data_sheet_1_Soluble CD83 Alleviates Experimental Autoimmune Uveitis by Inhibiting Filamentous Actin-Dependent Calcium Release in Dendritic Cells.PDF

Soluble CD83 (sCD83) is the extracellular domain of the membrane-bound CD83 molecule, and known for its immunoregulatory functions. Whether and how sCD83 participates in the pathogenesis of uveitis, a serious inflammatory disease of the eye that can cause visual disability and blindness, is unknown. By flow cytometry and imaging studies, we show that sCD83 alleviates experimental autoimmune uveitis (EAU) through a novel mechanism. During onset and recovery of EAU, the level of sCD83 rises in the serum and aqueous humor, and CD83+ leukocytes infiltrate the inflamed eye. Systemic or topical application of sCD83 exerts a protective effect by decreasing inflammatory cytokine expression, reducing ocular and splenic leukocyte including CD4+ T cells and dendritic cells (DCs). Mechanistically, sCD83 induces tolerogenic DCs by decreasing the synaptic expression of co-stimulatory molecules and hampering the calcium response in DCs. These changes are caused by a disruption of the cytoskeletal rearrangements at the DC–T cell contact zone, leading to altered localization of calcium microdomains and suppressed T-cell activation. Thus, the ability of sCD83 to modulate DC-mediated inflammation in the eye could be harnessed to develop new immunosuppressive therapeutics for autoimmune uveitis.

可溶性CD83（sCD83）是膜结合型CD83分子的胞外结构域，已知其具备免疫调节功能。目前尚不清楚sCD83是否参与葡萄膜炎（uveitis）——一种可导致视力障碍乃至失明的严重眼部炎症性疾病——的发病机制，以及其具体参与方式。本研究通过流式细胞术（flow cytometry）与成像实验证实，sCD83可通过全新机制缓解实验性自身免疫性葡萄膜炎（experimental autoimmune uveitis，EAU）。在EAU的发病与恢复阶段，血清与房水中的sCD83水平升高，且CD83阳性白细胞会浸润炎症眼部。全身给药或局部外用sCD83，可通过降低炎症细胞因子表达、减少眼部及脾脏内包括CD4阳性T细胞与树突状细胞（dendritic cells，DCs）在内的白细胞浸润，发挥保护作用。从机制上看，sCD83可通过下调共刺激分子（co-stimulatory molecules）的突触表达、抑制树突状细胞内的钙应答，诱导产生耐受性树突状细胞。上述变化源于树突状细胞-T细胞接触区的细胞骨架重排（cytoskeletal rearrangements）遭到破坏，进而导致钙微结构域（calcium microdomains）定位异常并抑制T细胞活化。因此，sCD83调控眼部树突状细胞介导的炎症的能力，可被用于开发针对自身免疫性葡萄膜炎的新型免疫抑制治疗手段。