糖基转移酶B3GNT2调控强直性脊柱炎巨噬细胞的作用及机制

强直性脊柱炎（AS）是以遗传变异为基础的自身免疫性疾病，其巨噬细胞功能紊乱可致脊柱炎症、异位骨化，但机制仍不明确。申请人前期发现AS遗传变异位点可调控糖基转移酶-B3GNT2表达（Ann Rheum Dis，2019，一作）。进而发现，B3gnt2-/- AS模型小鼠疾病进展速度增快；同时多种免疫细胞功能检测发现，巨噬细胞促炎、促成骨因子表达量升高。巨噬细胞主要通过表面受体识别外界的刺激，从而具有不同功能。因此B3GNT2可能通过调控表面受体糖基化影响巨噬细胞功能。据此，本项目拟1）利用B3gnt2敲除及过表达小鼠，明确AS巨噬细胞中糖链修饰的关键表面受体与位点；2）利用造模小鼠和巨噬细胞模型，解析B3GNT2致巨噬细胞功能紊乱的关键分子和作用机制；3）利用肌腱组织和模型小鼠，评价上述关键分子对巨噬细胞免疫调控，以及致脊柱炎症、成骨的作用，为AS及其他自免病遗传机制和防治策略提供新方向。

Ankylosing spondylitis (AS) is an autoimmune disease based on genetic variation. Macrophage dysfunction can cause spinal inflammation and ectopic ossification, but the mechanism is still unclear. We found that the loci of rs6759298 can regulate the expression of glycosyltransferase-B3GNT2 (Ann Rheum Dis, 2019). Furthermore, it was found that the AS mouse model with B3gnt2-/- had faster disease progression; and at meantime, it revealed that macrophages increased expression of proinflammatory and osteogenetic cytokines by functional assay of multiple immune cells. Macrophages are able to have different function through surface receptors that recognize external stimulation. Therefore, B3GNT2 may affect macrophage function by regulating glycosylation of the surface receptor. Based on this, this project intends to 1) determine the sugar chain modified receptors and sites in AS macrophages in B3gnt2 knockout and over-expressing mice; 2) analyze the key molecules and mechanisms of B3GNT2-induced macrophage dysfunction in mouse and macrophage models; 3) evaluate the role of above key molecules in macrophages, and inflammation and osteogenesis of the spine by the mouse model and tendon tissues of AS patients, which provides new directions for the genetic mechanism and prevention strategies of AS and other autoimmune diseases.