SUPPORTED BY AN EDUCATIONAL GRANT FROM NOVARTIS PHARMA
AND NOVARTIS PHARMACEUTICALS CORPORATION
Role of aeroallergens in atopic eczema:
Proof of concept with the atopy patch test
Johannes Ring, MD, PhD,a,b Ulf Darsow, MD,a,b and Heidrun Behrendt, MDb Munich, Germany
W e define atopy as familial tendency to devel-
op certain diseases (bronchial asthma,
allergic rhinoconjunctivitis, and/or atopic
eczema) on the basis of hypersensitivity of skin and
mucous membranes to environmental substances
together with increased IgE production and/or altered
nonspecific reactivity.1,2 This definition includes the
two dimensions of atopy, namely, IgE production on
the one hand and nonspecific altered reactivity on the
other. Contrary to respiratory atopic diseases, the role
of allergy in the pathophysiology of atopic eczema
(AE) is still controversial.
The most common theories on the pathophysiolo-
gy of AE are shown in Table I, focusing from dry skin,
superinfection, psychosomatic influence to different
types of allergic inflammation. The dilemma starts
with morphology. The disease has the appearance of
eczema, and eczema is defined as a spongiotic epi-
dermodermal inflammation with lymphocytic infil-
trate, characteristically induced by type IV reactions
(according to Coombs and Gell).1,3 The morphology
of an immediate type I reaction (IgE-mediated allergy)
in the skin is a wheal-and-flare reaction, such as that
seen in urticaria. Further arguments against the role
of allergy, brought forward mainly by Marchionini,4
regarded the commonly seen positive prick test reac-
From the Department of Dermatology and Allergy, Technical
University of Municha and the Division of Environmental
Dermatology and Allergy GSFITUM, Munich.b
This article is part of a supplement sponsored by Novartis Pharma
AG and Novartis Pharmaceuticals Corporation.
Presented at the International Consensus Conference on Atopic
Dermatitis, November 5-6, 1999, Rome, Italy.
Disclosures: Dr Ring is a participant of a multicenter ascomycin deriv-
ative trial for Novartis Pharmaceutical Corporation and a partici-
pant in a multicenter tacrolimus trial for Fujisawa Healthcare Inc.
Drs Darsow and Behrendt have no conflicts of interest to disclose.
Reprint requests: Johannes Ring, MD, PhD, Technical University of
Munich, Director, Department of Dermatology and Allergy,
Biedersteiner Str 29, Munchen, 80802 Germany. E-mail:
www.derma_allergie.med.tu-muenchen.de.
J Am Acad Dermatol 2001;45:S49-52.
Copyright 2001 by the American Academy of Dermatology, Inc.
0190-9622/2001/$35.00 + 0 16/0/117015
doi:10.1067/mjd.2001.117015
AG
tions as mere epiphenomena on the basis of con-
comitant respiratory atopy.
On the other hand, none of the atopic diseases
shows so highly elevated serum IgE concentrations
as AE; many atopic sensitizations are directed
against allergens not relevant for asthma or rhinitis.
Some patients experience exacerbation after contact
with aeroallergens.
THE CONCEPT OF IgE AND
LANGERHANS CELLS IN AE
The conflict started to be solved by the demonstra-
tion of IgE on the surface of epidermal Langerhans
cells (LCs) by Bruijnzeel-Koomen et al5 and the subse-
quent detection of all types of known IgE receptors on
the same cells by Bieber et al.6,7 Later, Maurer et al8
showed the role of IgE in antigen presentation and
Tanaka, Anan, and Yoshida9 demonstrated the major
allergen of house dust mite in close proximity to IgE
on the LC surface.
Expression of the high-affinity receptor for IgE, pre-
viously only described for mast cells and basophils,
opened our eyes to a new concept, particularly after it
had been shown that this expression of FcRI is signif-
icantly pronounced in lesional atopic skin compared
with normal skin, nonlesional skin or in other inflam-
matory diseases such as contact dermatitis, psoriasis,
or mycosis fungoides.10
Therefore theoretically it does appear that allergy
contributes to the pathophysiology of AE; all the
major components of an IgE-mediated reaction are
present in the epidermis. But does allergy play a role
in practice?
PROOF OF CONCEPT BY THE ATOPY
PATCH TEST
The proof of our concept came through a proce-
dure we called the atopy patch test (APT).11-17 We
performed investigations in several hundred
patients with the aim to standardize the APT with
regard to vehicle, dose, clinical covariates, and mode
of application to bring it to clinical routine.18-22
First, we found that petrolatum was the best vehi-
cle.19 Second, we showed that there is a clear-cut dose
response with the amount of allergen in the prepara-
S49
S50 Ring, Darsow, and Behrendt
Table I. Atopic eczema: Pathophysiologic concepts
Genetic background (atopy, skin function)
Barrier disturbance (dry skin)
Microbial colonization
Autonomic nervous system dysregulation
Psychosomatic interaction
Inflammation
Nonimmune
Allergic, classic delayed-type hypersensitivity (TH1)
Allergic, atopic (TH2)
tion.20,21 Third, we demonstrated that the percentage
of positive APT reactions was significantly elevated in
patients with an air-exposed eczema distribution pat-
tern.20 It was also possible to elicit a positive APT reac-
tion with native pollen grains.22 Interestingly, when
we patch-tested the same person with aeroallergens
in the APT or classic contact allergens (lanolin or nick-
el), the morphology of the positive patch test reaction
was similar. However, the barrier disruption mea-
sured as transepidermal water loss was significantly
more pronounced in the APT compared with the pos-
itive contact allergy patch test.23 We speculated that
this might be due to the more pronounced
eosinophil infiltrate observed in APT reactions.24
In a large multicenter trial in Germany in more
than 280 patients we found house dust mite to be
the most common positive reaction, followed by
grass pollen, cat epithelium, birch pollen, and mug-
wort pollen (Table II). Most of the patients were pos-
itive only to one allergen, rarely to 2 or 3. The reac-
tion peaked at 48 hours and then decreased slightly
in the following 24 hours. The concomitant use of
negative control patches with petrolatum proved
that APT reactions were no irritant phenomenon.21
Positive reactions occurred only in patients with AE
and not in normal persons or in patients with pure
respiratory atopy.19
When we closely followed the history of the
patients, it was obvious that positive APT reactions
were much more frequent in patients with a specific
history of eczema flare after allergen contact (eg, cat,
grass, pollen). The history for house dust mite expo-
sure was much more difficult to obtain; however,
there was still a significant difference.21 Now we
understand the previously unexplained or UV-attrib-
uted flares of some AE patients in spring and sum-
mer to be an allergic skin reaction to pollen and
manifesting as AE.22
COMPARISON OF APT WITH SKIN PRICK
TEST AND RADIOALLERGOSORBENT TEST
There was no complete concordance between
APT and skin prick test or radioallergosorbent test
J AM ACAD DERMATOL
JULY 2001
Table II. Results of the APT multicenter study in
Germany*
Skin RAST APT 48-h
Clear-cut positive results prick (%) (%) (%)
Dust mite (N = 253) 59 56 34
Cat dander (N = 253) 54 49 12
Grass pollen (N = 253) 65 75 18
Birch pollen (N = 88) 65 65 11
Mugwort pollen (N = 88) 36 53 3
One allergen, 22%; 2 allergens, 8%, 3 allergens, 5% (APT 48 h).
*Reactivity to different allergens in different test systems; percent-
ages calculated referring to N. Reprinted from Darsow U, Ring J. In:
Leung DYM, Greaves MW, editors. Allergic skin disease. New York:
Marcel Dekker; 2000. p. 435-47, by courtesy of Marcel Dekker, Inc.
(RAST) results.19 Cross-table analysis and logistic
regression in a large group of patients revealed sig-
nificant concordances of APT results with history,
skin prick test, and specific corresponding IgE for
house dust mite, cat epithelium, and grass pollen (P
< .001).21 However, the results also showed that
high allergen-specific IgE in serum is not mandatory
for a positive APT; the same holds true for the corre-
lation with skin prick tests. At the first Georg Rajka
symposium on atopic eczema in 1998, Taieb showed
exciting data with APTs in infants who were prick test
and RAST negative, but were APT positive to foods.
These were not irritant reactions. On the other
hand, it has to be kept in mind that IgE plays a role
in APT because most APT-positive patients also
showed elevated specific IgE compared with those
patients with negative APT.21,25
To evaluate the relevance of APT as a diagnostic
test, we analyzed the results on the background of
disease history. In 79 patients, significantly higher fre-
quencies of positive APTs were seen in patients with a
history of eczema exacerbation in summer months
than in patients without a summer eruption of AE. We
were able to calculate precision data of APT. With
regard to a predictive history of grass polleninduced
eczema exacerbation, the APT specificity exceeded
the specificity of the skin prick test and RAST where-
as sensitivity was lower. Similar results were obtained
in the German multicenter study.21
MECHANISM OF THE APT REACTION
Regarding the correlation of APT with skin prick
test and specific IgE results, no complete concor-
dance was observed. This means that with APT a dif-
ferent dimension of atopic skin inflammation is reg-
istered than in the skin prick test or RAST. The aller-
gen-specific nature of APT reactions has been shown
by several groups. Langeland, Braathen, and Borch26
transferred APT reactivity to egg, performing a
J AM ACAD DERMATOL
VOLUME 45, NUMBER 1
Prausnitz-Kstner test. van Reijsen et al27 character-
ized allergen-specific T-cell clones derived from skin
specimens taken from APT sites. Mite allergen has
been demonstrated in the epidermis under natural
conditions28 and in APT sites9,16 in proximity to LCs.
Because LCs carry all 3 human IgE binding struc-
tures, namely, the high- and low-affinity IgE recep-
tors (FcRI and II) and the -binding protein,5-7 they
are capable of binding allergens via specific IgE on
their surface. According to their known function as
antigen-presenting cells, they may also internalize,
process, and present these allergens to T cells.8 We
and others described a significant association of pos-
itive APT reactions and specific serum IgE. This
might explain how IgE-associated activation of aller-
gen-specific T cells can lead to eczematous skin
eruptions in the APT.
A similar situation is found in natural lesions of AE
and APT sites characterized by a predominance of
CD4+ T cells.29,30 APT reactions were significantly
more frequent in patients with elevated CD54+ or
CD30+ T cells after in vitro stimulation with the cor-
responding allergen. Positive APTs were associated
with an allergen-specific lymphocyte proliferation (P
< .001).31 These data sustain the clinical results on
allergen specificity of APT reactions.
When serial biopsies of APT were performed to
analyze the cytokine pattern, marked time-depen-
dent differences were seen: interleukin 4 messenger
(m)RNA as marker of the TH2 response was noted
after 24 hours, followed by a switch to a TH1-like
cytokine response with increased levels of interferon
gamma mRNA after 48 hours.32 Other cell popula-
tions may also be involved in the initiation and per-
petuation of APT reactions. Among these are
basophils, present in the infiltrate after 48 hours,13
and activated eosinophils.24 Eosinophil-derived basic
proteins (MBP, ECP, EPX) can be detected in AE
lesions by immunohistochemical staining, even with
low eosinophil counts in normal hematoxylin-eosin
staining. These eosinophil products may have a role
in barrier impairment, thus perpetuating allergen
penetration. In addition, the role of mast cells
remains to be elucidated. With regard to neutrophil
density, marked differences of APT (low numbers)
versus experimental late-phase reactions (high num-
bers) were described.33
CONCLUSIONS
By the APT we have shown that AE can be elicited
by external contact with an aeroallergen, suggesting
something like atopic contact eczema. In contrast to
classic contact dermatitis in which a TH1 reaction is
elicited by a hapten, atopic (contact) eczema is char-
acterized by a TH2 type pathophysiology triggered by
Ring, Darsow, and Behrendt S51
Table III. Classification of eczema/dermatitis
Classic (contact) eczema/dermatitis
Irritative, toxic
Allergic
Atopic eczema/dermatitis
Extrinsic
Intrinsic
Others
Seborrheic eczema/dermatitis
Nummular eczema/dermatitis
a protein. To avoid confusion, we suggested adding
the term classic to the traditional term contact
eczema/contact dermatitis (Table III).
However, we should not forget that there are
some AE patients (maybe 10%-20%) without
detectible IgE elevation in the serum or positive skin
prick tests or RAST. Wthrichs concept of extrinsic
(allergic) versus intrinsic (cryptogenic) AE seems
valid to explain this heterogeneity.
This is not the end of the story. AE starts in the
acute phase with a TH2 reaction.32 Later, during the
chronic stage, TH1 secretion patterns are found32;
recently Valenta et al34 have described IgE autoanti-
bodies against an epidermal allergen, Homo sapiens I,
which we measured in particularly high concentra-
tions in patients with very severe AE. In these
patients, the eczema perpetuates in the direction of
an autoimmune disease; these are the cases in which
allergen avoidance does not help and the use of
immunosuppressants will be the only chance of relief.
The message from our studies is the new con-
cept that AE is not only a disease of dry skin but
possibly also an allergic disease. Only if we find the
causal trigger factors and eliminate them will we be
able to help patients for longer periods. Avoidance
strategies play a role, and our concept means much
more than writing a prescription. We35 proposed
the term patient management for this combined
approach. Today, we prefer self-management and
tell our patients: You will be your own dermatolo-
gist. I shall teach you and you will know what your
skin needs.
REFERENCES
1. Ring J. Angewandte Allergologie. 2nd ed. Munich: MMV
Medizin Verlag; 1991.
2. Ring J. Atopy: condition, disease or syndrome? In: Ruzicka T,
Ring J, Przybilla B, editors. Handbook of atopic eczema. Berlin:
Springer; 1993. p. 3-8.
3. Leung DYM, Rhodes AR, Geha RS, Schneider LC, Ring J. Atopic
dermatitis (atopic eczema). In: Fitzpatrick TB, Eisen AZ, Wolff K,
Freedberg IM, Austen KF, editors. Dermatology in general med-
icine. 4th ed. New York: McGraw-Hill; 1993. p. 1543-63.
4. Marchionini A. Neuere Untersuchungen ber die Neuro-
dermitis constitutionalis. In: Fortschritte der praktischen
S52 Ring, Darsow, and Behrendt
Dermatologie und Venerologie Bd3. Berlin: Springer; 1960. p.
47-62.
5. Bruijnzeel-Koomen C, van Wichen DF, Toonstra J, Berrens L,
Bruynzeel PLB. The presence of IgE molecules on epidermal
Langerhans cells in patients with atopic dermatitis. Arch
Dermatol Res 1986;278:199-205.
6. Bieber T, Rieger A, Neuchrist C, Prinz JC, Rieber EP, Boltz-
Nitulescu G, et al. Induction of FCeR2/CD23 on human epider-
mal Langerhans cells by human recombinant IL4 and IFN. J Exp
Med 1989;170:309-14.
7. Bieber T, de la Salle C,Wollenberg A, Hahimi J, Chizzonite R, Ring
J, et al. Constitutive expression of the high affinity receptor for
IgE (FCeR1) on human Langerhans cells. J Exp Med 1992;175:
1285-90.
8. Maurer D, Ebner C, Reininger B, Fiebiger E, Kraft D, Kinet JP, et al.
The high affinity IgE receptor mediates IgE-dependent allergen
presentation. J Immunol 1995;154:6285-90.
9. Tanaka Y, Anan S, Yoshida H. Immunohistochemical studies in
mite antigen-induced patch test sites in atopic dermatitis. J
Dermatol Sci 1990;1:361-8.
10. Wollenberg A, Wen S, Bieber T. Langerhans cells phenotyping: a
new tool for differential diagnosis of inflammatory skin dis-
eases. Lancet 1997;346:1626-7.
11. Ring J, Kunz B, Bieber T,Vieluf D, Przybilla B.The atopy patch test
with aeroallergens in atopic eczema. J Allergy Clin Immunol
1989;82:195.
12. Rostenberg A, Sulzberger MD. Some results of patch tests. Arch
Dermatol 1937;35:433-54.
13. Mitchell E, Chapman M, Pope F, Crow J, Jouhal S, Platts-Mills T.
Basophils in allergen-induced patch test sites in atopic der-
matitis. Lancet 1982;1:127-130.
14. Sager N, Feldmann A, Schilling G, Kreitsch P, Neumann C. House
dust mite-specific T cells in the skin of subjects with atopic der-
matitis: frequency and lymphokine profile in the allergen patch
test. J Allergy Clin Immunol 1992;89:801-10.
15. Adinoff A, Tellez P, Clark R. Atopic dermatitis and aeroallergen
contact sensitivity. J Allergy Clin Immunol 1988;81:736-42.
16. Gondo A, Saeki N, Tokuda Y. Challenge reactions in atopic der-
matitis after percutaneous entry of mite antigen. Br J Dermatol
1986;115:485-93.
17. Imayama S, Hashizume T, Miyahara H, Tanahashi T, Takeishi M,
Kubota Y, et al. Combination of patch test and IgE for dust mite
antigens differentiates 130 patients with atopic dermatitis into
four groups. J Am Acad Dermatol 1992;27:531-8.
18. Vieluf D, Kunz B, Bieber T, Przybilla B, Ring J. Atopy Patch Test
with aeroallergens in patients with atopic eczema. Allergy J
1993;2:9-12.
19. Darsow U, Vieluf D, Ring J. Atopy patch test with different vehi-
cles and allergen concentrations: an approach to standardiza-
tion. J Allergy Clin Immunol 1995;95:677-84.
20. Darsow U, Vieluf D, Ring J. The atopy patch test: an increased
rate of reactivity in patients who have an air exposed pattern of
atopic eczema. Br J Dermatol 1996;135:182-6.
21. Darsow U, Vieluf D, Ring J, and the APT study group. Evaluating
the relevance of aeroallergen sensitization in atopic eczema
with the atopy patch test: a randomized, double-blind multi-
center study. J Am Acad Dermatol 1999;40:187-93.
22. Darsow U, Behrendt H, Ring J. Gramineae pollen as trigger fac-
tors of atopic eczema: evaluation of diagnostic measures using
the atopy patch test. Br J Dermatol 1997;137:201-7.
23. Gfesser M, Rakoski J, Ring J. Disturbance of epidermal barrier
function in atopy patch test reactions in atopic eczema. Br J
Dermatol 1996;135:560-5.
J AM ACAD DERMATOL
JULY 2001
24. Bruijnzeel-Koomen C, van Wichen D, Spry C, Venge P, Bruijnzeel
P. Active participation of eosinophils in patch test reactions to
inhalant allergens in patients with atopic dermatitis. Br J
Dermatol 1988;118:229-38.
25. Darsow U, Ring J. The atopy patch test: its role in the evaluation
and management of atopic eczema. In: Leung DYM, Greaves
MW, editors. Allergic skin disease. New York: Marcel Dekker;
2000. p. 435-47.
26. Langeland T, Braathen L, Borch M. Studies of atopic patch tests.
Acta Derm Venereol Suppl (Stockh) 1989;144:105-9.
27. van Reijsen FC, Bruynzeel-Koomen CAFM, Kalthoff FS, Maggi E,
Romagnani S, Westland JKT, et al. Skin-derived aeroallergen-
specific T-cell clones of TH2 phenotype in patients with atopic
dermatitis. J Allergy Clin Immunol 1992;90:184-92.
28. Maeda K, Yamamoto K, Tanaka Y, Anan S, Yoshida H. House dust
mite (HDM) antigen in naturally occurring lesions of atopic der-
matitis (AD): the relationship between HDM antigen in the skin
and HDM antigen-specific IgE antibody. J Dermatol Sci 1992;3:
73-7.
29. Reitamo S,Visa K, Khnen K, Stubb S, Salo OP. Eczematous reac-
tions in atopic patients caused by epicutaneous testing with
inhalant allergens. Br J Dermatol 1986:114:303-9.
30. Leung DYM, Bhan AK, Schneeberger EE, Geha RS.
Characterization of the mononuclear cell infiltrate in atopic
dermatitis using mononuclear antibodies. J Allergy Clin
Immunol 1983:71:47-56.
31. Wistokat-Wlfing A, Schmidt P, Darsow U, Ring J, Kapp A, Werfel
T. Atopy patch test reactions are associated with T-lymphocyte
mediated allergen-specific immune responses in atopic der-
matitis. J Allergy Clin Immunol 1998;101:196-7.
32. Grewe M, Walther S, Gyufko K, Czech W, Schpf E, Krutmann J.
Analysis of the cytokine pattern expressed in situ in inhalant
allergen patch test reactions of atopic dermatitis patients. J
Invest Dermatol 1995;105:407-10.
33. Langeveld-Wildschut EG, Thepen T, Bihari IC, van Reijsen FC, de
Vries IJM, Bruijnzeel PLB, et al. Evaluation of the atopy patch test
and the cutaneous late-phase reaction as relevant models for
the study of allergic inflammation in patients with atopic
eczema. J Allergy Clin Immunol 1996;98:1019-27.
34. Valenta R, Maurer D, Steiner R, et al. Immunglobulin E response
to human proteins in atopic patients. J Invest Dermatol 1996;
107:203-8.
35. Ring J, Brockow K, Abeck D.The therapeutic concept of patient
management in atopic eczema. Allergy 1996;51:206-15.
DISCUSSION
Dr Leung: In your original model you showed
that IgE-positive Langerhans cells are critical for the
APT. One would expect that IgE would also bind on
mast cells, and you might see a positive skin prick
test. Why do these patients have a negative skin
prick test?
Dr Ring: I do not know why, but it is the fact.
Dr Leung: Would you expect that those people
would develop wheals and flares after an intradermal
injection?
Dr Ring: We did the intradermal injections and
they were negative.