Proteolytic Cleavage of a Self-Antigen Following Xenobiotic-Induced Cell Death Produces a Fragment with Novel Immunogenic Properties

Abstract

The heavy metal mercury elicits a genetically restricted autoantibody response in mice that targets the nucleolar autoantigen fibrillarin. HgCl2-induced cell death of macrophages resulted in the proteolytic cleavage of fibrillarin. A prominent feature of mercury-induced cell death was the generation of a 19-kDa fragment of fibrillarin that was not found following apoptotic or nonapoptotic cell death induced by stimuli other than mercury. Proteolysis of fibrillarin lacking cysteines, and therefore unable to bind mercury, also produced the 19-kDa fragment, suggesting that a mercury-fibrillarin interaction was not necessary for the unique cleavage pattern of this self-Ag. In contrast to immunization with full-length fibrillarin, the 19-kDa fragment produced anti-fibrillarin Abs with some of the properties of the HgCl2-induced anti-fibrillarin response. We propose that cell death following exposure to an autoimmunity-inducing xenobiotic can lead to the generation of novel protein fragments that may serve as sources of antigenic determinants for self-reactive T lymphocytes.

Exposure to inorganic mercury in vivo attenuates extrinsic apoptotic signaling in Staphylococcal aureus enterotoxin B stimulated T-cells

“…Additionally, the heavy metals gold and mercury (Hg) have been implicated in metal-induced autoimmune disease in humans (Verwilghen et al, 1992;Bagenstose et al, 1999;te Boekhorst et al, 1999). Hg in particular has been demonstrated to play a significant role in the initiation and progression of autoimmune disease in animal models (Monestier et al, 1994;Hultman et al, 1995;Takeuchi et al, 1995;Hultman et al, 1996;Pollard et al, 1997;Bagenstose et al, 1999;Pollard et al, 2000). In these models, MHC as well as non-MHC genes have been identified as susceptibility factors for Hg-induced autoimmunity (HgIA).…”

Autoimmune Diseases: The Role of Environment and Gene Interactions

“…This means that identification of potential SLE susceptibility loci in humans offers the chance to compare data from murine models of SLE induced by xenobiotics such as mercury. Mercury-induced cell death (MeICD) is processed through proteolytic breakdown of fibrillarin, a 34kDa MWt macrophage degradable protein component of small nucleolarribonucleoprotein particles (snRNPs); the generation of a unique (19kDa) proteolytic fragment required no preinteraction between mercury and fibrillarin (Pollard et al, 1997(Pollard et al, , 2002 (Pollard et al, 1997(Pollard et al, , 2002. This finding endorses a longstanding belief that SLEprone patients could generate self-autoantibodies spontaneously even without any physical presence of observable inducers of auto-antigens.…”

“…These strains of animals do develop lupus-like disease that imitate closely a simplified version of human systemic lupus erythematous (SLE), with the production of autoantibodies and the subsequent development of immune-complex mediated glomerulonephritis (Theofilopoulos et al, 1985). The general consensus is that the dose of mercury, duration of exposure as well as the genetic background of the exposed animal (Hanley et al, 2002;Hultman et al, 1992Hultman et al, , 1993Jiang and Möller, 1995;Kono et al, 1998;Pollard et al, 2002) contributes to disease outcome. The H-2 haplotype plays important role in the specificity of resulting autoantibody as well as susceptibility to immune complex generation; but there is a role for involvement of non-MHC genes in MeIA susceptibility also.…”

“…The process involves the antinuclear autoantibody, (AnoA Abs) response directed against fibrillarin. The AnoA Abs response directed against fibrillarin is one of the most representative manifestations of MeIA that is linked to H-2 s (Hanley et al, 2002;Hultman et al, 1992;Hultman et al, 1993;Pollard et al, 2002) and, more specifically, to the class II I-A s molecule, by analysis of H-2 congenic mice (Pollard et al, 2002) and is described below. The discovery of potential SLE inducibility on mercury exposure in humans offers the opportunity for comparison with data from murine models of SLE.…”

“…This finding endorses a longstanding belief that SLEprone patients could generate self-autoantibodies spontaneously even without any physical presence of observable inducers of auto-antigens. Cell demise through MeICD was found to be mediated through both nonapoptotic and apoptotic protease activities but the processing pathway of fibrillarin was different enough to suggest the action of different proteases (Casiano et al, 1996;Pollard et al, 1997Pollard et al, , 2002. It was surmised that the cleavage patterns for a number of auto-antigens must differ between non-apoptosis (HgCl 2 , heat, ethanol) and apoptosis (anti-Fas) induced cell death (Casiola-Rosen et al, 1995;Pollard et al, 1997).…”