Autoimmune disorders in women

PMC

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Why Women Are More Prone to Autoimmune Diseases

An estimated 75% of people with autoimmune diseases are female, according to the American Autoimmune Related Diseases Association. In the case of lupus, the gender difference is even more severe, as nine out of 10 of those afflicted are women.

What’s more, autoimmune diseases are among the leading causes of death and disability in girls and women 65 years of age and younger.

Asa Tivesten, MD, professor of medicine at Sahlgrenska Academy, Sweden, was part of a team of researchers who recently explored why women are more susceptible to these diseases, hoping to provide better treatment for the diseases in the future.

“We know testosterone reduces the number of B cells, a type of lymphocyte that releases harmful antibodies,” she says. “Our scientific question was we wanted to find out what the mechanism behind testosterone to the relation of the number of B cells in the spleen was. We wanted to understand what the connection actually looks like, mechanisms that have so far been unknown.”

The study, published in Nature Communications, provided findings on possible mechanisms behind gender differences in the occurrence of rheumatism and other autoimmune diseases.

Read: How Using DNA Banks Can Improve Autoimmune Disease Treatment

Tivesten and her research team began studying mice, as there are cell-specific knockouts and castration experiments where you take away the testes and thereby take away the testosterone production of the mouse. It next confirmed its results in a cohort of healthy men, studying blood samples from 128 males.

“We looked at the testosterone levels in these men and we defined a subpopulation of them as having low testosterone levels and we saw that those men with low testosterone levels had higher BAFF levels,” Tivesten says.

The data revealed that if you eliminate testosterone, you get more BAFF and thereby more B cells in the spleen because they survive to a greater extent. This recognition of a link between testosterone and BAFF is something that hasn’t been known before.

“What we have found is a physiological regulation, a hormone regulates an important factor in the immune system and that is actually physiology,” Tivesten says. “But the finding has implications for pathophysiology, we think, because BAFF is so tightly coupled to development of autoimmune disorders and especially SLE.”

BAFF inhibitors is the first drug that has become registered for SLE in more than 30 years, which Tivesten notes is an extremely long time without any new medications for this very serious disease. And yet in her clinic, these BAFF inhibitors have been a little bit of a disappointment and haven’t lived up to expectations.

“So, there has been a question of how well is BAFF coupled to autoimmune pathophysiology?” she says. “There was a very important paper in the New England Journal of Medicine last summer where they looked at genetic variations in the BAFF gene and they could see that people with genetic variants that resulted in higher BAFF levels are more prone to develop SLE and multiple sclerosis. I think those were the major diseases that could be coupled to BAFF.”

Additionally, the findings compare closely to a previous study showing that genetic variations in BAFF could be connected to the risk of diseases such as lupus.

“That’s why understanding how the body regulates the levels of BAFF is so important, so we’re able to continue to put the pieces together and try to understand which patients should have BAFF inhibitors and which should not,” Tivesten says. “Our study serves as a basis for further research on how the medicine can be used in a better way. I think this information is important for those that treat and form and design clinical studies with BAFF inhibitors and it will be interesting to see if the findings will lead to any new study schemes or stratifications of patients.”

Keith Loria is an award-winning journalist who has been writing for major newspapers and magazines for close to 20 years, on topics as diverse as sports, business, and healthcare.

Why do autoimmune diseases affect women more often than men?

My sister-in-law, Donna Cimons, 77, a retired nurse anesthetist who lives on a farm near Cambridge, Ohio, began losing her hair as a teenager. She woke up each morning to find tufts of hair scattered across her pillow. By age 50, she was bald. She knew this problem ran in her family — her mother had it, too — but not much else.

“It had a name, alopecia areata, but that was all,” she says, speaking of the scant knowledge 60 or more years ago. “We really didn’t know what it was.”

Today we know that it is one of more than 80 autoimmune diseases that can be life-altering, even life-threatening. These occur when the immune system goes awry and mistakenly attacks healthy parts of the body rather than infectious invaders such as bacteria and viruses. It’s often described as the body’s inability to distinguish “self” from “non-self.”

Autoimmune diseases afflict 23.5 million Americans, according to the Department of Health and Human Services, although the American Autoimmune Related Diseases Association estimates the number at more than twice that.

These disorders disproportionately strike women — who account for nearly 80 percent of all cases — for reasons not well understood. Most often, they hit women in their reproductive years, often complicating pregnancy.

“Autoimmune diseases carry a huge burden for affected individuals and their families because of their devastating and chronic nature,” says Daniel Rotrosen, director of the division of allergy, immunology and transplantation at the National Institute of Allergy and Infectious Diseases. “They can require a lifetime of treatment, often with potent immunosuppressive medications that can have worrisome side effects,” such as raising the risk of osteoporosis.

A malfunctioning process

The immune system produces a type of B cell that secretes autoantibodies. These substances can bind to the body’s cells and tissues. In people with healthy immune systems, several mechanisms keep these B cells in check and purge them from the body. However, the process can malfunction. When this happens, these B cells proliferate, producing autoantibodies that go on the attack — and an autoimmune disease results.

Autoantibodies can damage joints, the digestive system, the heart, lungs, kidneys and other organs, the nerves, hair follicles and the connective tissue in the skin and blood vessels. Although each disorder is distinct, they frequently share such symptoms as fatigue, dizziness and low-grade fever. Inflammation is a hallmark of all of them, both at the target site, such as the joints, as well as in the blood.

Among the more common autoimmune diseases are rheumatoid arthritis, which attacks the lining of the joints; Type 1 diabetes, which destroys cells needed to make blood-sugar-controlling insulin; multiple sclerosis, which damages linings around the nerves, affecting the brain and spinal cord; Crohn’s disease and irritable bowel syndrome, which harm the gastrointestinal tract; scleroderma, which causes abnormal growth of connective tissue in the skin and blood vessels; psoriasis, in which new skin cells rise up too fast, resulting in thick red patches and scales; Hashimoto’s disease, which attacks the thyroid gland; and systemic lupus erythematosus, often just called lupus, which can hurt the joints, skin, heart, lungs and kidneys. Lupus is especially prevalent in African American women, who are two to three times as likely to develop it as are Caucasians.

Very debilitating

Many of these diseases can be debilitating.

“If you tell your friends and teachers that you have cancer, they understand it, but if you tell them you have lupus, they don’t understand that it took you three hours to get out of bed because your joints were so sore and inflamed,” says Judith James, chair of the Oklahoma Medical Research Foundation. “Lupus can also affect your brain and cause depression, and affect your ability to think. It’s a terrible disease.’’

Sarah Feinberg, 42, of Silver Spring, Md., a planner at the U.S. Holocaust Memorial Museum, has lived with Crohn’s disease for nine years, although it wasn’t clear what was wrong with her when she began having symptoms at age 33.

Crohn’s, an inflammatory bowel disorder, also can affect the eyes, skin and joints — which is what happened to Feinberg initially. Her first symptom was an inflammation in the iris of one eye, followed by a painful rash under the skin, then temporary arthritis in her hips, knees and ankles.

“Then my stomach kicked in, and I started having to go to the bathroom eight, 10, 12 times a day,” she says. “Anything I ate went right through me. I was constantly excusing myself from meetings and going to the bathroom. I also couldn’t walk because of the arthritis, so I was hobbling to the bathroom.”

Finally, she underwent a colonoscopy — “which you don’t do for an eye problem,’’ she says — and was diagnosed with Crohn’s. She’s lucky, however. Her disease is mild and responds well to medication.

Researchers believe that gene mutations, the environment and even the human microbiome are involved in autoimmune diseases, citing such environmental stimuli as smoking, obesity, sun exposure and infection with the Epstein-Barr virus. These diseases often run in familiesand, while rare, some people can suffer from more than one at the same time, known as polyautoimmunity.

While my sister-in-law’s mother had alopecia, her daughter — my niece — developed a different autoimmune disorder, Hashimoto’s disease, when she was 10.

Smoking gun remains hidden

“Autoimmune diseases appear to be a mismatch between genes and the environment,” says David Hafler, chairman of the department of neurology at the Yale School of Medicine. “It’s not one gene; there are hundreds of common genetic variants which together lead to disease. But all this also raises the question of why we have not found the smoking gun that defines the gender risk.”

Women typically mount a more vigorous immune response than men to infections and vaccinations, producing higher levels of antibodies. In the case of autoimmune disorders, this trait seems to backfire. “Robust immunity in females can be good evolutionarily, but too much immunity can be bad if directed toward self,” says Rhonda Voskuhl, a professor of neurology at UCLA who studies multiple sclerosis.

Scientists believe that sex hormones also may play a role, because many autoimmune disorders occur in women soon after puberty. Some studies, in fact, suggest that the female hormones estrogen and prolactin stimulate the growth of B cell autoantibodies.

Scientists also think that sex chromosomes, specifically the X chromosome, may have an influence. (Everyone normally has one pair of sex chromosomes in each cell; women have two X chromosomes, while men have one X and one Y chromosome.)

The symptoms of some autoimmune diseases, including lupus, often worsen during pregnancy, while in others, such as rheumatoid arthritis, they may improve. “We’re trying to figure out why two diseases with a lot of similarities behave differently during pregnancy,” says Eliza Chakravarty, a rheumatologist at the Oklahoma Medical Research Foundation. “It’s not uncommon for women to have their first episode of lupus during pregnancy. It probably would have developed anyway, but it tends to come on during pregnancy.”

A murky relationship

The relationship between autoimmune diseases and menopause is even murkier. “It used to be said that some of these diseases burn out with time,” says Betty Diamond, director of the Center for Autoimmune and Musculoskeletal Diseases at the Feinstein Institute for Medical Research in Manhasset, N.Y. “If you manage to have the kind of autoimmune disease that doesn’t kill you, it may smolder a little less by then. On the other hand, there is a certain incidence of women who get an autoimmune disease after menopause, which tells you the whole problem is not hormones.”

Interestingly, men who develop these diseases often experience worse symptoms than women, probably because they lack “whatever factors protect men or make it easier for women to get these diseases,” Hafler says.

These are chronic diseases; there are no cures, only medications to treat the symptoms, some of them with serious side effects.But the drugs are getting better. More than 300 medicines for autoimmune diseases are in the research pipeline.

Nothing, however, has helped my sister-in-law restore her hair. “I’m resigned to it,” she says. “I kept hoping something would happen, that they would make some kind of discovery that would get my hair back, but they didn’t.”

She copes. She owns three wigs, each of a different length. “Real hair grows, so I pretend,” she says. “I wear the short one for a while, then the medium one and then the longer one. And then I get a ‘haircut’ and start all over again.’’

She knows things could be worse. While alopecia has drastically affected her appearance, it won’t kill her. “I know I’m not going to die from this disease,” she says. “But it would be nice to have hair.”

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