Deciphering the endotypes and signature of non-response in a humanized murine model of PsA - Psoriatic arthritis (PsA) is a chronic inflammatory disease characterized by involvement of the skin, peripheral joints, axial skeleton, and entheses. The heterogeneity in clinical presentation and diverse tissue resident cells suggests that inflammation in different tissue compartments arises from distinct yet overlapping cellular and molecular mechanisms. However, the immune endotypes driving pathology across tissue domains remain poorly defined. Consequently, personalized treatment strategies are lacking, and despite multiple FDA-approved therapies, remission is rare, and frequent medication adjustments are needed to manage tissue-specific flares. A major barrier to targeted therapy is the absence of biomarkers that identify tissue-specific immune pathways. To address this challenge, we developed a humanized mouse model of PsA by injecting sera and PBMCs from PsA patients into immunodeficient NSG-SGM3 mice. These mice recapitulated key clinical features—arthritis, enthesitis, psoriasis, axial involvement, and dactylitis. In contrast, mice receiving samples from healthy donors did not develop disease. Spatial transcriptomics of joint tissues revealed enrichment of IL-32 and CXCL14-expressing CD8+ T cells. Strong expression of IL-17 was noted in axial tissues and dorsal root ganglia. Notably, disease development required human serum antibodies, and we identified hornerin, a defensin protein, as a candidate autoantigen. Importantly, mice humanized with blood from PsA patients unresponsive to TNF inhibitors developed skin and joint inflammation that did not respond to TNF blockade but improved with other biologics, mirroring patient treatment responses. This proposal aims to: (1) identify cellular and molecular signatures across PsA tissue domains; (2) define shared and distinct CD8+ T cell clonotypes to uncover candidate autoantigens; (3) test whether hornerin-specific autoantibodies promote inflammation via antigen presentation; (4) elucidate plasmablast-driven autoantibody production; and (5) evaluate IL-32 blockade in humanized mice derived from biologic-refractory PsA patients. These studies will provide mechanistic insights into PsA pathogenesis and enable the development of precision therapies*
