Autoimmune disorders result from loss of epigenetic control following chromosome damage
Introduction
Most research on multiple sclerosis (MS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) has focused on identifying a specific genetic basis for each of the diseases. In addition, since there is an autoimmune component to these diseases, they have been viewed as originating primarily from malfunctions of the immune system. However, since: (1) no definitive genetic pattern has been discovered to explain the origin of any of these diseases; (2) the autoimmune response is often focused in lesions; and (3) the appearance of lesions (such as seen in MS [1]) can precede a local immune response, we should consider other possibilities for the cause(s) of these diseases, in addition to the genetic and immune system aspects. The possibility that these diseases result from epigenetic events and that those events originate outside of the immune system should be considered.
The common features of MS, SLE, and RA suggest the possibility of similar mechanisms. They may, in fact, have the same mechanism but have different consequences based on the cell type(s) in which the mechanism occurs. Previously, a hypothesis was presented that described these diseases as based on epigenetic, autoantigen-driven events [2], [3], [4]. That hypothesis described how the autoantigens could originate following chromatin disruption but that hypothesis did not give details on how the chromatin disruption occurs. Here, an expansion of the hypothesis will describe the earlier events of the chromatin disruption.
Section snippets
The hypothesis
Chromosome damage can lead to a loss of epigenetic control, especially when the chromatin is distributed unevenly to daughter cells. Overexpression of the underlying genes can interfere with tissue-specific processes, generate autoantigenic complexes, and induce apoptosis.
Genetics versus epigenetics
‘Genetic changes’ refers to irreversible alterations in the DNA sequence of a gene or the gene’s promoter so that there are permanent changes in the expression of the protein that can be generated from that gene. Mutations, insertions, and deletions of DNA are considered genetic changes. These changes can lead to permanent alterations in the transcription rate of the gene or alterations in the amino acids incorporated into the protein, so that the normal activity of the protein is changed or
X chromosome inactivation
Normal human female cells have two X chromosomes whereas male cells have only one. A majority of genes on the X, however, are not sex-specific and, therefore, should have equivalent expression in males and females. This equilibration, or dosage compensation, is maintained by inactivating one X chromosome in each female cell [5]. The inactive X, or Xi, has several distinct features relative to other chromatin including: late replication and packaging in the cell cycle; extensive methylation in
The problem
DNA aberrations (e.g. insertions, deletions, or breaks) could interfere with X inactivation of genes located on the other side of the aberration from the XIC. Those genes could then become reactivated in daughter cells, resulting in a loss of epigenetic control, also referred to as a loss of dosage compensation (LODC). The X chromosome has numerous sites particularly susceptible to breakage [6]. Increased rates of chromosome abnormalities, a majority apparently originating from the X, have been
Polyamines
The polyamines: putrescine (+2 charge), spermidine (+3 charge), and spermine (+4 charge), are ubiquitous polycations with numerous interactions in the cell [9]. Many agents, including estrogen, UV light, and viral infection, can induce polyamine synthesis. Polyamine synthesis begins with conversion of ornithine (derived from arginine) to putrescine by ornithine decarboxylase (ODC) (Fig. 4). Putrescine is then converted to spermidine by spermidine synthase (SpdS) using decarboxylated S
The consequences
Increased spermine levels can have numerous effects in the cell and surrounding tissues. Increased spermine can interfere with Ca2+ and K+ channels in cell membranes, disrupting signal flow through neurons or disrupting bone formation by osteocytes [10], [11]. This would also alter the ionic milieu surrounding chromatin. Spermine can stabilize Z-DNA, altering chromatin and modulating gene expression. Spermine can modulate chromatin binding by receptors, including the vitamin D and estrogen
The autoimmune reaction
Disruption of the chromatin by chromosome breaks, possibly accompanied by overexpression of polyamines, could lead to autoantigen formation as described previously [2], [3], [4]. For example, the chromatin disruption in the X chromosome and elsewhere resulting from chromosome breaks and interference with chromatin epigenetic patterns could open other genes and pseudogenes to overexpression, such as Alu and LINE L1 sequences, leading to abnormal RNA polymerase III activity and even endogenous
Support for the hypothesis
The mechanism described here fits with the female predominance among autoimmune disorders. Males with Klinefelter’s syndrome (XXY) would also be susceptible since they have an Xi. Autoimmune disorders in XY males resulting from this mechanism could occur due to X chromosome breakage followed by a failure of that fragment to migrate with the X from which it originated (Fig. 2). The hypothesis also fits with a recent report that cell damage in MS initiates before any local autoimmune reaction [1].
Setting the stage for the disorder
The polyamines could have a critical role in early events leading to the chromosome damage that develops into LODC problems. Polyamines protect DNA by serving as free radical scavengers. It is important that polyamine expression levels are established at sufficiently high levels early in life, otherwise DNA damage may occur and remain undetected. Since polyamine synthesis can be induced by UV-B light, regular exposure to sunlight in pre-adults is important. Sunlight during youth can stimulate
Testing the hypothesis
The mechanism described here would occur in only a few cells at a time so it is difficult to observe. It may require several cell generations between the initial damage and the subsequent loss of epigenetic control of fragments. It is also difficult to observe a distinct pattern for the mechanism since there are numerous fragile sites throughout the genome where chromosome fragmentation could occur. Breaks at different sites and on different chromosomes would lead to different patterns of loss
Conclusions
This hypothesis can be divided into three sections: (1) the initial chromatin damage with repair problems; (2) the subsequent chromatin disruption, loss of epigenetic control, and tissue specific consequences; and (3) the development of autoantigens and an autoimmune reaction. The previous description of the hypothesis dealt primarily with the development of the autoantigens [2], [3], [4]. That work is still valid. This present work gives more detail to the earlier events leading up to the
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