Immune cell contributions to inflammatory arthritis - Psoriatic arthritis (PsA) is characterized by dactylitis, enthesitis, synovitis, and bone erosions, leading to significant morbidity and disability. Current treatment strategies targeting inhibition of TNF, IL-23, IL-17A, JAKs, or PDE4 inhibitors slow down but do not prevent, PsA pathogenesis. Similarly, treatment with the T cell targeted therapy cyclosporine has limited efficacy on PsA symptoms and progression. These findings suggest that other cell types or inflammatory proteins contribute to PsA pathogenesis. B cells are present in PsA patient synovial fluid and colocalize with T cells in PsA synovial tissue, consistent with ectopic lymphoid neogenesis. In this immune cell-dense region, B, T, and antigen-presenting cells interact to modulate and drive inflammation. PsA patients treated with rituximab, a B cell inhibitor, have improved arthritis clinical outcomes. Despite these observations, it remains unclear how B cells contribute to the pathogenesis of PsA. We recently engineered a mouse model of PsA (called Klk6+) that spontaneously develops a phenotype modelling human PsA, including dactylitis, enthesitis, synovitis, and radiographic erosive changes to the axial and appendicular skeletons. Klk6+ mice have decreases in anti-inflammatory IL-10+ Breg cells and increases in proinflammatory IL-6+ Beff cells that occur concomitant with increases in Th1 and Th17 cells, paralleling findings reported in PsA patients. Thus, the Klk6+ PsA mouse model represents a highly relevant model for studying B cell contributions to inflammatory arthritis and uniquely positions us to delineate the mechanisms by which this occurs. Using Klk6+ animals and samples obtained from PsA patients, we will test the conceptually innovative hypothesis that decreases in anti-inflammatory IL-10-producing Bregs and increases in proinflammatory IL-6- producing Beff cells promote Th17 cell inflammation and PsA development. Using a combination of innovative mouse molecular genetics approaches, cutting-edge single-cell sequencing and spatial transcriptomics, CyTOF, flow cytometry, and careful examination of improvement in individual PsA domains in mice, we will: 1. demonstrate that the PsA phenotype observed in Klk6+ mice is mediated by proinflammatory IL-6-producing Beff cell populations that promote Th17 and Th1 T cell inflammation and loss of the anti-inflammatory IL-10-producing Breg population; 2. elucidate the cellular and molecular mechanisms by which this occurs and 3. translate these findings to PsA patients. Collectively, our studies will identify B cells as new pathogenic contributors to PsA etiology and will identify the cellular mechanisms mediating B cell-T cell interactions that promote inflammatory arthritis. Our ability to translate and confirm our findings in PsA patients may lead to a paradigm shift in understanding PsA pathogenesis and the repurposing of existing FDA-approved drugs for treating PsA.
