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Evolutionary origin of autoreactive determinants (autogens).

T Kieber-Emmons, H Kohler

    Proceedings of the National Academy of Sciences of the United States of America
    |April 1, 1986
    PubMed
    Summary
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    This study investigates if the immune system randomly targets self proteins or selectively reacts to specific sites. It introduces a new method to identify "autogens," protein regions prone to autoimmune reactions.

    Area of Science:

    • Immunology
    • Molecular Biology
    • Biochemistry

    Background:

    • The immune system's response to self-antigens, like cytochrome c and lysozyme, is complex.
    • Previous research suggested a link between autoreactive regions and evolutionary instability in proteins.

    Purpose of the Study:

    • To determine if autoantibody production is random or selective for specific protein determinants.
    • To develop a refined method for identifying protein regions prone to autoimmune reactions.

    Main Methods:

    • Analysis of evolutionary sequence variation, distinguishing between surface-altering and surface-neutral substitutions.
    • Development of a quantitative algorithm incorporating "surface consensus" to rank autoantigenic determinants.
    • Generation of a "surface variability" plot to map regions with autoimmune reactivity.

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    Main Results:

    • A refined approach to analyzing protein sequence variation provides a more accurate prediction of autoantigenic sites.
    • The study identifies specific protein determinants, termed "autogens," that are preferentially targeted by autoimmune responses.
    • The findings challenge the notion of random autoantibody production, suggesting a selective process.

    Conclusions:

    • Autoimmune reactions are not random but are directed towards specific protein determinants ("autogens").
    • The "surface variability" plot is a valuable tool for predicting regions of a protein likely to elicit autoimmune responses.
    • This research offers new insights into the mechanisms underlying autoimmunity and self-tolerance.