Over the past decade, controversy about whether ANCA is itself directly pathogenic has largely abated, primarily based on convincing animal models of small vessel vasculitis in mice and rats mediated by MPO ANCA. But as this issue is laid to rest, a new burning question has emerged in the field: if ANCA cause disease, what causes ANCA? Specifically, why are the ANCA antigens PR3 and MPO turned on in the neutrophils of ANCA patients, and not in their normally silenced state (as in healthy controls). This question hints at the regulation of gene expression itself, and brings us to the rapidly expanding field of epigenetics.
Epigenetics, the study of changes in phenotype and/or gene expression that are independent of the underlying DNA sequence, is one of the hottest areas of basic science research at the moment. Recently, the Jennette and Falk group in Chapel Hill examined whether high expression of the major auto antigens in ANCA patients, MPO and PR3, might have an epigenetic basis. The reason this is a good bet is that, although mature neutrophils from healthy subjects do not express MPO and PR3, these proteins are expressed in developing neutrophils. This suggests that there is transcriptional silencing of MPO and PR3 during development, which is the hallmark of epigenetic control.
They showed that levels of a specific histone methylation (H3K27me3) were reduced at the MPO and PR3 loci in ANCA neutrophils compared to those from healthy controls. H3K27me3 is associated with the formation of heterochromatin, which is inaccessible to transcription and often causes gene silencing. They went on to show that Jmjd3, the demethylase responsible for removing this particular histone methylation is upregulated in ANCA patients. This suggests that Jmjd3-mediated changes in histone methylation status may be responsible for aberrant expression of MPO and PR3 in mature ANCA neutrophils. This study throws up a number of areas for further research. For example, elucidation of what causes the initial failure of gene silencing mechanisms will give further insight into the pathogenesis of the disease, whilst insight into the pathways which both establish and maintain silence of MPO and PR3 in healthy patients may suggest new therapeutic approaches.
Thomas Oates MD