ABSTRACT
Evidence shows that tissue macrophages (MPhis), in mice undergoing AA amyloidosis, endocytose acute-phase humoral serum amyloid A (SAA) and traffic it to lysosomes where it is degraded. Incomplete degradation of SAA leads to intracellular nascent AA fibril formation. In vitro, cathepsin (Cat) B is known to generate amyloidogenic SAA derivatives, whereas Cat D generates non-amyloidogenic SAA derivatives, and interferon (IFN-gamma)-treated MPhis show selective increase in Cat B concentration, a factor conducive to AA amyloidogenesis. To understand the cumulative effect of these factors in AA amyloidosis, humoral levels of SAA, IFN-gamma, tumour necrosis factor (TNF-alpha) and granulocyte-macrophage colony-stimulating factor were determined in azocasein (AZC)-treated CD-1 mice. We correlated these responses with the spatio-temporal distribution of SAA, Cat B- and Cat D-immunoreactive splenic reticuloendothelial (RE) cells. AZC-treated CD-1 mice similar to that of A/J mice showed partial amyloid resistance; their peak humoral IFN-gamma and SAA responses overlapped during the pre-amyloid phase. Unexpectedly, Cat D immunoreactivity (IR), instead of Cat B IR, was predominant in the splenic RE cells, indicating an apparent lack of causal relationship between IFN-gamma-mediated increase in Cat B expression. Partial amyloid resistance in CD-1 mice, probably a genetic trait, may be linked to high levels of Cat D expression, causing a delay in nascent AA fibril formation.
