Recent Insights into the Pathogenesis of Type AA Amyloidosis

Abstract

The amyloidoses are a group of life-threatening diseases in which fibrils made of misfolded proteins are deposited in organs and tissues. The fibrils are stable, insoluble aggregates of precursor proteins that have adopted an antiparallel β-sheet structure. In type AA, or reactive, amyloidosis, the precursor protein of the fibrils is serum amyloid A (SAA). SAA is a 104-amino-acid protein that is produced in the liver in response to proinflammatory cytokines. Although the protein that is produced by the liver contains 104 amino acids, only the N-terminal 66–76 amino acids are found in amyloid fibrils. Furthermore, SAA has been shown to have an α-helical structure primarily. Thus, for SAA to be incorporated into an amyloid fibril, two processes have to occur: C-terminal cleavage and conversion into a β-sheet. Only a minority of patients with elevated SAA levels develop amyloidosis. Factors that contribute to the risk of amyloidosis include the duration and degree of SAA elevation, polymorphisms in SAA, and the type of autoinflammatory syndrome. In the Hyper-IgD syndrome, amyloidosis is less prevalent than in the other autoinflammatory diseases. In vitro work has shown that the isoprenoid pathway influences amyloidogenesis by farnesylated proteins. Although many proteins contain domains that have a potential for self-aggregation, amyloidosis is only a very rare event. Heat shock proteins (HSPs) are chaperones that assist other proteins to attain, maintain, and regain a functional conformation. In this review, recent insights into the pathogenesis of amyloidosis are discussed, in addition to a new hypothesis for a role of HSPs in the pathogenesis of type AA.

Chronische Entzündung und AA-Amyloidose

“…Die Nierenfunktion ist in diesem frühen Stadium meist noch normal [27]. Bei unbehandelten Patienten wird die Proteinurie unweigerlich in ein nephrotisches Syndrom mit einer Proteinurie von bis zu 20 g/Tag und in eine zunehmende Nierenfunktionseinschränkung bis zur terminalen Niereninsuffizienz fortschreiten.…”

“…Es besteht aus 104 Aminosäuren und kann durch Cathepsin D, Matrixmetalloproteinasen und andere Enzyme gespalten werden [23,27]. AA-Fibrillen bestehen überwiegend aus den N-terminalen 66 bis 76 Aminosäuren des SAA-Vorläuferproteins.…”

Amyloidosis Associated to Leishmania Infection in Murine Model

“…On the other hands, BALB/c mice did not present amyloid deposition probably due to high susceptibility to L. amazonensis, what lead to generalized disease at 60 or 90 days post infection. Thus, several factors such as sex, duration and type of infection and polymorphism can contribute to onset of AA amyloidosis van der Hilst, 2011). The pathogenesis of leishmaniasis is related to the genetic background of the host and the Leishmania species and the modulation of T-cell immune response can be influenced by the infective Leishmania species as described by Silveira et al (2009), since the clinical manifestation of cutaneous depends on both the host immune response and the specie of Leishmania involved.…”

Primary Amyloidosis(A Rare Disorder): Clearing Myths and Fallacies

“…It is a clonal disorder characterised by the deposition of the insoluble fibrillar AL amyloid protein in organs resulting in their dysfunction [1,2]. When the composition of these fibrils consists of the precursor serum amyloid A protein (persistently elevated in response to a chronic inflammatory stimulus) it is labelled as secondary or AA amyloidosis [3] and is the second most common type of amyloidosis. A relatively rare type of amyloidosis called LECT2 -where the protein is leucocyte chemotactic factor protein is the fibril precursor -is the third most common amyloid type in northern India [3].…”

“…When the composition of these fibrils consists of the precursor serum amyloid A protein (persistently elevated in response to a chronic inflammatory stimulus) it is labelled as secondary or AA amyloidosis [3] and is the second most common type of amyloidosis. A relatively rare type of amyloidosis called LECT2 -where the protein is leucocyte chemotactic factor protein is the fibril precursor -is the third most common amyloid type in northern India [3]. Congo red staining with exhibition of an apple-green birefringence is the gold standard for a histopathologic diagnosis of amyloidosis [4].…”