Abstract
Currently, we have a limited understanding of mechanisms leading to systemic lupus erythematosus, but we know that genetics, environmental factors, and epigenetics contribute to the disease. One common aspect of the various environmental triggers is that they can cause cellular stress. When extraordinary stress occurs, such as viral activation, a cell’s response can include increased nucleolar volume and activity to produce more machinery (e.g., ribosomes) to help the cell recover. However, nucleolar expansion can disrupt the epigenetic control in neighboring heterochromatin that comprises the nucleolar shell. This disruption can open underlying vulnerabilities that provoke an autoimmune reaction. Here, we review the “X chromosome-nucleolus nexus” hypothesis, which explains how nucleolar stress can disrupt epigenetically silenced chromatin, especially the neighboring inactive X chromosome (aka the nucleolar satellite). Chromatin disruption can lead to the expression of sequestered DNA, such as Alu elements and fully functional LINE-1 reverse transcriptase genes. In addition, Alu transcripts can disrupt the nucleolar structural integrity, leading to nucleolar disintegration. Such disintegration can leave nucleolar components and products in autoantigenic forms, such as abnormal conformations or incomplete macromolecular assemblies. Recent research on DNA sensing pathways can now be incorporated into the hypothesis to provide further details explaining how autoantibodies to endogenous nucleic acids arise.
Highlights
The Complexity of Autoimmune DiseasesAutoimmune diseases, in which the immune system attacks one’s own body, are some of the most complex diseases confronting modern medical research since autoimmune diseases are multifactorial, presenting a broad array of triggers, symptoms, and autoantigens
Induction of SAT1 can provide an alternate route that creates putrescine to feed into polyamine synthesis to create even more spermidine and spermine, which would interfere with the overall epigenetic control of chromatin due to the competition for acetyl-CoA and SAM
In Xp22; 3) a functional “hot” LINE-1 element in Xp22; 4) spermine synthase (SMS) at Xp22.1, an enzyme involved in polyamine synthesis; and 5) spermidine/spermine N1 acetyltransferase (SAT1) at Xp22.1, an enzyme involved in polyamine recycling
Summary
Autoimmune diseases, in which the immune system attacks one’s own body, are some of the most complex diseases confronting modern medical research since autoimmune diseases are multifactorial, presenting a broad array of triggers, symptoms, and autoantigens. Other autoimmune diseases can target some of these same SLE-associated autoantigens Both SLE and RA can have autoantibodies targeting Z-DNA, a normally transient conformation of DNA with left-handed coiling of the DNA double helix as opposed to the predominant form, right-handed coiling B-DNA [10]. The slow appearance and variability of symptoms can delay a definitive diagnosis, which makes it difficult to assemble cohorts for clinical trials and for thoroughly defining characteristics of a specific autoimmune disease. For this discussion, we will focus on SLE, which is considered to be the prototypical autoimmune disease since SLE presents much of the breadth of symptoms and autoantigens seen in autoimmune diseases. Some new ideas are discussed that expand the hypothesis with regards to DNA sensing and autoantigenic nucleic acids
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