As the weather gets cooler and winter begins to set in, we’re reminded that the immune system is our first line of defense against foreign pathogens and helps prevent us from getting sick. The immune system is comprised of different types of cells that are able to recognize and destroy disease-causing microbes, such as bacteria, viruses and parasites.
This advanced system has aided humans in fighting off intruders for thousands of years – and good thing, because no one likes to be stuck in bed all day with a cough and the sniffles. However, when the immune system is too active, it can mount a full attack on its own cells, wreaking havoc on the body and leading to an autoimmune disease. Epigenetic insights from recent studies might be able to guide us in combating this from happening for a range of autoimmune diseases.
Epigenetics and Autoimmune Disease
Approximately 1 in every 5 Americans has an autoimmune disease – that’s 20% of the entire population, according to American Autoimmune Related Diseases Association (AARDA). Autoimmune disorders are characterized as abnormal immune response in which the immune system is unable to distinguish between foreign invaders and its own cells and therefore begins attacking the very cells that work to protect the body. There are over 80 different autoimmune diseases and some of the most common include Type 1 diabetes, rheumatoid arthritis, lupus, inflammatory bowel disease, celiac, and multiple sclerosis.
Recent research has shown that unique epigenetic signatures, particular DNA methylation patterns, exist in different types of arthritis and even in different joints. DNA methylation is an epigenetic mechanism characterized by the addition of a methyl group onto DNA which suppresses the expression of genes. This could help explain why one targeted therapy for arthritis might work for knees but not for hips. Other studies have shown that a sugar known as beta-glucan might turn on an epigenetic “control switch” and restore immune cells in those with a compromised immune system.
Although the cause of autoimmune disorders is not known, these disorders tend to run in the family, which points to a genetic component. Previous studies have shown that genetics plays a role in an individual’s susceptibility or resistance to autoimmune diseases. Animal studies have also confirmed that exposure to certain environmental factors can either initiate or exacerbate the manifestation of an autoimmune disease.
Ultimately, scientists believe that autoimmune diseases are caused by interactions between genetics and environmental factors. Interestingly, in the study of epigenetics, environmental factors have been shown to affect gene expression. Examples of epigenetics include changes in DNA methylation as a result of environmental factors, such as smoking, air pollutants, and alcohol. Adjustments in methylation pattern and posttranslational modification are believed to trigger a range of immune responses.
Lupus: Inhibiting DNA Methyltransferases (DNMTs)
Systemic lupus erythematous (SLE) is the most common type of lupus and is characterized by the immune system attacking its own cells and tissue. Unlike other autoimmune disorders, lupus is a systemic disease that impacts various organs.
Patients with active SLE have decreased levels of total deoxymethylcytosine (dmC) and DNMT-1 (DNA Methyltransferase 1) transcriptase that causes an increase in gene expression and changes in epigenetic patterns of T lymphocytes, or T cells. This triggers the activation and antibody production in auto-reactive B-cells.
Studies have demonstrated that CD4+ T-cells treated with 5-azacytidine, a DNMT1 inhibitor, have become reversibly auto-reactive, suggesting that treatment with an agent that inhibits DNMT1 –and thereby inhibits DNA methylation – could help those suffering from SLE. This study provides insight into possible mechanisms that may be used in the future to treat systemic lupus erythematous.
Rheumatoid Arthritis: Epigenetic Marks on Synovial Fibroblasts
In rheumatoid arthritis (RA), the immune system mistakenly attacks the synovium, the lining of the membrane that surrounds joints, causing inflammation, swelling and joint pain. This inflammation leads to bone erosion, the destruction of the cartilage, and loosening of tendons and ligaments which results in loss of joint alignment.
Recent studies have demonstrated that altered methylation patterns of RA synovial fibroblasts, RASF, are critical for the onset of rheumatoid arthritis. Synovial fibroblasts are a very unique cell type characterized by a round, large pale nucleus with prominent nucleoli. Their activation seems to play a critical role in rheumatoid arthritis. It has also been demonstrated that increased levels of polyamine-modulated factor 1-binding protein 1 (PMFBP1) and spermidine/spermine N1-acetyltransferase (SSAT-1) are contributing factors in the hypomethylation of RASF.
A recent mouse study has given light to a novel therapeutic approach in which diminazene acerturate, an inhibitor of SSAT-1, can be given to rheumatoid arthritis patients in order to prevent ongoing joint destruction. This epigenetic approach could help alleviate the pain and difficulties that a rheumatoid arthritis patient may experience through the progression of the disease.
Multiple Schlerosis: Harnessing HDAC Inhibitors
Multiple sclerosis (MS) is an autoimmune disorder in which the immune system attacks the central nervous system, resulting in chronic demyelination of neurons. During an immune response, T cells attack the myelin sheath that covers nerve fibers and either slow down or prevent nerve impulses from passing through the neuron’s axon.
Research has shown the citrullination of basic myelin protein by peptidyl arginine deiminase type2, PAD2, gene may cause the production of immunologically dominant peptides, synthesizing T cells and increasing the inflammatory response of MS. Epigenetic-based therapies performed on special mice that are modeled after MS, have shown that histone deacetylase (HDAC) inhibitors – such as vorinostat and valproic acid – reduce the inflammation and demyelination of the central nervous system.
Histone deacetylation is the process in which an acetyl group is removed from histones, whereas histone acetylation is the addition of an acetyl group. Histone acetylation affects chromatin structure by opening up the DNA and histones and increasing gene expression. On the other hand, histone deacetylation, activated by HDACs, close up the chromatin structure and reduce gene expression.
The vorinostat treatment inhibits Th1 and Th17 cells, while valproic acid shift Th1 and Th17 profiles resulting in the downregulation of pro-inflammatory cytokine transcripts. Both of these studies provide a promising approach for the treatment of MS through epigenetic-based therapies.
Numerous recent studies have demonstrated how epigenetic changes could explain the mechanisms in which B cells and T cells become overactive, leading to different autoimmune diseases. Research being performed on the epigenetic component on how these disorders manifest has led to the development of new epigenetic-based therapies that can alter DNA patterns and expression.
There are about 50 million people in the United States that are affected by autoimmune diseases. Current research provides new and promising treatments and medications for the millions of individuals who live with these disorders every day. Further studies are necessary to not only confirm the underlying mechanisms involved in these disorders, but also in different epigenetic methods that may be used as medication and treatments for the future.
Source: Ahmadi et al. (2017). Epigenetic modifications and epigenetic based medication implementation of autoimmune diseases. Biomedicine & Pharmacotherapy, 87:596-608.