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Oral Mucosa Patch Test: A New Tool to Recognize and Study the Adverse Effects of Dietary Nickel Exposure


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On contact with the skin, nickel may cause allergic contact dermatitis, which can be diagnosed by an epicutaneous patch test. Nickel exposure via the intestinal mucosa can induce diarrhea, abdominal pain, and swelling. The aim of the present study was to investigate the relationship between these symptoms and nickel intake by means of a novel oral mucosa patch test. Eighty-six patients with intestinal symptoms related to ingestion of nickel-containing foods were submitted to epicutaneous and oral mucosa patch tests for nickel. All patients with positive oral mucosa patch test results were subject to a low-nickel diet and monitored over time. Skin lesions were observed in 33 out of 86 (38.4%) patients evaluated by the epicutaneous patch test. Mucosal lesions were seen in 53 out of 86 (61.6%) patients given the oral mucosa patch test. After 2 months of a low-nickel diet, 52 out of 53 (98.1%) patients showed an improvement of their symptoms. There is a significant correlation between response time of the oral mucosa patch test and the latency of symptoms after ingestion of nickel-containing foods. Consequently, the oral mucosa patch test can be used to recognize and study the adverse effects of dietary nickel exposure that could be defined as allergic contact mucositis. A low-nickel diet is also shown to be an effective treatment for this condition.
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Oral Mucosa Patch Test: A New Tool to Recognize
and Study the Adverse Effects of Dietary Nickel Exposure
Antonio Picarelli &Marco Di Tola &Anna Vallecoccia &
Valerio Libanori &Mirella Magrelli &Marta Carlesimo &
Alfredo Rossi
Received: 2 November 2009 /Accepted: 10 February 2010
#Springer Science+Business Media, LLC 2010
Abstract On contact with the skin, nickel may cause allergic contact dermatitis, which can be
diagnosed by an epicutaneous patch test. Nickel exposure via the intestinal mucosa can induce
diarrhea, abdominal pain, and swelling. The aim of the present study was to investigate the
relationship between these symptoms and nickel intake by means of a novel oral mucosa patch
test. Eighty-six patients with intestinal symptoms related to ingestion of nickel-containing
foods were submitted to epicutaneous and oral mucosa patch tests for nickel. All patients with
positive oral mucosa patch test results were subject to a low-nickel diet and monitored over
time. Skin lesions were observed in 33 out of 86 (38.4%) patients evaluated by the epicutaneous
patch test. Mucosal lesions were seen in 53 out of 86 (61.6%) patients given the oral mucosa
patch test. After 2 months of a low-nickel diet, 52 out of 53 (98.1%) patients showed an
improvement of their symptoms. There is a significant correlation between response time of the
oral mucosa patch test and the latency of symptoms after ingestion of nickel-containing foods.
Consequently, the oral mucosa patch test can be used to recognize and study the adverse effects
of dietary nickel exposure that could be defined as allergic contact mucositis. A low-nickel diet
is also shown to be an effective treatment for this condition.
Keywords Allergic contact dermatitis .Allergic contact mucositis .Celiac disease .
Epicutaneous patch test .Intestinal symptoms .Nickel .Low-nickel diet .
Oral mucosa patch test
Nickel (Ni) is a transition metal found in the environment, some drugs, cosmetics,
detergents, jewelry, watches, keys and other commonly used metallic utensils. Contact with
Biol Trace Elem Res
DOI 10.1007/s12011-010-8652-y
A. Picarelli (*):M. Di Tola :A. Vallecoccia :V. Libanori :M. Magrelli
Center for Research and Study of Celiac DiseaseDepartment of Clinical Sciences, Policlinico Umberto
ISapienza University, Viale del Policlinico, 155, 00161 Rome, Italy
M. Carlesimo :A. Rossi
Department of Skin-Venereal Diseases and Plastic Reconstructive Surgery, Policlinico Umberto I
Sapienza University, Viale del Policlinico, 155, 00161 Rome, Italy
this ubiquitous element may easily occur by inhalation, ingestion, or through the skin. Its
absorption depends on the solubility of the chemical form of Ni. In the blood, Ni is mainly
bound to albumin. Its circulating levels reflect the degree of exposure to soluble compounds
rather than insoluble salts or unabsorbed deposits of Ni metal in the lungs. The distribution
of Ni in tissues depends on the type and length of exposure, with the kidneys as the primary
route of elimination [1].
The main clinical manifestation caused by skin contact with Ni is allergic contact dermatitis
(ACD), for which the epicutaneous patch test (ePT) is considered the gold standard for its
diagnosis [2]. Similarly, Ni exposure through the intestinal mucosa following the ingestion of
Ni-containing foods can result in other clinical conditions, including contact stomatitis [2,3].
Several studies have also reported that even small amounts of Ni ingested with a normal diet
are enough to flare up a preexistent ACD [46]. However, these observations are occasional
and fragmentary, so the sensitivity to dietary Ni is a condition still poorly understood.
In our own experience, several intestinal symptoms not attributable to any known
pathological condition, such as diarrhea, abdominal pain, and swelling, are often reported
by patients after the ingestion of Ni-containing foods. The aim of the present study was to
investigate the relationship between intestinal symptoms and Ni intake by a novel oral
mucosa patch test (omPT), based on recent studies that have shown a close association
between oral and intestinal mucosal compartments in patients with celiac disease, a
complex autoimmune enteropathy induced by dietary gluten [79]. The omPT is described
for the first time in the present study.
Materials and Methods
Eighty-six subjects (six male and 80 female), with a mean age of 40.8 years (range 14
66 years), were chosen from outpatients from our gastrointestinal unit (GU) during the
period from December 2006 to May 2008.
Patients who presented intestinal and extra-intestinal symptoms related to the ingestion
of Ni-containing foods were included in the study. Informed consent was obtained from
each patient and all procedures in this study were in accordance with the ethical standards
of the institutional committee for human experimentation.
The patients carried a detailed food diary and were given a full medical evaluation to
assess the adverse effects of dietary Ni exposure, as well as the presence of other clinical
conditions (e.g., celiac disease and lactase deficiency). The main clinical data of
participants are given in Table 1. Both ePT and omPT for Ni were given to each patient.
Those who tested positive for omPT were put on a low-Ni diet and were monitored over
time to follow the course of their symptoms.
Patch Tests for Nickel
Epicutaneous Patch Test
A patch containing 5% solution of Ni sulfate (NiSO
O) in Vaseline was applied on the
upper back of patients. After 48 h the patch was removed to look for any lesion or reaction
in the test site, repeating the inspection at 96 h. The presence of erythema, edema, and/or
vesicles on the test site was considered a positive result.
Picarelli et al.
Oral Mucosa Patch Test
The omPTwas performed inside the upper lip after removal of excess saliva with sterile gauze.
Briefly, a 5-mm filter paper disk saturated with a 5% solution of Ni sulfate in Vaseline was
applied on the test site and held in place by an adhesive transparent film (Tegaderm, 3M) that in
turn, was covered with a small absorbent pad. After 2 h, the patch was removed and the site of
application was closely observed to determine the presence of any lesion or reaction, repeating
the inspection at 24 and 48 h. Even the occurrence of any general reaction was carefully
evaluated. If the patients showed adverse effects before 2 h, the patch was immediately
removed, the reaction time was annotated, and the presence of any local and/orgeneral reaction
was assessed. Specifically, the appearance of erythema, edema, and/or vesicles on the test site,
as well as itching and dermographia, were considered as positive result.
Low-Nickel Diet and Follow-Up
The ubiquity of Ni makes it virtually impossible to eliminate it from the diet. To prevent the
adverse effects caused by the ingestion of this element, a low-Ni diet is the only resource at hand.
For this reason, patients showing positive omPT results received a list of foods containing high
amounts of Ni (Table 2), with the recommendation to introduce these in very limited quantities
and to not consume more than one Ni-containing food in the same meal [10]. All patients
assessed the adherence to the low-Ni diet by means of a food diary compiled daily, while the
clinical effects of the dietary Ni restriction were carefully evaluated after 2 months of treatment.
Statistical Analysis
The differences between qualitative data were assessed by means of the chi-square test,
while differences between quantitative data were evaluated by the Student two-tailed ttest
Table 1 Clinical Data of the Participants
Pts/total (%) Extra-intestinal
Pts/total (%) Other
Pts/total (%)
Abdominal swelling 56/86 (65.1%) Itching 15/86 (17.4%) CD 18/86 (20.9%)
Abdominal pain 45/86 (52.3%) Hives 11/86 (12.8%) LD 13/86 (15.1%)
Diarrhea 23/86 (26.7%) Headache 6/86 (7.0%) T 5/86 (5.8%)
Constipation 9/86 (10.5%) Erythema 5/86 (5.8%) IgAD 3/86 (3.5%)
Stomatitis 5/86 (5.8%) Dizziness 4/86 (4.7%) OAs 3/86 (3.5%)
Dyspepsia 4/86 (4.7%) Asthenia 2/86 (2.3%) ACD to X 2/86 (2.3%)
Nausea 4/86 (4.7%) Conjunctivitis 2/86 (2.3%) P 2/86 (2.3%)
Meteorism 3/86 (3.5%) Dermographia 2/86 (2.3%) V 2/86 (2.3%)
Vomiting 3/86 (3.5%)
Belching 2/86 (2.3%)
Each patient presented at least one intestinal symptom referable to the ingestion of Ni-containing foods, but
not everyone had an extra-intestinal Ni-related symptom or was suffering from another disease. The
symptoms as well as other diseases with a frequency less than 2% were not included in this table
CD celiac disease, LD lactase deficiency, Tthyreopathy, IgAD IgA deficiency, OAs other allergies (to eggs,
wheat, and atopic dermatitis), ACD to X allergic contact dermatitis to metals other than Ni (cobalt and
palladium), Ppsoriasis, Vvitiligo
Oral Mucosa Patch Test for Ni-Sensitivity
for independent data. Linear regression was used to evaluate the correlation index between
quantitative data. In all statistical tests, the significance level was set at p0.05.
Appearance of erythema, edema, and/or vesicles on the epicutaneous test site was observed
in 33 out of 86 (38.4%) patients. The omPT resulted in erythema, edema, and/or vesicles on
the test site (Fig. 1ac), as well as itching and dermographia (Fig. 1d) in 53 out of 86
(61.6%) patients. The percentage of patients presenting positive results was significantly
higher (p=0.004) for the omPT than for those undergoing the ePT (Fig. 2).
The number of Ni-related symptoms was significantly higher in patients who gave
positive results in either of the patch tests than that of patients with negative results (p=
0.010 for the ePT and p< 0.001 for the omPT). The number of Ni-related symptoms
reported by patients with negative ePT was significantly higher (p=0.002) than for patients
with negative omPT (Fig. 3).
Of the 86 patients included in the study, 18 (20.9%) and 13 (15.1%) had a previous diagnosis
of celiac disease and lactase deficiency, respectively (Table 1). The percentage of patients with
celiac disease or lactase deficiency giving positive results for both patch tests is not significantly
different from that of patients with the same illnesses and with negative results (Table 3).
Among the 53 patients with positive omPT results, 39 (73.6%) showed local lesions and/
or general reactions after 2 h. In eight cases (15.1%), the response to Ni was evident after
more than 2 h and in six (11.3%) within 30 min from the test start (Fig. 4). A significant
correlation (p<0.0001) was found between the omPT response time and the latency of
symptoms described by the patients after ingesting Ni-containing foods (Fig. 5).
Furthermore, after the omPT, all patients showing positive results reported a relapse of
the intestinal and extra-intestinal symptoms previously registered in their clinical history.
All participants completed the study with excellent compliance of the low-Ni diet. After
2 months of dietary Ni exposure reduction, 52 out of 53 (98.1%) patients who had positive
omPT results showed an improvement of their intestinal and extra-intestinal symptoms.
In the present study, the omPT is introduced as a new tool to recognize and study the
adverse effects of dietary Ni exposure.
Table 2 Foods That Contain a High Amount of Nickel
Foodstuffs Ni-containing foods
Fishes Herring, mackerel, salmon, shellfish, tuna
Vegetables Fresh and dried legumes (chickpeas, lentils, peanuts, peas, red kidney beans, soya beans
and soy products), garlic, green leafy vegetables (spinach), onion, raw carrots, tomatoes
Fruits Fresh and dried fruits (almonds, hazelnuts, walnuts)
Cereals Buckwheat, maize, millet, oat, rye, whole grain, whole wheat
Beverages Beer, coffee, initial water flow from the tap (especially in the morning), red wine, tea
Others Baking powder, canned foods, cocoa and chocolate, foods cooked in stainless steel utensils
(especially if acidic foods as tomatoes), gelatin, linseeds, marzipan, Ni-containing vitamin
supplements, strong licorice, sunflower seeds
Picarelli et al.
A Ni patch is able to determine lesions of the oral mucosa including erythema, edema,
and vesicle formation. This is consistent with reports of gingival abnormalities caused by
Ni-based alloy prosthesis in orthodontic patients sensitive to Ni [11].
Recent studies have also shown a close association between oral and intestinal mucosa
in patients with celiac disease, a complex autoimmune enteropathy induced by dietary
gluten [79]. Consequently, the Ni-patch-induced oral mucosa lesions are probably related
to bowel damage that occurs after ingestion of Ni-containing foods that in turn, causes the
Fig. 1 Local and general reactions observable after the oral mucosa patch test for nickel. Appearance of
erythema (a), edema (b), and vesicles (c) on the test site, as well as development of itching and dermographia
(d) after performing the oral mucosa patch test in Ni-sensitive patients
ePT results omPT results
Posi tive Negative
Fig. 2 Percentage of patients
showing positive patch tests for
nickel. The percentage of patients
presenting positive results for the
epicutaneous and oral mucosa
patch tests was plotted in this
graph. The χ
and pvalues refer
to chi-square test applied between
these parameters. ePT epicutane-
ous patch test, omPT oral mucosa
patch test
Oral Mucosa Patch Test for Ni-Sensitivity
intestinal symptoms frequently reported by Ni-sensitive patients such as diarrhea,
abdominal pain, and swelling.
A Ni patch may also cause development of general reactions such as itching and
dermographia, suggesting that the omPT can effectively identify Ni-sensitive patients.
Furthermore, besides reinforcing the observations that Ni intake causes contact stomatitis
[2,3] and may trigger a preexistent ACD [46], our results show that the omPT is more
sensitive than the epicutaneous version in recognizing the adverse effects of ingesting Ni-
Pts ePT+ Pts ePT- Pts omPT+ Pts omPT-
(n=33) (n =53) (n=53) (n=33)
t=2.650, p=0.010 t=6.228, p<0.001
t=3.229, p=0.002
No. of Ni-related symptoms
Fig. 3 Number of nickel-related symptoms in relation to the results of patch tests. The number of Ni-related
symptoms reported by participants was plotted in this graph (mean±SD) in relation to the results of
epicutaneous and oral mucosa patch tests. The tand pvalues refer to the Student two-tailed ttest for
independent data applied between these parameters. Pts ePT+ patients presenting positive epicutaneous patch
test results, Pts ePTpatients with negative epicutaneous patch test results, Pts omPT+ patients showing
positive oral mucosa patch test results, Pts omPTpatients with negative oral mucosa patch test results
Table 3 Percentage of Patients with Celiac Disease or Lactase Deficiency in Relation to the Results of Patch
Tests for Nickel
Pts No pts χ
Pts ePT þn¼33ðÞ 8 (24.2%) 25 (75.8%) 0.104 0.747 (ns)
Pts ePT n¼53ðÞ 10 (18.9%) 43 (81.1%)
Pts omPT þn¼53ðÞ 9 (17.0%) 44 (83.0%) 0.754 0.385 (ns)
Pts omPT n¼33ðÞ 9 (27.3%) 24 (72.7%)
Pts ePT þn¼33
ðÞ 4 (12.1%) 29 (87.9%) 0.091 0.762 (ns)
Pts ePT n¼53ðÞ 9 (17.0%) 44 (83.0%)
Pts omPT þn¼53ðÞ 10 (18.9%) 43 (81.1%) 0.849 0.357 (ns)
Pts omPT n¼33ðÞ 3 (9.1%) 30 (90.9%)
The χ
and pvalues refer to chi-square test applied between these parameters
CD celiac disease, LD lactase deficiency, Pts ePT+ patients presenting positive epicutaneous patch test
results, Pts ePTpatients with negative epicutaneous patch test results, Pts omPT+ patients showing positive
oral mucosa patch test results, Pts omPTpatients with negative oral mucosa patch test results, ns not
Picarelli et al.
containing foods in a population of symptomatic patients. In this regard, the significant
portion of Ni-sensitive patients identified by the omPT, as well as the substantial clinical
differences between positive and negative omPT patients further support this simple test as
an effective diagnostic tool.
It is interesting to note that several individuals with positive omPT results are celiac
disease or lactase deficiency patients, even if there is no evidence of a causal association.
The high prevalence of celiac disease and lactase deficiency among the participants in this
study could be simply due to a clinical bias because most of the patients that refer to our
GU are suffering from these conditions. However, given that gluten-free diet usually
include foods rich in Ni, the elective treatment for celiac disease could unmask a sub-
clinical form of Ni-sensitivity. The latter hypothesis should be carefully considered in the
monitoring of patients suffering from celiac disease.
The different response time to Ni among patients presenting positive omPT results is
also of interest. Most patients react to Ni 248 h from the test start and are classified as late
responders. There are also early responders, who have a response time of 30 min or less. It
010 20 30 40 50
Latency of Ni-relate d symptoms
Response time to Ni
Fig. 5 Response time to nickel in relation to the latency of nickel-related symptoms. The response time to
Ni observed during oral mucosa patch test and the latency of symptoms described by the patients after
ingestion of Ni-containing foods were plotted in this graph. The rand pvalues refer to linear regression used
to evaluate the correlation index between these parameters
<30 min
2 hrs*˚
>2 hrs (6 hrs )
>2 hrs (12 hrs )
>2 hrs (24 hrs )
>2 hrs (48 hrs )
χ χ
=39.542, p<0.001 vs <30 min °
=34.403, p<0.001 vs >2 hrs
Fig. 4 Percentage of patients with different response times to nickel. The percentage of patients showing
different response times to Ni during oral mucosa patch test (<30 min, 2 h, and >2 h) was plotted in this
graph. The response times >2 h were split in other four time points (6, 12, 24, and 48 h). The χ
and pvalues
refer to chi-square test applied between these parameters
Oral Mucosa Patch Test for Ni-Sensitivity
is possible that these results are due to differences in the response mechanism. Late
responders could react to Ni mainly by a delayed-type hypersensitivity or Th1 response,
while early responders could do so predominantly by an immediate-type hypersensitivity or
Th2 response.
For a long time, the scientific community has considered that the Ni-induced ACD
response is of the Th1-type. By analyzing the cytokine secretion profile in peripheral blood
of ACD patients, it has been shown that the majority of Ni-specific CD4+ T lymphocytes
produce Th1 cytokines such as interleukin (IL)-2 and interferon (IFN)-γ[12]. Other authors
have stressed the crucial role of Ni-specific CD8+ T cells in the pathogenesis of ACD [13
15]. Beyond the hypothesis based on the Th1-type mechanism, it has also been shown that
Ni-specific CD4+ T lymphocytes from both peripheral blood and skin lesions of ACD
patients are able to produce Th2 cytokines such as IL-4 and IL-5 [1618]. Concurrently,
other authors have shown that serological and urinary Ni levels correlate with the amounts
of CD3+CD25+ and CD4+CD45RO+ T cells, CD5+CD19+ B cells, and IL-13 that may be
found in peripheral blood of ACD patients in a pattern that reminds a Th2 response [19]. A
more recent study has finally shown that Ni exposure leads to a concomitant production of
Th1 (IFN-γ), Th2 (IL-4, IL-5, IL-13), and regulatory (IL-10) cytokines by peripheral blood
mononuclear cells isolated from ACD patients [20].
Although the aforementioned studies are somewhat contradictory, they suggest that an
imbalance among Th1, Th2, and regulatory pathways could be responsible for the
immunological response that takes place in ACD patients during Ni exposure. Likewise,
this mechanism could be taken as a model to explain the different response times to Ni
observed in our investigation. Other studies will follow to fully elucidate the molecular
bases of mucosal response to Ni.
Our data also highlighted that, in the course of omPT, patients showing positive results
respond to Ni with the same latency than that described following ingestion of Ni-
containing foods. Inversely, after a low-Ni diet, patients presenting positive omPT results
show symptom relief. In this manner, we show for the first time a close relationship
between Ni intake and intestinal symptoms commonly reported by Ni-sensitive patients.
Finally, although previous data on the usefulness of dietary Ni restriction in ACD patients
are slightly contradictory [2123], we have shown that a low-Ni diet is effective in restoring
the patients general state of health.
In conclusion, the omPT can be used to recognize and study the adverse effects of dietary Ni
exposure that could be defined as allergic contact mucositis (ACM). We suggest that patients
with this condition be placed in a diet consisting of foods with the lowest possible Ni content
over a reasonable period of time, during which the patients response should be periodically
evaluated. The high prevalence of Ni-sensitivity in North America and Western Europe, recently
estimated to be 8.6% [24], stresses the relevance of the new acquisitions. However, the
molecular role of Ni in ACM as well as in other intestinal disorders is still to be elucidated.
Acknowledgment The authors are grateful to Dr. Oralia Lopez for revision of the manuscript and assistance
with the English style.
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Oral Mucosa Patch Test for Ni-Sensitivity
... After Ni omPT and the first symptom questionnaire, all patients followed a balanced low-Ni diet for three months. Since Ni is present in almost all foods and its absolute removal from the diet is impossible, we recommended to avoid only foods with an estimated high content of Ni (Table 1) [49]. The quantity of Ni in food is extremely variable as it is conditioned by many factors: Quantity of Ni in soil and irrigation water, the plant species, any fertilizers and/or pesticides used. ...
... Its prevalence is estimated to be over 30% [5]. Symptoms triggered by the ingestion of Ni-rich foods in Ni-sensitive patients are mainly gastrointestinal, but they can also be systemic, involving the skin, the nervous and the reproductive system [49]. A low-Ni diet can improve symptoms in Ni-sensitive patients, though foods high in Ni are largely consumed, especially in the Mediterranean diet, such as tomatoes, cocoa, beans, mushrooms, broadleaf vegetables, and whole flour [47]. ...
... A low-Ni diet can improve symptoms in Ni-sensitive patients, though foods high in Ni are largely consumed, especially in the Mediterranean diet, such as tomatoes, cocoa, beans, mushrooms, broadleaf vegetables, and whole flour [47]. As Ni ePT is useful for the diagnosis of Ni ACD, so Ni omPT has proved to be a specific and sensitive tool for Ni ACM diagnosis [5,47,[49][50][51]. ...
Full-text available
Alimentary nickel (Ni) may result in allergic contact mucositis (ACM), whose prevalence is >30% and may present with IBS-like and extra-intestinal symptoms. These symptoms are also frequent in endometriosis, and Ni allergic contact dermatitis has already been observed in endometriosis. Therefore, intestinal and extra-intestinal symptoms in endometriosis may depend on a Ni ACM, and a low-Ni diet could improve symptoms. We studied the prevalence of Ni ACM in endometriosis and focused on the effects of a low-Ni diet on gastrointestinal, extra-intestinal, and gynecological symptoms. We recruited 84 women with endometriosis, symptomatic for gastrointestinal disorders. Thirty-one out of 84 patients completed the study. They underwent Ni oral mucosa patch test (omPT), questionnaire for intestinal/extra-intestinal/gynecological symptoms, and a low-Ni diet. Clinical evaluation was performed at baseline (T0) and after three months (T1). Twenty-eight out 31 (90.3%) patients showed Ni omPT positive results, with Ni ACM diagnosis, whereas three out of 31 (9.7%) patients showed negative Ni omPT. After three months of low-Ni diet, all gastrointestinal, extra-intestinal and gynecological symptoms showed a statistically significant reduction. Ni ACM has a high prevalence in endometriosis and a low-Ni diet may be recommended in this condition to reduce gastrointestinal, extra-intestinal and gynecological symptoms.
... However, in predisposed subjects, skin contact or ingestion of foods containing Ni can cause inflammatory and allergic clinical manifestations [20]. Ni-rich foods include tomato, cocoa, beans, mushrooms, corn, soybeans, onion, nuts, canned food, tea, and many others [21][22][23]. ...
... Two hours after the administration of Ni-OMPT, the presence of mucosal hyperemia, oedema, as well as the appearance of blisters and burning at the application site were evaluated by the same clinician. General reactions, such as diarrhea, bloating, abdominal pain, foggy-mind, itching, headache, and arthralgia have also been reported within 48 h of testing [4,22]. ...
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The clinical examination of patients often includes the observation of the existence of a close relationship between the ingestion of certain foods and the appearance of various symptoms. Until now, the occurrence of these events has been loosely defined as food intolerance. Instead, these conditions should be more properly defined as adverse food reactions (AFRs), which can consist of the presentation of a wide variety of symptoms which are commonly identified as irritable bowel syndrome (IBS). In addition, systemic manifestations such as neurological, dermatological, joint, and respiratory disorders may also occur in affected patients. Although the etiology and pathogenesis of some of them are already known, others, such as non-celiac gluten sensitivity and adverse reactions to nickel-containing foods, are not yet fully defined. The study aimed to evaluate the relationship between the ingestion of some foods and the appearance of some symptoms and clinical improvements and detectable immunohistochemical alterations after a specific exclusion diet. One hundred and six consecutive patients suffering from meteorism, dyspepsia, and nausea following the ingestion of foods containing gluten or nickel were subjected to the GSRS questionnaire which was modified according to the “Salerno experts’ criteria”. All patients underwent detection of IgA antibodies to tissue transglutaminase, oral mucosal patch tests with gluten and nickel (OMPT), and EGDS, including biopsies. Our data show that GSRS and OMPT, the use of APERIO CS2 software, and the endothelial marker CD34 could be suggested as useful tools in the diagnostic procedure of these new pathologies. Larger, multi-center clinical trials could be helpful in defining these emerging clinical problems.
... In addition to the better known Ni-ACD, there is also a clinical condition defined Nickel Allergic Contact Mucositis (Ni-ACM) (Borghini et al., 2017) that can affect sensitized subjects after the ingestion of Ni-containing foods. Tomatoes, mushrooms, cocoa, coffee, legumes, corn, soy, onion and many other foods are rich in Ni (Picarelli et al., 2011). Bloating, abdominal pain, diarrhea and heartburn frequently characterize this clinical entity (Braga et al., 2013). ...
... Ni-ACM causes hyperemia and edema of the oral mucosa (Picarelli et al., 2011) that can be revealed by laser doppler perfusion imaging techniques showing a significant increase in mucosal perfusion (Borghini et al., 2016). ...
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As reported in the recent literature, Nickel has become an important part of our daily life since the last decades. We can find it in skincare products, occupational exposures and foods. Only recently, research has started to show a link between Nickel and many health disorders, including adverse reactions to food containing nickel. Nowadays, the relationship between nickel-containing foods and well-being is becoming a topic of growing interest in clinical practice and will play an even larger role in the future. The use of foods with a high nickel content, largely present in a gluten free diet, could explain the lack of clinical remission in celiac patients and dispel a diagnosis of refractory celiac disease.
... The MELISA test is a modified form of the lymphocyte transformation test (LTT) used to analyze the local and systemic effects of mucosal-sensitizing allergens in vitro [22]. Celebrant et al. [82] compared the Patch Test, MELISA test, and conventional LTT and pointed out that the MELISA test is accompanied by a high number of false positives, whereas the Patch Test should be considered the gold standard for investigating the presence of metal allergy. Oral mucosa patch tests may be introduced to assess Titanium allergy, as previously proposed for dietary Nickel [83]. ...
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The present umbrella review aimed to assess the prevalence of cases diagnosed with lesions potentially due to Titanium (alloy) and other metal nanoparticles released from dental implants and implant-supported restorations, characterizing lesions’ macroscopic, imaging, and microscopic features. Secondary aims were to categorize the reported lesions as resembling or ascribable to peri-implant mucositis and peri-implantitis, reactive lesions of the peri-implant mucosa, or hypersensitivity reactions, and to evaluate their relationship with cases’, dental implants, and implant-supported restorations’ characteristics, and with the evidence of Titanium allergy. The study protocol, developed in advance and compliant with the PRISMA statement, was registered on PROSPERO (CRD42022354676). Systematic reviews were searched through the Web of Science, Scopus, MEDLINE/PubMed, Cochrane library databases, and the PROSPERO register until 19 August 2022; reference lists were also screened. Data from four systematic reviews of critically low/low quality (AMSTAR 2), one including a meta-analysis, were analyzed qualitatively. An overall prevalence of 16.9% of cases was estimated. Reported lesions resembled or were ascribable to peri-implant mucositis and peri-implantitis (55.17%), reactive lesions (17.22%), and hypersensitivity reactions (24.12%); no oral contact lichenoid lesions were described. Titanium allergy was hardly and heterogeneously investigated. Due to the severely incomplete data, no definitive conclusions could be drawn on the potential role of cases’ and implant characteristics and Titanium allergy on lesions onset, development, and treatment responsiveness.
... However, the highest Cd and Pb concentrations in AdV (0.11 mg/kg fw for Cd and 0.16 mg/kg fw for Pb) were higher than the legal limit. As far as Ni is concerned, although garlic has been included by Picarelli et al. [38] in the list of food that contain high amounts of this PTE, values of tolerable daily intake for Ni (considering one clove of ca. 25 g of elephant garlic and a body weight of 70 kg) are well within the 13 μg/kg of body weight suggested by the European Food Safety Authority [39], even considering the highest concentration measured (8.7 mg/kg dw). ...
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The aim of this study was to provide, for the first time, data on the concentration of potentially toxic elements (PTEs) in soils and bulbs of elephant garlic (Allium ampeloprasum L.) cultivated in Valdichiana, a traditional agricultural area of Tuscany, Italy. Bulbs of elephant garlic and soil samples were collected in four cultivation fields and analyzed by inductively coupled plasma-mass spectrometry (ICP-MS) to determine the concentrations of As, Cd, Co, Cr, Cu, Ni, Pb, Sb, Tl, U, V, Zn. The concentrations of these PTEs in bulbs and cultivation soils were used to calculate geochemical, ecological and health risk indices. The results of this study suggest that, although bulbs of elephant garlic from the Valdichiana area may present slightly high concentrations of Cd, Ni and Pb, the associated health risk based on the daily intake is absolutely negligible. Cultivation soils had somewhat high Cu concentrations probably due to the diffuse use of Cu-based products in agriculture, but showed overall a very low ecological risk.
... Metal alloys will corrode with time after prolonged contact with the mucosa, releasing metal ions into the surrounding tissue. The resulting typical clinic manifestations of the oral mucosa are xerostomia, metal taste, burning sensation, stomatitis, and lichenoid lesions 2,53,54 . It is most possible that these clinical manifestations are partly due to metal ion induced cytotoxicity including apoptosis. ...
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Background Metal alloys, containing contact sensitizers (nickel, palladium, titanium) are extensively used in medical devices, in particular dentistry and orthopedic surgery. The skin patch test is used to test for metal allergy. Objective Determine whether metal salts, when applied to freshly excised skin at patch test relevant concentrations and using a method which mimics skin patch testing, results in changes in the epidermis and dermis. Methods tissue histology, apoptosis, metabolic activity, and inflammatory cytokine release were determined for two nickel salts, two palladium salts and four titanium salts. Results patch test relevant concentrations of all metal salts caused localized cytotoxicity. This was observed as epidermis separation at the basement membrane zone, formation of vacuoles, apoptopic nuclei, decreased metabolic activity and (pro-)inflammatory cytokine release. Nickel (II) sulphate hexahydrate, nickel (II) chloride hexahydrate, titanium (IV) bis(ammonium lactato)dihydroxide and calcium titanate were highly cytotoxic. Palladium (II) chloride, sodium tetrachloropalladate (II), titanium (IV) isopropoxide and titanium (IV) dioxide showed mild cytotoxicity. Conclusion the patch test in itself may be damaging to the skin of the patient being tested. These results need further verification with biopsies obtained during clinical patch testing. The future challenge is to remain above the elicitation threshold at non-cytotoxic metal concentrations. This article is protected by copyright. All rights reserved.
... Для диагностики Ni аллергического контрактного мукозита был предложен никелевый пластырь для слизистой оболочки (Ni omPT). Распространенность Ni аллергического контрактного мукозита в популяции может превышать 30 % [41]. После 2 часов воздействия пластыря на слизистую оболочку губ развиваются специфические локальные изменения слизистой у Ni-чувствительных пациентов, такие как отек и гиперемия, что, вероятно, связано с TLR 4-зависимым врожденным иммунным ответом. ...
IBS-like syndromes are one of the most important problems in gastroenterology. The clinical picture is identical to that of irritable bowel syndrome can be associated with inflammatory bowel disease, colorectal cancer, celiac disease, food allergy, lactase deficiency enteropathy, non-celiac sensitivity, gluten and other diseases. In this regard, irritable bowel syndrome is a diagnosis of exclusion and always requires a rather complex differential diagnosis to establish the true cause of the disease, conduct adequate therapy and achieve a stable remission. The purpose of the review was to obtain scientific knowledge about IBS-like syndromes and to develop optimal management tactics for these patients. The review demonstrates that the clinical manifestations of IBS are largely nonspecific due to the frequent transition of one form of the disease to another, which creates certain difficulties in making a diagnosis. Timely diagnosis of IBS-like syndromes, often superimposed on the already existing IBS pathology, significantly improves the results of treatment of patients with intestinal symptoms and ensures long-term preservation of remission of the disease.
... These patients may complain of CD-like symptoms, including recurrent oral ulceration receding after a GFD [185]. Recent studies have introduced a new concept according to which adverse effects of dietary antigen exposure may be defined as allergic contact mucositis (ACM) based on a specific oral mucosa patch test (OMPT) [186][187][188]. Picarelli et al. [189] evaluated local and general reactions triggered by direct contact with gluten. ...
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Most prevalent food allergies during early childhood are caused by foods with a high allergenic protein content, such as milk, egg, nuts, or fish. In older subjects, some respiratory allergies progressively lead to food-induced allergic reactions, which can be severe, such as urticaria or asthma. Oral mucosa remodeling has been recently proven to be a feature of severe allergic phenotypes and autoimmune diseases. This remodeling process includes epithelial barrier disruption and the release of inflammatory signals. Although little is known about the immune processes taking place in the oral mucosa, there are a few reports describing the oral mucosa-associated immune system. In this review, we will provide an overview of the recent knowledge about the role of the oral mucosa in food-induced allergic reactions, as well as in severe respiratory allergies or food-induced autoimmune diseases, such as celiac disease.
... Diagnosis of dietary nickel sensitivity can be performed with a skin or oral mucosa patch test [110,112]. All patients reporting to a gastroenterology unit with IBS symptoms and suspected sensitivity to nickel containing foods had a positive response to an oral mucosa patch test characterized by local hyperemia and/or edema, compared to no response in a control group [113]. ...
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Significant shortcomings in irritable bowel syndrome (IBS) diagnosis and treatment may arise from IBS being an "umbrella" diagnosis that clusters several underlying identifiable and treatable causes for the same symptom presentation into one classification. This view is compatible with the emerging understanding that the pathophysiology of IBS is heterogeneous with varied disease mechanisms responsible for the central pathological features. Collectively, these converging views of the pathophysiology, assessment and management of IBS render the traditional diagnosis and treatment of IBS less relevant; in fact, they suggest that IBS is not a disease entity per se and posit the question "does IBS exist?" The aim of this narrative review is to explore identifiable and treatable causes of digestive symptoms, including lifestyle, environmental and nutritional factors, as well as underlying functional imbalances, that may be misinterpreted as being IBS.
Objectives: The oral mucosa is exposed to a large number of antigenic agents contained in toothpastes. These agents are reported to stimulate recurrent aphthous stomatitis (RAS) pathogenesis, and toothpastes that do not contain probable allergenic substances reduced the number and frequency of aphthous ulcers. We aimed to determine whether the skin patch test (SPT) can be used to determine if toothpaste allergens play a role in the etiology of RAS. Study design: Sixty-three patients with RAS and 47 healthy volunteers were skin patch tested with sodium lauryl sulfate, cocamidopropyl betaine, propylene glycol, aluminum chloride hexahydrate, menthol, triclosan, and titanium dioxide, which are present in most of the toothpastes. Fisher's exact test and the Yates chi-square test were used to compare categorical variables and patch test results between 2 groups. Results: The SPT was positive in 8 (22.2%) patients with RAS and 11 (23.4%) control subjects, and the difference between the groups was not statistically significant (P < .05). Sodium lauryl sulfate, titanium dioxide, and menthol were the most common positive allergens in both groups. Conclusions: Allergens in toothpastes did not appear to stimulate the formation of RAS. However, in order to determine a clearer relationship, a study in a larger patient series employing intraoral patch testing with more toothpaste ingredients is suggested.
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To determine the prevalence of nickel allergy in a sample of orthodontic patients and longitudinally compare the clinical periodontal status of these individuals with that of a group of nonallergic patients. The initial sample consisted of 96 patients selected randomly from a databank of patients who sought orthodontic care at a teaching institution. Following the selection and beginning of treatment, periodontal status was assessed over a 12-month period (one evaluation every 3 months-T(1), T(2,) T(3,) T(4)) using the Loe index. The evaluations were performed blindly by a single, calibrated examiner and were followed by prophylaxis and orientation regarding oral hygiene. The prevalence of nickel allergy was determined by the patch test 9 months after the beginning of treatment and occurred in 16 individuals (17.2%). Two groups were then established: the allergic group (AG, n = 16) and the age-paired nonallergic control group (NAG, n = 16). Data were analyzed using the Mann-Whitney U-test and Friedman's analysis of variance (ANOVA) tests (P < or = .05). Significant differences were present between groups at the T(3) and T(4) evaluations for the LOE index (P = .045 and .009), with allergic individuals showing higher mean values than nonallergic individuals (hyperplasia, change in color, and bleeding). No significant differences were found in the intragroup evaluations between the four evaluations (P > .05). The results suggest a cumulative effect from nickel throughout orthodontic treatment associated with clinically significant periodontal abnormalities in allergic individuals over time.
Nickel is an essential element for at least several animal species. These animal studies associate nickel deprivation with depressed growth, reduced reproductive rates, and alterations of serum lipids and glucose. Although there is substantial evidence of an essential status for nickel in animals, a deficiency state in humans has not been clearly defined. Nickel is a silver-white metal with siderophilic properties that facilitate the formation of nickel-iron alloys. In contrast to the soluble nickel salts (chloride, nitrate, sulfate), metallic nickel, nickel sulfides, and nickel oxides are poorly water-soluble. Nickel carbonyl is a volatile liquid at room temperature that decomposes rapidly into carbon monoxide and nickel. Drinking water and food are the main sources of exposure for the general population with the average American diet containing about 300 μg Ni/d. Nickel is highly mobile in soil, particularly in acid soils. There is little evidence that nickel compounds accumulate in the food chain. Nickel is not a cumulative toxin in animals or in humans. Almost all cases of acute nickel toxicity result from exposure to nickel carbonyl. The initial effects involve irritation of the respiratory tract and nonspecific symptoms. Patients with severe poisoning develop intense pulmonary and gastrointestinal toxicity. Diffuse interstitial pneumonitis and cerebral edema are the main cause of death. Sodium diethyldithiocarbamate is an investigational drug used to chelate nickel following exposure to nickel carbonyl. Nickel is a common sensitizing agent with a high prevalence of allergic contact dermatitis. Nickel and nickel compounds are well-recognized carcinogens. However, the identity of the nickel compound or compounds, which cause the increased risk of cancer, remains unclear. Currently, there are little epidemiological data to indicate that exposure to metallic nickel increases the risk of cancer, or that exposure to the carcinogenic forms of nickel causes cancer outside the lung and the nasal cavity.
This study investigates lymphocyte subsets in both the gastrointestinal mucosa and blood, in patients with nickel allergic contact dermatitis, after 10 mg oral nickel challenge (double-blind, placebo-controlled). 6 such patients with cutaneous symptoms induced only by skin contact with nickel (group A), 6 with a flare-up of cutaneous symptoms after food nickel ingestion (group B) and 6 healthy controls (group C) were enrolled. Blood lymphocyte subsets (CD4, CD45RO, CD8) were analyzed before and after 4 and 24 h from the challenge (test 1, 2, and 3), and intestinal biopsies were performed 2 days later. Challenges were positive in group B and negative in group A and controls. Serum and urine nickel levels significantly increased after nickel ingestion, with no differences between the 3 groups. At test 3, a significant decrease of the all CDs studied was found in group B. Biopsies of this group showed higher levels of CD45RO+ cells in the lamina propria and in the epithelium and lower levels of epithelial CD8+ lymphocytes. This study confirms that ingested nickel may induce flare-up of cutaneous reactions in some nickel-allergic patients, independently of the degree of sensitization and the intake of metal. In these patients, oral nickel stimulates the immune system, inducing maturation of T lymphocytes from virgin into memory cells; these latter cells seem to accumulate in the intestinal mucosa. The immunoreaction also involves CD8+ cells, whose role is not yet clear.
Abstract Exposure to nickel is a major cause of allergic contact dermatitis which is considered to be an inflammatory response induced by antigen-specific T cells. Here we describe the in vitro analysis of the nickel-specific T-cell-derived cytokine response of peripheral blood mononuclear cells from 35 nickel-allergic and 30 non-nickel-allergic individuals. Peripheral blood mononuclear cells were stimulated with 10–4 and 10–5 mol/l NiSO4 for 6 days and then additionally with ionomycin and phorbol myristate acetate for 24 h. Culture supernatants were analysed for interleukin-4 (IL-4), IL-5, interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α) by quantitative ELISA. The analysis showed that the synthesis of IL-4 and IL-5 but not of IFN-γ or TNF-α was significantly higher in the nickel-allergic individuals. The finding of preferential synthesis of Th2 cytokines was somewhat of a surprise, since previous studies have suggested a Th1 response in nickel-mediated allergic contact dermatitis. Subsequently, the nickel-allergic individuals were randomized to experimental exposure to nickel or vehicle in a double-blind design. A daily 10-min exposure of one finger to 10 ppm nickel solution for 1 week followed by 100 ppm for an additional week evoked a clinical response of hand eczema in the nickel-exposed group. Blood samples were drawn on days 7 and 14 after the start of this exposure to occupationally relevant concentrations of nickel. No statistically significant differences were observed in the nickel-induced in vitro cytokine response during the exposure period. Our results indicate the possibility that IL-4 and IL-5 are involved in the pathogenesis of nickel-mediated contact dermatitis.
The term systemic contact dermatitis is used to describe dermatitis in persons with contact sensitivity who are exposed to the hapten orally, transcutaneously, intravenously, or by inhalation. Well-known examples are eczematous eruptions seen after medicaments are administered to persons with contact sensitivity to the specific medicament. Other causes include the ingestion of the metals mercury, nickel, cobalt, and dichromate, and plant allergens such as sesquiterpene lactones. Typical clinical features are flare-up reactions of previous dermatitis or previously positive patch test sites, widespread dermatitis, vesicular palmar, and/or plantar dermatitis and flexural dermatitis. Systemic contact dermatitis is rare compared with other types of contact dermatitis.
Numerous studies have investigated the prevalence and risk factors of hand eczema in the general population. These studies are of high value as they tend to be less biased than studies using clinical populations and as they are important for healthcare decision makers when they allocate resources. This study aimed to review the epidemiology of hand eczema in the general population. Literature was examined using Pubmed-Medline, Biosis, Science Citation Index, and dermatology text books. On the basis of studies performed between 1964 and 2007, the point prevalence of hand eczema was around 4%, the 1-year prevalence nearly 10%, whereas the lifetime prevalence reached 15%. Based on seven studies, the median incidence rate of hand eczema was 5.5 cases/1000 person-years (women = 9.6 and men = 4.0). A high incidence rate was associated with female sex, contact allergy, atopic dermatitis, and wet work. Atopic dermatitis was the single most important risk factor for hand eczema. Hand eczema resulted in medical consultations in 70%, sick leave (> 7 days) in about 20%, and job change in about 10%. Mean sick time was longer among those with allergic hand eczema than those with atopic and irritant hand eczema. Moderate to severe extension of hand eczema was the strongest risk factor for persistence of hand eczema. Other risk factors included early onset of hand eczema and childhood eczema. The aetiology of hand eczema is multifactorial and includes environmental as well as genetic factors. Future studies should focus on unresolved areas of hand eczema, for example, genetic predisposition.
Panels of nickel-specific T-lymphocyte clones (TLC) were prepared from nickel-allergic and non-allergic donors. TLC from both panels showed similar levels of expression of TCR alpha/beta, CD4, CD2, CD25, and CD29 and recognized nickel in association with class II HLA molecules with restriction determinants in HLA-DR, HLA-DP, and HLA-DQ. The lymphokine secretion was analyzed in TLC from both panels upon antigen-specific or non-specific stimulation and was compared with the secretion profiles of representants of pre-established human atopen-specific Th1 and Th2 cells. Nickel-specific TLC from both panels showed a lymphokine secretion pattern similar to the atopen-specific Th1 cells, although there was some variation from clone to clone. Most TLC secreted substantial amounts of IFN-gamma, IL-2, TNF-alpha, and GM-CSF, but little or no IL-4 and IL-5. The variation observed mainly concerned IL-2 secretion that could be low or absent in some of the TLC. The general secretion pattern did not change upon different modes of stimulation, including activation via CD3, CD2, or CD28. Because nickel-specific TLC from allergic and non-allergic individuals show a similar Th1 secretion pattern, the present results give no evidence that aberrant lymphokine secretion by CD4+T cells determines the contact allergic state, as was found for atopic allergy in a previous study.
The T cell response to nickel-modified endogenous peptides is involved in the immunopathogenesis of nickel-induced contact dermatitis. Nickel-reactive T cells described so far display a TH1 lymphokine secretion pattern characterized by high amounts of IFN gamma, but little or no IL-4 and IL-5. In this paper we demonstrate that nickel-reactive T cells can belong to the TH0 and even to the TH2 CD4+ T cell subset. Nickel-reactive T cell clones (TCC) were derived from the lesion of a patient with nickel contact dermatitis. These TCC responded to nickel with the production of high levels of IL-5 and variable amounts of IFN-gamma and IL-4 resembling TH2- or TH0-like cytokine secretion pattern. None of the nickel-reactive TCC showed a clear cut TH1 profile. We show that IL-4 was a growth factor for the TH2 and some of the TH0 TCC. We conclude that nickel is able to induce TH2 cells and that in this patient with a typical nickel-induced contact dermatitis TH2 cells are prevalent and might contribute to the immunopathogenesis of contact dermatitis.
Allergic contact dermatitis is a delayed-type hypersensitivity reaction, secondary to hapten-specific T lymphocyte activation in sensitized individuals. The present study reports on the establishment of T cell lines from peripheral blood mononuclear cells (PBMC) of nickel-allergic patients, initially cultured with nickel, IL-2, or PHA and IL-2. It was possible to derive hapten-specific T cell lines from the three protocols, and the best proliferative responses to nickel were observed when PBMC were cultured in the presence of nickel in vitro. T cell lines initially cultured with IL-2 always gave better specific proliferative responses to nickel than those derived with PHA and IL-2. Phenotypical analysis of the nickel-specific T cell lines showed that they were mainly composed of activated CD8+ TcR alpha beta + T lymphocytes. These results emphasize the importance of initial culture conditions for the generation of hapten-specific T cell lines and suggest that CD8+ lymphocytes could play an important role in the pathogenesis of allergic contact dermatitis.
Nickel-sensitive patients may experience persistent dermatitis even if they avoid cutaneous contact with nickel-plated items. The purpose of the study was to determine whether reduced nickel intake in food reduces the activity of dermatitis in selected nickel-sensitive persons. Ninety nickel-sensitive patients who had a flare of dermatitis after oral challenge with 2.5 mg of nickel but had no reaction to a placebo were instructed to adhere to a low-nickel diet. Fifty-eight of the 90 patients benefited in the short term from the diet, whereas 15 others had possible benefit. Seventeen patients did not benefit in the short term. Fifty-five patients who adhered to the diet for at least 4 weeks, and whose dermatitis had cleared or improved at the end of this time, responded to a questionnaire follow-up 1 to 2 years later. Forty of these patients had long-term improvement of their dermatitis. Patients with strongly positive patch tests to nickel had less benefit from the diet than patients with moderately positive patch tests. Reduction of the dietary intake of nickel may benefit some nickel-sensitive patients.