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Pathogenesis of beta(2)-microglobulin amyloidosis: role of monocytes/macrophages
F F Hou1, D N Reddan, W K Seng
1Division of Nephrology, Nanfang Hospital, Guangzhou, Peoples Republic of China.
Abstract:
beta(2)-microglobulin (beta(2)M) amyloidosis (A beta(2)M) is a serious, often incapacitating complication for patients undergoing long-term hemodialysis. Amyloid deposits composed of beta(2)M 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)-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(2)M enhances chemotaxis of monocytes and stimulates macrophages to release bone-resorbing cytokines, such as IL-1 beta, TNF-alpha and IL-6. Via a RAGE-mediated pathway, AGE-modified, but not unmodified beta(2)M, significantly delays constitutive apoptosis of human peripheral blood monocytes. Monocytes survival in an advanced glycation end product (AGE) beta(2)M-containing microenvironment is associated with their phenotypic alteration into macrophage-like cells that generate more reactive oxygen species and elaborate greater quantities of IL-1 beta and TNF-alpha. Thus through regulation of their survival and differentiation, AGE beta(2)M in amyloid deposits may be able to influence the presence and quantity of infiltrated monocytes, and hence their biologic effects.
Insights
Advanced glycation end product-modified beta(2)-microglobulin (AGE beta(2)M) promotes monocyte survival and differentiation into macrophages. This process contributes to beta(2)M amyloidosis pathogenesis by influencing monocyte infiltration and cytokine release.
Area of Science:
- Immunology
- Nephrology
- Rheumatology
Background:
- Beta(2)-microglobulin (beta(2)M) amyloidosis (A beta(2)M) is a debilitating complication of long-term hemodialysis.
- Amyloid deposits primarily affect joints and bone, causing pain and joint destruction.
- The role of monocytes/macrophages in A beta(2)M pathogenesis is not fully understood.
Purpose of the Study:
- To investigate the mechanisms by which advanced glycation end product-modified beta(2)M (AGE beta(2)M) influences monocyte and macrophage behavior.
- To elucidate the role of AGE beta(2)M in the pathogenesis of beta(2)M amyloidosis.
Main Methods:
- Immunohistochemical staining of tenosynovial tissues to identify macrophage markers (CD13, CD14, CD33, HLA-DR, CD68) and cell adhesion molecules (LFA-1, Mac-1, VLA-4).
- Assessment of cytokine production (IL-1 beta, TNF-alpha, IL-6) by macrophages.
- Evaluation of monocyte chemotaxis and apoptosis in response to AGE beta(2)M using a RAGE-mediated pathway.
- Analysis of reactive oxygen species generation by monocytes in an AGE beta(2)M microenvironment.
Main Results:
- Macrophages in A beta(2)M tissues express specific surface antigens and produce pro-inflammatory cytokines (IL-1 beta, TNF-alpha, IL-6).
- AGE beta(2)M enhances monocyte chemotaxis and stimulates macrophages to release bone-resorbing cytokines.
- AGE beta(2)M significantly delays monocyte apoptosis via a RAGE-mediated pathway.
- Monocytes in an AGE beta(2)M environment differentiate into macrophage-like cells with increased reactive oxygen species and cytokine production.
Conclusions:
- AGE beta(2)M plays a critical role in beta(2)M amyloidosis by promoting monocyte survival and differentiation.
- AGE beta(2)M influences monocyte infiltration and biologic effects within amyloid deposits.
- Targeting AGE beta(2)M interactions may offer therapeutic strategies for A beta(2)M.