Anti-Serum Amyloid A monoclonal antibody, clone A505

Abundantly expressed serum amyloid A (SAA) protein under chronic inflammatory conditions gives rise to insoluble aggregates of SAA derivatives in multiple organs resulting in reactive amyloid A (AA) amyloidosis, a consequence of rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, familial Mediterranean fever, and Castleman's disease. An inflammation-responsive transcription factor, SAF (for SAA activating factor), has been implicated in the sustained expression of amyloidogenic SAA under chronic inflammatory conditions. However, its role in the pathogenesis of AA amyloidosis has thus far remained obscure. In this paper we have shown that SAF-1, a major member of the SAF family, is abundantly present in human AA amyloidosis patients. To assess whether SAF-1 is directly linked to the pathogenesis of AA amyloidosis, we have developed a SAF-1 transgenic mouse model. SAF-1-overexpressing mice spontaneously developed AA amyloidosis at the age of 14 mo or older. Immunohistochemical analysis confirmed the nature of the amyloid deposits as an AA type derived from amyloidogenic SAA1. Furthermore, SAF-1 transgenic mice rapidly developed severe AA amyloidosis in response to azocasein injection, indicating increased susceptibility to inflammation. Also, during inflammation SAF-1 transgenic mice exhibited a prolonged acute phase response, leading to an extended period of SAA synthesis. Together, these results provide direct evidence that SAF-1 plays a key role in the development of AA amyloidosis, a consequence of chronic inflammation.

Serum amyloid A (SAA) is an acute-phase response protein in the liver, and SAA1 is the major precursor protein involved in amyloid A amyloidosis. This amyloidosis has been reported as a complication in chronic inflammatory conditions such as arthritis, lupus, and Crohn's disease. Obesity is also associated with chronic, low-grade inflammation and sustained, elevated levels of SAA1. However, the contribution of elevated circulating SAA1 to metabolic disturbances and their complications is unclear. Furthermore, in several recent studies of transgenic (TG) mice overexpressing SAA1 that were fed a high-fat diet (HFD) for a relatively short period, no relationship was found between SAA1 up-regulation and metabolic disturbances. Therefore, we generated TG mice overexpressing SAA1 in the liver, challenged these mice with an HFD, and investigated the influence of elevated SAA1 levels. Sustained, elevated levels of SAA1 were correlated with metabolic parameters and local cytokine expression in the liver following 16 weeks on the HFD. Moreover, prolonged consumption (52 weeks) of the HFD was associated with impaired glucose tolerance and elevated SAA1 levels and resulted in systemic SAA1-derived amyloid deposition in the kidney, liver, and spleen of TG mice. Thus, we concluded that elevated SAA1 levels under long-term HFD exposure result in extensive SAA1-derived amyloid deposits, which may contribute to the complications associated with HFD-induced obesity and metabolic disorders.