Km. Pollard et al., Proteolytic cleavage of a self-antigen following xenobiotic-induced cell death produces a fragment with novel immunogenic properties, J IMMUNOL, 165(4), 2000, pp. 2263-2270
The heavy metal mercury elicits a genetically restricted autoantibody respo
nse in mice that targets the nucleolar autoantigen fibrillarin, HgCl2-induc
ed cell death of macrophages resulted in the proteolytic cleavage of fibril
larin, 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. Proteoly
sis of fibrillarin lacking cysteines, and therefore unable to bind mercury,
also produced the 19-kDa fragment, suggesting that a mercury-fibrillarin i
nteraction was not necessary for the unique cleavage pattern of this self-A
g. In contrast to immunization with full-length fibrillarin, the 19-kDa fra
gment produced anti-fibrillarin Abs with some of the properties of the HgCl
2-induced anti-fibrillarin response. We propose that cell death following e
xposure to an autoimmunity-inducing xenobiotic can lead to the generation o
f novel protein fragments that may serve as sources of antigenic determinan
ts for self-reactive T lymphocytes.