Immune cell contributions to inflammatory arthritis

Vanderbilt University Medical Center, Nashville TN

Investigators

Abstract

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.