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For 20 years, Emily Kischell of California suffered “unrelentingly painful and gruesome periods” before doctors found an “excruciating” chocolate cyst — a cyst containing old blood, fluids, and semisolid materials — on her left ovary that required surgery. A surgeon had to untangle her “mangled-by-adhesions fallopian tube” from the scar tissue that is a hallmark of the autoimmune disease endometriosis, in which tissue that normally stays inside the uterus grows outside of it and can be extremely painful and interfere with menstruation and reproduction.
Kischell was relieved to receive a diagnosis after years of vague answers from doctors.
But after the birth of her first child, she was hit with months of “severe joint and muscle pain” that began with what she thought was a sore throat and would later be diagnosed as an inflamed thyroid gland. “I could barely walk, every bone in my feet felt on fire, and I could barely lift my tiny newborn,” Kischell said.
Now her doctors had no answers for her — except to say that some women experience pain after childbirth. “I was completely frustrated and felt utterly nuts,” Kischell recalls. “How could I be suffering this acutely and not have something medically awry?”
It wasn’t until five years later, after the birth of her second child and the same acute pain flared up, that finally, after pressuring her doctor, she received a referral to a rheumatologist — a specialist in autoimmune diseases. A series of simple blood tests revealed that Kischell had a second autoimmune illness, Hashimoto’s disease, or autoimmune thyroiditis, where the immune system attacks the thyroid, leading to improper function of the gland. It’s common for autoimmune diseases to come in clusters.
If not for the ovarian cyst that revealed the endometriosis, she may have never been properly diagnosed: “My extreme monthly suffering for years would have continued to fall under the category of hysteria.” There doesn’t seem to be a similar term for men’s pain, and Kischell feels sure that if men were presenting with similar pain and symptoms in large numbers, “there would be more attention given to these diseases, and more medical professionals would have relevant training.”
Autoimmune diseases — where the body attacks its own tissues — are often the most baffling to doctors and the most difficult to treat. Considered incurable, those who live with them often must negotiate a life of chronic pain and debilitating fatigue.
Kent Holtorf, Philadelphia-based medical director of the Holtorf Medical Group and the nonprofit National Academy of Hypothyroidism, agrees that women are treated differently than men. He’s seen it in his own colleagues: “They’ll just say, ‘Oh, you’re stressed out,’ and you’ll get an antidepressant, when all along it’s an autoimmune disease,” Holtorf says. Whereas, his experience has shown him that “if a guy comes in with those symptoms, the doctor says, ‘Hey, there’s really something going on here.’”
Treatment for autoimmune diseases often include chemotherapy-like drugs that suppress the immune system and have numerous negative side effects, or “biologics,” drugs that target the inflammatory molecules of pain. Neither guarantee remission of the disease, and many people with autoimmune disease live with daily chronic pain that has to be managed with steroids and opioid pain medications.
So why is research so slow to catch up to a cure? Could it be that 78 percent of those afflicted by autoimmune disease are women? Medical research is still lagging in addressing the reality that women have greater vulnerability to illness and pain and different drug tolerance levels. In lieu of better research, the medical model still tends to treat women who report the kind of pain and fatigue associated with autoimmune diseases as emotional stress or hormones, often missing important diagnoses for years.
While receiving a diagnosis is the first step in getting treatment, a diagnosis of rheumatoid arthritis (RA) didn’t stop Sonya Huber, a creative writing professor and author of the essay collection Pain Woman Takes Your Keys and Other Essays from a Nervous System, from hearing “ridiculous things” from her doctors during her three-year journey to find answers for her chronic pain. One doctor actually told her, “You’re too young and attractive to have RA.”
Then Huber couldn’t find a specialist who would let her try the biologics that can cause remission in some patients if given soon after symptoms start. “Emotionally it was horrible, because I wanted the pain erased, and the grief involved in realizing I would never have my old life back was devastating.” Recently divorced, a single mom, and a tenure-track professor, Huber was already under a significant amount of stress.
She is convinced that inherent sexism in doctors’ attitudes makes it difficult for women and nonbinary people who present as female to get diagnosed and treated. “Almost every single medical interaction, with the exception of my current doctor, has involved doctors seeming repulsed or disbelieving about my level of pain. If you don’t have RA, you can’t understand how pervasive the pain is.”
Women and nonbinary folx with autoimmune disease may soon be vindicated when the results of a collaboration between Wesley H. Brooks, a research assistant professor of chemistry at the University of South Florida, and Yves Renaudineau, a professor of immunology at the University of Brest in France, make their way into the mainstream. More than 30 years of research have gone into their working hypothesis, “X chromosome-nucleolus nexus,” which posits that the main source of a female bias in autoimmune disease is neither the often-assumed female reproductive hormones nor emotional stress; the culprit appears to lie on the second, inactive X chromosome in cisgender women and those assigned female at birth.
To understand this, a bit of biology is necessary: When the egg and sperm cell fuse to make an embryo, each female cell in the embryo inherits a maternal and a paternal X chromosome—two in total—whereas the male cells inherit only the maternal X chromosome. Most genes on the X chromosome are not related to sexual development, so the female cell only needs one active X chromosome, like in the male cell.
“At some point, when there are only a few dozen cells in the developing female embryo, each cell decides which X chromosome will remain active and which will be inactivated—in effect, epigenetically silenced,” Brooks explains. The inactivated X nonetheless persists in expressing its RNA along the X chromosome, recruiting epigenetic factors to further suppress expression from most of that X chromosome’s genes.
That silenced X chromosome, also called the Barr body, becomes a densely packed structure that is pushed to the side of the nuclear membrane by all the active chromosomes spread out in the nucleus. When the cell divides, each resulting daughter cell essentially inherits the decision of the earlier embryonic cell.
In the best of times, cells remain relatively unstressed, and the inactive copies of gene, such as on the Barr body, remain dormant. However, during the cell’s synthesis phase, when the cell doubles everything (DNA, proteins, etc.) in order to split into two daughter cells, the Barr body is the last chromosome to be replicated.
This can leave the inactive X chromosome vulnerable, with some genes left “open” with the potential for later expression. (Keep in mind that the X chromosome is the eighth largest chromosome and has about 1,100 protein-coding genes, Brooks says.)
Under cellular stress, however, which can be induced by many different environmental factors — chemicals, drugs, viruses, bacteria, UV light, and more — a structure in the cell’s nucleus called the nucleolus expands in reaction, producing more “intracellular machines” such as ribosomes and transfer RNAs (tRNAs), which help the cell recover from the stress. “These machines are themselves RNA molecules and proteins that must be properly folded and assembled into ribonucleoprotein complexes [RNPs],” Brooks says.
The location of the Barr body adjacent to the nucleolus in about one-third of the cells makes these female cells vulnerable. “This puts one of the most active, dynamic, and multifunctional components of the cell, the nucleolus, right next to one of the most inactive components, the Barr body,” Brooks says.
Under stress, the expanding nucleolus disrupts the Barr body, which leads to overexpression of X-linked genes, now from both X chromosomes. Overexpression of some of these X-linked genes can cause the nucleolus to fragment and lose its ability to function efficiently.
If the resulting RNPs are improperly folded or assembled, the immune system interprets them as foreign material and produces autoantibodies to them. “Many of the main autoantigens in an autoimmune disease like lupus are actually components of the nucleolus, at least transiently,” Brooks says.
This hypothesis differs from many others in that it does not put the blame on the immune system or on a yet-to-be-discovered “lupus gene,” but rather on an accumulation of damage from stressful events at the cellular level that disrupt epigenetic control of X-linked genes.
As an even more compelling case in point, Brooks points out that men with Klinefelter syndrome, in which they have an extra X chromosome, have a 14 times greater chance of developing lupus compared to males with only one X chromosome. And in females with classic Turner syndrome, in which they have only one X chromosome, there are only one or two reported cases of lupus. “It points to a role for genes on the extra X chromosome in autoimmune disease development and involvement of cellular stress and the nucleolus,” he says.
Lastly, viruses are one of the more common culprits of cellular stress. In fact, dormant virus genes, of which our genome is partially comprised, can cause autoimmunity problems later in life by becoming active. “Ninety-five percent of us have had exposure to the Epstein-Barr virus, which can be inserted into our genome,” Brooks says. That’s the virus that causes mononucleosis, “the kissing disease,” in teenagers. If the Epstein-Barr virus is awakened later in life, it can trigger the autoimmune disease multiple sclerosis as much as 30 years after the mononucleosis episode.
The good news, Brooks says, is that researchers have identified some genes that can be targeted to block disruption of the nucleolus for new kinds of treatments that don’t suppress the subsequent immune response. He is hopeful for the future.
This biological vindication can’t come too soon for women and nonbinary folx who suffer from autoimmune diseases.
“I felt like a failure when my body didn’t respond ‘correctly,’ but my success has been in making a new life with it,” Huber says. It’s huge and life altering to get this kind of diagnosis.”
Kischell is grateful to have answers and medications, but treating her pain is an ongoing challenge that, in addition to medication, requires “self-taught” lifestyle changes, such as cutting out inflammatory foods, thanks to her own research and the advice of her fellow autoimmune community, not her doctors.
If Kischell could do things over again, she’d have gone straight to a rheumatologist. “It’s absolutely unconscionable that physicians are so ignorant to these diseases and their treatments and symptoms.”
Holtorf joins in the frustrated chorus but offers one suggestion: “Try to find a doctor that tries to be more of a detective.”
Writer. Author of 9 books, most recently “How to Write a Page Turner.” Published in The Atlantic. Mental Floss. NY Mag. Writer’s Digest. jordanrosenfeld.net
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