Targeting IL-33 and TSLP: A Novel Approach to Modulate Type 2 and Non-Type 2 Inflammatory Pathways in Pemphigus Vulgaris.

Abstract

Pemphigus vulgaris (PV) is an autoantibody-mediated blistering disorder in which pathogenic immunoglobulins target epidermal desmoglein proteins, leading to suprabasal acantholysis that manifests clinically as flaccid blisters and mucosal erosions. First-line management typically includes oral corticosteroids as well as B-cell-depleting therapies such as rituximab; however, these and other systemic immunosuppressants carry substantial toxicities and are not suitable for all patients, motivating the search for more targeted, well-tolerated alternatives. Although PV is fundamentally driven by anti-desmoglein autoantibodies, emerging evidence implicates type 2 inflammation as a secondary contributor to disease activity, and epithelial-derived cytokines interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP) have garnered interest as upstream modulators of this axis. Beyond canonical type 2 effects, IL-33 and TSLP can influence a broader inflammatory milieu, including modulating type 17 responses that may also contribute to PV immunopathology. No clinical evidence currently supports IL-33 or TSLP blockade in PV, and it remains to be determined if modulation of this secondary axis could potentially control disease as monotherapy. Nonetheless, given their upstream position in cutaneous immune processes, therapeutic blockade of IL-33 or TSLP warrants investigation in preclinical models and biomarker-informed trials, principally as an adjunct to current autoantibody-directed regimens.