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. 2022 Jul 29:13:955161.
doi: 10.3389/fimmu.2022.955161. eCollection 2022.

Impaired sweating in patients with cholinergic urticaria is linked to low expression of acetylcholine receptor CHRM3 and acetylcholine esterase in sweat glands

Yiyu Wang  1   2 , Jörg Scheffel  1   3 , Carolina Ayala Vera  1   3 , Wei Liu  2 , Dorothee Günzel  4 , Dorothea Terhorst-Molawi  1   3   4 , Marcus Maurer  1   3 , Sabine Altrichter  1   3   5
Affiliations

Impaired sweating in patients with cholinergic urticaria is linked to low expression of acetylcholine receptor CHRM3 and acetylcholine esterase in sweat glands

Yiyu Wang et al. Front Immunol. .

Abstract

Background: Cholinergic urticaria (CholU), a frequent form of chronic inducible urticaria, is characterized by itchy wheals and angioedema in response to sweating. As of now, the rate and pathophysiological relevance of impaired sweating in patients with CholU are ill-defined.

Aim: To assess in CholU patients the rate and extent of impaired sweating and its links to clinical and pathophysiological features of CholU.

Patients and methods: We assessed sweating in patients with CholU (n = 13) subjected to pulse-controlled ergometry (PCE) provocation testing. Pre- and post-PCE biopsies of lesional (L) and non-lesional (NL) skin were analyzed for the expression of acetylcholine receptor M3 (CHRM3) and acetylcholine esterase (ACh-E) by quantitative histomorphometry and compared to those of healthy control subjects (HCs). CholU patients were assessed for disease duration and severity as well as other clinical features.

Results: Of the 13 patients with CholU, 10 showed reduced sweating in response to PCE provocation, and 3 had severely reduced sweating. Reduced sweating was linked to long disease duration and high disease severity. CholU patients with impaired sweating responses showed reduced sweat gland epithelial expression of CHRM3 and ACh-E.

Conclusion: Reduced sweating is common in CholU patients, especially in those with long-standing and severe disease, and it can be severe. Reduced expression of CHRM3 and ACh-E may be the cause or consequence of CholU in patients with impaired sweating, and this should be explored by further studies.

Keywords: acetylcholine esterase; cholinergic; hypohidrosis/anhidrosis; muscarinic 3 receptor; sweat gland; urticaria; wheal.

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Conflict of interest statement

DT-M has received research funds/was an advisor for Celldex, Novartis, Sanofi, and Moxie. MM is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Amgen, Aralez, ArgenX, AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, GIInnovation, Innate Pharma, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Roche, Sanofi/Regeneron, Third HarmonicBio, UCB, and Uriach. SA has been a speaker and/or advisor for and/or has conducted studies for AstraZeneca, Allakos, GSK, Leo Pharma, Lilly, Moxie, Novartis, Thermo Fisher, and Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
(A) More than half of cholinergic urticaria (CholU) patients showed reduced sweating (RS); the remaining had either normal sweating (NS) or severely reduced sweating (SRS). CholU patients grouped via their sweating behavior show differences regarding (B) persistence of disease and (C) severity of disease (assessed by CholUSI). *p < 0.05; ns, not significant.
Figure 2
Figure 2
Representative immunohistochemical examination patterns of the expression of CHRM3 of HC and CholU patients separated per sweating group: (a/ c/ e/ g) non-lesional skin samples taken before provocation, (b) non-lesional skin after provocation from a sample of the HC group, and (d/ f/ h) lesional skin samples after provocation from CholU patients. Zoom-in boxes depict the cutouts in higher magnifications. HC, healthy controls; NS, normal sweating CholU; RS, reduced sweating CholU; SRS, severely reduced sweating CholU.
Figure 3
Figure 3
(A) CHRM3 expression on the sweat gland epithelium of HC and CholU patients’ skin before and after pulse-controlled ergometry (PCE). (B) CHRM3 expression within CholU patients was significantly reduced before PCE provocation in the SRS patient group. (C) A similar trend was seen in the skin samples after provocation, but here no significance level was reached. NS, normal sweating CholU; RS, reduced sweating CholU; SRS, severely reduced sweating CholU.
Figure 4
Figure 4
Representative immunohistochemical examination patterns of the expression of ACh-E of HC and CholU patients separated per sweating group: a/ c/ e/ g/ non-lesional skin samples taken before provocation, b non-lesion after provocation from the HC group, and d/ f/ h lesional skin samples after provocation from CholU patients. Zoom-in boxes depict the cutouts in higher magnifications. HC, healthy controls; NS, normal sweating CholU; RS, reduced sweating CholU; SRS, severely reduced sweating CholU.
Figure 5
Figure 5
(A) ACh-E expression on sweat gland epithelium in HC and CholU patients’ skin before and after PCE. (B) ACh-E expression within CholU patients was significantly reduced before PCE provocation in the SRS patient group. (C) Significant differences were seen between all sweating groups in CholU patients with high significance. HC, healthy controls; NS, normal sweating CholU; RS, reduced sweating CholU; SRS, severely reduced sweating CholU.
Figure 6
Figure 6
Representative immunohistochemical examination patterns of the expression of CHRM3 and ACh-E of non-lesional skin before provocation in HC (A–D) and CholU patients (E–H). (A, D) DAPI staining of nuclei of sweat glands; (B, E) CHRM3 staining (red); (C, F) ACh-E staining (FITC) d/g CHRM3 and ACh-E overlay.
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