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Peer-reviewedCC BY-NC-ND 4.0Journal of Cutaneous Pathology

Elevated IL‐4 and IL‐13 Expression in Hailey‐Hailey Disease: Evidence for Th2‐Mediated Pathogenesis and Targeted Treatment

  • Simonetta I. Gaumond1,2
  • Victoria Soto1
  • Beatriz Abdo Abujamra1
  • Franco Rongioletti3
  • John A. McGrath4
  • Ivan Jozic1
  • Paolo Romanelli1
4 affiliations
  1. 1Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Miami Florida USA
  2. 2Department of Biochemistry and Molecular Biology University of Miami Miller School of Medicine Miami Florida USA
  3. 3Unit of Clinic Dermatology Vita‐Salute San Raffaele University Milan Italy
  4. 4St John's Institute of Dermatology King's College London London UK
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Abstract

Background: Hailey‐Hailey disease (HHD) is a rare autosomal dominant blistering disorder caused by mutations in the ATP2C1 gene, which impair keratinocyte adhesion through disrupted calcium signaling. While traditionally considered a structural defect, recent studies suggest that Th2‐mediated inflammation may exacerbate disease pathology. Interleukin (IL)‐4 and IL‐13, central mediators of type 2 inflammation, have been implicated in barrier dysfunction in other dermatoses, yet their role in HHD remains poorly defined.

Methods: This retrospective study employed immunohistochemistry to assess IL‐4 and IL‐13 expression in lesional skin from patients with HHD (n = 7) compared to age‐, sex‐, and site‐matched atopic dermatitis (AD) controls (n = 6) and healthy control samples (n = 4).

Results: IL‐4 expression was significantly elevated in the epidermis of HHD compared to negative control tissue (mean 3966 cells/mm2 vs. 808 cells/mm2, p = 0.0219), whereas IL‐13 expression was markedly increased in the dermis (mean 5288 cells/mm2 vs. 629 cells/mm2, p < 0.0001), relative to healthy controls. No statistically significant difference was observed between AD and HHD samples.

Conclusions: These findings highlight a potential role for IL‐4 and IL‐13 in the pathogenesis of HHD, supporting the therapeutic relevance for targeting type 2 cytokines. Agents such as dupilumab and potentially JAK inhibitors may offer new avenues for effective disease management.

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Cite

BibTeXRIS
BibTeX
@article{gaumond2026elevated,
  title = {{Elevated IL‐4 and IL‐13 Expression in Hailey‐Hailey Disease: Evidence for Th2‐Mediated Pathogenesis and Targeted Treatment}},
  author = {Simonetta I. Gaumond and Victoria Soto and Beatriz Abdo Abujamra and Franco Rongioletti and John A. McGrath and Ivan Jozic and Paolo Romanelli},
  journal = {Journal of Cutaneous Pathology},
  year = {2026},
  month = jul,
  doi = {10.1111/cup.70156},
  url = {https://doi.org/10.1111/cup.70156},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Elevated IL‐4 and IL‐13 Expression in Hailey‐Hailey Disease: Evidence for Th2‐Mediated Pathogenesis and Targeted Treatment
AU  - Simonetta I. Gaumond
AU  - Victoria Soto
AU  - Beatriz Abdo Abujamra
AU  - Franco Rongioletti
AU  - John A. McGrath
AU  - Ivan Jozic
AU  - Paolo Romanelli
PY  - 2026
DA  - 2026/07/06
JO  - Journal of Cutaneous Pathology
DO  - 10.1111/cup.70156
UR  - https://doi.org/10.1111/cup.70156
AB  - Background: Hailey‐Hailey disease (HHD) is a rare autosomal dominant blistering disorder caused by mutations in the ATP2C1 gene, which impair keratinocyte adhesion through disrupted calcium signaling. While traditionally considered a structural defect, recent studies suggest that Th2‐mediated inflammation may exacerbate disease pathology. Interleukin (IL)‐4 and IL‐13, central mediators of type 2 inflammation, have been implicated in barrier dysfunction in other dermatoses, yet their role in HHD remains poorly defined.  Methods: This retrospective study employed immunohistochemistry to assess IL‐4 and IL‐13 expression in lesional skin from patients with HHD (n = 7) compared to age‐, sex‐, and site‐matched atopic dermatitis (AD) controls (n = 6) and healthy control samples (n = 4).  Results: IL‐4 expression was significantly elevated in the epidermis of HHD compared to negative control tissue (mean 3966 cells/mm2 vs. 808 cells/mm2, p = 0.0219), whereas IL‐13 expression was markedly increased in the dermis (mean 5288 cells/mm2 vs. 629 cells/mm2, p < 0.0001), relative to healthy controls. No statistically significant difference was observed between AD and HHD samples.  Conclusions: These findings highlight a potential role for IL‐4 and IL‐13 in the pathogenesis of HHD, supporting the therapeutic relevance for targeting type 2 cytokines. Agents such as dupilumab and potentially JAK inhibitors may offer new avenues for effective disease management.
SN  - 0303-6987
SN  - 1600-0560
ER  -