Arthritis is a major health concern to the Veteran population who have 35% incidence rates. Ankylosing spondylitis (AS), a type of inflammatory arthritis that results in chronic back pain, sacroiliac joint and/or vertebral joint fusion and permanent spinal deformity. Although the cause of AS is not known, genetic studies suggest that CD4+ T helper cells that produce the pro-inflammatory cytokine IL-17 (Th17 cells) drive the pathogenesis of AS. In support, pharmacological inhibition of IL-17 (IL-17i) has had great utility in moderating AS symptoms. Although Th17 responses appear to be key in driving symptomatic disease, less is understood of the underlying innate cellular mechanisms that initiate pathologic Th17 cell responses. Given our limited understanding of immunopathogenesis of AS physicians are challenged with administering one of several approved anti-rheumatic biologics (i.e. IL-17i, TNFi, JAKi) to patients without mechanistic insight into who will respond best to each drug. Thus, development of treatment response biomarkers is urgently needed to increase therapeutic responses and alleviate pain in patients suffering from this debilitating disease. To move this field forward we are in urgent need of more research to reveal genetic and molecular mediators of IL-17- mediated AS. An emerging paradigm suggests that self-reactive T cells (autoimmune) and aberrant innate immunity (autoinflammation) conspire to drive AS pathogenesis. In support, a mutation in the microbial- signaling molecule CARD9 (i.e. rs4077515) is associated with increased susceptibility to AS. The CARD9- signaling axis is essential for fungal immunity, yet how dysregulation of CARD9 might regulate sterile inflammation in AS has not been studied. This application is based on our finding that CARD9 is a genetic determinant of AS in genetically susceptible SKG mice. CARD9 appears to be functioning within neutrophils to induce arthritogenic Th17 responses. Given our data we hypothesize that CARD9 is an important regulator of arthritogenic Th17 cells in AS. The goal of this Merit proposal is to determine the mechanism by which innate cellular processes induce arthritogenic Th17 cells in AS and use this information to develop a biomarker of IL- 17i treatment responders in the clinic. Importantly, clinical studies proposed in this application will be focused on AS patients previously enrolled in or newly enrolled in from the Veteran Program to Understand Longterm Outcomes of Spondyloarthritis (PULSAR). These studies will reveal crucial cellular networks and molecules that cause AS and ultimately contribute knowledge needed to develop future patient-tailored treatment strategies to improve the health of Veterans.