Autoimmune Disease: Does Sex Matter?

Current Theories

Michael D. Lockshin, MD
Michael D. Lockshin, MD
Attending Rheumatologist, Hospital for Special Surgery
Director, Barbara Volcker Center for Women and Rheumatic Disease

Introduction

Autoimmune rheumatic illnesses tend to affect women more often than they do men. Patients, physicians, and researchers ask why this is so. What are the correlations between gender (or, more precisely, sex) and rheumatic disease?

For many years the best explanation to explain this female predominance has been the hormone theory: the thought that female hormones (estrogens – there are several forms) render women more susceptible to such diseases as systemic lupus erythematosus (lupus), Sjogren's syndrome and rheumatoid arthritis. Recent research offers other possible explanations. Current possible explanations include:

  1. Hormone theory
  2. Environmental factors
  3. Genetic influences
  4. Whole-organism factors.

The discussion of these causes is somewhat complicated by disagreements on the definition of autoimmune disease. Most physicians agree that the following are all autoimmune diseases:

  • systemic lupus erythematosus (lupus)
  • rheumatoid arthritis
  • Sjogren's syndrome
  • scleroderma
  • myositis
  • vasculitis
  • primary biliary cirrhosis
  • autoimmune hepatitis
  • Graves’ disease
  • Goodpasture's disease
  • autoimmune hemolytic anemia
  • idiopathic thrombocytopenic purpura
  • Hashimoto's thyroiditis.

Some (but not all) physicians include the following on this list:

  • ankylosing spondylitis
  • reactive arthritis (sometimes called Reiter’s syndrome)
  • chronic Lyme disease
  • pemphigus
  • vitiligo
  • myasthenia gravis
  • multiple sclerosis
  • juvenile onset (type 1) diabetes.

Still other physicians include illnesses that have biological features similar to those in autoimmune diseases but which are not usually thought of as autoimmune diseases, such as ulcerative colitis and Crohn’s disease.

Current Theories of Sex Predominance

Hormone Theory

Hormone theory refers to the belief that high levels of estrogen increase women’s risk to develop autoimmune disease (or that the testosterone in males reduces their risk). Scientific data from mice and humans indicate that estrogen increases immune responses measured in many different ways. This supports the concept that the female predominance in lupus and other autoimmune rheumatic diseases is caused by the immune system overreacting to the body's own tissues more often in women than in men.

A problem with this analysis, however, is that the female-to-male ratio varies greatly, depending on which disease is analyzed. In lupus and Hashimoto's thyroiditis the ratio is 9 to 1, but in scleroderma and rheumatoid arthritis it is only 2 to 1. The ratio is also 2 to 1 in some other autoimmune diseases, such as autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura, which are both very similar to lupus. Conversely, in Goodpasture's syndrome (in which the body creates antibodies that attack the lungs and kidneys in a manner very similar to what happens in lupus) it is males that predominate, with a ratio of 3 to 1.

In addition, one might expect that, if estrogen were the main factor driving disease, the severity as well as the frequency of the illness would be greater in women. But this is not the case. In fact, according to some researchers, males with autoimmune diseases have more severe cases than their female counterparts. Women do appear to respond more vigorously to immunizations (experiencing higher production of antibodies production), but it is unknown whether this is related to their being more susceptible to autoimmune diseases. Estrogen levels change during the menstrual cycle, during pregnancy (in which estrogen levels are extremely high), and with menopause, but disease severity varies little, if at all, during the menstrual cycle. Pregnancy does not exacerbate lupus. Birth control pills before menopause or hormone replacement therapy after (both of which affect estrogen levels) do not change the course of lupus.

For all these reasons, it is unlikely that estrogen is the most important cause of the sex discrepancy of autoimmune illness.

Environmental Factors

Some autoimmune diseases appear to be caused by exposure to external toxins, such as medications or environmental pollutants. Scleroderma, for example, once occurred at unusually high frequency among male gold and coal miners. This circumstance was attributed to their exposure to silica. After better protections against silica were devised, this unusual frequency of scleroderma in males disappeared. Drug-induced lupus was common illness in the 1960s and 1970s, usually induced by medications used to treat high blood pressure and abnormal heart rhythms. Drug-induced lupus occurred mostly in men, because they were the ones who were most likely to receive the causative drugs.

In the 1970s, in Spain, an epidemic of scleroderma-like disease affected 10,000 people, almost all of whom were women. The cause of the epidemic was contamination of a commonly used brand of cooking oil. The reason for this sex difference appears to be that, while both men and women ate the food cooked with the contaminated oil, more women tasted the food as it was cooking, before heat destroyed the contaminant. Fully cooked food was not harmful.

Another example is an epidemic of scleroderma that occurred in men who manufacture polyvinyl chloride (PVC, a common plastic used in many products). To make PVC, a slurry of single (called monomeric) vinyl chloride molecules is heated to a very high temperature in large vats, whereupon the monomeric pieces fuse together to become polyvinyl chloride. The men who cleaned the vats inhaled the residual monomeric vinyl chloride that was still in the air and developed scleroderma. The manufacturing process was changed and the epidemic ended.

In a specific river area of Brazil, an autoimmune skin disease called pemphigus foliaceus is associated with bites of a black fly that lives near the river. Men who fish this river are more likely to develop the disease than are women, who do not go near the river; elsewhere in the world, pemphigus foliaceus is primarily found in women.

Recently, scientists have started looking at a different kind of environmental factor – the microbiome – as a possible cause for sex discrepancy. The term “microbiome” describes the families of bacteria that live on all normal healthy people – in their mouths, on their skins, in their intestines and (in women) in their vaginas. Men and women differ in their microbiomes, and specific microbiome patterns are associated with specific illnesses. Details of how and why these associations occur are not yet known. Future studies may find that differences in male and female microbiomes are related to sex ratios of autoimmune illnesses.

The above examples support the idea that the different environmental exposures of the sexes may determine who develops autoimmune illnesses, but we do not yet have a smoking gun. Semi-seriously, researchers have even considered whether exposure to hair dye or lipstick might explain the differences, but to date there is no single cause-and-effect link.

Finally, behavior can influence development of disease. Examples include osteoporosis (which develops more frequently in people who do not exercise), atherosclerosis (which is affected by diet and cholesterol), and injury-related osteoarthritis (for which competitive athletes have an increased risk). Diseases associated with venereal infection do not occur in those who have not been exposed. However, there is no known no specific behavior that is associated with any autoimmune disease.

Genetic Influences

Genetic differences, specifically those related to the X (female) chromosome, constitute another potential explanation for sex differences in illness. (Except for rare circumstances, women have two X chromosomes – one from each parent: Men have one X chromosome [from the mother] and one Y chromosome [from the father].) Every cell in every man's body is different from every cell in every woman's because of the X chromosome.

Women who have been pregnant carry their baby's cells in their bloodstream for years after the pregnancy ends – even in cases of miscarriage – a circumstance called microchimerism. In normal women, the number of fetal cells in their bloodstreams decreases after birth. In women with autoimmune diseases, the cells continue at higher numbers for a much longer period of time, sometimes many decades. Diseases characterized by high levels of microchimeric cells include scleroderma, primary biliary cirrhosis, Sjogren's syndrome, and autoimmune thyroid disease. In women who have thyroid nodules and who have been pregnant with male children, the cells within the nodules are often male (from the fetus), while the normal part of the thyroid is made up of female cells (the mother’s own). Women who breastfeed pass their own cells to their children, and sometimes the child’s cells pass backward through the breast to the mother. Some, but not all, researchers think microchimerism may be related to autoimmune disease but, as fascinating as this information is, scientists have not yet figured out its significance.

A new field, called epigenetics, offers a different kind of insight. Epigenetic science states that it is not a gene’s presence that is important, but how active that gene is. In other words, genes do not work exclusively in an off/on mode, but they produce their products, usually a protein, in varying amounts, with those variations being controlled by a variety of influences on the gene.

The most direct of these influences is what is called the “silencing” of one X chromosome in women. Chromosomes are made up of long strings of individual genes. Because women have two X chromosomes, the genes of one of the X chromosomes must be shut off or “silences”, so that a woman does not make twice the amount of protein as does a man. This silencing process fails in about 15% of the genes, and in a somewhat random way, so every woman is different. In the 15% of body processes controlled by genes which are not silenced, each individual woman will have either (a) twice as much gene activity as do men with the same gene or (b) active versions of both her father’s version of the gene and her mother’s version of the gene. Gene silencing patterns can even be different between two female identical twins.

There is also a different way in which epigenetics may work. In some cases, an X-chromosome gene that is not correctly silenced may sometimes govern the activity of genes on other (non-X) chromosomes. There is now strong evidence that X-chromosome-controlled epigenetic activation of some genes associated with abnormal inflammation is closely associated with such diseases as lupus.

Finally, if this were not confusing enough, epigenetic gene activation can be altered by some external factors, including diet and medications. There is even evidence that what a pregnant woman eats can affect how her baby’s immune system will respond in future life – and that the effect will be different for baby boys than for baby girls!

Whole-organism Issues

Whole-organism issues – things that have nothing directly to do with sex or genes – may also be a part of the picture.

For example, osteoporosis is, in part, dictated by body size. Very heavy people are less likely to develop osteoporosis than are very thin people because their bones must become stronger to support the extra weight. In addition, since the disease depends in part on how big the bones are, among heavier persons, taller people (who have larger bones) are less likely to develop osteoporosis than shorter people.

Other examples of whole-organism issues in disease: The likelihood of a woman developing breast cancer may be influenced by how many children she has, and Alzheimer's disease is linked with aging. (Some researchers think that autoimmune disease reflects premature aging of the immune system.) Of course, all of these things can be influenced by heritage, environment and many other events. The influence of whole-organism issues in autoimmune disease is weighed based on such multifactors, not just a single component.

Many researchers think that autoimmune illness begins long before it causes symptoms and that, someday, we will be able to detect the disease by blood tests long before a patient experiences the first symptom. If and when this happens, it is likely we will then begin looking at very different potential causes of autoimmune illness – those occurring, perhaps, just before the time of the true onset of disease (as opposed to the onset of symptoms). Perhaps these new thoughts regarding the origins of autoimmune rheumatic diseases will explain sex differences in a completely unexpected way.

Conclusion

There are many possible ways to explain why more women suffer from autoimmune rheumatic diseases than do men. Reasons might include environment, hormones, behavior, genetic differences, a combination of some or all of these factors, or things we do not yet understand. Today the most accepted explanation for the female predominance of autoimmune rheumatic disease is the way the X chromosome controls genes related to inflammation and immunity. It is also likely that hormones modify disease processes in some way. We have not excluded – and some strange epidemics in fact suggest – that an environmental exposure is a contributing factor to disease development.

What we understand today about the sex differences of autoimmune disease is just the beginning of an ongoing investigation and discussion that may, in the future, lead to completely new ways of thinking about, diagnosing, and treating autoimmune disease.

Additional Reading

If you are interested in reading more about the relationship between sex and disease, you may be interested in the following sources.

Books for sophisticated but not technically expert readers

Exploring the Biological Contributions to Human Health: Does Sex Matter? This book compiles a vast range of writings on the role of sex in a range of diseases, not just autoimmune illnesses. It is available for purchase or for free in PDF form online at www.nap.edu/catalog/10028.html.

The X in Sex: How the X Chromosome Controls Our Lives by David Bainbridge. (ISBN-10: 0674010280 or ISBN-13: 978-0674010284)

Y: The Descent of Men by Steve Jones. (ISBN-10: 0618565612 or ISBN-13: 978-0618565610)

Recent, highly technical reviews

Rubtsova K, Marrack P, Rubtsov AV: TLR7, INFγ, and T-bet: their roles in the development of ABCs in female-based autoimmunity. Cell Immunol 2015 April; 294(2): 80-83.

Margery-Muir AA, Bundell C, Nelson D, McGroth DM, Wetherall JD. Gender balance in patients with systemic lupus erythematosus. Autoimmunity Reviews 2017;16: 258-268.

Klein SL, Flanagan KL. Sex differences in immune responses. Nature Rev Immunol 2016; 16:626-638. Doi: 10.1038/nri.2016.90

 

 

 

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