Pathogenesis of beta(2)-microglobulin amyloidosis: Role of monocytes/macrophages

beta (2)-microglobulin (beta M-2) amyloidosis (A beta M-2) is a serious, of ten incapacitating complication for patients undergoing long-term hemodialy sis. Amyloid deposits composed of beta M-2 fibrils as the major constituent protein are mainly localized in joints and periarticular bone and lead to chronic arthralgias, carpal tunnel syndrome, and eventually destructive art hropathy. Although recent histologic studies have shown the accumulation of monocytes/macrophages around amyloid deposits, the factor(s) causing their infiltration and pathologic involvement have yet to be fully elucidated. I mmunohistochemical staining reveals that macrophages in tenosynovial tissue s express CD13, CD14, CD33, HLA-DR, and CD68 antigens on their surfaces and express interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, and IL -6. Many of these cells also express LFA-1 (CD11a/CD18), Mac-1 (CD11b/CD18) , and VLA-4 (CD49d/CD29) on their surfaces. AGE-modified beta M-2 enhances chemotaxis of monocytes and stimulates macrophages to release bone-resorbin g cytokines, such as IL-1 beta, TNF-alpha and IL-6. Via a RAGE-mediated pat hway, AGE-modified, but not unmodified beta M-2, significantly delays const itutive apoptosis of human peripheral blood monocytes. Monocytes survival i n an advanced glycation end product (AGE) beta M-2-containing microenvironm ent is associated with their phenotypic alteration into macrophage-like cel ls that generate more reactive oxygen species and elaborate greater quantit ies of IL-1 beta and TNF-alpha. Thus through regulation of their survival a nd differentiation, AGE beta M-2 in amyloid deposits may be able to influen ce the presence and quantity of infiltrated monocytes, and hence their biol ogic effects.