STK17B/DRAK2 in Axial Spondyloarthritis: Expression Patterns in Blood and Tissue
T cells play a central role in axial spondyloarthritis (axSpA). The serine-threonine kinase DRAK2, encoded by STK17B, modulates T cell activation and survival. In autoimmune models, it promotes autoreactive T cell persistence and reduces regulatory T cell (Treg) abundance.[1,2] We previously found STK17B upregulation in peripheral blood mononuclear cells (PBMCs) of axSpA patients who were non-responders to tumor necrosis factor inhibitors (TNFi).[3] To clarify whether this reflects disease-associated inflammation or treatment resistance, we compared STK17B/DRAK2 expression (i) between axSpA patients and healthy controls and (ii) between responders and non-responders to IL-17 inhibitor (IL-17i) therapy. We also examined STK17B/DRAK2 expression in the SKG mouse model of SpA. Human spinal tissue from axSpA patients and spinal trauma controls was analyzed by immunohistochemistry (IHC) to localize DRAK2 expression, and by immunofluorescence (IF) to compare expression between CD4 + and CD8 + T cells. PBMCs from patients and controls were sorted by fluorescence-activated cell sorting (FACS), and STK17B expression in each subset was quantified by qPCR. Parallel IHC was performed on ankle, tail, and ileum of curdlan-treated and PBS-treated SKG mice. To corroborate findings at higher resolution, STK17B expression in mature CD4 + and CD8 + T cells was queried from our pre-biologic single-cell RNA-sequencing and multiome datasets. In human spinal tissue, DRAK2 + immune infiltrates were more abundant in axSpA than in controls (Figure 1A), with stronger IF staining in CD4 + than CD8 + T cells. In PBMCs, STK17B was preferentially expressed in CD4 + T cells and trended higher in axSpA compared with controls. Single-cell and multiomic analyses confirmed this pattern, showing modest STK17B increases in CD8+ T cells but markedly higher levels in CD4+ T cells of axSpA patients, particularly in effector T cells and Tregs. Notably, pre-biologic STK17B expression was higher among patients who were later identified as non-responders to IL-17i compared with responders (Figure 1B). Consistent with the human findings, curdlan-treated SKG mice exhibited increased DRAK2 + infiltrates in ankle, tail, and ileum relative to PBS-treated controls, paralleling the observation in human tissues (Figure 1C). Figure 1. (A) Histopathology of spinal tissues from AS and control patients with IHC staining for anti-DRAK2. (B) STK17B expression in mature CD4+ T cells of pre-biologic axSpA patients and controls. (C) Histopathology of the tissues from curdlan- vs PBS-SKG mice for anti-DRAK2. Across humans and mouse models, STK17B/DRAK2 expression is increased in inflammatory lesions and enriched in CD4 + effector and regulatory T cells, particularly in patients with inadequate IL-17i response. These findings suggest that DRAK2 upregulation contributes both to axSpA-related inflammation and to treatment resistance, warranting further mechanistic investigation. [1.] Ramos S. J Immunol 2008;181:7606-16. [2.] Mandarano A. Cell Rep 2023;42:112106. [3.] Talukdar A. [Abstract]. Arthritis Rheumatol 2024;76 Suppl 9.