Cellular stress-induced eccrine gland dysfunction as a potential mechanism in acquired idiopathic generalized...

Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder characterized by systemic anhidrosis or hypohidrosis of unknown etiology. Although autoimmune responses targeting eccrine glands and/or ducts have been proposed as a potential mechanism, the pathophysiology remains largely unclear. Corticosteroid pulse therapy is widely used for treatment, yet its mechanism of action is not fully understood. To elucidate the underlying mechanisms, we analyzed skin lesions from patients with AIGA before and after corticosteroid pulse therapy through histological and single-cell RNA-sequencing analyses. AIGA cases were histologically classified into pauci-inflammatory, mild inflammatory, and severe inflammatory types on the basis of lymphocytic infiltration around the eccrine unit. Corticosteroid pulse therapy improved sweating function across all groups, including pauci-inflammatory cases with little immune infiltration. Single-cell RNA sequencing of pauci-inflammatory AIGA skin revealed significant upregulation of eccrine marker genes such as MUCL1 and DCD alongside downregulation of cellular stress response pathways associated with unfolded protein responses after therapy. Immunohistochemistry confirmed increased expression of eccrine markers and reduced cellular stress markers, including advanced glycation end products and 4-hydroxynonenal, in eccrine glands after treatment. These findings suggest that unfolded protein response-associated cellular stress-mediated eccrine dysfunction contributes to AIGA pathogenesis, providing a basis for exploring cellular stress modulation as a potential therapeutic approach.