







































 

_____________________________________________________________________________________________________ 
 
*Corresponding author: E-mail: celso@alergoimuno.med.br; 
 
Cite as: Olivier, Celso Eduardo, Daiana Guedes Pinto, Ana Paula Monezzi Teixeira, Cibele Silva Miguel, Raquel Acácia 
Pereira Gonçalves Santos, Jhéssica Letícia Santos Santana, and Regiane Patussi Santos Lima. 2024. “Assessing Cellular and 
Humoral Immunoreactivity to Lanolin: A Retrospective Cohort Study in Atopic and Contact Dermatitis Patients”. Asian Journal 
of Immunology 7 (1):316-25. https://doi.org/10.9734/aji/2024/v7i1154. 

 
 

Asian Journal of Immunology 
 
Volume 7, Issue 1, Page 316-325, 2024; Article no.AJI.128121 
 

 
 

 

 

Assessing Cellular and Humoral 
Immunoreactivity to Lanolin:  

A Retrospective Cohort Study in  
Atopic and Contact Dermatitis Patients 

 
Celso Eduardo Olivier a*, Daiana Guedes Pinto a,  

Ana Paula Monezzi Teixeira a, Cibele Silva Miguel a,  

Raquel Acácia Pereira Gonçalves Santos a,  

Jhéssica Letícia Santos Santana b  

and Regiane Patussi Santos Lima c 
 

a Instituto Alergoimuno de Americana, Brazil. 
b Instituto de Ensino e Pesquisa do Hospital de Amor de Barretos, Brazil. 

c Lavoisier Laboratórios, São Paulo, Brazil. 
 

Authors’ contributions  
 

This work was carried out in collaboration among all authors. The author CEO is responsible for the 
conceptualization, data curation, formal analysis, literature review, and writing the original draft. 
Authors DGP, APMT, CSM, JLSS and RPSL performed laboratory procedures. Author RAPGS 

performed cutaneous tests. All authors read and approved the final manuscript. 
 

Article Information 
 

DOI: https://doi.org/10.9734/aji/2024/v7i1154  
 

Open Peer Review History: 
This journal follows the Advanced Open Peer Review policy. Identity of the Reviewers, Editor(s) and additional Reviewers,  

peer review comments, different versions of the manuscript, comments of the editors, etc are available here: 
https://www.sdiarticle5.com/review-history/128121  

 
 

Received: 24/10/2024 
Accepted: 26/12/2024 
Published: 28/12/2024 

 

Original Research Article 

https://doi.org/10.9734/aji/2024/v7i1154
https://www.sdiarticle5.com/review-history/128121


 
 
 
 

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ABSTRACT 
 

Background: Several publications report lanolin as responsible for hypersensitivity reactions in 
patients with atopic dermatitis and/or contact dermatitis, as diagnosed by in vivo provocation tests. 
There is no standardized lab exam that can endotype the mechanisms responsible for these 
phenotypes. 
Aim: To evaluate the potential of the Tube Titration of Precipitins (TTP) and the Leukocyte 
Adherence Inhibition Test (LAIT) to discriminate and endotype immunoreactivity against lanolin in 
patients with atopic dermatitis and/or contact dermatitis. 
Methods: We retrospectively examined the medical charts of two cohorts of patients diagnosed 
with atopic dermatitis and/or contact dermatitis with clinical suspicion of lanolin hypersensitivity, 
who were investigated with the help of TTP or ex vivo challenge tests monitored by LAIT against 
lanolin. The registered results were distributed in ranges through cascade distribution charts. The 
statistical characteristics of these cohorts were calculated.  
Results: The TTP results spread a distribution concentrated over the more diluted titrations             
(Fig. 1). There was no negative result. The mean was estimated at 1:343; the median was 1:512; 
the standard deviation was estimated at 1:187; the mode was 1:512 (appeared 53 times). The LAI 
ranged from 0% to 95%. The mean was 41.5%; the median was 41.5%; the standard deviation was 
27.3%; the mode was 0% (appeared sixteen times). The cascade distribution demonstrates a 
widespread distribution of LAI results. 
Conclusion: TTP and LAIT performed with lanolin solution were able to discriminate diverse 
degrees of humoral and cellular immunoreactivity in patients suffering from atopic and/or contact 
dermatitis. It is worthwhile conducting more in-depth studies to evaluate the usefulness of TTP and 
LAIT in endotyping Non–IgE-mediated hypersensitivity to lanolin. 

 

 
Keywords: Atopic dermatitis; contact dermatitis; endotype; hypersensitivity; lanolin; leukocyte 

adherence inhibition test; precipitins; precision medicine. 
 

ABBREVIATIONS 
 
LAI : Leukocyte Adherence Inhibition 
LAIT : Leukocyte Adherence Inhibition Test 
TTP  : Tube Titration of Precipitins 
 

1. INTRODUCTION  
 

In the past, when synthetic garments were not 
yet produced, natural wools were dominant 
allergens in cold months, associated with atopic 
dermatitis, eczema, or textile contact dermatitis, 
especially in infants [1]. Wool allergy has been 
traditionally diagnosed by scratch, patch, and 
intracutaneous tests with wool extracts [2]. Wool 
allergy has been successfully treated by 
desensitization since the 1930s [3]. 
Concomitantly, the cause of wool allergy was 
attributed to the wool fat: lanolin [4]. Lanolin is a 
complex mixture of free fatty acids, fatty acid 
esters, cholesterols, and other hydrocarbons 
extracted from sheep's wool [5]. Lanolin is 
produced from the secretion of the sebaceous 
glands of sheep to serve as a wool's protective 
coating, which is a composition that varies 
according to the breed of sheep, geographic 
location, method of extraction, and level of 
purification [6]. The first extraction of this "wool 

wax" is attributed to the ancient Greeks, who 
documented, in 700 BC, boiling wool in water 
produced a top layer of greasy froth that could be 
skimmed [7]. In 1882, the Germans Otto Braun 
and Oscar Liebreice applied a patent describing 
a sequential centrifugation of the wool froth along 
with water to incorporate both elements, resulting 
in a suspension which, after refrigeration, boiling, 
and alkalinization became what they coined 
"lanolin" (US Letters Patent No. 271,192 dated 
January 23, 1883) [8]. Nowadays, several more 
sophisticated modified techniques are employed 
to produce several varieties of lanolin-based 
products and derivatives through physical              
and chemical modifications (hydrolysis. 
hydrogenation, acetylation, ethoxylation, 
transesterification, and so forth) [9]. Very soon, 
the industrial production of lanolin was 
widespread. It began to be incorporated into 
skin-cream products as an emulsifier, stabilizer, 
emollient, and skin moisturizer, such as toilet 
articles, shaving creams, toilet soaps, hair 
lotions, shampoos, hair conditioners (to prevent 
hair drying, scaling and brittleness), cosmetic 
creams, lipsticks, nail polish removers, eye 
make-up (for more uniformly dispersion of the 
pigment), hair sprays (as a plasticizer), hair 
bleaching agents, and used by pharmacists as 



 
 
 
 

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an excipient for topical medications [10]. Studies 
done by freeze-fracture and transmission 
electron microscopy of stratum corneum found 
that most applied lanolin occupied intercellular 
spaces. Some penetrated corneocytes and had a 
special affinity for the cell junction [11]. 
 
Allergic contact dermatitis to lanolin was first 
described by Ramirez and Eller in 1929 [12]. 
Very soon, several case reports of 
hypersensitivity to lanolin were published 
worldwide [13-15]. The 1950s saw the beginning 
of studies on the allergenic components of 
lanolin, as well as on the differences in 
immunoreactivity between the different versions, 
demonstrating, through patch tests, that the main 
allergenic components could be into the 
hydroalcoholic or the fatty lanolin components 
[16,17]. 
 
Allergy to lanolin is more common in children 
(4.5%) than in adults (3.2%) and patients with a 
previous history of eczema and hay fever [18]. 
Although lanolin is considered a weak sensitizer 
over undamaged skin, there is a higher risk of 
sensitization when applied over skin-damaged 
conditions such as contact dermatitis, atopic 
dermatitis, psoriasis, dermatitis herpetiformis, 
seborrheic dermatitis, stasis dermatitis, leg 
ulcers, perineal dermatitis, and so forth [19].  
 
In the eighties, the widespread use of this 
moisturizer exposed a lanolin allergic "crisis", 
which was also described as a "myth", and a 
"comedy", when several pharmaceutical 
ointments began to declare on their packages to 
be "lanolin free" [20, 21].  

 
The presence of lanolin is unanimous among the 
diverse batteries historically recommended for 
making diagnostic contact test kits (patch tests) 
[22]. The biggest obstacle to diagnosing 
hypersensitivity to lanolin is its multiple varieties, 
components, allergens, versions, contaminants, 
and additives, such as preservatives and 
antioxidants [14]. The standard patch test agent 
for diagnosing lanolin contact allergy is lanolin 
alcohol 30% in petrolatum [23, 24]. 

 
However, this method alone has a very low 
sensitivity to diagnosis of lanolin hypersensitivity, 
a fact that had been contributing to the "lanolin 
paradox", leading the physicians to use for tests 
the suspected materials brought in by the 
patients [25]. Several papers report 
discrepancies among cutaneous tests performed 
with lanolin derivatives such as lanolin alcohols 

and Amerchol L101 (a mixture of 10% lanolin 
alcohols and mineral oil) [26, 27].  
 
Atopic Dermatitis and Contact Dermatitis are 
interrelated phenotypes with several associated 
endotypes [28]. While the Atopic Dermatitis 
phenotypes usually develop in patients 
presenting hypersensitivity to food allergens or 
House Dust Mites, the typical Contact Dermatitis 
phenotype develops in patients presenting 
hypersensitivity to organic and inorganic 
contactants [29]. Some patients presenting 
predominantly the Atopic Dermatitis phenotypes 
may also present less evident Contact Dermatitis 
phenotypes and vice versa [30].  
 
There is not yet a satisfactory laboratory exam to 
diagnose the non-IgE-mediated Atopic Dermatitis 
or Contact Dermatitis endotypes. Several trial 
evaluations were conducted on the relationship 
between leukocytes and allergy tests. However, 
the results did not significantly yield definitive 
conclusions [31].  
 
The better way to diagnose lanolin 
hypersensitivity is the exclusion/provocation test 
when the patient excludes the use of the 
suspected allergen(s) until the symptoms 
disappear, and then the allergen is re-introduced 
to observe reactions. However, this is particularly 
difficult when polysensitization dominates the 
clinical picture. In order to shorter the list of 
suspected allergens, we performed in our 
facilities the Leukocyte Adherence Inhibition Test 
(LAIT) and the Tube Titration of Precipitins (TTP) 
as triage tests to elect the allergens that will be 
emphasized in the exhaustive in vivo 
exclusion/provocation tests [32-37].  
 
The present study hypothesizes that the LAIT 
and the TTP may help differentiate diverse 
endotypes and degrees of immunoreactivity 
against lanolin among patients suffering from 
atopic dermatitis and/or contact dermatitis. To 
evaluate the potential of the LAIT and the TTP to 
endotyping Non–IgE-mediated immunoreactivity 
against lanolin, we retrospectively compiled the 
electronic medical charts of patients with these 
conditions who were investigated with these 
procedures.  
 

2. MATERIALS AND METHODS  
 

2.1 Subjects 
 
After receiving Institutional Review Board 
approval from the Instituto Alergoimuno de 



 
 
 
 

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Americana (Brazil; 10/2024), we proceeded with 
the electronic chart review of 9,700 outpatients 
who attended our facility from January 2018 to 
November 2024.  
 
A cohort of 100 outside patients had been 
submitted to TTP with lanolin solution for 
presenting non–IgE-mediated atopic dermatitis 
and/or contact dermatitis. This cohort counted 23 
males; mean age 38.9 years; SD 19.9 years; 
range 7 to 91 years; median 37.5 years; modes: 
16; 23; 37; and 70 years (each appeared 4 
times); geometric mean = 32.8 years.  
 
A cohort of 100 outside patients had been 
submitted to an ex vivo allergen challenge test 
with lanolin solution monitored with LAIT for 
presenting non– IgE-mediated atopic and/or 
contact dermatitis. This cohort counted 25 males; 
mean age 40.9 years; SD 18,5 years; range 3 to 
86 years; median 40.5 years; mode = 50 
(appeared Five times); geometric mean = 35.0 
years.  
 
This study did not include patients under 
biological and/or systemic anti-inflammatory 
therapy. These procedures were offered to 
patients with clinical suspicion of lanolin 
hypersensitivity who demonstrated a non-
reactive or inconclusive skin test against lanolin 
solution [38]. 
 

2.2 Lanolin Solution  
 
In a Becker flask, 10 mL of lanolin (Farma 
Norte™) and 10 mL of glycerin [Glycerin P.A. – 
ACS, C3H5(OH)3, Dinâmica™] were 
homogenized and kept under refrigeration (4 °C) 
to perform the allergic skin tests, TTP, and       
LAIT.  
 

2.3 Ex vivo Investigation: Leukocyte 
Adherence Inhibition Test 

 

2.3.1 Procedure for allergen ex vivo 
challenging  

 
We performed the LAIT as previously described 
[39-49]. Shortly, each donor's fresh plasma was 
divided into two parts and used in paralleled ex 
vivo challenging tests with lanolin solution and 
the unchallenged plasma assay. We collected 
plasma with high leukocyte content (buffy coat) 
from the heparinized tube after one hour of 
sedimentation at 37 °C. Then, we distributed 
aliquots of 100 μL into Eppendorf tubes kept 
under agitation for 30 minutes (200 rpm at 37 °C) 

with lanolin solution (10μL) or without lanolin 
solution (when used as control). 
 
2.3.2 Procedure for adherence assay  
 
After incubation, the plasma was allocated into a 
standard Neubauer hemocytometer counting 
chamber with a plain, non-metallic glass surface 
and left to stand for 2 hours at 37 °C in the 
humidified atmosphere of the covered water bath 
to allow leukocytes to adhere to the glass. Next, 
we counted the leukocytes, removed the 
coverslip, and washed the chamber by 
immersion in a beaker with PBS (phosphate-
buffered saline) at 37 °C. Then, we added a drop 
of PBS to the hemocytometer's chamber and 
allocated a clean coverslip over it. The remaining 
cells were counted in the same squares as 
previously examined.  
 
2.3.3 Procedure for calculation  
 
The percentage of Leukocyte Adherence (LA) of 
each assay was estimated as: (the number of 
leukocytes observed on the hemocytometry 
chamber after washing divided by the number of 
leukocytes observed on the hemocytometry 
chamber before washing) and multiplied by 100 
(%). The Leukocyte Adherence Ratio (LAR) was 
estimated based on the ratio between the LA 
from the antigen-specific challenged plasma and 
the LA from the unchallenged control plasma: 
LAR = LA of the challenged sample divided by 
LA of unchallenged control plasma multiplied by 
100 (%). To further calculate the Leukocyte 
Adherence Inhibition (LAI), we subtracted the 
LAR from 100 (%). We employed the LAI results 
for the cascade distribution chart and the 
statistics calculations, both performed with the 
help of the Microsoft Excel® statistical package. 
 

2.4 In vitro Investigation: Tube Titration 
of Precipitins (TTP) 

 
As previously reported, a transparent vitreous 
tube array performed the semi-quantitative TTP 
against the lanolin solution [50-54]. Shortly, the 
patient's blood was collected in a clot-activator 
collecting tube. After separation, the serum was 
centrifugated at 2,000 rpm for 10 minutes. The 
allergen extracts were allocated in sets of eleven 
glass tubes at progressive duplicated serum 
dilutions. The progressive dilutions were 
combined with the 15 μL of the antigen solution 
with 250 μL of the patient's serum, progressively 
diluted into physiological saline solution (NaCl 
0,9%) in the dilution ratios of 1:1; 1:2; 1:4; 1:8; 



 
 
 
 

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1:16; 1:32; 1:64; 1:128; 1:256; and 1:512. One 
tube was a blank control done with the water and 
serum to observe occasional spontaneous 
precipitation (Sia Test). After 24 hours, the tubes 
were examined, and the titers (the highest 
dilution factor that yields a positive reading) were 
recorded [55]. 
 

3. RESULTS 
 
As a retrospective survey, there was no research 
protocol; therefore, we report the incidental 
immune investigation as registered in the digital 
medical charts.  

 
 

Fig. 1. Cascade distribution chart of the tube titration of precipitins (x-axis %) resulting from 
the lanolin solution against the serum of a cohort of 100 tests/subjects (y-axis) 

 

 
 

Fig. 2. Cascade distribution chart of the range groups of Leukocyte Adherence Inhibition (LAI) 
results (x-axis %) of ex vivo lanolin solution monitored by the Leukocyte Adherence Inhibition 

Test (LAIT), according to the respective number of outcomes over a cohort with 100 
tests/subjects (y-axis) 

 



 
 
 
 

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The TTP showed a distribution concentrated over 
the more diluted titrations (Fig. 1). There was no 
negative result. The mean was estimated at 
1:343; the median was 1:512; the standard 
deviation was estimated at 1:187; the mode was 
1:512 (appeared 53 times). All Sia tests were 
negative.  
 
The LAIT showed a wide distribution range of 
results. The LAI ranged from 0% to 95%. The 
mean was 41.5%; the median was 41.5%; the 
standard deviation was 27.3%; the mode was 0% 
(appeared sixteen times). The cascade 
distribution demonstrates a wide range spread of 
LAI results (Fig. 2). Half of the patients presented 
moderate immunoreactivity during the ex vivo 
challenge test (LAI = 22 to 60%). At the same 
time, one quarter displayed strong 
immunoreactivity, while the other quarter 
displayed low or no immunoreactivity. 
 

4. DISCUSSION 
 
Lanolin-based creams are frequently prescribed 
for patients with atopic and/or contact dermatitis 
due to their emollient properties [54]. 
 
The American Contact Dermatitis Society elected 
lanolin as the "Allergen of the Year 2023" [55].  
 
Despite the emphasis borrowed by this title, 
there is a total lack of scientific studies about the 
physiopathology of the hypersensitivity (or 
hypersensitivities) against lanolin. The only tools 
to verify hypersensitivity against lanolin are the 
cutaneous tests.  
 
There is no record in the literature of any 
standardized lab examination (such as specific 
IgE, associated cytokines, or any serologic 
technique) to diagnose lanolin hypersensitivity or 
suggest lanolin immunoreactivity. Endotyping the 
mechanisms responsible for allergic phenotypes 
is crucial, not only for diagnosis but also for 
supervising treatments under the perspective of 
personalized Medicine and recognizing 
differential diagnosis among phenotypes [56]. 
 
As a proof of concept, we submitted lanolin to an 
ex vivo challenge monitored by the LAIT to testify 
to cellular immunoreactivity. In the same proof-
of-concept mentality, we research precipitins 
against lanolin to testify to humoral 
immunoreactivity through the TTP. Despite non-
reactive or inconclusive skin tests, we propose 
these procedures to patients with atopic 
dermatitis and/or contact dermatitis with a strong 

clinical suspicion of hypersensitivity against 
lanolin. The clinical reasoning to indicate these 
tests is in the assumption that they may function 
as triage tests to reinforce the need for a more 
exhaustive exclusion-provocative test (when the 
patients exclude the suspected allergen until the 
symptoms disappear and then re-introduces the 
allergen to observe the reactions). 
 

There was no prospective plan. We 
spreadsheeted the results of a retrospective 
compilation of data produced by TTP and TIAL, 
exploring humoral and cellular immunoreactivity 
against lanolin. These assays provide clues 
about humoral and cellular immunoreactivity, and 
the results distribute themselves in an extensive 
spectral range between immune tolerance and 
symptomatic hypersensitivity. Results provided 
by LAIT and TTP were interpreted as markers of 
the immune response after contact with the 
specific antigen, configuring themselves as 
techniques to identify exposition to the antigen, 
as proposed by the exposome-wide association 
study [57]. 
 

This retrospective survey demonstrated 
significative cellular and humoral 
immunoreactivity demonstrated by the TTP and 
the ex vivo challenge test monitored by LAIT 
against lanolin in two cohorts of patients with 
atopic and/or contact dermatitis. All patients 
evaluated with TTP demonstrated some degree 
of humoral immunoreactivity (there was no 
negative result), and most presented positivity by 
the more diluted titrations, demonstrating that 
lanolin allergens are widespread among patients 
with dermatitis and are highly immunogenic. 
Sixteen patients did not present cellular 
immunoreactivity against lanolin (LAI = zero%). 
In contrast, others presented an extensive range 
of inhibition of the leukocyte adherence after the 
ex vivo provocation test, suggesting that cellular 
immunoreactivity must be a better parameter to 
differentiate hypersensitivity reactions among 
patients.  
 

None of our patients presented an exclusive 
reaction to lanolin. We assessed every patient 
simultaneously with several chemical and 
biological allergens, demonstrating positive 
results for some of them, according to the clinical 
suspicions. The most vital suggestion driven by 
the results is that allergic patients may impair 
their symptoms by using creams or cosmetics 
produced with lanolin. 
 

In our practice, we have observed immediate 
cutaneous reactions (obtained by the skin scrape 



 
 
 
 

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test) and delayed reactions obtained by a forty-
eight-hour contact test or a photosensitized 
ninety-six-hour contact test (patch test). Based 
on this clinical experience, we can hypothesize 
that at least three endotypes are associated with 
lanolin hypersensitivity. The results presented by 
this work demonstrated that there is yet a lot 
unknown about the endotypes responsible for 
lanolin hypersensitivity, which may be produced 
by at least three mechanisms: a predominantly 
humoral, a predominantly cellular, and a 
compound of both. 
 

5. LIMITATIONS 
 

This study is a retrospective analysis of data 
collected over six years. There was no protocol 
research, and the subject's data was limited to 
the essentials available on our electronic sheets. 
Therefore, we could not establish a cross-
comparison between positive and negative 
controls to validate the results. The number of 
subjects is appropriate for a preliminary study; 
however, future studies must be more 
comprehensive. The lack of a research protocol 
implies the possibility of a bias produced by the 
physician's point of view, who suggested the 
exam barely on clinical suspicion led purely by 
the anamnesis and physical examination. The 
study lost many of these patients to follow-up, so 
assuring the relationship between the 
immunoassays' results and the patient's clinical 
outcome is impossible. 
 

6. CONCLUSION 
 

Our preliminary results show that the LAIT and 
TTP may differentiate diverse cellular and 
humoral immunoreactivity degrees against 
lanolin in patients clinically diagnosed with Non–
IgE-mediated allergies. This methodology can 
provide a socioeconomic impact since the 
technologies to perform TIAL and TTP are 
inexpensive and can be performed in a single lab 
room attached to the facilities with minimum 
laboratory equipment. However, the 
propaedeutic meaning of these results and the 
possibility of interferents must be better 
established [58]. More studies focused on the 
quality-by-design approach with prospective 
larger double-blind cohorts need to evaluate the 
potential contribution of LAIT and TTP for 
endotyping immunoreactivity of patients 
suspected of symptomatic hypersensitivity 
against lanolin and other similar food processing 
additives [59]. We are planning future work with 
control groups to draw more substantiated 
conclusions. 

7. FUTURE DIRECTIONS AND 
RECOMMENDATIONS FOR CLINICAL 
PRACTICE 

 
The primary intended use of in vitro or ex vivo 
allergen challenge tests is to spare the patients 
from being submitted to unnecessary, 
exhaustive, and dangerous in vivo challenge 
tests. Exploring the humoral and the cellular 
arms of immune systems, the TTP and TIAL 
alone or combined may represent, in the near 
future, a tool for allergists to construct an 
etiologic diagnosis from their patients, as well as 
determine the endotypes (mechanisms) of 
hypersensitivity, in order to choose more 
convenient and personalized therapies for them.  
 

DISCLAIMER (ARTIFICIAL INTELLIGENCE) 
 
Author(s) hereby declare that NO generative AI 
technologies such as Large Language Models 
(ChatGPT, COPILOT, etc.) and text-to-image 
generators have been used during the writing or 
editing of this manuscript.  
 

ETHICAL APPROVAL 
 
As a retrospective survey of results recorded in 
cognito, consent was given collectively by the 
institution's ethics committee following the 
principles of the Declaration of Helsinki [60]. 
 

ACKNOWLEDGEMENTS 
 

The Instituto Alergoimuno de Americana funded 
this work. We want to thank the laboratory 
technicians Alessandra Vieira de Oliveira and 
Luciana Sacilotto Carvalho for their help with the 
exams.  
 

COMPETING INTERESTS 
 
Authors have declared that no competing 
interests exist. 
 

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