Pathogenesis of β₂-microglobulin amyloidosis: Role of monocytes/macrophages

β₂-microglobulin (β₂M) amyloidosis (Aβ₂M) is a serious, often incapacitating complication for patients undergoing long-term hemodialysis. Amyloid deposits composed of β₂M 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 arthropathy. 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. Immunohistochemical staining reveals that macrophages in tenosynovial tissues express CD13, CD14, CD33, HLA-DR, and CD68 antigens on their surfaces and express interleukin (IL)-Iβ, tumor necrosis factor (TNF)-α, 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 β₂M enhances chemotaxis of monocytes and stimulates macrophages to release bone-resorbing cytokines, such as IL-1β, TNF-α and IL-6. Via a RAGE-mediated pathway, AGE-modified, but not unmodified β₂M, significantly delays constitutive apoptosis of human peripheral blood monocytes. Monocytes survival in an advanced glycation end product (AGE) β₂M-containing microenvironment is associated with their phenotypic alteration into macrophage-like cells that generate more reactive oxygen species and elaborate greater quantities of IL-lβ and TNF-α. Thus through regulation of their survival and differentiation, AGE β₂M in amyloid deposits may be able to influence the presence and quantity of infiltrated monocytes, and hence their biologic effects.