X chromosome reactivation perturbs intracellular self/not-self discrimination
[by increasing aggregation pressure so predisposing females to autoimmune disease]
[This latter part of the title was too long for ICB and so had to be omitted from
the final paper]
Donald R. Forsdyke
and Cell Biology (2009)
New reports indicate a chromosomal rather than hormonal basis for the susceptibility of females to autoimmune disease. It is held that if females reactivate an inactivated X chromosome there will be overexpression of certain X-located genes affecting immune function. Hence, normal mechanisms of self/not-self discrimination might be impaired resulting in immune reaction to self antigens.
However, the data are also consistent with the long-held view that the demands of intracellular self/not-self discrimination have driven the evolution of X-chromosome dosage compensation. It was proposed that, whether cells are in male or female bodies, concentrations of proteins are fine-tuned up to their aggregation thresholds. A disruption of this equilibrium, by agents originating either externally (e.g. virus) or internally (e.g. reactivated X chromosome), generates homoaggregates that trigger responses against the respective not-self or self antigens.
Thus female susceptibility to autoimmune disease may not be because certain immune system genes happen to be X-located, but because self/not-self discrimination was the raison d'etre for X chromosome dosage compensation in the first place.
Keywords: autoimmunity; dosage compensation; double-stranded RNA; protein aggregation; systemic lupus erythematosus; X chromosome
X CHROMOSOME DOSAGE COMPENSATION
REACTIVATION OF THE INACTIVE X CHROMOSOME
INTRACELLULAR SELF/NOT-SELF DISCRIMINATION