What is it about?
Kim et al reported lower levels of the key polyamines, spermine and spermidine and acetylated forms in lupus patients. Polyamines have important roles in many cellular processes such as replication, transcription and ribonucleoprotein (RNP) assembly. Polyamines are critical in the nucleolar assembly of RNPs but altered levels could interfere with proper assembly and leave some RNPs incomplete or in abnormal conformations that provoke an autoimmune response. Many of the autoantigens in lupus are, at least transient, components of the nucleolus. The nucleolus under stress could also disrupt neighboring heterochromatin, including the inactive X chromosome (Barr body) leading to reactivation of genes including polyamine genes involved in polyamine synthesis and recycling. Wasteful synthesis and recycling of polyamines would lower S-adenosylmethionine (SAM) needed for DNA methylation and would eventually lower the key polyamines, thereby interfering with other functions that depend on polyamines. This is part of the "X chromosome-nucleolus nexus" hypothesis.
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Why is it important?
If we understand what the initial steps are in creation of autoantigens, then we can work towards preventing the worst of the autoimmune disease, rather than simply trying to suppress symptoms by trying to suppress autoantibodies. Understanding how stress can lead to disruption of the nucleolus and the inactive X chromosome (and other heterochromatin) can show us therapeutic targets, such as suppressing viral stress (e.g. EBV) that can overly stimulate the nucleolus.
Perspectives
Slowly autoimmune researchers are discovering the importance of epigenetics in autoimmune diseases and are realizing that there may not be a simple genetic explanation with a single "lupus gene" that they can point to as being mutated. The "X chromosome-nucleolus nexus" hypothesis explains most of the steps in the origination of abnormal material that is interpreted as autoantigens in their abnormal form and later, through epitope spreading to normal sections of the RNP, provokes a broader autoimmune response to the RNP in its normal form. The "X chromosome-nucleolus nexus" hypothesis explains how the stressed nucleolus can disrupt the inactive X chromosome and then, with some reactivation, gene products from previously sequestered alleles on the X can disrupt the nucleolus, leading to nucleolar fragmentation and inefficiency, even termination, of nucleolar RNP production. Consider that nucleolin, splicing components, ribosome components, centromere components, Ro and La are major autoantigens and they all are created and/or active in the nucleolus.
Dr Wesley H Brooks
University of South Florida
Read the Original
This page is a summary of: The mysterious polyamines, the enigmatic Barr body, and lupus: comment on the article by Kim et al., Lupus, February 2018, SAGE Publications,
DOI: 10.1177/0961203318757929.
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