Amyloid protein A (AA) amyloidosis is a consequence of some long-standing inf lammatory conditions, and subsequently, an N-terminal fragment of the acute phase protein serum AA forms ␤-sheet fibrils that are deposited in different tissues. It is unknown why only some individuals develop AA amyloidosis. In the mouse model, AA amyloidosis develops after Ϸ25 days of inf lammatory challenge. This lag phase can be shortened dramatically by administration of a small amount of amyloid extract containing an as yet undefined amyloid-enhancing factor. In the present study, we show that preformed amyloid-like fibrils made from short synthetic peptides corresponding to parts of several different amyloid fibril proteins exert amyloidogenic enhancing activity when given i.v. to mice at the induction of inf lammation. We followed i.v. administered, radiolabeled, heterologous, synthetic fibrils to the lung and to the perifollicular area in the spleen and found that new AA-amyloid fibrils developed on these preformed fibrils. Our findings thus show that preformed, synthetic, amyloid-like fibrils have an in vivo nidus activity and that amyloid-enhancing activity may occur, at least in part, through this mechanism. Our findings also show that fibrils of a heterologous chemical nature exert amyloidenhancing activity.

Susceptibility to most autoimmune diseases is dependent on polygenic inheritance, environmental factors, and poorly defined stochastic events. One of the significant challenges facing autoimmune disease research is in identifying the specific events that trigger loss of tolerance and autoimmunity. Although many intrinsic factors, including age, sex, and genetics, contribute to autoimmunity, extrinsic factors such as drugs, chemicals, microbes, or other environmental factors can also act as important initiators. This review explores how certain extrinsic factors, namely drugs and chemicals, can promote the development of autoimmunity, focusing on a few better characterized agents that, in most instances, have been shown to produce autoimmune manifestations in human populations. Mechanisms of autoimmune disease induction are discussed in terms of research obtained using specific animal models. Although a number of different pathways have been delineated for drug/chemical-induced autoimmunity some similarities do exist and a working model is proposed.

We have studied the effect of gender, genetics, and toxicokinetics on immune parameters in mercury-induced autoimmunity in mice. Data strongly suggest that the mechanism for mercury-induced autoimmunity involves modification of the autoantigen fibrillarin by mercury followed by a T-cell-dependent immune response driven by the modified fibrillarin. Mice with different H-2 haplotypes were treated with (203)HgCl(2) in a dose of 0.5-16 mg Hg/L drinking water for 10 weeks. Whole-body accumulation and renal accumulation of mercury were assessed. Serum antinuclear antibodies were used to evaluate the autoimmune response, and serum immunoglobulin E (IgE) to study effects on T-helper cells of type 2. Strains with a susceptible H-2 haplotype developed autoantibodies to the nucleolar protein fibrillarin (AFA) in a dose-dependent pattern within 2 weeks. The substantially lower whole-body and organ mercury level needed to induce AFA in the susceptible A.SW strain compared with the H-2 congenic B10.S strain demonstrates that genetic factors outside the H-2 region modify the autoimmune response. Mouse strains without the susceptible haplotype did not develop any autoimmune reaction irrespective of dose and organ deposition of mercury. In susceptible mouse strains, males and females had different thresholds for induction of autoimmune reactions. In susceptible strains, serum IgE increased dose dependently and reached a maximum after 1-2.5 weeks. A susceptible H-2 haplotype is therefore a prerequisite for the autoimmune response. Mercury exposure will modulate the response, qualitatively through the existence of dose-related thresholds for autoimmune response and quantitatively as increasing doses cause increasing autoimmune response. Further, gender and non-H-2 genes modulate both the induction and subsequent development of AFA. Induction of IgE seems not to be mechanistically linked to the AFA response.

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