ARTICLE
Atopic dermatitis (AD), a chronic inflammatory disease of the skin, affects
mainly children and teenagers, and has an unknown, probably multifactorial,
etiology.
The diagnosis is based on the clinical criteria proposed by Hanifin
and Rajka. These criteria are subdivided into major criteria (pruritus,
typical morphology and localisation of the lesions, chronic or chronically
relapsing course, family and/or personal history of atopy) and minor criteria
(cutaneous xerosis, keratosis pilaris, itch when sweating, cheilitis,
skin-test [type 1] reactivity, orbital darkening and/or Dennie-Morgan
infra-orbital fold, etc.) [1].
Several authors have suggested an IgE-mediated mechanism in the pathogenesis
of AD. The high frequency of personal and/or history of atopy, high levels
of serum IgE, positive skin-tests for several allergens, and the exacerbation
of the symptoms in the presence of inhalant and/or food allergens, suggest
the importance of an IgE-mediated mechanism. But there are still a considerable
number of patients who do not present any of these characteristics.
Several clinical and experimental studies have suggested the importance
of food allergens as provoking agents of AD with an IgE-mediated and/or
cell-mediated pathogenic mechanism [2-10]. However, the diagnosis of food
allergy is not easy because more than one food allergen can be responsible
for the exacerbation of cutaneous symptoms, and serum specific IgE determination
often gives false positive or false negative results [11]. Furthemore,
food allergens, like fruits and vegetables, are often unstable: allergic
patients can tolerate these foods when cooked or preserved, and the extraction
of food allergens for allergologic examination can cause the loss of their
allergenicity.
Several studies have also stressed the importance of inhalant allergens
(pollens, mites, moulds) in AD [12-14]. Several authors, following the
studies of Platts-Mills and Mitchell, have tried to demonstrate a relationship
between sensitivity to aeroallergens and AD, inducing local eczematous
reactions using modified patch tests containing aeroallergens, mainly
Der-P1 of Dermatophagoides pteronyssinus (Dpt) [15-28]. In particular,
Imayama et al., combining the results of serum levels of mite-specific
IgE (high and low or absent) and those of patch-tests (positive or negative)
for dust mite antigens, classified 130 patients with DA into four categories:
patch-test positive and low or not detectable mite-specific IgE (14.6%),
patch-test positive and high mite-specific IgE (24.6%), patch-test negative
and high mite-specific IgE (32.3%), and patch-test negative and low or
not detectable mite-specific IgE (28.5%). They observed marked differences
in the clinical morphology of the lesions in the four different groups.
Therefore, on the basis of the finding that the combined results correlated
well with the clinical morphology in nearly 70% of the AD patients (patch-test
positive, high Dpt-specific IgE, or both) they concluded that dust mite
antigens were involved in the development of the patient's skin lesions
[23].
Furthermore, the avoidance of house dust mites in the environment is
associated with an improvement of AD [29, 30].
The aim of the present study is to assess food and inhalant hypersensitivity
in patients affected by AD using skin-tests, patch-test and specific
IgE antibodies assays and classify such subjects according to the
immunological mechanisms involved in the pathogenesis of this disease.
Materials and methods
Patients
A total of 72 patients, 37 females and 35 males, with an average age
of 8.01 ± 6.14 years (range 1-25) affected by active AD were selected
for our study. All these patients presented at least three major criteria
and three minor criteria of the classification proposed by Hanifin and
Rajka [31]. According to the extension, intensity and periodicity of the
clinical manifestation of AD, the patients were divided into three groups
according to the authors' symptom-severity scale: low (between 3 and 4:
19 patients, 26.39%), medium (between 5 and 7: 28 patients, 38.89%) and
high (between 8 and 9: 25 patients, 34.72%). 73.61% of the patients had
a family history of atopy; 52.77% suffered from rhinitis and/or bronchial
asthma.
Patients discontinued all pharmacological therapy (antihistamines and/or
steroids) at least one week before the performance of the tests.
Fifteen healthy people were selected as negative controls for the study.
The average age of the controls was 9.87 ± 6.61 years (range 4-25).
None of them presented a family or personal history of atopy.
All patients or their parents gave informed consent prior to the tests.
Skin prick-test
All patients were tested by skin prick-tests with the main inhalant
allergens (house dust mites, graminae, parietaria, moulds, trees and animal
danders) and the following food allergens: milk, soy, apple, fish, tomato,
wheat and egg white (Bayropharm DHS, Milan, Italy). Positive and negative
control tests were performed with histamine chlorhydrate 10 mg/ml and
glycerine solution 50%, respectively.
Patch-tests
Patch-tests were performed on a healthy area of the skin, on the back,
using adhesive strips (Curatest Lonhmann, Germany) containing four different
concentrations of purified extracts (alpha fractions) of Dpt and graminae
(100, 200, 400 and 800 AUR) and 100 µl of the same commercial food
extracts used for prick-tests (Bayropharm DHS, Milan, Italy).
Negative controls were performed with patch-tests containing 100 µl
of 50% glycerine solution. The reading of the test was carried out after
48 hrs. The skin was pre-treated only with alcohol to take off the grease.
Measurement of specific and total IgE
Specific IgE to the same allergens tested by prick and patch-tests were
measured by Pharmacia CAP System RAST FEIA (Kabi-Pharmacia AB, Uppsala,
Sweden). Values > 0.7 KU/L were considered positive. Total IgE were
measured using Pharmacia CAP System IgE FEIA (Kabi-Pharmacia).
Results
Skin prick-test
Twenty-eight (38.88%) of the 72 patients showed positive prick-tests
to inhalant allergens (25 to Dpt, 7 to gramineae, 5 to parietaria, 2 to
moulds) and only 4 (5.56%) presented positivity to food allergens (1 to
wheat, 1 to soy, 2 to egg white, and 2 to fish). Three of the patients
with positivity to food allergens were also positive to inhalant allergens.
None of the controls presented any positivity to either inhalant or food
allergens.
Patch-test
Thirty (41.67%) patients were positive, with patch-tests, to one or
more of the diverse concentrations of Dpt (8 patients to the concentration
of 100 AUR, 19 to 200 AUR, 23 to 400 AUR and 19 to 800 AUR). Eight of
these patients were also positive to at least one food allergen. The positivities
to food allergens were: 2 to wheat, 4 to soy, 2 to apple, 2 to egg white,
2 to milk, 1 to fish and none to tomato. Only one patient, who was also
positive to Dpt and food allergens (milk and egg white), resulted positive
to graminae (200 AUR). None of the controls presented any positivity to
patch-tests.
Specific IgE
Twenty-seven patients (37.5%) showed specific IgE against aeroallergens
(26 to Dpt, 7 to graminaea, 3 to parietaria and 1 to moulds) and 14 (19.44%)
against at least one food allergen. Nine of the patients with specific
IgE to food allergens also had specific IgE against aeroallergens. Positive
assays of specific IgE to food allergens were: 5 to wheat, 6 to soy, 5
to apple, 5 to egg white, 5 to milk, 3 to fish and 4 to tomato. None of
the controls showed specific IgE to either inhalant or food allergens.
Total IgE
Twenty-seven patients (37.5%) showed high levels of serum IgE for their
age; 24 of the 39 patients who presented specific IgE (to any allergen)
hay high levels of total IgE. All the controls had normal levels of serum
total IgE for their age.
Comparative results
According to the results obtained with skin prick-tests, patch-tests
and specific IgE, we have classified the 72 patients into four groups:
Group 1 consisted of 19 patients (26.39%) who presented positive
results to prick-tests and/or presence of specific IgE, but were negative
to patch-tests. In this group, 16 patients (84.21%) were positive to prick-tests
with aeroallergens (13 to Dpt, 6 to gramineae, 4 to parietaria and 1 to
moulds). One patient who was positive to aeroallergens was also positive
to food allergens. Only 1 patient resulted positive only to food allergens.
Two patients were negative to prick-tests, but presented specific IgE.
Sixteen patients (84.21%) showed specific IgE to aeroallergens (15 to
Dpt, 5 to gramineae and 2 to parietaria). Nine patients (47.36%) presented
specific IgE to food allergens. Five of the latter patients also presented
specific IgE to aeroallergens. Fourteen patients who presented specific
IgE to aeroallergens showed positivity with the same allergen in prick-tests.
Only one patient showed a correlation between prick-tests and serum specific
IgE to food allergens.
Group 2 consisted of 13 patients (18.06%) who showed positive
prick-tests and/or the presence of specific IgE and positive patch-test.
Twelve (92.30%) patients showed positive prick-tests to aeroallergens,
2 of which were also positive to food allergens. All patients of this
group showed specific IgE, 8 only to aeroallergens, 2 only to food allergens,
and 3 to both. All patients with specific IgE to aeroallergens also showed
positive prick-tests to the same allergens. A positive correlation between
prick-tests and specific IgE to food allergens was found in only 2 patients.
All 13 patients were positive to patch-tests containing Dpt, but not other
aeroallergens, while 3 of them were also positive to food allergens.
Group 3 consisted of 17 patients (23.61%) who were positive only
to patch-tests. All patients showed positive reactions to one or more
concentrations of Dpt. Only one patient was positive with a patch-test
containing gramineae. Five patients also reacted to food allergens. In
this group, it is important to note that, in contrast with groups 1 and
2, only 17.6% of the patients showed high levels of total IgE for their
age.
Group 4 consisted of 23 patients (31.94%) who did not present
any positive reaction to prick and patch-tests and had no specific IgE.
Only one of these patients had high total IgE levels for his age.
Among the 38 patients suffering from rhinitis and/or bronchial asthma,
32 (84.21%) belonged to groups 1 and 2; 4 to group 3, and the remaining
2 to group 4.
The profiles of the patients of each group are described in Table
I.
Discussion
In this article we have classified the patients affected by AD in four
groups according to the results of skin prick-tests, specific IgE and
patch-tests. This classification is designed to separate the patients
according to the involvement of immunological type I and/or type IV mechanisms.
Thus, we considered group 1 as AD with a major involvement of the
immunological mechanism of type I; group 2 as AD with involvement
of both mechanisms, type I and type IV; group 3 as AD with involvement
of only type IV mechanism; and group 4 as AD with apparently no
immulogical imbalance.
Our results are quite similar to those reported by Imayama et al.
[23]; however, they evaluated immediate hypersensitivity to Dpt using
only assays of serum specific IgE, while we performed prick-tests and
RAST. Moreover, we assessed hypersensitivity to other inhalant and food
allergens by patch-tests, skin tests and RAST. We found the greatest difference
in the third group (patch-test positivity and prick-test and RAST negativity):
23.6% of our group (all showing positive reactions to patch-tests with
Dpt) vs 14.6% of Imayama's analogous group. As far as the 38 patients
with rhinitis and bronchial asthma are concerned, 84.21% belonged to groups
1 and 2, as observed by the aforementioned authors.
The exact pathogenesis of AD is not known. IgE-mediated hypersensitivity
plays an important role as well as the lymphocytes producing interleukine-4
(IL-4). The association of AD with personal and/or family history of atopy,
positive skin tests for several allergens, and the exacerbation or improvement
of the symptoms in presence or absence, respectively, of inhalants or
food allergens to which patients presented skin-test and/or RAST positivity,
suggest the importance of an IgE mediated mechanism. Our results show
that the patients in groups 1 and 2 (32 patients, 44.5%)
had the characteristics of a type I mechanism: 72% of these patients presented
high levels of total IgE, 85% had a personal and/or family history of
atopy, and all were positive to skin prick-tests and/or presented specific
IgE. But there still remain a considerable number of patients (55.5% in
our study) who do not show the involvement of an IgE mediated pathogenesis.
Although the latter (from groups 3 and 4) also had a high
percentage of personal and/or family histories of atopy, only 10% of them
presented high levels of total IgE, none reacted to skin prick-tests and
none had specific IgE in the serum.
There is increasing evidence that T cell responses to environmental
allergens are also important for the pathogenesis of AD [32]. In addition
to house dust mite, sensitization to pollen or animal dandruff may be
associated with eczematous skin reactions [33]. In AD there is evidence
of the presence of activated, inhalant allergen-specific T cells derived
from the analysis of lesional skin [34, 35] or T cell clones that had
been generated from biopsies of patch-test lesions [36, 37]. The results
of two of the latter studies support the specific nature of Dpt-induced
patch-test lesions in patients with AD, and also demonstrate that a considerable
proportion of lesional T cells are allergen-specific, IL-4 producing T
cells (Th2) which are capable of enhancing IgE production [36, 37]. However,
the T cell cytokine profiles of the other study show characteristics of
T helper-1 (Th1) cell-mediated reaction [38]. Moreover, Santamaria Babi
LF et al. investigated proliferative responses in circulating T
lymphocyte subpopulations, observing a mite-specific response in patients
with AD sensitized to house dust mites in the subset expressing the skin
homing molecule (cutaneous lymphocyte-associated antigen-CLA). In contrast,
in sensitized patients with allergic bronchial asthma, house-dust-mite-dependent
proliferation was found in the CLA negative subset. These observations
strongly support the idea that immunological mechanisms exist which target
inhalant allergen-specific Th2 cells to the skin in AD [39].
All this leads to the concept of a T cell mediated specific immune response
to environmental allergens with clinical implications in AD [32]. Thus,
AD patients with positive patch tests and little (or no) specific IgE
may be considered to represent cases of chronic, recurrent contact dermatitis
caused by Dpt or different environmental allergens.
The histological characteristics of the eczematous
reaction (hyperplastic epidermis, hyperkeratosis with parakeratosis and
an inflammatory infiltrate of monocytes, macrophages, lymphocytes, mast
cells and overall Langerhans cells) confirm the involvement of a type
IV cell mediated mechanism. As these characteristics are a common finding
in patients affected by AD, we could expect a high percentage of patients
who are positive to patch tests. Instead, we have observed that 58.3%
of patients apparently do not show an involvement of the type IV mechanism.
An involvement of both type I and type IV immunological mechanisms is
also possible. Recently, it has been demonstrated that Langerhans cells
have an important role as antigen presenting cells (APC) [32], expressing
the IgE low affinity receptor (CD23/FcFRII) and the IgE high affinity
receptor (FcFRI) [40, 41]. Furthermore they also express the B7 molecule,
characteristic of the professionnal APC [42]. An allergen is able to bind
the IgE molecules bound to the specific FcFRI on Langerhans cells present
in the skin and can be presented to allergen-specific T cells [43]. Thepen
et al. performed atopy patch-tests (APTs) with house dust mite
allergen in AD patients and then took punch biopsy specimens from APT
sites, carrying out an immunocytochemical study [44]. On the basis of
their results, which demonstrated a biphasic response to allergen, the
authors proposed a model in which the allergen-specific Th2 response
possibly activated by IgE-mediated antigen presentation by Langerhans
cells in the skin on contact with an allergen initiates the local
inflammation by release of IL-4 and interleukine-5 (IL-5). This allergen-specific
Th2 response is followed by a Th1 response, characterized by the production
of interleukine-2 (IL-2) and interferon-gamma (IFN-gamma), which may be
responsible for chronicization of the inflammation. The mechanism behind
this Th2- to Th1-switch in the reaction pattern is not known. A possible
candidate is interleukine-12 (IL-12), released by macrophages and eosinophils
[45].
To sum up, eczematous responses can be induced by inhalant allergens
in AD patients. IgE bound to FcepsilonRI-positive Langerhans cells and
allergen-specific CLA-positive Th2 cells play a major role [46].
As we mentioned above, there are many studies which try to explain the
pathogenesis of AD. Some authors propose an IgE mediated mechanism, others
a cell mediated mechanism, and the majority a combination of both mechanisms.
In the present study we have found a group (group 1) that seems
to have an IgE mediated mechanism, another (group 3) that suggests
a cell mediated mechanism, and group 2 which seems to involve both
mechanisms. But another group also remains (group 4) that apparently
does not involve any of the above mentioned mechanisms.
Delayed hypersensitivity reactions to foods and/or cutaneous infections
may have played a role in the AD pathogenesis of some of our patients.
We did not investigate the delayed type of food allergy with oral challenges
or in vitro tests in addition to skin and patch-tests, as others
did [8-10].
With regard to cutaneous infections, different groups have focused their
attention on the role of some micro-organisms in the resident microflora
of the skin of AD patients in the pathogenesis of this disease [47]. Neuber
et al., demonstrated that Staphylococcus aureus can induce
IgE synthesis and CD23 expression in patients with AD [48]. The same authors
suggest that S. aureus could act as a permanent stimulus for allergic
skin reactions via an IgE-mediated mechanism [49].
Other studies demonstrate that in response to infection some accessory
cells, like macrophages, may induce the production of IL-12, which leads
to the differentiation of Th1 cells [50, 51] and could even switch the
dominant Th2 phenotype, in atopic patients, towards a Th1 phenotype [52-54].
The first paper suggests the importance of an IgE mediated mechanism on
the role of micro-organisms in the pathogenesis of AD, while the second
one hypothesizes a cell mediated mechanism caused by micro-organisms.
We are now following up patients with negative results in the allergologic
workup. Our intention is also to investigate the potential etiological
role of these factors.
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