Lupus is complex!  Epigenetics is  a new frontier in lupus research and therapy that combines what we know about genetics with all of the environmental and lifestyle factors that can affect our health.  It may be the key to not only unlocking some of the mysteries of the disease, but also its cure!

• • Introduction
  • An Overview of Epigenetics
  • Epigenetics and Lupus
  • What does this mean for you?
  • In Conclusion

Introduction

We know that lupus is a very difficult disease to diagnose and treat.  It does not have an easily identifiable cause; it is unpredictable, and it can affect each person very differently. So, understanding and possibly curing lupus requires many approaches.  Until recently, the focus of research has been on two possible risk factors for developing lupus: genetics and environmental risk factors.

1. Genetics studies the unique set of genes that are coded in the DNA (deoxyribonucleic acid) of almost each cell of your body. We already know that some genes (at least 100 so far) have been shown to be related to lupus in some way, and that lupus can run in families. Yet, there is still no identifiable gene that causes lupus, and in the case of genetically “identical” twins, if one gets lupus, there is a 20% to 50% chance that the other will as well.
2. Environmental Factors relate to the external influences that can bring about the onset of the disease itself, as well as subsequent lupus flares. These include such triggers as exposure to sunlight (UV radiation), a person’s diet or use of tobacco and alcohol, medications, infections by viruses like Epstein-Barr, and even the amount of stress a person has in their life.  However, there is still no one particular environmental factor that can be seen as a cause for lupus in the same way that smoking has been shown to be a cause of lung cancer.

In the past, for most of medical research, these were the only two areas of study; these were the only two options to finding a cause or a cure.  Yet, now there is a third risk factor, and it as to do with the relationship between the environment and a person’s genes – epigenetics.

This third area of research makes the study of lupus more complicated, but also may provide a more practical path toward a true cure.  How?  Read on!

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An Overview of Epigenetics

The focus of epigenetics is to identify the molecular biology that takes place when a person’s environment affects how or whether their genes are turned on (expressed) or turned off (masked).  It is about the control switches for genes, not the genes themselves.

Even before DNA was discovered, it was known that characteristics were inherited from parents and somehow distributed to the various cells of the body. Yet, if cells had all of this information, how did each cell know which genes to use?  How did skin cells know not to act like brain cells?  In the 1940’s, the term “epigenetics,” meaning “beyond genetics,” was first used to describe this unknown and mysterious process.

Once the chemical structure of DNA was discovered in 1953 by James Watson, Francis Crick, (as well as Rosalind Franklin and Maurice Wilkins), scientists could study the molecular basis for genetics, and begin to discover how DNA might be guided and controlled.  These studies would become the molecular basis for epigenetics.

There are three important discoveries from the study of epigenetics.

1. Genes are turned on and off all of the time.

The cells of your body do not simply read your DNA like a blueprint and build whatever is coded in those genes.  There are all sorts of molecules that hide parts of the DNA, mask entire groups of genes, and they do so without actually changing any part of the DNA sequence itself.  This is why a skin cells and brain cells can have the same DNA in their chromosomes, but still look and function so differently.

This is called the regulation of gene expression. It is a very necessary process for every cell in the body to function appropriately.  However, it adds another level of complexity for the cell, and when something goes wrong, such as, perhaps with lupus, it can have very serious consequences.

Note:  If there is a change in the actual DNA sequence, it is called a mutation, and that is a separate issue with its own health implications.

2. Genes can be affected by the environment – they can be turned on and off by what you do and how you feel!

Epigenetic studies have shown that the environment can actually affect which genes are masked and which are not.  This is reflected in the fact that even “identical” twins are not truly identical.  As they grow, differences in their environments can make small or significant differences on how their genes are expressed – depending upon how differently they experience life.  For example, as you probably know, even genetically identical twins develop different fingerprints, but they can also develop different interests and personalities, and can also react very differently to diseases.  As mentioned earlier, more often than not, if one twin gets lupus, the actually other won’t.  So each twin’s environment can express or hide different genes.

This aspect of epigenetics is important to both medical researchers and sociologists alike.  Why?  As it turns out, an unhealthy environment can ”turn on” unhealthy genes that might never be expressed if the person lived in a healthy environment.  This has led to the discovery of what we know as social determinantsof health.  Socioeconomic status, poverty, homelessness and the stress that they cause can have significant, and statistically predictable effects on a person’s health.  This has lead to the observation that your likelihood of getting certain diseases has as much to do with your area code, as it does with your genetic code. Currently, this is a very important area of study for lupus and other autoimmune conditions.

3. Epigenetics can be inherited – genes can be turned on and off by how your parents lived!

There is mounting evidence that your epigenetics can actually be inherited from your parents – just like your genes. What does this mean?  It means that the affects of an unhealthy environment – pollution, stress, or unhealthy diet – can be transmitted from parents to children.  There is still a great deal of study that needs to be done, and it has not yet been shown to occur specifically with lupus.  However, it has been demonstrated that some social determinants of health have been shown pass on an increase in the likelihood of such health problems such as obesity and diabetes to children even before they are born and before they experience a life of poverty themselves.

Epigenetics and Lupus

So, what does this mean for lupus and autoimmunity?

Epigenetic studies suggest that all of us have the genes that might lead to creating autoantibodies and the inflammatory factors that are seen in lupus and other autoimmune conditions.  Yet, in healthy individuals, these genes are usually inhibited by special regulatory molecules – at least until they are needed to fight an infection.  The point is that the genes of our immune response are always in the state of being ready to go.  It is just that when we are in a normal, healthy state, our epigenetics is there to put the brakes on this immune response.  Research has shown that the B cells and the CD4+ helper T cells of patients with lupus have fewer of these regulatory molecules controlling those genes than most healthy individuals. These cells are particularly important because they produce many of the autoantibodies and inflammatory factors found in lupus.  Since, in lupus patients, these genes are not controlled, they are over-expressed, over-active and ready to create the damage that we find with lupus.

This understanding of epigenetics not only may provide answers to the underlying causes for lupus, but may also hold the key to future therapies. It is possible that the tools of epigenetics might be used to control the genes in T cells and B cells that are over-expressed, so that they don’t become a problem in the first place.  If that is possible, then many of the medications that are currently used by those with lupus – with their own side-effects – may not be needed.  That is the ultimate goal of epigenetic studies with lupus!

What can you do?

Simply stated, the lessons of epigenetics tell us to that unhealthy environments matter … and the best thing about epigenetic changes is that, unlike genetic ones, they are reversible!  So, here are things to consider:

1. Avoid exposing yourself to ultraviolet light; wear sunscreen and avoid tanning booths.
2. Avoid exposing yourself to toxins:  smoking, air pollution, pesticides, and phthalates that are found in some plastics.
3. Take care of viral infections, in particular Epstein-Barr virus, herpes, CMV and parvovirus.
4. Maintain good nutrition; avoid processed foods.
5. Manage your stress … as much as you can!

In Conclusion

Lupus is an autoimmune disease that has complex causes, very few effective therapies and no real cure.  Both the causes and the cures seem to be found in a combination of genetics with environmental factors and in the recently discovered mechanisms of the epigenetic control of genes.  The promise of the new field of epigenetics is in the ability to fundamentally control the expression of a person’s genes without having to actually change a person’s DNA sequence.  Unlike genetic diseases or changes, epigenetic changes are reversible!  The more we understand these fundamental processes, the more likely we are to come to truly effective ways to perhaps make lupus a thing of the past.

 

References

Choudhuri, S. (2011). From Waddington’s epigenetic landscape to small noncoding RNA: some important milestones in the history of epigenetics research. Toxicology Mechanisms & Methods, 21(4), 252–274. https://doi.org.proxy.lib.pdx.edu/10.3109/15376516.2011.559695

Harley, I.T., Kaufman, K.M., Langefeld, C.D., Harley, J.B., & Kelly, J.A. (2009). Genetic susceptibility to SLE: New insights from fine mapping and genome-wide association studies. National Review of Genetics,10(5), 285-290.

Miceli-Richard, C. (2015). Epigenetic and lupus. Joint Bone Spine, 82(2), 90-93.  https:doi-org//10.1016/j.jbspin.2014.03.004

Sestak, A.L., Fürnrohr, B.G., Harley, J.B., Merrill, J.T., & Namjou, B. (2011). The genetics of systemic lupus erythematosus and implications for targeted therapy. Annals of Rheumatic Diseases, 2011(70), i37-i43. https://doi.org10.1136/ard.2010.138057

Ulff-Moller, C.J., Svendsen, A.J., Viemose, L.N., Jacobsen, S. (2018). Concordance of autoimmune disease in a nationwide Danish systemic lupus erythematosus twin cohort. Seminars in Arthritis and Rheumatism, 47(4), 538-544. https://doi.org/10.1016/j.semarthrit.2017.06.007

Xiao, G. & Zuo, X. (2016). Epigenetics in systemic lupus erythematosus. Biomedical Reports, 2016(42), 135-139. Retrieved from doi: 10.3892/br.2015.556

Zouali, M. (2011). Epigenetics in lupus. The Year in Immunology, 1217(1), 154-165. https://doi.org/10.1111/j.1749-6632.2010.05831.x

 

Author: Greg Dardis, MS

Professor Dardis was formerly the Chair of the Science Department at Marylhurst University and is currently an Assistant Professor at Portland State University.  His focus has been human biology and physiology with an interest in autoimmunity.

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