Epigenetics and complementary proteins.

Although studies on the immunopathogenesis of anti-neutrophil cytoplasm antibody (ANCA) vasculitis have been directed at understanding the autoantibody, there is growing evidence that points to the importance of ANCA autoantigen genes and their regulation. Transcriptional analysis indicates that ANCA autoantigen genes are active in mature neutrophils of ANCA vasculitis patients compared to healthy controls. The unusual transcriptional state of neutrophils from ANCA vasculitis patients appears to be a consequence of failed or disrupted epigenetic silencing. Defective epigenetic silencing could have global effects, by altering the transcriptional and phenotypic state of neutrophils, or local effects by permitting transcription of autoantigen genes from both strands resulting in anti-sense transcripts. Although the role of anti-sense transcripts is currently unknown, there are two intriguing possibilities. Anti-sense transcripts could function (as described for other genes) in transcriptional silencing of autoantigen genes, which takes place in normal neutrophil progenitors. In the setting of failed epigenetic silencing, the fate of anti-sense transcripts may be pathological and serve as a template for production of complementary autoantigens. The observation that ANCA vasculitis patients have anti-sense transcripts and antibodies to complementary proteins is consistent with a role of anti-sense transcripts in complementary protein production. A better understanding of epigenetic silencing and complementary proteins in ANCA vasculitis may unlock the underlying pathology of this condition.