Project description:Generalized pustular psoriasis (GPP) is a rare, debilitating, and often life-threatening inflammatory disease characterized by episodic infiltration of neutrophils into the skin, pustule development, and systemic inflammation, which can manifest in the presence or absence of chronic plaque psoriasis (PV). Current treatments are unsatisfactory thus a better understanding the pathogenesis of GPP is warranted. To assess the pathophysiological differences between GPP and PV we performed a gene expression study on formalin-fixed paraffin-embedded biopsies of GPP (n=30) and PV (n=12) lesions and healthy control (n=20) skin. Compared with healthy skin, GPP lesions yielded 365 and PV 898 differentially expressed genes respectively, with 190 upregulated in both diseases. We detected higher expression of IL-1 and IL-36 cytokines in GPP lesions compared with PV, and this occurred proximal to neutrophils. We show both activated neutrophils and isolated neutrophil proteases can activate IL-36. Diverging from the Th1/Th17 pathophysiology of PV, significantly fewer IL23A, IL17A, IFNG, CXCL9, CXCL10 and MX1 transcripts were detected in GPP lesions. Our data indicate a level of sustained activation of IL-1 and IL-36 in GPP, inducing neutrophil chemokine expression, infiltration and pustule formation, suggesting that the IL-1 and IL-36 inflammatory axes are the main drivers of disease pathology in GPP.
Project description:Epigenetics plays a role in the pathogenesis of psoriasis vulgaris and generalized pustular psoriasis (GPP) through DNA methylation modifications that cause changes in immune responses. Psoriasis vulgaris is dominated by autoimmune responses, driven by Th17 cells producing IL-17, whereas GPP is dominated by autoinflammatory responses resulting from IL-36 dysregulation and neutrophil hyperactivation. Objective: This study aims to determine the DNA methylation profile and analyze the differences in IL-17 and IL-36 levels in both psoriasis phenotypes and healthy controls. Method: This study employed a cross-sectional design, comprising 20 patients with psoriasis vulgaris, three patients with GPP, and 13 healthy controls. DNA methylation profiles were assessed using Reduced Representation Methylation Sequencing, while IL-17 and IL-36 levels were assessed using ELISA. Results: Increased 5-methyl cytosine (5mC) was identified in psoriasis vulgaris and GPP compared to healthy controls. Increased 5mC at the FOXP3 promoter was identified in GPP and psoriasis vulgaris with high IL-17 levels, while decreased 5mC at the CARD14 promoter was identified in psoriasis vulgaris with high IL-17 levels. GPP showed higher IL-17 levels than healthy controls (p<0.05). IL-17 levels in psoriasis vulgaris showed no significant difference compared to GPP and healthy controls (p>0.05). IL-36 levels did not differ significantly among the three groups, with the highest IL-36 levels observed in psoriasis vulgaris (p>0.05). Conclusion: Increased DNA methylation in the FOXP3 gene promoter is predicted to cause high IL- 17 levels in psoriasis vulgaris and GPP, while IL-36 levels are higher only in psoriasis vulgaris.
