Role of peroxidase deficiencies and elucidation of further disease genes in rare psoriatic subtypes affecting skin and skeleton

• Applicants: Professorin Dr. Ulrike Hüffmeier; Privatdozentin Dr. Ulrike Steffen
• Subject Area: Human Genetics ; Rheumatology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549931867

Psoriasis is a common inflammatory skin disorder. Besides the common forms psoriasis vulgaris (PsV) and psoriatic arthritis (PsA), the psoriatic spectrum comprises several rare subtypes that are rather mono- or oligogenic. In this project, we will focus on genetic variants in genes encoding for peroxidases (myeloperoxidase; MPO and prostaglandin-endoperoxide synthase 1; PTGS1) that are associated with generalized pustular psoriasis (GPP) and the syndrome of Synovitis Acne-Pustulosis-Hyperostosis-Osteitis (SAPHO). MPO encodes myeloperoxidase that is strongly expressed in neutrophils and to lesser extent also in other myeloid cells and involved in pathogen defence. Our preliminary data show that Mpo deficiency exacerbates disease in a murine PsA model associated with increased expression of IL-36 family members especially in inflamed skin. Human GPP patients carry MPO variants more often with additional variants in IL36RN encoding the IL-36 receptor antagonist than could be expected by chance. MPO-deficiency correlates with increased activity of serine proteases which in turn enhance activity of IL-36 family members. In WES studies, we identified several variants in PTGS1 in patients with SAPHO syndrome or other rare psoriatic subtypes as a new genetic contributor. In transfection studies with recombinant PTGS1, we found that the variants lead to deficiency of its product COX-1. COX-1 is involved in prostaglandin synthesis, and we hypothesize that COX-1 deficiency negatively affects resolution of inflammation. In this project, we aim to decipher the role of genetic variants in MPO and PTGS1 on skin and joint inflammation using PsA mouse models including therapeutic approaches with blocking antibodies, human peripheral blood monocytic cells (PBMCs), skin biopsies, and ex vivo cell cultures. In addition, we will enlarge genotyped patient cohorts, perform systematic genotype phenotype analyses in rare psoriatic subtypes and sequence genomes to find additional disease genes. With the results, we hope to shed light into the mechanisms of rare psoriatic subtypes and to find common disease pathways that might also help to improve therapy for more common psoriasis forms.

• DFG Programme: Research Grants