单核/巨噬细胞在透析相关性淀粉样变发病学中的作用

THE ROLE MONOCYTE/MACROPHAGE IN THE PATHOGENESIS OF DIALYSIS RELATED AMYLOIDO-SIS

透析相关性淀粉样变 (DRA)是导致透析病人骨关节破坏性病变的致残性并发症 ,发病机制不明。淀粉样沉积周围有单核 /巨噬细胞浸润是DRA的组织病理学特征 ,但导致单核细胞浸润的原因及其在DRA发病学中的作用尚未阐明。笔者近期的研究证实 ,淀粉样纤维中的β2 微球蛋白 (β2 m)可通过与晚期糖基化终产物 (AGE)修饰的I型胶原的结合 ,在原位被AGE所修饰。AGE修饰的 β2 m(AGE β2 m)通过直接趋化作用或通过对关节滑膜成纤维细胞趋化因子生成的调节募集单核细胞 ,AGE β2 m并能延缓单核细胞的自发性凋亡 ,从而导致关节局部的单核细胞聚集。单核 /巨噬细胞的募集、活化又可通过释放促炎症细胞因子导致局部组织的炎症反应并刺激滑膜细胞表达粘附分子和产生降解基质蛋白的胶原酶 。

The pathogenesis of dialysis related amyloidosis, which occurs preferentially in osteo articular tissues, is still incom pletely understood. Although recent histological studies have shown the accumulation of monocytes/macrophages around amyloid deposits, the factor(s) causing their infiltration and pathological involvement have yet to be fully elucidated. The present studies demonstrate that β 2 microglobulin (β 2 m), the major constituent protein in amyloid fibrils, can be modified in situ by advanced glycation end products (AGE) through binding to AGE modified collagen. AGE β 2 m attracts monocytes via direct chemotaxis and through regulation of synoviocyte derived chemokine. AGE modified β 2 m significantly delays spontaneous apoptosis of human monocytes via a pathway mediated by the receptor for AGE (RAGE), processes which may increase the accumulation of inflammatory monocytes. In addition to recruit monocytes, AGE β 2 m stimulates macrophages to release IL 1β, TNF α and IL 6.These proinflammatory cytokines upregulate the expression of adhesion molecules such as ICAM 1 and VCAM 1 by synovial cells and induce the release of synoviocyte derived collagenase which may contribute to the degradation of matrix. These AGE β 2 m induced perturbation of monocytes and cellular inflammatory reactions eventually result in osteo articular tissue damage and destruction seen in DRA.