Transgenic Mouse Model of AA Amyloidosis

Solomon, Alan; Weiss, Deborah; Schell, Maria; Hrncic, Rudi; Murphy, Charles L.; Wall, Jonathan S.; McGavin, M. D.; Pan, Hong Jun; Kabalka, George W.; Paulus, Michael J.

doi:10.1016/s0002-9440(10)65378-3

Cited by 71 publications

(67 citation statements)

References 26 publications

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“…Systemic AA amyloid deposition is always accompanied by increased SAA production, whether triggered by tissue damage, infection, or abnormal proinflammatory cytokine activity (26)(27)(28)(29)(30). The transgenic mice reported here allowed us to induce expression of the amyloidogenic mouse SAA isoform, SAA2, by oral administration of doxycycline, completely independently of any inflammatory stimulus.…”

Section: Discussionmentioning

confidence: 96%

Pathogenetic mechanisms of amyloid A amyloidosis

Simons

Al‐Shawi

Ellmerich

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Systemic amyloid A (AA) amyloidosis is a serious complication of chronic inflammation. Serum AA protein (SAA), an acute phase plasma protein, is deposited extracellularly as insoluble amyloid fibrils that damage tissue structure and function. Clinical AA amyloidosis is typically preceded by many years of active inflammation before presenting, most commonly with renal involvement. Using dose-dependent, doxycycline-inducible transgenic expression of SAA in mice, we show that AA amyloid deposition can occur independently of inflammation and that the time before amyloid deposition is determined by the circulating SAA concentration. High level SAA expression induced amyloidosis in all mice after a short, slightly variable delay. SAA was rapidly incorporated into amyloid, acutely reducing circulating SAA concentrations by up to 90%. Prolonged modest SAA overexpression occasionally produced amyloidosis after long delays and primed most mice for explosive amyloidosis when SAA production subsequently increased. Endogenous priming and bulk amyloid deposition are thus separable events, each sensitive to plasma SAA concentration. Amyloid deposits slowly regressed with restoration of normal SAA production after doxycycline withdrawal. Reinduction of SAA overproduction revealed that, following amyloid regression, all mice were primed, especially for rapid glomerular amyloid deposition leading to renal failure, closely resembling the rapid onset of renal failure in clinical AA amyloidosis following acute exacerbation of inflammation. Clinical AA amyloidosis rarely involves the heart, but amyloidotic SAA transgenic mice consistently had minor cardiac amyloid deposits, enabling us to extend to the heart the demonstrable efficacy of our unique antibody therapy for elimination of visceral amyloid.

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Section: Discussionmentioning

confidence: 96%

Pathogenetic mechanisms of amyloid A amyloidosis

Simons

Al‐Shawi

Ellmerich

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Section: Discussionmentioning

confidence: 99%

“…In contrast, in IL-6-transgenic mice, also engineered to express the transgene under control of a liver-specific promoter, i.e., metallothionein I (26), amyloid A amyloidosis is found in spleen, liver, and kidneys, including the mesangium, together with high levels of circulating SAA (27). On the other hand, NNT-1/BSF-3-transgenic mice show the presence in the mesangium of a peculiar type of fibrils of distinctive ultrastructure that has not been observed in IL-6-transgenic mice despite electron microscopic analysis (27). Intriguingly, the accumulation of fibrils and tubular structures in the glomeruli of NNT-1/BSF-3-transgenic mice is reminiscent of a group of rare glomerulopathies of unknown etiology described in patients with proteinuria and often the nephrotic syndrome and reported as fibrillary or immunotactoid glomerulopathies (17-20, 28, 29).…”

Section: Discussionmentioning

confidence: 99%

Regulatory Effects of Novel Neurotrophin-1/B Cell-Stimulating Factor-3 (Cardiotrophin-Like Cytokine) on B Cell Function

Senaldi

Stolina

Guo

et al. 2002

The Journal of Immunology

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We describe regulatory effects that a novel neurotrophin-1/B cell-stimulating factor-3 (NNT-1/BSF-3; also reported as cardiotrophin-like cytokine) has on B cell function. NNT-1/BSF-3 stimulates B cell proliferation and Ig production in vitro. NNT-1/BSF-3-transgenic mice, engineered to express NNT-1/BSF-3 in the liver under control of the apolipoprotein E promoter, show B cell hyperplasia with particular expansion of the mature follicular B cell subset in the spleen and the prominent presence of plasma cells. NNT-1/BSF-3-transgenic mice show high serum levels of IgM, IgE, IgG2b, IgG3, anti-dsDNA Abs, and serum amyloid A. NNT-1/BSF-3-transgenic mice also show non-amyloid mesangial deposits that contain IgM, IgG, and C3 and are characterized by a distinctive ultrastructure similar to that of immunotactoid glomerulopathy. NNT-1/BSF-3-transgenic mice produce high amounts of Ag-specific IgM, IgA, and IgE and low amounts of IgG2a and IgG3. Normal mice treated with NNT-1/BSF-3 also produce high amounts of Ag-specific IgE. NNT-1/BSF-3 regulates immunity by stimulating B cell function and Ab production, with preference for Th2 over Th1 Ig types.

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“…Mice carrying the hIL-6 gene under control of the mouse MT-1 or histocompatibility H 2 -L d promoter were obtained from Gennaro Ciliberto and Michael Potter, respectively, and generated as described previously (6). At 4 wk the mice were weaned, and the presence of the transgene was confirmed through analysis of genomic DNA derived from tail snips.…”

Section: Methodsmentioning

confidence: 99%

“…To determine whether amyloid-containing food products exhibit amyloid enhancing factor (AEF) activity, we used a more robust in vivo murine model of AA amyloidosis involving mice carrying the human IL-6 (hIL-6) gene under control of either the murine metallothionein-1 (MT-1) (MT-1/hIL-6) or histocompatibility H2-L d (H2/hIL-6) promoter (6). Typically, AA amyloid develops in these animals at Ϸ5 mo of age and is initially located predominately in the perifollicular regions of the spleen.…”

mentioning

confidence: 99%

Amyloidogenic potential of foie gras

Solomon

Richey

Murphy

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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103

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The human cerebral and systemic amyloidoses and prionassociated spongiform encephalopathies are acquired or inherited protein folding disorders in which normally soluble proteins or peptides are converted into fibrillar aggregates. This is a nucleation-dependent process that can be initiated or accelerated by fibril seeds formed from homologous or heterologous amyloidogenic precursors that serve as an amyloid enhancing factor (AEF) and has pathogenic significance in that disease may be transmitted by oral ingestion or parenteral administration of these conformationally altered components. Except for infected brain tissue, specific dietary sources of AEF have not been identified. Here we report that commercially available duck-or goose-derived foie gras contains birefringent congophilic fibrillar material composed of serum amyloid A-related protein that acted as a potent AEF in a transgenic murine model of secondary (amyloid A protein) amyloidosis. When such mice were injected with or fed amyloid extracted from foie gras, the animals developed extensive systemic pathological deposits. These experimental data provide evidence that an amyloid-containing food product hastened the development of amyloid protein A amyloidosis in a susceptible population. On this basis, we posit that this and perhaps other forms of amyloidosis may be transmissible, akin to the infectious nature of prion-related illnesses.amyloid protein A amyloidosis ͉ amyloid-enhancing factor ͉ protein aggregation ͉ rheumatoid arthritis ͉ transmissibility A myloid protein A amyloidosis (AA) occurs in patients with rheumatoid arthritis and other chronic inflammatory diseases and results from a sustained elevation of the apolipoprotein serum amyloid A (SAA) protein produced by hepatocytes under regulation by interleukin (IL)-1, IL-6, and tumor necrosis factor (1). This acute-phase reactant is cleaved into an Ϸ76-residue N-terminal fragment deposited as amyloid predominately in the kidneys, liver, and spleen. The disorder also can be induced experimentally in susceptible strains of mice by inflammatory stimuli that result in an Ͼ1,000-fold increase in SAA concentration (2). Further, the lag phase of this process is greatly decreased by injecting or feeding animals extracts of amyloidladen spleens of affected mice (2-5).To determine whether amyloid-containing food products exhibit amyloid enhancing factor (AEF) activity, we used a more robust in vivo murine model of AA amyloidosis involving mice carrying the human IL-6 (hIL-6) gene under control of either the murine metallothionein-1 (MT-1) (MT-1/hIL-6) or histocompatibility H2-L d (H2/hIL-6) promoter (6). Typically, AA amyloid develops in these animals at Ϸ5 mo of age and is initially located predominately in the perifollicular regions of the spleen. Over the next 2-3 mo, the deposits spread rapidly into the liver parenchyma, renal glomerular and intertubular regions, cardiac muscle, tongue, and gastrointestinal tract and lead to death at Ϸ8-9 mo. However, by injection into 8-wk-old transgenic mice of a ...

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Transgenic Mouse Model of AA Amyloidosis

Cited by 71 publications

References 26 publications

Pathogenetic mechanisms of amyloid A amyloidosis

Pathogenetic mechanisms of amyloid A amyloidosis

Regulatory Effects of Novel Neurotrophin-1/B Cell-Stimulating Factor-3 (Cardiotrophin-Like Cytokine) on B Cell Function

Amyloidogenic potential of foie gras

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