The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (4 page)

Because the immune system is so complicated, it’s hard to pinpoint a single cause for any autoimmune disease. You may need to be susceptible (usually a matter of genes), you may need to encounter some kind of environmental trigger (maybe sunlight or even an infection), but for sure your immune cells have to misfire.

We normally have small numbers of autoreactive B cells and T cells floating around the immune system, but self-tolerance is usually maintained. However, in susceptible people, that tolerance can be disrupted. Some people may be genetically programmed to produce large numbers of overreactive immune cells or too many damaging cytokines. Some genes may also result in problems with T cell education in the thymus. Some T cells may turn traitor after exposure to viruses or other environmental factors.
⁴
Infections, environmental toxins (such as mercury), medications, and even sun exposure may also activate B cells. For example, excess iodine can be toxic to thyroid tissue,
causing autoantibody production and thyroid disease. Some studies have tied exposure to
Epstein-Barr virus (EBV)
, which causes infectious mononucleosis, to lupus, MS, and other autoimmune diseases.

Recent research suggests that bacteria and other organisms normally found in our body, called the
microbiome
, may play a role in autoimmunity.

Our gastrointestinal system (the GI tract or “gut” for short) is around 30 feet long, stretching from the mouth to the anus. The gut is home to more than 500 species of bacteria, as well as yeast and other organisms. Some bacteria are harmless and some are even “friendly” helping us to digest food and maintain the health of the GI tract, such as
Lactobacillus
(also found in live yogurt cultures). But some bacteria are not so friendly. Certain types of the coliform bacteria
Escherichia coli (E. coli)
can cause serious infections when ingested in contaminated food.

The delicate balance of good and bad organisms in the microbiome can be upset by toxins, infections, and antibiotics that kill off beneficial bacteria and allow potentially harmful types to increase. Even stress can disrupt the balance. The resulting
dysbiosis
activates T cells and triggers overproduction of inflammatory cytokines that can leak into the bloodstream.
⁵

The single layer of
epithelial
cells lining the intestines is usually tightly joined together, forming a barrier against outside toxins. These cellular junctions open and close when signaled by antigens, allowing properly digested fats, proteins, and carbohydrates to pass into the bloodstream. When dysbiosis occurs, the “tight junctions” between the epithelial cells may loosen and become “leaky,” allowing inflammatory cytokines and harmful bacteria to slip through.

Gut dysbiosis, or “leaky gut,” is thought to underlie inflammatory bowel disease (see
page 243
).
⁴
Recent research also suggests that an immune reaction to certain GI bacteria may trigger type 1 diabetes,
⁶
and a reaction to the oral bacteria that cause gum disease could be linked to rheumatoid arthritis (RA).
⁷

The shape of some cells in the body actually resembles viruses or bacteria, so T cells may mistake one for the other and attack both. Such
molecular mimicry
happens in rheumatic fever; proteins on the surface of strep bacteria have a similar structure to proteins in cardiac muscle. Molecular mimicry is thought to be involved in a number of autoimmune diseases.

Genes also play a role, and more than one gene may be to blame for a single disease. Think of genes as minicomputers, packed with complex codes
that deliver instructions to cells, telling them which proteins to produce to grow and which proteins to produce to perform different functions.

The genetic code is made up of sequences of building blocks, or bases, often referred to by the first letters of their names: A (adenine), T (thymine), C (cytosine), and G (guanine). These are the basic components that make up DNA. Sometimes there’s a “typo,” a missing or transposed letter or letters in a particular DNA sequence that results in a genetic mutation. Genes that predispose people to autoimmune diseases are often those called human leukocyte antigens (HLAs), which contain the codes for proteins that label a cell self or nonself. In some autoimmune diseases, these HLA genes mistakenly identify cells as nonself, setting off an attack. Several autoimmune diseases may have genes in the same HLA group in common; for example, genes in the DR4 group are linked to both rheumatoid arthritis and type 1 diabetes, among other diseases. Other genes regulate cytokines, causing too many or too few to be produced.

Autoimmune diseases and their related genes can run in families, but the same faulty genes don’t always produce the same problem. One family member may have immune cells that react against the thyroid, while another may suffer an autoimmune attack on the joints. Even if you’re an identical twin, your chances of developing the same autoimmune disease can vary.

All told, autoimmune reactions either cause or are involved in more than 100 chronic illnesses. The most common of these are thyroid disorders, including Hashimoto’s thyroiditis and Graves’ disease, which affect at least 3 percent of all adult women.

Many of these illnesses share the same autoantibodies, feature tissue or organ destruction caused by the same hordes of immune cells and inflammatory molecules, or have common genes. And the same medication can be used to treat different diseases.

For example, long before the concept of autoimmune disease (or the common factor of inflammation) was recognized, the corticosteroid drug
prednisone
was used to treat a variety of these disorders. The fact that the same drug might be used to treat diseases that vary in what organs they attack does not
necessarily mean autoimmunity represents a single disorder. However, these diseases do have some key elements in common.

Medications developed to target a specific mechanism in one disease have been found to effectively combat that same factor in others. For example, patients with some autoimmune diseases have high levels of
tumor necrosis factor-alpha (TNFα)
, an inflammatory molecule that contributes to organ and tissue damage. One anti-TNF drug,
etanercept (Enbrel)
, soaks TNF up like a sponge, inactivating it; another drug,
infliximab (Remicade)
, uses a “smart bomb” molecule called a monoclonal antibody to disable TNFα. Etanercept is not only approved as a treatment for rheumatoid arthritis but is also used to treat people with Crohn’s disease, autoimmune inflammatory bowel disease, and vasculitis. Remicade was initially approved for patients with Crohn’s disease but is now being used to treat rheumatoid and psoriatic arthritis.

Newer medications that target the cytokine
interleukin-6 (IL-6)
, such as
tocilizumab (Actemra)
, and the
Janus kinase (JAK)
inhibitor
tofacitinib (Xeljanz)
are approved for RA and are also being tested against other autoimmune diseases. Additional target-specific drugs are currently under development.

While autoimmune diseases may target different areas of the body, the genes that affect immune responses may be the same. For example, genes that govern cytokines may have a mutation that causes too many inflammatory molecules to be released. Defective genes common to autoimmune diseases may also affect the way T cells are programmed to recognize antigens, the number of receptors they carry, the number of T cells with a faulty memory, or how many defective T cells are eliminated. Gene therapy to correct these mistakes may one day be possible.

Many autoimmune diseases have the same inflammatory molecules and immune cells that cause damage. For example, one small study found the same autoreactive T cells in people with type 1 diabetes and multiple sclerosis, targeting similar antigens in the pancreas and in the central nervous system (CNS).

Canadian researchers studied T cell autoreactivity in 38 people with MS, 54 children newly diagnosed with type 1 diabetes, and 105 of their close family members, comparing them to a group of healthy controls. To their surprise, they found T cells from the MS patients also targeted self-antigens on insulin-producing islet cells in the pancreas, and T cells from two-thirds of
the children with diabetes and their parents or siblings also showed responses to at least one autoantigen seen in MS—including myelin basic protein, one of the building blocks of the “insulation” around nerve cell fibers.
⁸
The research suggests not only that type 1 diabetes and MS may be more closely linked than anyone thought but also that there may be a lengthy “clinically silent” phase in both diseases that could be a potential target for future preventive therapy. In fact, emerging knowledge about autoimmunity as a cause of disease may lead to treatments that could halt such reactions before they have a chance to cause serious damage.

As you can see from the following table, women are prime targets for many autoimmune diseases (although disease severity doesn’t always differ between the sexes). While the ratios can vary according to geography
⁹
and differing research,
¹⁰
one reason for the high incidence of some diseases may be that women may be exposed more often to possible triggers, like viruses,
medications, or even cosmetics.
¹¹
Some explanations are likely found in sex-related biological differences in certain immune functions.

But it may all begin with the very thing that makes us female in the first place: having two X chromosomes.

Humans inherit two sets of 23 chromosomes—one set of 22
autosomes (non-sex chromosomes)
, plus an X or Y, the
sex chromosomes
—from each parent. In a developing embryo, having two X chromosomes promotes expression of female hormones and female sex characteristics. Embryos that have one X and one Y chromosome develop as males. Being a double X may also affect autoimmune responses.

Studies of the X and Y chromosomes in mice at the University of California Los Angeles found that female mice have higher levels of autoantibodies than males. When male mice were genetically altered to have two X chromosomes, it resulted in greater disease severity and organ damage in lupus and other experimental models of autoimmunity than having the XY combination.
¹²

Autoimmune disease–specific genes may also be associated with the X chromosome. Scientists at the Arthritis Research UK epidemiology unit at the University of Manchester examined DNA samples from more than 27,000 patients with and without RA, most of whom were women, and found 14 genes associated with RA.
¹³
This discovery may help explain why women are three times more likely than men to develop RA, the researchers say.

Of course, one biological difference is our ability to bear children. During pregnancy we’re able to carry a baby in the womb without the immune system attacking a technically half-“foreign” body (a fetus has genes and immune components from both parents).
¹⁴
Recent research suggests that fetal cells from past pregnancies can survive in some women’s bloodstreams for more than 20 years and may trigger an immune response akin to the rejection of a transplanted organ—perhaps causing diseases like scleroderma or rheumatoid arthritis.

Key elements in this reaction are the
human leukocyte antigens (HLAs)
, which, as you’ll recall, are governed by genes. In a bone marrow transplant, the donor and recipient must have compatible HLAs (also called
histocompatibility antigens
), otherwise the transplanted cells will see the recipient’s body tissues as “foreign” and attack. This is called graft-versus-host disease, which
can often resemble autoimmune disease. In fact, the HLA genes involved in graft-versus-host disease are also involved in autoimmune diseases.

While our own HLAs are self-antigens, the combination of self and nonself HLAs in fetal cells means they are part foreign. The fact that fetal cells remain in a woman’s circulation results in a condition called
chimerism
, a word that derives from the mythical creature called a chimera that has the head of one animal and the tail of another. The existence of these fetal cells is called
microchimerism
, and it may contribute to an autoimmune reaction by confusing the immune system.
¹⁵

The greatest risk for some autoimmune diseases seems to occur when there’s a close but not identical match between HLA molecules. This confusion between the two sets of HLA molecules may disrupt normal communication within the immune system and provoke a wrongful attack on self. “You can directly inherit genes from your mother or father that put you at risk for disease. But these are genes that come from your prior pregnancy that are in your bloodstream,” explains J. Lee Nelson, MD, of the Immunogenetics Program at the Fred Hutchinson Cancer Research Center and a professor at the University of Washington in Seattle.

Those same HLA genes (some of which may be linked to susceptibility to autoimmune disease) may also determine whether fetal cells that survive in the mother’s blood have a detrimental effect on the mother. For example, if a child has the same HLA gene as the mother, it seems to be a strong risk factor for some diseases in the woman. In her research, Dr. Nelson found 20 times more persistent fetal cells in women with scleroderma, compared to women who’d also had children but didn’t have the disease. Similar evidence of persistent fetal cells has been found in women with other diseases such as lupus, multiple sclerosis, and autoimmune thyroid disease. It may be that in some women these cells gravitate to certain sites in the body, the thyroid for example, and contribute to an autoimmune reaction.

However, the effects of persistent fetal cells are not all adverse. “Interestingly, for rheumatoid arthritis, which usually gets better during pregnancy, women carrying a child that is not HLA-compatible have a better chance of a remission,” says Dr. Nelson.
¹⁶
Recent research by Dr. Nelson and her colleagues find that while having had a baby provides a modest protective effect against RA,
¹⁷
a complicated pregnancy (such as having a premature or very low-birthweight baby) may mean a higher risk of RA.
¹⁸

The same foreign cell “transfer” might occur from maternal cells that get into fetal circulation while the immune system is developing, Dr. Nelson adds. Maternal cells may also transfer to male offspring, increasing their risk of some autoimmune diseases, or sometimes decreasing risk, depending on the specific HLAs.

But microchimerism is only a small piece of the puzzle. Our immune systems are unique in other ways. Women produce more antibodies and autoantibodies than men, which may be related to those X chromosomes.
¹³
Men and women also have differing responses to organ transplantation. Organs donated by women are more likely to be rejected, and women receiving transplants have a lower survival rate compared to men.
¹⁹
This could be partly due to genes, partly due to hormonal influences, or perhaps caused by differences in cellular immune responses.

Estrogen can stimulate certain immune responses. For example, it can stimulate the production of helper T cell cytokines and enhance the production of others, remarks Michael Lockshin, MD, director of the Barbara Volcker Center for Women and Rheumatic Diseases at the Hospital for Special Surgery in New York City. Estrogen can also increase agents that protect cells against programmed cell death and foster a break in B cell tolerance.

Estrogens also increase antibody production, promoting B cell mediated autoimmune diseases like RA. In contrast, androgens act as natural immunosuppressants.
⁹
However, emphasizes Dr. Lockshin, estrogen alone cannot explain sex differences in autoimmune diseases.

Some autoimmune diseases may worsen in pregnancy, while rheumatoid arthritis and multiple sclerosis get better. High estrogen levels during pregnancy may improve disease through decreased T cell mediated immune responses. On the other hand, pregnancy can trigger other autoimmune diseases, such as thyroid disease and myasthenia gravis.

In some instances, the elevations in estrogen during the first part of your menstrual cycle (the
follicular
phase) may coincide with disease flares. In multiple sclerosis or myasthenia gravis, symptoms may worsen premenstrually (when progesterone is elevated). However, early data suggest that women do not have an increased risk of flares when undergoing ovulation induction (where potent hormones are given to stimulate the ovary to produce several eggs for assisted reproduction). Also, in pregnancy, very few lupus patients
have a serious flare, even with estrogen levels 100 times as high as during the peak menstrual cycle. Some diseases, like Sjögren’s, occur more often after menopause, when estrogen levels are decreased.

“The effects of pregnancy on the different diseases, and of the menstrual cycle, menopause, or hormone therapy, are different in different diseases, and that isn’t consistent with a single cause, like hormones,” stresses Dr. Lockshin. “What’s more likely is that hormones may act as an on-off switch in some autoimmune diseases.”

That on-off switch may be estrogen or other hormones influenced by estrogen. For instance, research at the National Institutes of Health (NIH) suggests that inflammatory autoimmune diseases are influenced by corticotropin releasing hormone (CRH), produced by the hypothalamus in the brain and by the placenta and immune tissues. CRH triggers release of stress hormones like
cortisol
(a natural steroid) when we’re under stress and during pregnancy. Cortisol modulates certain aspects of immune activity in the body, including an increase in inflammatory cytokines. Research suggests that CRH may also stimulate production of a protein that helps shield the fetus from an immune attack.
²⁰

On the other hand, male hormones (androgens) like testosterone appear to be protective, acting as natural immunosuppressants in some autoimmune diseases.
⁹

For example, women with Sjögren’s syndrome are known to have lower levels of testosterone, and correcting the imbalance may help symptoms. There are now eyedrops containing androgen for women with Sjögren’s.

What makes things more difficult for women is that many of the symptoms of autoimmune disease are nonspecific.

You just know that you’re bone tired, and you can’t seem to get yourself out of bed. And everything seems worse because of it. You get your period, and the cramps seem much worse—every little muscle ache and pain seems intensified. Your joints hurt . . . but is it water retention or is the RA worse? You often don’t know what’s arthritis, what’s PMS, what’s fibromyalgia . . . and what’s simply being tired. Any new symptom that crops up, you often just don’t know what to make of it. Most of the time your doctor just says, “Oh, it’s your RA.” And unless you make it your business to learn everything you can, you probably would think that, too.

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