Fighting Herself.

Why does a woman's immune system sometimes turn on her?

Whether or not you believe that men are from Mars and women are from Venus, a growing body of scientific research suggests that when it comes to health, men and women differ.

One of the biggest gender gaps lies in the fact that a woman is more likely to suffer an attack by the immune system than a man is. Like conversations between men and woman, immune signals can become confused and sometimes go berserk. Then, the body destroys its own tissue.

This process, called autoimmunity, underlies more than 80 diseases. Many are well known. Multiple sclerosis, for example, describes an autoimmune reaction against nerve cells, and rheumatoid arthritis denotes an attack against the connective tissue of joints. In type I, or juvenile, diabetes, immune cells attack insulin-producing cells in the pancreas. Lupus, with its facial rash, photosensitivity, fatigue, joint and muscle pain, and widespread organ damage, represents a generalized immune reaction against many tissues of the body.

Taken individually, each autoimmune disease is relatively rare. However, roughly 50 million people in the United States suffer from some kind of autoimmune disease, according to the American Autoimmune Related Diseases Association in East Detroit, Mich.

Heredity seems to play a role in some autoimmune diseases. Recent studies, however, suggest that a familial tendency toward autoimmune diseases, considered collectively, may be as common as a tendency to inherit any one disease. In other words, heredity may cause one family member to have lupus, another multiple sclerosis, and a third rheumatoid arthritis (see "Autoimmune diseases: All in the family?"). Environmental factors, too, are presumed to contribute to the onset of disease, but as yet, scientists know little about the nature of these triggers.

Most estimates show women accounting for nearly three out of four cases of such disease, although a few autoimmune diseases are more common in men than in women. Among U.S. women, autoimmune disorders collectively represent the fourth-largest cause of disability--after cancer, heart disease, and mental illness.

As yet, there isn't any one explanation for why women are more susceptible to autoimmune diseases than men are. Varying exposures to infections or environmental chemicals may help account for the gender differences, says Michael D. Lockshin of the Weill Medical College of Cornell University in New York. But other researchers are looking at sex hormones and long-lasting effects of pregnancies.

"Studying sex-related differences could help us understand what pushes some people over the brink into autoimmune diseases," says Noel R. Rose of Johns Hopkins University School of Medicine in Baltimore. Furthermore, he adds, understanding the reasons behind the gender disparity in autoimmune disorders may offer new targets for prevention and treatment in both men and women.

To explain why women are especially susceptible to autoimmune diseases, researchers began investigating whether the sex hormones estrogen and testosterone affect the immune system. There had been several hints that the hormones influence the onset or progression of the disorders.

Most autoimmune diseases that are more common among women than among men appear in the young-adult years. Lupus, for example, is more than 10 times as common in women than in men, and it tends to strike women during their prime childbearing years. Both women and men with lupus have higher than normal concentrations of estrogens in their bloodstream.

However, the incidence of some autoimmune diseases, such as chronic thyroiditis, peaks in women during menopause, when blood concentrations of estrogen are low. When rheumatoid arthritis and some other autoimmune diseases appear early in adulthood, symptoms often improve during pregnancy, as estrogen concentrations in the blood rise, and worsen after the birth, as estrogen falls.

Disappointingly, however, using sex hormones to treat these autoimmune diseases has had inconclusive results.

Other hormones may also affect the progress of autoimmune diseases, says Sara E. Walker of the University of Missouri in Columbia. In San Francisco this February at the annual meeting of the American Association for the Advancement of Science, she reported that blocking prolactin, a hormone released during pregnancy, improved the condition of seven women with mild lupus.

Not all inherited differences between males and females show up when scientists study hormones, contends Denise Faustman of Massachusetts General Hospital and Harvard Medical School in Boston. She and her colleagues argue that, at least in mice, the cells of males and females differ in how they process newly made proteins. These differences, she believes, contribute to women's increased susceptibility to autoimmune diseases.

All normal cells make a set of proteins that form a structure called the major histocompatibility complex on cell surfaces. Like an easel set up for display, this complex holds and presents small pieces of proteins to inquisitive white blood cells called T lymphocytes. These T cells can then distinguish whether the fragment, known as an antigen, came from a friend or a foe. If the antigen is judged alien, T cells marshal other white blood cells to produce antibodies that attack and destroy the invader.

Faustman and her colleagues have found that, in an inbred strain of mice prone to diabetes, defects in a cellular structure called the proteosome can prevent female cells from chopping up proteins as required for antigen presentation. The same defects in cells taken from male mice result in antigens that are bigger than normal but still get mounted on the easel and attract white blood cells, she reports. Faustman suspects that this sex difference underlies the female predilection to autoimmune diseases.

She and her colleagues have discovered a way to take advantage of the proteosome defect. Once these defective cells are circulating through the body, the proteosome defect makes them unusually susceptible to cell death triggered by a signaling molecule in the immune system called tumor necrosis factor alpha, or TNF-alpha.

A drug called CFA causes a mouse's body to produce extra TNF-alpha, Faustman says. She has shown that a 40-day course of CFA injections kills the autoimmune cells in diabetic mice and enables three-quarters of the animals to grow without diabetes for the rest of their lives. This work appears in the July JOURNAL OF CLINICAL INVESTIGATION.

"This is fascinating work and an important venue to investigate," says J. Lee Nelson of the Fred Hutchinson Cancer Research Center in Seattle.

Many researchers, along with Faustman, are also looking at various aspects of cells' natural suicide, or apoptosis, to explain autoimmune diseases. Various cellular interactions have been linked to abnormal apoptosis of immune cells. Resistance to apoptosis, for example, might explain how some self-attacking cells can escape the processes that normally destroy them, researchers speculate.

Some researchers focusing on apoptosis are examining various tissues to see if in people with an autoimmune disease, the targeted organs undergo apoptosis more easily than they do in other people. As the cells die, proteins inside the cells are exposed. These proteins, which normally wouldn't appear at such high concentrations, might foment a chronic immune attack.

Another explanation for gender differences in autoimmune diseases may lie in cells from one person that lurk in another. In 1996, Diana W. Bianchi of the New England Medical Center in Boston reported the surprising finding that fetal cells remain in a mother's blood for decades (SN: 2/10/96, p. 85). In 1999 came news that, conversely, a mom's cells could transfer to the baby and linger there for years after birth (SN: 5/1/99, p. 287).

People may also receive cells from a twin in the womb or a stranger through a blood transfusion, Nelson says. The researchers can even detect fetal cells in the blood of many women who were pregnant but didn't carry a baby to term. A tantalizing possibility is that any of these introduced cells might trigger autoimmune diseases.

"This is one of the neatest ideas in the arena," says Lockshin.

Indeed, Bianchi and her colleagues have shown that women with an autoimmune disease called scleroderma--chronic hardening of the skin and sometimes internal organs--seem to have higher numbers of fetal cells in their blood than women without immune disorders do.

Gender Differences

                                  Primary
Disease                        Tissue Targeted

Hashimoto's disease               Thyroid
Systemic lupus erythematosus      Connective tissue
Chronic active hepatitis          Liver
Grave's disease                   Thyroid
Rheumatoid arthritis              Joints
Scleroderma                       Connective tissue
Multiple sclerosis                Central nervous system
Type I diabetes                   Insulin-producing cells
Ankylosing spondylitis            Spine and joints

                                     Approximate
Disease                           Female:Male Ratio

Hashimoto's disease                      10:1
Systemic lupus erythematosus             6:1
Chronic active hepatitis                 8:1
Grave's disease                          7:1
Rheumatoid arthritis                   2.5:1
Scleroderma                              3:1
Multiple sclerosis                       2:1
Type I diabetes                          1:1
Ankylosing spondylitis                   1:3

Adapted from IOM report

Nelson suspects that something beyond the number of fetal cells influences the onset of autoimmune disease. She has looked at subtle genetic differences in mother and child that show up in the immune system.

Sometimes a mom's immune system, as characterized by the proteins of the major histocompatibility complex, is very different from that of her baby. Nelson finds that in this case, the mother's immune system detects the difference and destroys cells left over from the fetus. When the immune cells of mother and infant are more similar, the maternal immune system can get confused. It may touch off inappropriate activity that leads to autoimmune disease, such as scleroderma, says Nelson.

Some women contain cells from both their mothers and their children. These cells can interact with the woman's immune system, Nelson says, "causing a war across generations taking place in your body." These women are at least seven times as likely as others to develop scleroderma, Nelson says.

In a study yet to be published, Nelson and her colleagues examined tissues from five women who died of scleroderma. They found that fetal cells seem to be present primarily in the organs attacked by the disease.

Are the long-lasting foreign cells a trigger or a response to immune system abnormalities? It's possible that a woman with autoimmune disease has higher concentrations of fetal cells because her immune system is not functioning properly. Thus, Nelson, Bianchi, and others are now examining the mechanisms by which the foreign cells interact with a person's immune system.

None of these explanations for gender differences in autoimmune diseases--hormones, antigen presentation, or maternal and fetal cell transfer--excludes another, notes Nelson.

In fact, these three ideas are just the tip of the iceberg, adds Lockshin.

He suggests that in many unrecognized ways, women and men differ in cellular and molecular activity. In a report on gender differences and disease released this April, the Institute of Medicine, a federal advisory agency, recommended that all researchers report the sex of study participants as part of their results. Even scientists working on human cells in laboratories should state whether the original tissue was male or female, the agency said.

"It's almost never looked at," Lockshin says. He also proposes that as-yet-unidentified differences in environmental exposure to toxins, infections, or other potential triggers for autoimmune disease will explain much of the sex difference.

Though these topics are rarely studied, Lockshin says, men may be exposed to higher concentrations of toxic industrial chemicals while women are exposed to more toxins from detergents or cosmetics. Gender differences might also derive from varying exposure to other diseases that might trigger autoimmunity, he adds.

"We're a long way from conclusive answers," says Nelson. Most researchers hold that autoimmune diseases are caused by a constellation of events, some of which may predispose women to disease, she says.

The tantalizing hints uncovered so far about the underlying explanations for gender differences may eventually lead to treatments that prevent the immune system from raging against the body itself.

RELATED ARTICLE: Autoimmune diseases: All in the family?

Though breast cancers, prostate cancers, and lung cancers have different attributes, most people recognize that those diseases are related. Chances are, however, that a person wouldn't immediately categorize rheumatoid arthritis, diabetes, multiple sclerosis, lupus, and the many other autoimmune diseases as a single family.

According to some scientists, that's a big problem. "There are undoubtedly certain fundamental principles behind the process [underlying the autoimmune diseases], and it would pay to study them," says Noel Rose of Johns Hopkins University in Baltimore.

"In the big picture, there's a problem because autoimmune diseases are defined by the target destroyed," says Denise Faustman of Massachusetts General Hospital and Harvard Medical School in Boston. "People don't think of them as a whole group even though, in our mind, they're probably identical" on a genetic level.

Faustman has reached this conclusion, at least in part, because of a mouse model of rheumatoid arthritis that she and her colleagues developed. They bred the small percentage of mice genetically prone to diabetes that somehow resisted developing diabetes. These mice have aggressive joint disease, Faustman reported this February in San Francisco at the annual meeting of the American Association for the Advancement of Science. As in people, the mouse arthritis is more common in females than in males and goes into remission during pregnancy.

"If we can take genetically identical mice with a susceptibility towards diabetes and turn that into rheumatoid arthritis, that suggests there are only subtle differences" in the two diseases, Faustman says.

"There may be genes that raise the threshold [of risk] of developing autoimmune diseases generally," agrees Rose. "Faustman's work may give us a hint of what is going on."

Another approach is a nationwide study just initiated by scientists at the National Institutes of Health in Bethesda, Md. The researchers plan to enroll people from families with multiple autoimmune diseases--such as diabetes, arthritis, lupus, and Crohn's disease--and look for common genes.

Already, the scientists have linked multiple autoimmune disorders to variations in some of the genes that code for the major histocompatibility complex proteins--the proteins that cells use to proffer antigens to the immune system.

"It would be difficult for one physician to handle patients with diabetes, lupus, multiple sclerosis, and rheumatoid arthritis," cautions Michael D. Lockshin of the Weill Medical College of Cornell University in New York. "In terms of the science of autoimmunity, however, there is some sexiness to the concept [of grouping the diseases] because there are some deep similarities."

Rose points out that many advances in treating cancers have come from studying the overall disease process instead of from focusing on cancers of particular tissues. "It's only been recently, and haltingly, that we've begun to think of autoimmune diseases as a consortium, but this could offer great benefits," he says. --D.C.