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Systemic single-cell analysis of GPP reveals treatment-responsive and persistent immune signatures

ABSTRACT: Generalized pustular psoriasis (GPP) is a rare autoinflammatory skin disease characterized by recurrent episodes of widespread sterile pustulation and systemic inflammation. Although biologic therapies targeting the IL-23/Th17 axis have demonstrated clinical efficacy, the systemic immune alterations associated with disease activity and treatment response remain incompletely understood, particularly in pediatric familial GPP associated with IL36RN mutations. In this study, we performed single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from two pediatric siblings with familial GPP before and after biologic treatment, together with two unaffected mutation-negative sibling controls. Single-cell transcriptomic profiling was used to characterize immune-cell-specific alterations associated with disease and treatment response.

ORGANISM(S): Homo sapiens

PROVIDER: GSE335590 | GEO | 2026/08/12

REPOSITORIES: GEO

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Project description:Background. Generalized pustular psoriasis (GPP), palmoplantar pustular psoriasis (PPP) and Acrodermatitis continua suppurativa Hallopeau (ACH) are 3 prototypes of pustular psoriasis. Treating them with the established psoriasis armamentarium of immunomodulating therapies is more or less a trial-and-error game because pathophysiology has not been uncovered in detail yet. Objectives. To promote the decoding of immunological pathways in GPP as the maximal variant of pustular psoriasis. Methods. Focusing on transcriptomic differences in GPP versus PPP, bulk RNA sequencing of affected skin and healthy skin of 3 GPP and 3 PPP patients was performed, and results were compared to each other and to matching healthy skin samples. Results. Analysis of heatmaps confirmed the expected up-regulation of Interleukin (IL-) 17, IL-23 and IL-36 pathways, especially in GPP. Interestingly, in our GPP patients we detected an unexpected marked atopic-like milieu with an upregulated T-helper cell (Th) type 2 profile. This raises the bar concerning personalized medicine as recently introduced IL-36 blockage will probably not be able to succeed as a monotherapy in GPP. In PPP-patients the ‚typical‘ immune signatures, although differentially regulated, struck with a notable heterogeneity. The atopic markers were not as overregulated as in GPP. Further findings might elucidate clinical features of GPP: Severity of symptoms was accompanied by up-regulated SERPIN B4 and L-selectin. And, an overexpression of KYNU and TDO2 as a sign for imbalance in tryptophan metabolism could deliver an explanation for psychological findings like anxiety and depression during an acute flare of GPP. Conclusions. GPP has an atopic component next to notorious drivers of classical psoriasis and IL-36. Key factors for aggressiveness of disease and psychological distress during flares could be overexpression of SERPIN B4/L-selectin respectively KYNU/TDO2. Trials with a greater number of patients and even more meticulous transcriptome analysis possibly supported by artificial intelligence should be considered.

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Systemic single-cell analysis of GPP reveals treatment-responsive and persistent immune signatures

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