The self antigen heme evades immune recognition by sequestration in some hemoproteins

Authors

  • Robyn M. Sutherland,

    1. Department of Microbiology, University of Pennsylvania, Philadelphia, USA
    Current affiliation:
    1. Department of Veterinary Pathology, University of Sydney, Sydney NSW 2006, Australia
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  • Stephen Brassell,

    1. Department of Microbiology, University of Pennsylvania, Philadelphia, USA
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  • Qiang Liu,

    1. Department of Microbiology, University of Pennsylvania, Philadelphia, USA
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  • Yvonne Paterson

    Corresponding author
    1. Department of Microbiology, University of Pennsylvania, Philadelphia, USA
    • Department of Microbiology, 209 Johnson Pavilion, University of Pennsylvania, Philadelphia, PA 19104-6076, USA (Fax: 2 15-898-9557)
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Abstract

Heme is a non-protein autoantigen which is ubiquitous in vivo, primarily complexed in various hemoproteins or bound to specialized carrier molecules. Nevertheless, heme is able to stimulate a high frequency of CD4+, class II-restricted T cells, freshly explanted from unprimed mice, to proliferate in vitro. In this study, we show that heme incorporated into various species of mammalian cytochrome c (cyt c), including murine cyt c, represents a facultative cryptic determinant, able to be recalled only at high doses of native cyt c. By contrast, avian cyt c is of comparable antigenicity to free heme. Artificially denatured carboxymethylated (CM) mammalian cyt c exhibited greatly increased antigenicity, comparable to that of heme and avian cyt c, indicating that the crypticity of heme in native mammalian cyt c is due to the resistance of the native conformation of this molecule to antigen processing within murine antigen-presenting cells. Thus, tolerance to the heme group of at least some hemoproteins, may be maintained by the crypticity of the heme, rather than by deletion of hemereactive T cells. Given the high frequency of heme-reactive T cells in unprimed mice, these findings suggest that heme may become an important modulator during an inflammatory response.

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