A local dermatologist has a healthy 33-year-old who when she exercises and sweats developed hives, generally where she sweats. It was not the typical sounding cholinergic urticaria. She's not had frank anaphylaxis. She had apparently heard of something called "sweat antigens", where apparently in places like Japan, they attempt desensitization. There is a reference in British medical journal from 2009. And a few others. I was wondering if the Academy had heard of this as an actual scientific entity.


Thank you for your inquiry.

There is an abundant body of literature incriminating a role for antigens (allergens) found in sweat in the production of not only cholinergic urticaria, but also atopic dermatitis. Much of this literature has appeared in reputable peer-reviewed journals. However, as you note, the majority, if not all, of the studies come from Japan. Desensitization to sweat antigens has also been performed and reported to be successful.

For your convenience, as well as for the convenience of our readers, I have copied a number of abtracts below that discuss this phenomenon. One of these articles is a nice review (Bito T, et al. in Allergology International).

So, in summary, there is reasonable evidence that the phenomenon of IgE-mediated reactions to sweat antigens can play a role in the production of cholinergic urticaria, but this evidence comes from a geographically-limited group, and at this time, to my knowledge, these studies have not impacted the day-to-day therapy of this condition.

Thank you again for your inquiry and we hope this response is helpful to you.

Allergol Int. 2012 Dec;61(4):539-44. doi: 10.2332/allergolint.12-RAI-0485. Epub 2012 Oct 25.
Pathogenesis of cholinergic urticaria in relation to sweating.
Bito T, Sawada Y, Tokura Y.
Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Hyogo, Japan.
Cholinergic urticaria (CU) has clinically characteristic features, and has been frequently described in the literature. However, despite its comparatively old history, the pathogenesis and classification remains to be clarified. CU patients are occasionally complicated by anhidrosis and/or hypohidrosis. This reduced-sweat type should be included in the classification because the therapeutic approaches are different from the ordinary CU. It is also well-known that autologous sweat is involved in the occurrence of CU. More than half of CU patients may have sweat hypersensitivity. We attempt to classify CU and address the underlying mechanisms of CU based on the published data and our findings. The first step for classification of CU seems to discriminate the presence or absence of hypersensitivity to autologous sweat. The second step is proposed to determine whether the patients can sweat normally or not. With these data, the patients could be categorized into three subtypes: (1) CU with sweat hypersensitivity; (2) CU with acquired anhidrosis and/or hypohidrosis; (3) idiopathic CU. The pathogenesis of each subtype is also discussed in this review.

Allergol Int. 2011 Sep;60(3):277-81. doi: 10.2332/allergolint.10-OA-0269. Epub 2011 Feb 25.
Rapid desensitization with autologous sweat in cholinergic urticaria.
Kozaru T, Fukunaga A, Taguchi K, Ogura K, Nagano T, Oka M, Horikawa T, Nishigori C.
Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Hyogo, Japan.
Background: The majority of patients with cholinergic urticaria presents with strong hypersensitivity to autologous sweat. Patients with severe cholinergic urticaria are frequently resistant to H(1) antagonists which are used in conventional therapies for various types of urticaria. It has been reported that desensitization using partially purified sweat antigen was effective in a patient with cholinergic urticaria.
Methods: The aim of this study is to determine the usefulness of rapid desensitization with autologous sweat in severe cholinergic urticaria, because rapid desensitization has proven to be a quick and effective immunotherapy for allergies to various allergens. Six patients with severe cholinergic urticaria who are resistant to H(1) antagonists and have sweat hypersensitivity were enrolled in a rapid desensitization protocol.
Results: In all six patients, the responses for skin tests with autologous sweat were attenuated after rapid desensitization with autologous sweat. Two of the three cholinergic urticaria patients showed reduced histamine release with autologous sweat after the rapid desensitization with autologous sweat. Further, the rapid desensitization and subsequent maintenance treatment reduced the symptoms in five of the six patients.
Conclusions: This study provides evidence that rapid desensitization with autologous sweat is beneficial for treating cholinergic urticaria patients resistant to conventional therapy who have sweat hypersensitivity.

Br J Dermatol. 2009 Feb;160(2):426-8. doi: 10.1111/j.1365-2133.2008.08862.x. Epub 2008 Sep 20.
Sweat antigen induces histamine release from basophils of patients with cholinergic urticaria associated with atopic diathesis.
Takahagi S, Tanaka T, Ishii K, Suzuki H, Kameyoshi Y, Shindo H, Hide M.
Department of Dermatology, Programs for Biomedical Research, Division of Molecular Medical Science, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
Background: We previously demonstrated that the semipurified human sweat antigen causes skin reactions and histamine release from basophils via specific IgE in patients with atopic dermatitis (AD). Patients with cholinergic urticaria (ChU) also develop skin reactions and histamine release of basophils in response to autologous sweat.
Objectives: To study whether or not patients with ChU share sensitivity for the sweat antigen with patients with AD and to study the clinical characteristics among patients with ChU and the relationship with histamine-release activity of basophils.
Methods: The sweat antigen that induces histamine release from basophils of patients with AD was prepared by Con-A, anion-exchange and reverse-phase chromatography. Relationships between histamine-release activity against the sweat antigen and clinical features of patients with ChU were analyzed.
Results: Twenty-three of 35 patients with ChU showed > 5% net histamine release in response to the semipurified sweat antigen, whereas none of healthy controls did so. In patients with ChU, histamine release in response to semipurified sweat antigen significantly correlated with the level of serum IgE and eosinophil numbers in peripheral blood. Incidence of each atopic disease in patients with ChU tended to be higher than in the general Japanese population. When the patients were categorized according to their responses in the histamine release test, the positive group tended to show a higher incidence of AD and bronchial asthma compared with the negative group.
Conclusions: ChU and AD may share hypersensitivity to common antigens in sweat. The sweat allergy and atopic diathesis are associated with each other.

Exp Dermatol. 2006 Apr;15(4):283-90.
Semi-purification of the immunoglobulin E-sweat antigen acting on mast cells and basophils in atopic dermatitis.
Tanaka A, Tanaka T, Suzuki H, Ishii K, Kameyoshi Y, Hide M.
Department of Dermatology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Background: Sweating aggravates the symptoms of atopic dermatitis (AD). We have recently reported positive skin reactions and histamine release from basophils in response to autologous sweat in patients with AD.
Objective: To characterize the biochemical and immunological properties of the substance in sweat that evokes histamine release and to study the usability of the basophil-histamine release test with the sweat antigen for AD.
Methods: Sweat collected from healthy volunteers was purified using chromatographies. Serum immunoglobulin (Ig)E of four patients with AD were purified using an affinity-chromatography column with anti-IgE antibodies. The amount of semi-purified sweat antigen (138 ng protein/ml) that induced a half-maximum reaction of basophils of a patient with AD was utilized for the basophil histamine release test. The involvement of specific IgE and high-affinity IgE receptor (FcepsilonRI) in the reactions was examined using basophils of healthy volunteers, a human mast cell line (LAD2), and a rat basophilic leukemia cell line transfected with human alpha-subunit of FcepsilonRI (RBL-48).
Results: The semi-purified sweat antigen induced histamine release from the basophils of 47 of 61 (74.6%) patients with AD and four of 46 (8.7%) healthy controls. Both basophils and mast cells sensitized with the patient-derived IgE showed degranulation upon stimulation with the sweat antigen. However, no reaction was observed when cells were sensitized with myeloma IgE or the antigen was treated with proteases.
Conclusion: The semi-purified standardized sweat antigen consists of a protein that induces degranulation of basophils and mast cells via antigen-specific IgE and FcepsilonRI in patients with AD.

J Allergy Clin Immunol. 2013 Sep;132(3):608-615.e4. doi: 10.1016/j.jaci.2013.03.047. Epub 2013 May 29.
Fungal protein MGL_1304 in sweat is an allergen for atopic dermatitis patients.
Hiragun T, Ishii K, Hiragun M, Suzuki H, Kan T, Mihara S, Yanase Y, Bartels J, Schröder JM, Hide M.
Department of Dermatology, Integrated Health Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Japan.
Background: Sweat is a major aggravating factor of atopic dermatitis (AD) and approximately 80% of patients with AD show type I hypersensitivity against sweat.
Objective: To identify and characterize an antigen in sweat that induces histamine release from basophils of patients with AD.
Methods: Basophil histamine-releasing activity in sweat was purified by a combination of chromatographies, and proteins were analyzed with mass spectrometry. Recombinant proteins of the sweat antigen were generated, and their biological characteristics were studied by immunoblots, histamine release tests, and neutralization assays.
Results: We identified a fungal protein, MGL_1304, derived from Malassezia globosa (M globosa) in the purified sweat antigen. Recombinant MGL_1304 induced histamine release from basophils of most of the patients with AD, in accordance with the semi-purified sweat antigen. Moreover, recombinant MGL_1304 abolished the binding of serum IgE of patients with AD to the semi-purified sweat antigen, or vice versa in immunoblot analysis, and attenuated the sensitization of RBL-48 mast cells expressing human FcɛRI by serum IgE. Studies of truncated mutants of MGL_1304 indicated that IgE of patients with AD recognized the conformational structure of MGL_1304 rather than short peptide sequences. Western blot analysis of the whole lysate, the culture supernatant of M globosa, and the semi-purified sweat antigen showed that MGL_1304 was produced as a minor immunological antigen of M globosa with posttranslational modification, cleaved, and secreted as a 17-kDa major histamine-releasing sweat antigen.
Conclusion: MGL_1304 is a major allergen in human sweat and could cause type I allergy in patients with AD.

Arch Dermatol Res. 2012 Oct;304(8):647-54. doi: 10.1007/s00403-012-1236-2. Epub 2012 Apr 19.
Histamine release-neutralization assay for sera of patients with atopic dermatitis and/or cholinergic urticaria is useful to screen type I hypersensitivity against sweat antigens.
Shindo H, Ishii K, Yanase Y, Suzuki H, Hide M.
Programs for Biomedical Research, Division of Molecular Medical Science, Department of Dermatology, Graduate School of Biomedical Sciences, Hiroshima University, Kasumi, Minami-ku, Hiroshima, Japan.
We previously reported that about 80 % of patients with atopic dermatitis and 60 % with cholinergic urticaria revealed type I allergy against sweat, by means of skin test against autologous sweat and/or histamine-release test for peripheral blood basophils with semi-purified sweat antigen. In this study, we developed an assay for sera to neutralize histamine-releasing activity of semi-purified sweat antigen. The semi-purified sweat antigen was pre-incubated with serially diluted sera for 30 min at 37 °C and was subjected to histamine-release activity. Histamine release-neutralization (HRN) activities were calculated by measuring the amount of histamine release from basophils in the presence or absence of semi-purified sweat antigen. Of 62 subjects, 39 showed positive histamine release (≥5 %) from their basophils in response to semi-purified sweat antigen, and sera of 34 out of 39 subjects (87.2 %) were also positive in HRN activity (≥10 %). The specificity of the HRN assay was 0.522. Moreover, HRN activities in sera were largely correlated with degrees of histamine release from peripheral blood basophils of the same donors in response to sweat antigen. To identify the substance that neutralizes histamine-release activity, we removed IgE and IgG from the sera of HRN (+) subjects by column chromatography. The HRN activities in 30 out of 42 sera were largely reduced by the removal of IgG. On the other hand, sera of four subjects lost HRN activity by the removal of IgE, suggesting that the majority of HRN (+) subjects have serum IgG against the sweat antigen as well as IgE bound to peripheral basophils. Thus, the HRN assay maybe useful for the screening of type I allergy against sweat antigen.

Arerugi. 2007 Jan;56(1):54-7.
[Cholinergic urticaria successfully treated by immunotherapy with partially purified sweat antigen].
[Article in Japanese]
Tanaka T, Ishii K, Suzuki H, Kameyoshi Y, Hide M.
Department of Dermatology, Graduate School of Biomedical Sciences, Hiroshima University.
A 24-years-old man was referred to our University Hospital because of one and a half-year history of disabling symptoms related to physical exertion. Multiple small round-shaped wheals with severe itch were induced by exercise, warmth and psychological stress. These symptoms were resistant to histamine H1-receptor antagonists. Similar eruptions were induced by sauna-bathing, and skin test with autologous sweat showed a flare and wheal reaction. Incubation of his peripheral-blood leukocytes with partially purified sweat antigen evoked marked histamine release, indicating that he has been IgE-sensitized to an antigen(s) in human sweat. Specific immunotherapy using partially purified sweat antigen was performed every other week. Both pruritus and wheals improved gradually, and the reactivity of his peripheral blood leukocytes against sweat antigen decreased as immunotherapy was proceeded. Specific immunotherapy using sweat antigen may be valuable for patients with cholinergic urticaria with type I hypersensitivity to sweat antigen(s).

Phil Lieberman, M.D.

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