell, mast-cell and basophil components. This realization has focused attention on the causes of inflammation. Although there are many different factors that can contribute to asthma, the only well delined experimental model for the disease is the inhalation of an allergen (usually pollen, dust mite or cat allergen) by an individual who has immediate hypersensitivity to that allergen. It is now well established that inhaling allergen can produce an inflammatory response in the lung, which is associated with both immediate (20 min) and late (4-12 h) increases in airway resistance. It is also clear that inhaling allergen can produce a prolonged (i.e. weeks) increase in non-specific bronchial hyper-reactivity (BHR). Thus, detailed studies of the mechanisms of lung inflammation are an important part of current research on asthma and the model used in these studies is inhalation of allergens. Understanding the etiology and Immunology of AD was hampered both by poor understanding of the relevant allergens and lack of a relevant model or challenge procedure. In 1982, Mitchell et al. [2] reported that purified mite allergen (Der p I) applied to the skin of patients with severe AD and high levels of IgE antibodies to Derp I, produced a patch of eczema. This patch-test response was characterized by an infiltrate of cells such as eosinophils, T cells, mast cells and basophils. Because of improved techniques for staining biopsies, measuring mediator production in blisters and growing T cells out of biopsies, it is now possible to study the details of skin responses to allergen in detail. This review of allergens in ‘atopic allergy’ will focus on work carried out over the past two years in the following areas: analysis of allergen exposure and the relationship between exposure and disease; investigation of evidence
Abbreviations AD-atopic 874
dermatitis;
IFN-interferon;
@ Current
IL-interleukin;
Biology
RAST-radio
Ltd ISSN 0952-7915
allergosorbant
test.
Atopic
that the ini%unmatoryresponse in the lung is related to exposure and is a causeof asthma;and studieson the immune events occurring in the skin of patients with atopic dermatitis.
Exposure to indoor allergens Using monoclonal antibodies it is now possible to measure major allergensfrom three important indoor sources: dust mites of the genus Dermatopbagoides,the domestic cat, and German cockroaches [ 1,3,4-l. For each allergen, samplinghas been carried out on floor dust, and the levels of exposure are being considered as threshold levels for diseaseon the basisof settled or reservoir dust [5]. For AD, the level of allergen in dust may be directly related to exposure, but for asthma,allergen hasto become airborne in order to be inhaled. Measurements of airborne allergen have identified striking properties of different allergensthat make it difficult or impossible to use airborne levelsasan index of exposure. Thus, in all studies mite allergen has only been found airborne during disturbances and it falls rapidly afterwards [6]. Without a meansof standardizing disturbance it is impossible to define a threshold level of airborne mite allergen for exposure. A recent article [7*] claiming that airborne mite allergen related better to diseasethan the level of allergen in settled dust was marred by a lack of any definition of the level of airborne allergen regarded as positive or of the disturbance used.Furthermore, other authors continue to have great dilficulty producing consistent measurements of airborne mite allergen. The implication is that exposure to mite allergen probably occurs at times when the patient is close to a source of allergen (i.e. pillow, sofa or bedding) or during disturbance (i.e. vacuum cleaning) [81. The definition of a major cat allergen [9] and development of monoclonal antibodies to it [3] has made it possible to measurethis allergen both in dust samplesand airborne. Previous studiesusing radio allergosorbent test (RAST) inhibition demonstrated airborne allergen even in undisturbed housesand showed that cat allergen be comes airborne over a range of particle sizes [101. Using very sensitiveassaysfor Fef d I, the major feline allergen, it is clear that a large proportion of airborne cat allergen is presenton smallparticles and that this allergen remains airborne in undisturbed houses[ll.] . Analysis of the levels of airborne allergen during disturbancesshowed that in many housesit is possible to inhale 8 ng of allergen on particles 52.5 l.trn diameter in 10 min. This is a quantity that has been shown to induce acute increasesin airway resistancein bronchial provocation experiments. Thus, cat allergen is found airborne in the quantities and particle sizes that could produce rapid effects on the lung. In contrast, dust-mite allergen becomes airborne on relatively few, ‘large’ particles each of which contain high levels (approximately 0.2ng) of allergen and would be expected to produce multiple inflammatory foci, possibly without a detectable change in airflow resistanceat
allergy:
asthma and atopic dermatitis
Platts-Mills 875
the time of exposure. Thus, it has been argued that the form of exposure to dust-mite allergensis the ideal form to produce progressive increasesin bronchial inflammation and hyperactivity without the patient being aware of the association. Understanding the details of airborne exposure has led to better designed regimes for reducing exposure. The procedures recommended for mite allergens(i.e. removing or controlling reservoirs) [ 1,12*] are now very different from those recommended for controlling cat allergens [ll.].
Exposure and disease In 1987, the first threshold values for dust-mite exposure were proposed by an International Workshop [5]. Over the subsequent 3 years several studies have directly addressed the relevance of these thresholds. Studies from Marseilles and Berlin [13*,14] have reported that 2 Pg Group I mite allergen per gram of reservoir dust is a useful threshold above which the risk of sensitization and asthma increases A 10 year prospective study in England suggestedthat exposure to > 1Oug Group I allergen increasedthe risk of asthmaby almostfivefold [ 15*=]. In this study, I6 out of 17 children with asthma at the age of 11 years were sensitized to the dust mite and sensitization to the mite carried an increased relative risk for asthmaof 19.7. In keeping with previous prospective studies, only mite and cat sensitization were correlated sigdicady with chronic asthma [I6]. When exposure to an allergen is seasonalit is relatively easy to establish a causal relationship between exposure and a disease,for example pollen hay fever (as first shown by Blackley in 1873) or pollen asthma [17,18]. Recently, a very dramatic example of seasonalincreases in severity of chronic asthma was associatedwith seasonal increasesin outdoor Alternuria spores [19”]. It is very difficult to prove a causal relationship between chronic (i.e. year round) exposure and a chronic disease such asasthma.However, a recent study from our group [20] has provided more evidence that patients presenting to hospital with acute asthmaare both sensitized and exposed to allergens. Previous studies have shown that IgE antibodies to dust mite, cat and cockroach allergens are each sigticantly correlated with asthma. In Wllmington, Delaware it has now been shown that the risk of asthma associatedwith IgE antibody to cat or cockroach is restricted to those areasof the town with high levels of these allergens (Gelber L, Pollart S, Chapman M, Platt-Mills T, abstract, J Allergy Clln Immunol 1991, 87:233). It was reported that 38 out of 93 acute asthmaticswere both sensitizedand exposed to one of the three indoor allergens (RAST 2 100 units ml-1 and 10 ng IgE antibody); the comparable figure for controls was seven out of 93. More striking, the cockroach allergic asthrnatits who were exposed were separategeographically from the cat allergic asthmaticswho were exposed. These results suggestverv stronehr that the risk of asthma assocl-
876
Atopic
allergy
and
other
hypersensitivities
ated with sensitization is dependent on continued exposure to the relevant allergen.
Inflammatory dermatitis
changes
in asthma
and atopic
Asthma
The evidence to suggest that asthma is an inflammatory disease of the bronchi has been reviewed extensively. Suffice it to say that biopsies of the lungs of asthmatics have consistently demonstrated infIammatory changes with increased numbers of eosinophils [ 21-231. In addition, it is clear that bronchial provocation produces an influx of inflammatory cells, an increased production of mediators, and increased bronchial reactivity. As discussed above, it is striking that the only consistent method for producing experimental inUammation of the lung is to use nebulized allergen extract. Thus, there is good evidence to indicate that asthmatics are both allergic and exposed to indoor allergens, and that experimental provocation of these individuals can produce changes that are characteristic of the inflammation found in naturally occurring asthma. Studies of occupational asthma have shown it to be another example of a causal relationship between exposure and disease [24*] and have provided the clearest evidence that increases in bronchial reactivity induced by exposure to a foreign antigen may be irreversible. This phenomenon was seen after a single accidental exposure to an irritating gas [25] or following prolonged exposure to a low molecular weight antigen such as plicatlc acid or isocyanate [24.].
Atopic
dermatitis
The association between AD and sensitivity to house dust was spelled out by Louis Tuft, who also demonstrated that the conditions of the patients improved when their exposure was decreased [ 261. Recent epidemiologic evidence supports a role of dust-mite exposure in AD [ 271. However, the causal role of dust allergens in AD has not been widely accepted. Because of the ability to purify mite allergens it has become clear that adults and older children with AD have IgE antibodies as weU as IgG antibodies and circulating CD4+ T cells for Group I mite allergens [ 28,291. The way in which mite allergens contribute to a chronic inflammatory disease of the skin is still not understood. In 1982, it was first shown that application of mite allergen to the skin in a patch test induced an eczematous response [2]. The histology of the lesion included an in&ate of eosinophils, basophils and T cells. Detailed study of both induced and naturally occurring lesions has now yielded a better understanding of the cellular influx and also the hypothesis that IgE on Langerhans’ cells has an important role in antigen presentation [30**,31*]. The hypothesis, which states that IgE on Iangerhans’ cells increases the sensitivity of the response, addresses one of the central questions in atopic allergy, i.e. how these immune responses can be boosted by the
minute quantities of allergen that become airborne. Some estimates suggest that annual exposure to inhaled allergens can be as little as 1 pg year- l , or 10 ng day- i. The exquisite sensitivity of the 1gE system was demonstrated elegantly in rats by EUen Jarrett [ 321. The second major issue that has arisen recently is the role that T cells play locally in the skin. The nature of the T cells present in eczematous skin was demonstrated by Ieung and Geha [33]. Furthermore, the presence of basophils and mast cells in the patch-test responses could be taken as evidence for a role of T cells in recruiting these cells [ 2,34]]. Using skin biopsies from patients with AD, Reinhold et al. [35-l have reported the outgrowth of CD4+ T cells, which are responsive to interleukin (IL)2 and IL-4. It is also possible to clone T cells from patients with allergic contact dermatitis, in which T cells are presumed to be responsible for the eczematous reaction on the skin [36-l. Direct comparison of T cells in the skin of patients with contact sensitivity and T cells in the skin of patients with AD is now possible. It has also become possible to study the production of interleukins in the skin, using either RNA expression [37**] or blister techniques [381. To date, these techniques have been applied to late-phase responses following intradermal skin tests rather than AD. The Importance of understanding the mechanisms of the skin rash is underscored by new developments in the treatment of the disease. Two recent publications have suggested that recombinant interferons (IFNs) could be used to treat hyper IgE syndrome or AD [39*,40*]. There has also been a report that im mune complexes of dust-mite antigen and human autologous antibody can be effective in the immunotherapy of AD [41=]. Understanding the role of T cells in AD and asthma will be essential to interpreting the results of planned studies of immunotherapy using recombinant fragments of allergens that only react with T cells. Work has advanced with both cat and dust-mite allergens to a level where it is possible to test cloned fragments for reactivity with T cells. Interestingly, at present it is not clear what response of the T cells in vitro would correlate with a potentially successful response in vivo. Although there is still no reliable model for the chronic inflammatory response to allergens, it is encouraging that in some studies the patch-test response correlates with the ability of that allergen to exacerbate AD 142.1.
The nature with fungal
of atopic allergens
allergens:
comparison
The question why some foreign antigens produce IgE antibody responses in man remains unanswered. An increasing knowledge of the sequences of atopic allergens has not provided evidence for common structural features of these antigens (see Baldo, this issue pp 841-850. Thus, the most likely explanation is that repeated lowdose immunization by the nasal route favors IgE production. That is, it is the immunization schedule that determines the nature of the response. Although many aller-
Atopic
gens are also enzymes this probably reflects the natural role of proteins rather than suggesting the enzymic activity has a role in the response. The two major dust-mite allergens may be used to illustrate the current situation well, because although the Group 1 allergens (24 kD) are serine proteases involved in digestion, the Group II allergens (15 kD) are stable molecules with no enzymic activity and no known function [43]. Recently, renewed emphasis has been placed on those colonizing fungi that are also *allergens; these are not correctly called atopic allergens because it it not clear whether they behave as inhalants or if susceptibility is inherited together with the atopic state. Aspergi1fu.s fumigatu.5 is an important pathogen that can induce high levels of IgE antibody. Colonization of the lung occasionally occurs in allergic asthmatics but more commonly in children with cystic fibrosis. In these situations the fungus colonizes the lung and presumably creates a persistent focus of antigen production within the lung. Although there are only limited data about A.@ergihs allergens, recent purification has shown a striking parallel between an allergen and a cytoxin described previously [44--l. The suggestion that Aspergifhs allergens may play a dual role as toxins is also supported by the demonstration that a proteinase from A jbmigatus can induce epithelial-cell detachment [45]. The commonest of all fungal diseases are athletes foot and onychomycosis, caused most commonly by infection with dermatophytes of the species Tricbopbyton. These persistent low-grade infections can give rise to either delayed or immediate hypersensitivity. Immediate hypersensitivity to Tricbop@fon has been associated with a form of late onset asthma, which is responsive to antifungal therapy in some cases [46]. An allergen has been punfied from Tricbopkyton which does not appear to be one of the proteins that gives rise to delayed hypersensitivity [47-l. The sinuses represent yet another site where persistent fungal colonization can give rise to disease. Recently, a striking new condition has been reported, allergic fungal sinusitis. This is usually caused by a selected group of fungi including Bipolaris @ci&ra, is characterized by an expanding innammatory mass in the maxillary sinuses, and is restricted to individuals who have IgE antibodies to the relevant fungus [48*]. There are now several examples of local fungal infection associated with IgE antibody production and disease. It is possible that the common thread is persistent relatively low-dose immunization. However, Trikbopbyton infection can also induce delayed hypersensitivity, and it would be very interesting to understand the differences in genetic background and T-cell responses that dictate different patterns of response. The development of IgE antibody responses to antigens on the skin has also been reported with scabies mites. Recently, it has been shown that IgE antibodies to the dust mite Dermatophagoides will bind to proteins produced by Sarcoptes scubez’i [49’]. Thus, although the major causes of 1gE production in the western world are the inhalant allergens (dust mite, cat and the pollens), there are excellent examples of surface infections that given rise to IgE antibody responses, including
allergy:
asthma
and
atopic
dermatitis
Platts-Mills
fungi, scabies and schistosomiasis. Thus, as Ishizaka suggested in 1974, it remains most likely that the biological role of immediate hypersensitivity is as a ‘gate keeper’ to prevent entry of parasites and/or fungi through the skin or mucosal surfaces [50].
Conclusions The word ‘allergy’ originally described any altered state and was used for all forms of immunity. In keeping with this, the antigens that produced immediate hypersensitivity were initially called ‘atopic allergens’. However, usage changed and the word ‘allergen’ came to apply only to those antigens that gave rise to harmful reactions and particularly those associated with atopy. This led to the assumption that allergic reactions should be obvious to the patient. The wheel has now turned completely so that it is clear that the inflammatory role of allergens can be chronic and that in general this role is not apparent to the patients. Thus, much research now addresses the ways in which allergens produce a response that is both delayed in time course, and chronic. Attention has focused both on the mediators produced by mast cells and also on the inflammatory effects of T cells. Over the past 2 years progress has been rapid in several different areas of research. The epidemiology of the relationship between allergen exposure, sensitivity and asthma has progressed to the point where it is clearly appropriate to discuss a causal relationship. Direct measurements of exposure in houses have detined more clearly the sources and characteristics of airborne allergens, and made it possible to design better regimes for reduction of exposure. Multiple studies of the lung have demonstrated that almost all forms of asthma involve an inflammatory (eosinophilic) reaction of the bronchi. Although it has not been proved, it is almost certain that this immunologic inflammation is dire@ related to increased bronchial reactivity. There is limited evidence that T cells as well as mast cells play a roie in the lung Inflammation. The skin has proved to be a much easier model for studying immunologic events; using either intradermal skin tests, the ‘atopy patch test’ or blister techniques, it is possible to study cellular influx and mediator production in the skin. In addition, it is possible to grow out T cells from skin biopsies and to clone them. The nose has also been used successfully as a model to study the detailed changes that occur following allergen challenge
[51*1. Over the next few years there are real prospects, not only for better understanding of the ways in which allergen exposure causes chronic disease, but also (at long last> for changes In therapy as a consequence of Irnmunologic progress. Progress will probably come In a variety of directions, e.g. both in the design of regimes for reducing exposure and in new approaches to Immunotherapy. Currently, experiments are underway using recombinant fragments of allergens and immune complexes to treat allergic disease. In addition, recombinant IIs or IFNs
877
878
Atopic
allergy and other hypersensitivities
are being used with some promise. It is clear that specific diagnosisof sensitivity and exposure is essentialfor the investigation and managementof patients with these chronic inflammatory diseases,who often do not recog nize that their symptoms are ‘allergic’.
References and recommended
reading
11. .
LKZYN~KA CM, U Y, CHAPMAN MD, PLAI-II-MI~~ TAE: Airborne Concentrations and Particle Size Distribution of AUergen Derived from Domestic Cats (Felis domes&us): Measurements Using Cascade Impactor, Liquid Impinger and a Two Site Monoclonal Antibody Assay for Fel d 1. Am Ret’ Re.yI Dis 1990. 14 1:361-367. Derailed studies of the form in which cat allergens become airborne and the major sources within the house. Includes an analysis of diRerent techniques for reducing exposure leading to a proposed protocol for controlling cat allergen. 12.
OWEN
S, MORGAN~RN
M,
HEPWORTH
J, WOax0c~
A: Con-
trol of House Dust Mite Antigen in Bedding. Lancet 1990, 335:396. A straightforward demonstration that the single most effective procedure to reduce exposure to mite allergens is to cover the mattress and hot wash the bedding. These procedures reduced the level of Derp I from 24 pg g- t to 0.2 pg g- 1 i.e. from above proposed threshold levels to well below the threshold. .
Papers of have been . of .. of 1.
special interest, published highlighted as: interest outstanding interest
within
the annual period
Pmrrs-MIUS TAB, CHAPMAN MD: Dust Mites: Allergic Disease. and Environmental Control. Immunol 1987, 80~755-775.
of review,
Immunology, J Allergy Clin
2.
MITCHEU EB. CROW J, CHAPMAN MD, JOUHAL SS, Pope FM, PIAT%MIUS TAB: Basophii in Allergen-Induced Patch Test Sites ln Atopic Dermatitis. Lancer 1982, i:127-130.
3.
CHAPMAN MD, AAIBERSE RC, BROWN Monoclonal Antibodies to the Major I. II. Single Step AfRnity Purification Sequence Analysis, and Development site Immunoassay to Asses Fef d I 1988, 140:812-818.
MJ, PUTI?+MU TAE: Feline AUergen Fe1 d of Fe1 d I, N-terminal of a Sensitive TwoExposure. / frnmunof
4. .
POUART SM. SMITI-I TF, MOIUUS EC, GEIBER LE, PLUXWus TAE, CHAPMAN MD: Environmental Exposure to cockroach AlIergens: Analysis with Monoclonal Antibodybased Enzyme Imantnoassays. J AIIergV Clin lmmunol 1991, 87:50>521. Reports the detinItion of two major cockroach allergens and the development of monoclonal antibody-based assays suitable for analysis of the exposure to allergic individuals. DE WECK AL: Dust Mite Wide Problem. J Allergy
13. .
li\u S, FAIKENHORST G, WEBER A, WETH~IANN I, LIND P, BUETTNER-GOFIZ P, WAHN U: High Mite-allergen Exposure Increases the Risk of Sensitization in Atopic Children and Young Adults. J Allergy Clin lmmunol 1989? 851718-725. An&es of dust mite allergen in the houses of children presenting for treatment with asthma suggested highly significant increased levels of mite allergen (i.e. ~2 pg Group I allergen per gram) in the houses of children who were sensitive to mite allergen. 14.
CHARPUU D, BIRNBAUM J, HADDI E, GENARLI G, TOUNI M, VEVUXT D: Altitude and Allergy to House Dust Mites: An Epidemiological Study in Primary School Children. J Allergy Clin Immund 1990, 85:185.
15. ..
SPOIUK R, HOLGATE ST, PLUII-MI~~ TAE, Cocxv~u. JJ: House Dust Mite Mergen (Der p I) Exposure and the Development of Sensitization and Asthma in Childhood: A Prospcctive Study. N Erg/J Med 1993, 323502-507. Reports evidence to suggest that sensitization to dust-mite allergens is a major risk factor for the development of asthma (relative risk 19.5) and high levels of exposure in early childhood increase the risk of developing asthma by almost fivefold. 16.
SEARS MR, HERVISON GP, HOIDAWAY MD, H~wrl7~ CJ, FIANNERY EM, SILVA PA The Relative Risk of Sensitivity to Grass Pollen. House Dust Mite, and Cat Dander in the Development of Childhood Asthma Clin f&p Allergy 1989, 19:419-424.
5.
PLU+I%-MUJS TAE, Asthma-A World 1989, 83:41ti27.
AlIergens and Clin Immunol
6.
TOXY ER, CHAF%UN MD, WEU CW, PIATIS-MI~~ TAE: The Distribution of Dust Mite AlIergens In the Houses of Patients with Asthma Am Rev Reqir Dh 1981, 124:630-635.
17.
REID MJ, Moss RB, HSU YP, KWASN~CKI JM, COMMERFORD TM, NELSON BL: Seasonal Asthma In Northern California: Allergic Causes and Efficacy of Immunotherapy. J Allergy Clin Immunol 1986, 78:590-&l.
PRICE JA, POUOCK I, Lrrn~ SA, ~ZNGBO’ITOM J1 WARNER JO: Measurement of Airborne Mite Antigen in Homes of Asthmatic Children. Luncet 1990, 336:895-896. Documents measurement of airborne mite allergen and comparison with floor dust measurements. Conclusions are marred by the lack of a quantitative definition of the level of exposure considered to be positive and lack of definition of disturbance.
18.
POLLART SM, l&to MJ, FUNG JA, CHAPMAN MD, PIAT&MU TAE: Epidemiology of Emergency Room Asthma in Northem Carolina: Association with IgE antibody to Ryegrass Pollen. J Allergy Clin Immunol 1988, 82~224-230.
7. .
8.
DE BRAY F, CHAPMAN MD, PLQX-MIU AIk%gerz Environmental Control with 1991, 1431334-1339.
9.
OHMAN JL JR, LORUSSO JR, m S: Cat Allergen Content of Coplmercial House Dust Extracts: Comparison with Dust Extracts From Cat-containing Environment J Aliergy Gin Immunol1987, 79:955+59.
10.
TAE: Airborne Cat Cat In S&A Resp Dis
SWANSON MC, CAMPBEU AR, KLUJCK MJ, REED CE: Correlations Between Levels of Mite and Cat AIIergens In Settled and Airborne Dust. J Allergv CIin Immunol 1989, 83:776-783.
19. ..
O’HAUEREN MT, YUNGINGER JW, OFFORD KP, SOMEW MJ, O’CONNELL EJ, BAIURD DJ, SACHS Ml: Exposure to an AeroaIlergen as a Possible Precipitating Factor in Respiratory Arrest In Young Patients with Asthma N Eng J Med 1991, 324:35%363. Documents a retrospective anatysis of a series of cases of very severe asthma attacks indicating association with both sensitization and expo sure to Altemaria 20.
POURT SM, CHAPMAN MD, FIOCCO GP, ROSE G, PLU-IX-M.U TAE: Epidemiology of Acute Asthma: IgE Antibodies to Common Inhalant AlIergens as a Risk Factor for Emergency Room Visits. J Alkrgy Clin Immunol 1989, 83875-882.
21.
BOUSQUET J, CH~WEZ P, IACOSTE JY, ET AL: Eosinophilic Inflammation in Asthma. N Engl J Med 1990, 323:10331039.
Atopic 22.
23.
GLEICH GJ: The Understandings. DJUKANOV~C TWEN-IY~~AN
mation
Eosinophil J Allergy
R, R~CHE OP, H0w~~n-l
in Asthma.
24. CHAN-YEUNG M, . in Occupational Excellent discussion of posure and bronchial in bronchial reactivity bronchial inflammation.
and Bronchial Asthma: Current Clin Immunol 1990, 854224i36. WR, PH.
WI&ON HOLGATE
Am Rev Rezpir
JW, BEAXEY ST: MucosaI
Dis 1990, 142:434-457.
LAM S: Evidence for MucosaI lnEammation Asthma. Clin ,Ex~ A//erg)! 1990, 20:1-5. the evidence available both from natural exchallenge, which suggests that the increases with occupational exposure correlate with
25.
BROOK< SM, WEISS MA, BERNSTEIN IL: Reactive Airways Dysfunction Syndrome @ADS). Persistent Asthma Syndrome after High Level Irritatnt Exposures. Cbesf, 1985 88:376-384
26.
Turn DY Importance of InhaIant ABergen matitis. J fnvesf Derm 1949, 12:211-219.
and House
asthma
and
atopic
dermatitis
36.
KALISH
37. ..
KAY AB, YINC S, VARNEV V. GAGA M, R, WARD~AW AJ, HAMID Q: Messenger
38.
ZWEIMAN
Platts-Mills
879
RS: The Use of Human Lymphocyte-T Clones to Study T-cell Function in AIIergic- Contact Dermatitis to Urushiol. I Invest Dermatol 1990, 94:S108-Sill. Review of experiments on T ceiis derived from peripheral blood of patients with contact sensitivity to poison ivy. Clones were predominantiy CD8+ cells specific for Uroshiol. and the authors speculate that these T cells may have a suppressor role. Further experiments are described using T cells grown out of biopsies.
.
CRW, In&m-
in Atopic
allergy:
DURHAM
SR,
M~QBEL
RNA Expression of the Cytokine Gene Cluster, Interleukin-3 (IL-3) IL4, B-5, and Grantdocyte Macrophage Colony-stimulating Factor, in AIIergen-induced Late-phase Cutaneous Reactions in Atopic Subjects. J Exp Med 1991, 173:3:775-778. Biopsies of 24 h skin responses in atopic individuals demonstrate expression of cytokine genes of the IL-3, IL.4 and IL-5 group. The results support the hypothesis that the T cells entering the skin in response to allergen exposure are comparable to the mutine T helper type 2 subset.
Der-
27.
BECK H-I, KORSGAA~~ J: Atopic Dermatitis Mites. Br J Dermafol 1989, 120:245-251.
28.
CHAPMAN MD, ROWNIREE S, MITCHELL EB, DI PIUSCO DE FUENMAJOR MC, Pu\‘rrs-MILU TAE: Quantitative Assessments of IgG and IgE Antibodies to InhaIant AIIergens in Pa-
B, ADS
PC, VON LUMEN
C. GLE~CH
GJ: Release
of
Eosinophil Granule Proteins During IgE-mediated ABergen Skin Reactions. J Allergy Cfin Immunof 1991, 873984-992.
Dust
39.
tients with 72~27-33.
Atopic
Dermatitis.
J A/few
Clin Immunol
1983,
29.
RAWLE FC, MITCHELL EB, PLU-IX-MU TAE: T CeU Responses to the Major AIIergen from the House Dust Mite Dermatophagoides pteronyssinus, Antigen Pl: Comparison of Patients with Asthma, Atopic Dermatitis. and Perennial Rhiniti. J Immunof 1984. 133:195201.
30. ..
MUDDE GC, HANSEL TT, BRUIJNZEEL-KOOMEN CAFM:
VONREIJSEN IgE -
FC, OSTERHOFF An Immunoglobulin
BF,
Specialized in Antigen Capture. Immunof Toady 1998, 11:12:440443. Presentation of evidence to suggest that IgE antibodies are present on bangerhans’ ceiis in the skin of patients with AD and discussion of the evidence that this represents an enhanced system of antigen presentation. 31. .
BI!ZBER T, DANNENBERG B. Pwiz JC, RIEBER EP, STOIZ W, BRAUN-FALCO 0, RING R Occurrence of IgE-bearing Epider-
SOUIUET G, ROUSSFT F, DE VIUES JE: Alpha-interferon Treatment of Patient with Hyper IgE Syndrome. Lancer 1989, ii:1384. Demonstration that treatment with IFN-a can cause decreased IgE production and ciinicai improvement. Discussion of the evidence that IFN can interfere with the effects of IL-4 in vivo. *
40.
BOGU-
M, JAFFE JS, Lzu A, SUSAN
LEUNG
41.
JACQUEMIN
MG,
MACHIU
32.
J~aa!zrr EE, ST!ZVYART DC: Rat IgE Production: I. Effect of Dose of Antigen on Primary and Secondary Reaginic Antibody Responses. Immunology 1974. 27:365-381.
43.
33.
LEIJNG D, GEHA Atopic Dermatitis.
44.
ARRUDA
..
pergfllus fumigatus
45.
ROBINSON
34.
MITCHELL EB, CROW J, WILLIAMS G, PLYII-S-M~us In Skin Mast CeIIs FoEowing Chronic House posure. Br J Derm 1986, 114:6>73.
35.
R!ZNHOLD
V, KUKEL
S, GOEDEN
B, NEUMANN
TAE: Increase Dust Mite Ex-
U, WEHR~~ANN
W,
KRnsEL HW: InterleukInll Promotes the Expansion of Skin Inlihrating Lymphocytes from Atopic Dermatitis In Vitro. J Invest Dermufot 1991, 96:37C-375. Outgrowth of CD4+ T cells from skin biopsies of patients with atopic dermatitis. Demonstration of growth In response to IL-2 plus IL-4.
LEERUN
PM,
SAINT-REMY
JMR:
CIARK RAF, ADINOFF AD: The Relationship Between Positive AeroalIergen Patch Test Reactions and AeroaIIergen Exacerbations of Atopic Dermatitis. Clin Immunof Immunopurhol 1989, 53:S132-S140. Discussion of the evidence that the skin-patch-test response to aeroailetgens can predict the response of the patients skin to naNd expo sure.
42. .
in
JJ,
Successful Treatment of Atopic Dermatitis with Complexes of AIIergen and Speciiic Antibodies. Lzncet 1930, 335:1468-1469. This report on AD follows up the author’s report on treatment of asthma, Machiels el al, J Ciin Invest 1990, 85:1024-1035. At present it is not clear what quantity of ‘complexes’ is used in this treatment, nor is it clear what the mechanism is. .
mai Iangerhans’ CeIIs in Atopic Eczema: A Study of the Time Course of the Lesions and with Regard to the IgE Serum Level. J Invest Dermafol 1989, 93215219. Reports @E-bearing hangerhans’ cells in-biopsies from skin of patients with atopic dermatitis. These cells were present in almost aii the patients with totai serum IgE 2 300 IL!. The presence of &E-beating cells appears to be suppressed by local or systemic steroids.
R lmmunoregulatory Abnormalities Clin Rev Affeqy 1986, 4~67-86.
MJ, YORK D, GEHA RS,
DYM: Recombinant Gamma Interferon in Treatment of Patients with Atopic Dermatitis and Elevated IgE Levels. Am J Med 1990, 88:365-370. Progressive improvement in ciinicai parameters of AD during uncontrolled treatment with IFN-y. This response was not related to a faE in total serum IgE but in some patients there was reduced in uifm IgE production.
.
tiMBARDER0
HEYMANN
M,
PW,
PIA~TS-I&LIZ
TAE,
FOX
JW,
CHAPMAN MD: Conformational Stabiity of B CeU Epitopes on Group I and Group II Dermatophagoides spp. Allergens. J Immunol 1990, 144:135>1360. LK,
P~TIX-MIU
TAE,
FOX
JW,
CHAPMAN
MD:
&-
AlIergen I, A Major &E-binding Protein, is a Member of the MitogillinFamily of Cytotoxins. / E.$Med 1990, 172:152%1532.Reports purification and partial sequencing of an allergen of 18 kD derived from A Jkmigatux Demonstration of close homology in function and antigenicky of this allergen with a cytotoxin (Mitogiliin) derived from A reshiktus
.
BWS,
VENAUE
gens as Proteases: rectly Induces Cfin Immunol
TJ, MEDNIS
AHW,
An Aspe@ilusfunigatus
Human EpitheEaI 1990, 86:72&731.
MCAIEER
R: Akf-
Proteinase DiCelI Detachment. ] Auergy
880
Atopic 46.
allergy
and
other
hypersensitivities
WAFXI GW JR. KARLSSON G. ROSE G, PLA~YMIUS TAE: chophyton Asthma: Scnsitisation of Bronchi and Upper ways to Dermatophyte Antigen. Lnncet 1989, i:859-862.
TriAir-
47. .
DEUELL 8, ARRUDA LK, HAYDEN ML, CHAP~UN MD, PLVI’SMIUS TAE: Tricbophyron toonsurum Allergen I (Tti t I): Characterization of a Protein that Causes Immediate but not Delayed Hypersensitivity. J Immunol 1991, 147:96101. Documents purification of a Tricko~&owderived IgE-binding protein (i.e. allergen) that does not give delayed hypersensitivity skin responses. Reports preliminary evidence that some individuals who have delayed hypersensitivity have a wheal and flare preceding the delayed response that is not related to IgE antibodies. 48. .
GOURLEV DS, WHISMAN BA, JORGENSEN NL. MARTIN rME, Rm MJ: Allergic Bipolaris Sinusitis: Clinical and Immunopathogenetic Characteristics. J Allergy Clin Immtmol 1990. 85:58%591. Three cases of pansinusitis with impaction of maxillary sinuses wid3 ‘allergic mucus’; this caused pressure erosion of bone without any inMsion. The cultures grew Bipolaris @crJhu and each of the patients had specific IgE antibodies to this fungus, which is a member of the helminthosporium group. 49. .
ARUAN LG, VYXENSKI-MOHER DL, AH~~AD SG, Esm SA Cross Antigenicity Between the Scabies Mite, Surcoptes scubei, and the House Dust Mite, Dermatophagoides pteronyssinus J Invest Dermatoi 1991, 96~349-354.
Clear demonstration that patients sensitized to the dust mite pro. duced IgE antitxxlies that bind ro proteins produced by the scabies mite. A discussion of the relewnce to the manifestations of scabies. The genus Snrcoptes are reasonably close relatives of Ihe genus Dermutopkwg0ide-s 50.
STEINRERC mediated
P. ISHVm K. NORhfhN Reaction in Immunity.
PS: Possible Role of [email protected] AIlera) 1974, 54:359366.
51. .
ILIOPO~ILOS 0. PRO~III D. ADKINSON NF JR, NOR~ZAN PS. KACWSono-r~~ A, LICHI-ENSTEIN LM, NACIXRIO RM: Relationship Between the Early, Late and Rechallenge Reaction to Nasal Challenge with Antigen: Observations on the Role of Inflammatory Mediators and Cells. .I Allergy Clin Immunol 19’90, 86:851461. Analysis of the cellular and mediator responses to nasal challenge with ragweed extract, demonstrating thar late reaction in the nose is associated closely with increased mediator production. Results suggest that late reactions in the skin. late reactions in the nose and enhanccxl response to repeat nasal provocations are controlled independently.
TAE PlattsMills, lergy and Clinical USA
University of Virginia Medical Centre. Immunology, Box 225, Charlottesville,
Division Virginia
of Al22938.
allergy:
asthma Thomas
University
of Virginia
and atopic
dermatitis
A.E. Platts-Mills
Medical
Centre,
Charlottlesville,
Virginia,
USA
During the past 2 years much progress has been made in our understanding of allergic diseases: there is now increasing evidence for a direct causal relationship between exposure to allergen and the chronic diseases, asthma and atopic dermatitis; furthermore, it seems very likely that exposure to indoor allergens is the most common cause of the inflammation of the lungs that is characteristic of asthma. Current
Opinion
in Immunology
1991, 3:874-880
studies of T-cell responses, development of monoclonal antibodies and quantitation of exposure [ 11.
Introduction
Allergy covers a wide range of symptoms or reactions to substances in our environment, many of which have not been shown to have any connection with immunology. There is now good evidence to suggest that chronic exposure of allergic individuals to foreign proteins in houses is an important cause of two major chronic diseases: asthma and atopic dermatitis (AD). Atopic allergy describes those symptoms or diseases that are epidemiologically associated with, and thought to be caused by, immediate hypersensitivity to common inhaled allergens. Because patients with atopic allergy are identied by wheal and flare skin responses, which develop within 15min, and/or serum IgE antibodies, there has been a natural tendency to expect that their symptoms have the same rapid time relationship to exposure. Although this can be true for anaphylaxis caused by insect stings or acute rhinitis caused by high level exposure to pollen or cat allergies, it is generally not true for asthma and AD. Thus, most patients with asthma or AD are not aware of an immediate relationship between their disease and exposure to house dust, pollens or other environmental factors. Indeed, many patients and physicians do not include asthma or AD as forms of ‘allergy’. A second major reason for diEculty in understanding the causal role of inhalant allergens in these diseases has been the poor knowledge of the main source of allergens, which is house dust. Since 1920, studies of asthma and AD have shown a high prevalence of wheal and flare skin responses to house-dust extracts. As long as house dust was considered as a black liquid standardized in ‘vacuum cleaner bags per liter’, it was Impossible to quant&ate exposure and difficult to make any progress in understanding the role that house dust exposure played in these chronic diseases. Over the past 10 years the major protein allergens in house dust, as well as in pollens, have been increasingly well delined. This has included purRication, cloning and sequencing of the allergens, detailed
During the past 10 years it has become accepted that asthma is an inflammatory disease of the bronchi, characterized by eosinophil, T-cell, mast-cell and basophil components. This realization has focused attention on the causes of inflammation. Although there are many different factors that can contribute to asthma, the only well delined experimental model for the disease is the inhalation of an allergen (usually pollen, dust mite or cat allergen) by an individual who has immediate hypersensitivity to that allergen. It is now well established that inhaling allergen can produce an inflammatory response in the lung, which is associated with both immediate (20 min) and late (4-12 h) increases in airway resistance. It is also clear that inhaling allergen can produce a prolonged (i.e. weeks) increase in non-specific bronchial hyper-reactivity (BHR). Thus, detailed studies of the mechanisms of lung inflammation are an important part of current research on asthma and the model used in these studies is inhalation of allergens. Understanding the etiology and Immunology of AD was hampered both by poor understanding of the relevant allergens and lack of a relevant model or challenge procedure. In 1982, Mitchell et al. [2] reported that purified mite allergen (Der p I) applied to the skin of patients with severe AD and high levels of IgE antibodies to Derp I, produced a patch of eczema. This patch-test response was characterized by an infiltrate of cells such as eosinophils, T cells, mast cells and basophils. Because of improved techniques for staining biopsies, measuring mediator production in blisters and growing T cells out of biopsies, it is now possible to study the details of skin responses to allergen in detail. This review of allergens in ‘atopic allergy’ will focus on work carried out over the past two years in the following areas: analysis of allergen exposure and the relationship between exposure and disease; investigation of evidence
Abbreviations AD-atopic 874
dermatitis;
IFN-interferon;
@ Current
IL-interleukin;
Biology
RAST-radio
Ltd ISSN 0952-7915
allergosorbant
test.
Atopic
that the ini%unmatoryresponse in the lung is related to exposure and is a causeof asthma;and studieson the immune events occurring in the skin of patients with atopic dermatitis.
Exposure to indoor allergens Using monoclonal antibodies it is now possible to measure major allergensfrom three important indoor sources: dust mites of the genus Dermatopbagoides,the domestic cat, and German cockroaches [ 1,3,4-l. For each allergen, samplinghas been carried out on floor dust, and the levels of exposure are being considered as threshold levels for diseaseon the basisof settled or reservoir dust [5]. For AD, the level of allergen in dust may be directly related to exposure, but for asthma,allergen hasto become airborne in order to be inhaled. Measurements of airborne allergen have identified striking properties of different allergensthat make it difficult or impossible to use airborne levelsasan index of exposure. Thus, in all studies mite allergen has only been found airborne during disturbances and it falls rapidly afterwards [6]. Without a meansof standardizing disturbance it is impossible to define a threshold level of airborne mite allergen for exposure. A recent article [7*] claiming that airborne mite allergen related better to diseasethan the level of allergen in settled dust was marred by a lack of any definition of the level of airborne allergen regarded as positive or of the disturbance used.Furthermore, other authors continue to have great dilficulty producing consistent measurements of airborne mite allergen. The implication is that exposure to mite allergen probably occurs at times when the patient is close to a source of allergen (i.e. pillow, sofa or bedding) or during disturbance (i.e. vacuum cleaning) [81. The definition of a major cat allergen [9] and development of monoclonal antibodies to it [3] has made it possible to measurethis allergen both in dust samplesand airborne. Previous studiesusing radio allergosorbent test (RAST) inhibition demonstrated airborne allergen even in undisturbed housesand showed that cat allergen be comes airborne over a range of particle sizes [101. Using very sensitiveassaysfor Fef d I, the major feline allergen, it is clear that a large proportion of airborne cat allergen is presenton smallparticles and that this allergen remains airborne in undisturbed houses[ll.] . Analysis of the levels of airborne allergen during disturbancesshowed that in many housesit is possible to inhale 8 ng of allergen on particles 52.5 l.trn diameter in 10 min. This is a quantity that has been shown to induce acute increasesin airway resistancein bronchial provocation experiments. Thus, cat allergen is found airborne in the quantities and particle sizes that could produce rapid effects on the lung. In contrast, dust-mite allergen becomes airborne on relatively few, ‘large’ particles each of which contain high levels (approximately 0.2ng) of allergen and would be expected to produce multiple inflammatory foci, possibly without a detectable change in airflow resistanceat
allergy:
asthma and atopic dermatitis
Platts-Mills 875
the time of exposure. Thus, it has been argued that the form of exposure to dust-mite allergensis the ideal form to produce progressive increasesin bronchial inflammation and hyperactivity without the patient being aware of the association. Understanding the details of airborne exposure has led to better designed regimes for reducing exposure. The procedures recommended for mite allergens(i.e. removing or controlling reservoirs) [ 1,12*] are now very different from those recommended for controlling cat allergens [ll.].
Exposure and disease In 1987, the first threshold values for dust-mite exposure were proposed by an International Workshop [5]. Over the subsequent 3 years several studies have directly addressed the relevance of these thresholds. Studies from Marseilles and Berlin [13*,14] have reported that 2 Pg Group I mite allergen per gram of reservoir dust is a useful threshold above which the risk of sensitization and asthma increases A 10 year prospective study in England suggestedthat exposure to > 1Oug Group I allergen increasedthe risk of asthmaby almostfivefold [ 15*=]. In this study, I6 out of 17 children with asthma at the age of 11 years were sensitized to the dust mite and sensitization to the mite carried an increased relative risk for asthmaof 19.7. In keeping with previous prospective studies, only mite and cat sensitization were correlated sigdicady with chronic asthma [I6]. When exposure to an allergen is seasonalit is relatively easy to establish a causal relationship between exposure and a disease,for example pollen hay fever (as first shown by Blackley in 1873) or pollen asthma [17,18]. Recently, a very dramatic example of seasonalincreases in severity of chronic asthma was associatedwith seasonal increasesin outdoor Alternuria spores [19”]. It is very difficult to prove a causal relationship between chronic (i.e. year round) exposure and a chronic disease such asasthma.However, a recent study from our group [20] has provided more evidence that patients presenting to hospital with acute asthmaare both sensitized and exposed to allergens. Previous studies have shown that IgE antibodies to dust mite, cat and cockroach allergens are each sigticantly correlated with asthma. In Wllmington, Delaware it has now been shown that the risk of asthma associatedwith IgE antibody to cat or cockroach is restricted to those areasof the town with high levels of these allergens (Gelber L, Pollart S, Chapman M, Platt-Mills T, abstract, J Allergy Clln Immunol 1991, 87:233). It was reported that 38 out of 93 acute asthmaticswere both sensitizedand exposed to one of the three indoor allergens (RAST 2 100 units ml-1 and 10 ng IgE antibody); the comparable figure for controls was seven out of 93. More striking, the cockroach allergic asthrnatits who were exposed were separategeographically from the cat allergic asthmaticswho were exposed. These results suggestverv stronehr that the risk of asthma assocl-
876
Atopic
allergy
and
other
hypersensitivities
ated with sensitization is dependent on continued exposure to the relevant allergen.
Inflammatory dermatitis
changes
in asthma
and atopic
Asthma
The evidence to suggest that asthma is an inflammatory disease of the bronchi has been reviewed extensively. Suffice it to say that biopsies of the lungs of asthmatics have consistently demonstrated infIammatory changes with increased numbers of eosinophils [ 21-231. In addition, it is clear that bronchial provocation produces an influx of inflammatory cells, an increased production of mediators, and increased bronchial reactivity. As discussed above, it is striking that the only consistent method for producing experimental inUammation of the lung is to use nebulized allergen extract. Thus, there is good evidence to indicate that asthmatics are both allergic and exposed to indoor allergens, and that experimental provocation of these individuals can produce changes that are characteristic of the inflammation found in naturally occurring asthma. Studies of occupational asthma have shown it to be another example of a causal relationship between exposure and disease [24*] and have provided the clearest evidence that increases in bronchial reactivity induced by exposure to a foreign antigen may be irreversible. This phenomenon was seen after a single accidental exposure to an irritating gas [25] or following prolonged exposure to a low molecular weight antigen such as plicatlc acid or isocyanate [24.].
Atopic
dermatitis
The association between AD and sensitivity to house dust was spelled out by Louis Tuft, who also demonstrated that the conditions of the patients improved when their exposure was decreased [ 261. Recent epidemiologic evidence supports a role of dust-mite exposure in AD [ 271. However, the causal role of dust allergens in AD has not been widely accepted. Because of the ability to purify mite allergens it has become clear that adults and older children with AD have IgE antibodies as weU as IgG antibodies and circulating CD4+ T cells for Group I mite allergens [ 28,291. The way in which mite allergens contribute to a chronic inflammatory disease of the skin is still not understood. In 1982, it was first shown that application of mite allergen to the skin in a patch test induced an eczematous response [2]. The histology of the lesion included an in&ate of eosinophils, basophils and T cells. Detailed study of both induced and naturally occurring lesions has now yielded a better understanding of the cellular influx and also the hypothesis that IgE on Langerhans’ cells has an important role in antigen presentation [30**,31*]. The hypothesis, which states that IgE on Iangerhans’ cells increases the sensitivity of the response, addresses one of the central questions in atopic allergy, i.e. how these immune responses can be boosted by the
minute quantities of allergen that become airborne. Some estimates suggest that annual exposure to inhaled allergens can be as little as 1 pg year- l , or 10 ng day- i. The exquisite sensitivity of the 1gE system was demonstrated elegantly in rats by EUen Jarrett [ 321. The second major issue that has arisen recently is the role that T cells play locally in the skin. The nature of the T cells present in eczematous skin was demonstrated by Ieung and Geha [33]. Furthermore, the presence of basophils and mast cells in the patch-test responses could be taken as evidence for a role of T cells in recruiting these cells [ 2,34]]. Using skin biopsies from patients with AD, Reinhold et al. [35-l have reported the outgrowth of CD4+ T cells, which are responsive to interleukin (IL)2 and IL-4. It is also possible to clone T cells from patients with allergic contact dermatitis, in which T cells are presumed to be responsible for the eczematous reaction on the skin [36-l. Direct comparison of T cells in the skin of patients with contact sensitivity and T cells in the skin of patients with AD is now possible. It has also become possible to study the production of interleukins in the skin, using either RNA expression [37**] or blister techniques [381. To date, these techniques have been applied to late-phase responses following intradermal skin tests rather than AD. The Importance of understanding the mechanisms of the skin rash is underscored by new developments in the treatment of the disease. Two recent publications have suggested that recombinant interferons (IFNs) could be used to treat hyper IgE syndrome or AD [39*,40*]. There has also been a report that im mune complexes of dust-mite antigen and human autologous antibody can be effective in the immunotherapy of AD [41=]. Understanding the role of T cells in AD and asthma will be essential to interpreting the results of planned studies of immunotherapy using recombinant fragments of allergens that only react with T cells. Work has advanced with both cat and dust-mite allergens to a level where it is possible to test cloned fragments for reactivity with T cells. Interestingly, at present it is not clear what response of the T cells in vitro would correlate with a potentially successful response in vivo. Although there is still no reliable model for the chronic inflammatory response to allergens, it is encouraging that in some studies the patch-test response correlates with the ability of that allergen to exacerbate AD 142.1.
The nature with fungal
of atopic allergens
allergens:
comparison
The question why some foreign antigens produce IgE antibody responses in man remains unanswered. An increasing knowledge of the sequences of atopic allergens has not provided evidence for common structural features of these antigens (see Baldo, this issue pp 841-850. Thus, the most likely explanation is that repeated lowdose immunization by the nasal route favors IgE production. That is, it is the immunization schedule that determines the nature of the response. Although many aller-
Atopic
gens are also enzymes this probably reflects the natural role of proteins rather than suggesting the enzymic activity has a role in the response. The two major dust-mite allergens may be used to illustrate the current situation well, because although the Group 1 allergens (24 kD) are serine proteases involved in digestion, the Group II allergens (15 kD) are stable molecules with no enzymic activity and no known function [43]. Recently, renewed emphasis has been placed on those colonizing fungi that are also *allergens; these are not correctly called atopic allergens because it it not clear whether they behave as inhalants or if susceptibility is inherited together with the atopic state. Aspergi1fu.s fumigatu.5 is an important pathogen that can induce high levels of IgE antibody. Colonization of the lung occasionally occurs in allergic asthmatics but more commonly in children with cystic fibrosis. In these situations the fungus colonizes the lung and presumably creates a persistent focus of antigen production within the lung. Although there are only limited data about A.@ergihs allergens, recent purification has shown a striking parallel between an allergen and a cytoxin described previously [44--l. The suggestion that Aspergifhs allergens may play a dual role as toxins is also supported by the demonstration that a proteinase from A jbmigatus can induce epithelial-cell detachment [45]. The commonest of all fungal diseases are athletes foot and onychomycosis, caused most commonly by infection with dermatophytes of the species Tricbopbyton. These persistent low-grade infections can give rise to either delayed or immediate hypersensitivity. Immediate hypersensitivity to Tricbop@fon has been associated with a form of late onset asthma, which is responsive to antifungal therapy in some cases [46]. An allergen has been punfied from Tricbopkyton which does not appear to be one of the proteins that gives rise to delayed hypersensitivity [47-l. The sinuses represent yet another site where persistent fungal colonization can give rise to disease. Recently, a striking new condition has been reported, allergic fungal sinusitis. This is usually caused by a selected group of fungi including Bipolaris @ci&ra, is characterized by an expanding innammatory mass in the maxillary sinuses, and is restricted to individuals who have IgE antibodies to the relevant fungus [48*]. There are now several examples of local fungal infection associated with IgE antibody production and disease. It is possible that the common thread is persistent relatively low-dose immunization. However, Trikbopbyton infection can also induce delayed hypersensitivity, and it would be very interesting to understand the differences in genetic background and T-cell responses that dictate different patterns of response. The development of IgE antibody responses to antigens on the skin has also been reported with scabies mites. Recently, it has been shown that IgE antibodies to the dust mite Dermatophagoides will bind to proteins produced by Sarcoptes scubez’i [49’]. Thus, although the major causes of 1gE production in the western world are the inhalant allergens (dust mite, cat and the pollens), there are excellent examples of surface infections that given rise to IgE antibody responses, including
allergy:
asthma
and
atopic
dermatitis
Platts-Mills
fungi, scabies and schistosomiasis. Thus, as Ishizaka suggested in 1974, it remains most likely that the biological role of immediate hypersensitivity is as a ‘gate keeper’ to prevent entry of parasites and/or fungi through the skin or mucosal surfaces [50].
Conclusions The word ‘allergy’ originally described any altered state and was used for all forms of immunity. In keeping with this, the antigens that produced immediate hypersensitivity were initially called ‘atopic allergens’. However, usage changed and the word ‘allergen’ came to apply only to those antigens that gave rise to harmful reactions and particularly those associated with atopy. This led to the assumption that allergic reactions should be obvious to the patient. The wheel has now turned completely so that it is clear that the inflammatory role of allergens can be chronic and that in general this role is not apparent to the patients. Thus, much research now addresses the ways in which allergens produce a response that is both delayed in time course, and chronic. Attention has focused both on the mediators produced by mast cells and also on the inflammatory effects of T cells. Over the past 2 years progress has been rapid in several different areas of research. The epidemiology of the relationship between allergen exposure, sensitivity and asthma has progressed to the point where it is clearly appropriate to discuss a causal relationship. Direct measurements of exposure in houses have detined more clearly the sources and characteristics of airborne allergens, and made it possible to design better regimes for reduction of exposure. Multiple studies of the lung have demonstrated that almost all forms of asthma involve an inflammatory (eosinophilic) reaction of the bronchi. Although it has not been proved, it is almost certain that this immunologic inflammation is dire@ related to increased bronchial reactivity. There is limited evidence that T cells as well as mast cells play a roie in the lung Inflammation. The skin has proved to be a much easier model for studying immunologic events; using either intradermal skin tests, the ‘atopy patch test’ or blister techniques, it is possible to study cellular influx and mediator production in the skin. In addition, it is possible to grow out T cells from skin biopsies and to clone them. The nose has also been used successfully as a model to study the detailed changes that occur following allergen challenge
[51*1. Over the next few years there are real prospects, not only for better understanding of the ways in which allergen exposure causes chronic disease, but also (at long last> for changes In therapy as a consequence of Irnmunologic progress. Progress will probably come In a variety of directions, e.g. both in the design of regimes for reducing exposure and in new approaches to Immunotherapy. Currently, experiments are underway using recombinant fragments of allergens and immune complexes to treat allergic disease. In addition, recombinant IIs or IFNs
877
878
Atopic
allergy and other hypersensitivities
are being used with some promise. It is clear that specific diagnosisof sensitivity and exposure is essentialfor the investigation and managementof patients with these chronic inflammatory diseases,who often do not recog nize that their symptoms are ‘allergic’.
References and recommended
reading
11. .
LKZYN~KA CM, U Y, CHAPMAN MD, PLAI-II-MI~~ TAE: Airborne Concentrations and Particle Size Distribution of AUergen Derived from Domestic Cats (Felis domes&us): Measurements Using Cascade Impactor, Liquid Impinger and a Two Site Monoclonal Antibody Assay for Fel d 1. Am Ret’ Re.yI Dis 1990. 14 1:361-367. Derailed studies of the form in which cat allergens become airborne and the major sources within the house. Includes an analysis of diRerent techniques for reducing exposure leading to a proposed protocol for controlling cat allergen. 12.
OWEN
S, MORGAN~RN
M,
HEPWORTH
J, WOax0c~
A: Con-
trol of House Dust Mite Antigen in Bedding. Lancet 1990, 335:396. A straightforward demonstration that the single most effective procedure to reduce exposure to mite allergens is to cover the mattress and hot wash the bedding. These procedures reduced the level of Derp I from 24 pg g- t to 0.2 pg g- 1 i.e. from above proposed threshold levels to well below the threshold. .
Papers of have been . of .. of 1.
special interest, published highlighted as: interest outstanding interest
within
the annual period
Pmrrs-MIUS TAB, CHAPMAN MD: Dust Mites: Allergic Disease. and Environmental Control. Immunol 1987, 80~755-775.
of review,
Immunology, J Allergy Clin
2.
MITCHEU EB. CROW J, CHAPMAN MD, JOUHAL SS, Pope FM, PIAT%MIUS TAB: Basophii in Allergen-Induced Patch Test Sites ln Atopic Dermatitis. Lancer 1982, i:127-130.
3.
CHAPMAN MD, AAIBERSE RC, BROWN Monoclonal Antibodies to the Major I. II. Single Step AfRnity Purification Sequence Analysis, and Development site Immunoassay to Asses Fef d I 1988, 140:812-818.
MJ, PUTI?+MU TAE: Feline AUergen Fe1 d of Fe1 d I, N-terminal of a Sensitive TwoExposure. / frnmunof
4. .
POUART SM. SMITI-I TF, MOIUUS EC, GEIBER LE, PLUXWus TAE, CHAPMAN MD: Environmental Exposure to cockroach AlIergens: Analysis with Monoclonal Antibodybased Enzyme Imantnoassays. J AIIergV Clin lmmunol 1991, 87:50>521. Reports the detinItion of two major cockroach allergens and the development of monoclonal antibody-based assays suitable for analysis of the exposure to allergic individuals. DE WECK AL: Dust Mite Wide Problem. J Allergy
13. .
li\u S, FAIKENHORST G, WEBER A, WETH~IANN I, LIND P, BUETTNER-GOFIZ P, WAHN U: High Mite-allergen Exposure Increases the Risk of Sensitization in Atopic Children and Young Adults. J Allergy Clin lmmunol 1989? 851718-725. An&es of dust mite allergen in the houses of children presenting for treatment with asthma suggested highly significant increased levels of mite allergen (i.e. ~2 pg Group I allergen per gram) in the houses of children who were sensitive to mite allergen. 14.
CHARPUU D, BIRNBAUM J, HADDI E, GENARLI G, TOUNI M, VEVUXT D: Altitude and Allergy to House Dust Mites: An Epidemiological Study in Primary School Children. J Allergy Clin Immund 1990, 85:185.
15. ..
SPOIUK R, HOLGATE ST, PLUII-MI~~ TAE, Cocxv~u. JJ: House Dust Mite Mergen (Der p I) Exposure and the Development of Sensitization and Asthma in Childhood: A Prospcctive Study. N Erg/J Med 1993, 323502-507. Reports evidence to suggest that sensitization to dust-mite allergens is a major risk factor for the development of asthma (relative risk 19.5) and high levels of exposure in early childhood increase the risk of developing asthma by almost fivefold. 16.
SEARS MR, HERVISON GP, HOIDAWAY MD, H~wrl7~ CJ, FIANNERY EM, SILVA PA The Relative Risk of Sensitivity to Grass Pollen. House Dust Mite, and Cat Dander in the Development of Childhood Asthma Clin f&p Allergy 1989, 19:419-424.
5.
PLU+I%-MUJS TAE, Asthma-A World 1989, 83:41ti27.
AlIergens and Clin Immunol
6.
TOXY ER, CHAF%UN MD, WEU CW, PIATIS-MI~~ TAE: The Distribution of Dust Mite AlIergens In the Houses of Patients with Asthma Am Rev Reqir Dh 1981, 124:630-635.
17.
REID MJ, Moss RB, HSU YP, KWASN~CKI JM, COMMERFORD TM, NELSON BL: Seasonal Asthma In Northern California: Allergic Causes and Efficacy of Immunotherapy. J Allergy Clin Immunol 1986, 78:590-&l.
PRICE JA, POUOCK I, Lrrn~ SA, ~ZNGBO’ITOM J1 WARNER JO: Measurement of Airborne Mite Antigen in Homes of Asthmatic Children. Luncet 1990, 336:895-896. Documents measurement of airborne mite allergen and comparison with floor dust measurements. Conclusions are marred by the lack of a quantitative definition of the level of exposure considered to be positive and lack of definition of disturbance.
18.
POLLART SM, l&to MJ, FUNG JA, CHAPMAN MD, PIAT&MU TAE: Epidemiology of Emergency Room Asthma in Northem Carolina: Association with IgE antibody to Ryegrass Pollen. J Allergy Clin Immunol 1988, 82~224-230.
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8.
DE BRAY F, CHAPMAN MD, PLQX-MIU AIk%gerz Environmental Control with 1991, 1431334-1339.
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OHMAN JL JR, LORUSSO JR, m S: Cat Allergen Content of Coplmercial House Dust Extracts: Comparison with Dust Extracts From Cat-containing Environment J Aliergy Gin Immunol1987, 79:955+59.
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SWANSON MC, CAMPBEU AR, KLUJCK MJ, REED CE: Correlations Between Levels of Mite and Cat AIIergens In Settled and Airborne Dust. J Allergv CIin Immunol 1989, 83:776-783.
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O’HAUEREN MT, YUNGINGER JW, OFFORD KP, SOMEW MJ, O’CONNELL EJ, BAIURD DJ, SACHS Ml: Exposure to an AeroaIlergen as a Possible Precipitating Factor in Respiratory Arrest In Young Patients with Asthma N Eng J Med 1991, 324:35%363. Documents a retrospective anatysis of a series of cases of very severe asthma attacks indicating association with both sensitization and expo sure to Altemaria 20.
POURT SM, CHAPMAN MD, FIOCCO GP, ROSE G, PLU-IX-M.U TAE: Epidemiology of Acute Asthma: IgE Antibodies to Common Inhalant AlIergens as a Risk Factor for Emergency Room Visits. J Alkrgy Clin Immunol 1989, 83875-882.
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RS: The Use of Human Lymphocyte-T Clones to Study T-cell Function in AIIergic- Contact Dermatitis to Urushiol. I Invest Dermatol 1990, 94:S108-Sill. Review of experiments on T ceiis derived from peripheral blood of patients with contact sensitivity to poison ivy. Clones were predominantiy CD8+ cells specific for Uroshiol. and the authors speculate that these T cells may have a suppressor role. Further experiments are described using T cells grown out of biopsies.
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BI!ZBER T, DANNENBERG B. Pwiz JC, RIEBER EP, STOIZ W, BRAUN-FALCO 0, RING R Occurrence of IgE-bearing Epider-
SOUIUET G, ROUSSFT F, DE VIUES JE: Alpha-interferon Treatment of Patient with Hyper IgE Syndrome. Lancer 1989, ii:1384. Demonstration that treatment with IFN-a can cause decreased IgE production and ciinicai improvement. Discussion of the evidence that IFN can interfere with the effects of IL-4 in vivo. *
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Successful Treatment of Atopic Dermatitis with Complexes of AIIergen and Speciiic Antibodies. Lzncet 1930, 335:1468-1469. This report on AD follows up the author’s report on treatment of asthma, Machiels el al, J Ciin Invest 1990, 85:1024-1035. At present it is not clear what quantity of ‘complexes’ is used in this treatment, nor is it clear what the mechanism is. .
mai Iangerhans’ CeIIs in Atopic Eczema: A Study of the Time Course of the Lesions and with Regard to the IgE Serum Level. J Invest Dermafol 1989, 93215219. Reports @E-bearing hangerhans’ cells in-biopsies from skin of patients with atopic dermatitis. These cells were present in almost aii the patients with totai serum IgE 2 300 IL!. The presence of &E-beating cells appears to be suppressed by local or systemic steroids.
R lmmunoregulatory Abnormalities Clin Rev Affeqy 1986, 4~67-86.
MJ, YORK D, GEHA RS,
DYM: Recombinant Gamma Interferon in Treatment of Patients with Atopic Dermatitis and Elevated IgE Levels. Am J Med 1990, 88:365-370. Progressive improvement in ciinicai parameters of AD during uncontrolled treatment with IFN-y. This response was not related to a faE in total serum IgE but in some patients there was reduced in uifm IgE production.
.
tiMBARDER0
HEYMANN
M,
PW,
PIA~TS-I&LIZ
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FOX
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CHAPMAN MD: Conformational Stabiity of B CeU Epitopes on Group I and Group II Dermatophagoides spp. Allergens. J Immunol 1990, 144:135>1360. LK,
P~TIX-MIU
TAE,
FOX
JW,
CHAPMAN
MD:
&-
AlIergen I, A Major &E-binding Protein, is a Member of the MitogillinFamily of Cytotoxins. / E.$Med 1990, 172:152%1532.Reports purification and partial sequencing of an allergen of 18 kD derived from A Jkmigatux Demonstration of close homology in function and antigenicky of this allergen with a cytotoxin (Mitogiliin) derived from A reshiktus
.
BWS,
VENAUE
gens as Proteases: rectly Induces Cfin Immunol
TJ, MEDNIS
AHW,
An Aspe@ilusfunigatus
Human EpitheEaI 1990, 86:72&731.
MCAIEER
R: Akf-
Proteinase DiCelI Detachment. ] Auergy
880
Atopic 46.
allergy
and
other
hypersensitivities
WAFXI GW JR. KARLSSON G. ROSE G, PLA~YMIUS TAE: chophyton Asthma: Scnsitisation of Bronchi and Upper ways to Dermatophyte Antigen. Lnncet 1989, i:859-862.
TriAir-
47. .
DEUELL 8, ARRUDA LK, HAYDEN ML, CHAP~UN MD, PLVI’SMIUS TAE: Tricbophyron toonsurum Allergen I (Tti t I): Characterization of a Protein that Causes Immediate but not Delayed Hypersensitivity. J Immunol 1991, 147:96101. Documents purification of a Tricko~&owderived IgE-binding protein (i.e. allergen) that does not give delayed hypersensitivity skin responses. Reports preliminary evidence that some individuals who have delayed hypersensitivity have a wheal and flare preceding the delayed response that is not related to IgE antibodies. 48. .
GOURLEV DS, WHISMAN BA, JORGENSEN NL. MARTIN rME, Rm MJ: Allergic Bipolaris Sinusitis: Clinical and Immunopathogenetic Characteristics. J Allergy Clin Immtmol 1990. 85:58%591. Three cases of pansinusitis with impaction of maxillary sinuses wid3 ‘allergic mucus’; this caused pressure erosion of bone without any inMsion. The cultures grew Bipolaris @crJhu and each of the patients had specific IgE antibodies to this fungus, which is a member of the helminthosporium group. 49. .
ARUAN LG, VYXENSKI-MOHER DL, AH~~AD SG, Esm SA Cross Antigenicity Between the Scabies Mite, Surcoptes scubei, and the House Dust Mite, Dermatophagoides pteronyssinus J Invest Dermatoi 1991, 96~349-354.
Clear demonstration that patients sensitized to the dust mite pro. duced IgE antitxxlies that bind ro proteins produced by the scabies mite. A discussion of the relewnce to the manifestations of scabies. The genus Snrcoptes are reasonably close relatives of Ihe genus Dermutopkwg0ide-s 50.
STEINRERC mediated
P. ISHVm K. NORhfhN Reaction in Immunity.
PS: Possible Role of [email protected] AIlera) 1974, 54:359366.
51. .
ILIOPO~ILOS 0. PRO~III D. ADKINSON NF JR, NOR~ZAN PS. KACWSono-r~~ A, LICHI-ENSTEIN LM, NACIXRIO RM: Relationship Between the Early, Late and Rechallenge Reaction to Nasal Challenge with Antigen: Observations on the Role of Inflammatory Mediators and Cells. .I Allergy Clin Immunol 19’90, 86:851461. Analysis of the cellular and mediator responses to nasal challenge with ragweed extract, demonstrating thar late reaction in the nose is associated closely with increased mediator production. Results suggest that late reactions in the skin. late reactions in the nose and enhanccxl response to repeat nasal provocations are controlled independently.
TAE PlattsMills, lergy and Clinical USA
University of Virginia Medical Centre. Immunology, Box 225, Charlottesville,
Division Virginia
of Al22938.