Researchers Piecing Together Autoimmune Disease Puzzle
By NATALIE ANGIER
Published: June 19, 2001
Whether it's through drinking too hard or driving too fast, or picking fights with fists or pistols, men as a rule are said to engage in more self-destructive behaviors than women.
But why should women bother, when their bodies so often do the self-destructing for them?
For reasons that researchers are just beginning to understand, women are at a much greater risk than men of falling prey to an autoimmune disease, in which the body's immune system turns paranoid and begins to attack one or more of the body's organs.
The list of autoimmune diseases is long and varied, composed of more than 80 disorders afflicting virtually every sector of mortal flesh and function: the liver, the kidneys, the adrenal glands, the ovaries, the pancreas, the skin, the joints, the muscles, the myelin sheaths that buffer the nerves, the salivary ducts that spit, the tear ducts that weep.
Some of the conditions are cosmetically annoying but otherwise harmless, like vitiligo, in which patches of skin lose pigmentation. Others are debilitating yet manageable, while still others can be severe, progressive and even fatal. Systemic scleroderma, for example, a disease of the connective tissue that results in hyperproduction of collagen, can sometimes wreak unstoppable havoc on the body's organs, hardening them into woodlike uselessness.
And in all but a few autoimmune disorders, the sex ratio is wildly skewed toward women. In Hashimoto's disease, for example, in which the immune system assaults the thyroid gland, the proportion of female to male victims is 50 to 1. For systemic lupus erythematosus, an inflammation of connective tissue, the ratio is 9 to 1; for Graves' hyperthyroidism, 7 to 1. Even the less frankly ''feminine'' immune diseases like multiple sclerosis and Type 1, or juvenile, diabetes strike twice as many women as men.
''The numbers are pretty staggering,'' said Dr. Caroline C. Whitacre, a professor of molecular virology, immunology and medical genetics at Ohio State. ''Of the eight and a half million people with autoimmune diseases in this country, 6.7 million, or nearly 80 percent, are women.''
Now, propelled by an invigorated women's health movement and a heightened ability to explore the molecular mechanisms of the autoimmune response, researchers at last are making headway in understanding how and why the body sometimes wages war on itself. They are learning why women are particularly susceptible to aberrations of the immune system, and they are devising novel approaches to blocking the misguided attacks and allowing the scapegoated organs to heal.
One of the most intriguing new findings arises from the discovery that, during pregnancy, a mother and fetus exchange body cells that can persist in one or the other's circulation for years or even decades after birth. Now it seems that this lovely long-term bond can on rare occasions have dire consequences, producing an autoimmune reaction in either the bearer or the born.
In another study that will appear next month in The Journal of Clinical Investigation, Denise L. Faustman of the immunobiology laboratory of Harvard Medical School and her colleagues at Massachusetts General Hospital report that they effectively cured laboratory mice of Type 1 diabetes through a relatively short and simple therapy. The treatment, a 40-day course of injections with a drug called CFA, induces the body to produce so-called tumor necrosis factor alpha, a signaling molecule of the immune system. This necrosis factor in turn prompts the aberrant autoimmune cells to commit suicide through a carefully orchestrated program called apoptosis.
As Dr. Faustman describes, the mice that have been purged of autoimmune cells quickly regrow their islet cells, allowing the pancreas to reclaim its rightful role as insulin sweatshop. Three-quarters of the time, the mice remain free of diabetes for the rest of their lives, making this perhaps the first genuine cure for the harrowing disorder in a laboratory animal.
The treatment is a long way from proving its mettle in human patients, but Dr. Faustman suggests that it eventually may prove effective against a wide array of autoimmune conditions in addition to juvenile diabetes.
Indeed, many immunologists argue that the autoimmune diseases, which have been regarded as distinct conditions, each deserving of their own subspecialty and advocacy group, are better viewed as variations on a single grim theme.
''Only recently have we begun thinking of autoimmune diseases as a consortium, a related group of conditions that have many features in common,'' said Noel R. Rose, a professor at Johns Hopkins and head of the American Autoimmune Disease Association. ''By focusing on these common elements, we've advanced our understanding.''
For one thing, Dr. Rose pointed out, doctors have become aware that those who suffer from one autoimmune disease are at increased risk of contracting another. Moreover, researchers have seen that a generalized predisposition toward autoimmunity may run in families, with one person suffering from, say, lupus, another from rheumatoid arthritis, a third from Graves' disease. Knowing this kinship pattern, Dr. Rose said, may help a doctor more quickly diagnose an autoimmune condition.
Genetic predispostion, though, is only a part of the story of autoimmunity. A number of researchers are seeking to understand the link between immune disorders and sex hormones. Women's comparatively high levels of the so-called female hormone, estrogen, and low levels of the male-affiliated androgens are thought to explain some of the sex discrepancies in autoimmune disease, which is why many women first suffer the symptoms of an autoimmune syndrome in their 20's, when average monthly estrogen levels are at their peak.
In addition, the hormones of pregnancy clearly influence a number of autoimmune diseases, in some cases ameliorating the condition, in other instances possibly making it worse. Dr. Whitacre points out that women with rheumatoid arthritis or multiple sclerosis often experience a great improvement in their disorder while pregnant, particularly during the last trimester, when all the intersecting hormonal systems of pregnancy are humming at maximum capacity.
The glorious holiday of health, alas, is short-lived. ''At delivery, there's dramatic drop-off in both estrogen and progesterone levels, and you see an almost immediate return of the disease,'' Dr. Whitacre said. ''In the first three months after delivery, the disease may be much, much worse than it was before pregnancy.'' Eventually, she added, it reverts to its previous, prepregnancy state.
But autoimmunity is more than a simple matter of estrogen dosing. Not only have contraceptive pills proved disappointing as a treatment against most autoimmune conditions, but for some disorders, the high-E months of pregnancy feel less like a Club Med getaway than a foray to the Bates Motel. Women with lupus, for example, may find that their arthritic pains, mouth and nose sores, malaise, fatigue and butterfly facial rashes worsen during gestation, to the point where those who have had one child are reluctant to risk childbearing again.
Such observations, together with animal studies, have prompted researchers to examine other possible hormonal culprits. At a recent meeting in San Francisco of the American Association for the Advancement of Science, Dr. Sara Walker of the University of Missouri reported that prolactin, a pituitary hormone that soars late in pregnancy to begin stimulating milk production, can intensify lupus symptoms, and she described the modest but prolonged success of treating lupus with bromocriptine, a prolactin suppressant.
Dr. Walker also proposed that women may be at risk for autoimmune conditions not because they have too much estrogen, but because they have too little testosterone. She presented results in which lupus patients were treated over long periods of time with dehydroepiandrosterone, or DHEA, an androgen much weaker than testosterone and thus less likely to have unpleasant masculinizing side effects. Although not cured by any means, the patients on DHEA reported feeling more energetic and less symptomatic, and less likely to need an immune-suppressant drug, prednisone, than the group taking dummy pills.
Pregnancy may also influence autoimmune risk through entirely nonhormonal means. In research so new that scientists still aren't sure what to make of it, Dr. J. Lee Nelson of the Fred Hutchinson Cancer Research Center in Seattle and her colleagues have found that the perils of pregnancy may be akin to those of an organ transplant.
As a researcher at a cancer center, Dr. Nelson often observed the ugly effects of so-called graft-versus-host disease, when patients receive an imperfectly matched bone marrow transplant as part of their cancer treatment, and the immune cells of the installed marrow begin attacking their new home. Dr. Nelson noticed that the symptoms of graft-versus-host disease looked a lot like scleroderma and other severe autoimmune conditions.
When she learned in the mid-1990's of work showing that fetal cells persist in very low numbers in a mother's circulation for years, even decades, after birth, ''a light bulb went off,'' Dr. Nelson said. Could this state of persistent microchimerism -- the mixed population of her own and fetal cells in a mother's body -- explain some cases of autoimmune disease?
Recent research suggests that the answer is yes. Measuring the amount of fetal cell DNA in the blood of women whose scleroderma first arose after they had children, Dr. Nelson and her co-workers found that there was, on average, 20 times the number of persistent fetal cells in the scleroderma patients than in women who had given birth but who did not have scleroderma (although that still amounted to a very tiny number of fetal cells in any woman, sclerodermic or otherwise).
Moreover, the researchers have found that, as with graft-versus-host disease, the greatest risk seems to occur when there is a close but not identical match between mother host and fetal ''graft.'' The key lies in the relative compatibility of so-called HLA molecules, which help an individual's immune system distinguish between host and guest. When a mother's HLA molecule is very different from her baby's, her immune system seems able to clean up the fetal cells postpartum, and the cellular umbilicus is safely severed. But when the HLA molecules are a little too close for comfort, the maternal immune system apparently gets confused: which is real, and which the imposter? That bewilderment seems to help touch off an inappropriate autoimmune reaction against the mother's own molecules.
Lest mothers get smug about the ingratitude of children, Dr. Nelson said this is not a one-way risk: maternal cells can linger in a fetus's bloodstream, too. This cellular mother load, as it were, could explain some cases of autoimmune disease in men.
Preliminary evidence even suggests that there is such a thing as multigenerational microchimerism, in which a woman with an autoimmune disorder can blame both her mother and her children for her misery. In these bizarre instances, the woman harbors circulating cells from her mother and from her offspring that turn out to be more compatible in their HLA palette with each other than either is with the mother in the middle.
''If your mother is HLA compatible with your child, it gives you a sevenfold or higher risk for scleroderma,'' Dr. Nelson said. ''It's a uniquely female risk to have these transgenerational effects, this war taking place in the body.''
Dr. Nelson acknowledges that microchimerism accounts for only one piece of the autoimmune puzzle, but she hopes the new insights may lead to treatments that aim at the lingering souvenirs of symbioses past.
If you can't choose your family, you should at least be able to choose your family feuds.
Photos: Dr. Denise L. Faustman, above, has helped develop a therapy to cure lab mice of Type 1 diabetes. Left, Drs. Anne Stevens, left, J. Lee Nelson and Nathalie Lambert prepare fetal cells for study. (Evan Richman for The New York Times); (Clay Eals for The New York Times)(pg. F8) Drawings (Juan Velasco/The New York Times)(pg. F1) Chart: ''The Body's Friendly Fire'' Autoimmune diseases, in which the immune system attacks the body's own tissues, strike women far more often than men, especially during their childbearing years. HASHIMOTO'S DISEASE The immune system attacks the thyroid gland, a hormone producer that helps set the rate of metabolism. 50:1 FEMALE TO MALE RATIO OF AFFECTED PEOPLE (PREGNANCY IMPROVES SYMPTOMS) GRAVES' DISEASE Excessive production of thyroid hormone 7:1 SJOGREN'S SYNDROME Chronic, slowly progressive inability to secrete saliva and tears 9:1 PRIMARY BILIARY CIRRHOSIS Results in destruction of the bile ducts of the liver 9:1 CHRONIC ACTIVE HEPATITIS Continuing inflammation of the liver in which cells die 8:1 LUPUS Inflammation of the connective tissues; can affect multiple organs 9:1 RHEUMATOID ARTHRITIS Immune cells attack and inflame the tissue lining the joints 4:1 MULTIPLE SCLEROSIS Destruction of myelin, the material that insulates nerves. It can cause a wide range of neurological symptoms. 2:1 The Role of Pregnancy HORMONES The greater incidence in women may be related to the female hormone estrogen. Hormonal changes can affect the severity of symptoms. FETAL CELLS Fetal cells can remain in the mother's body for years. Some researchers theorize that when these cells are very similar to the mother's own, the immune system might get confused, attacking both fetal cells and the similar maternal cells. IDENTIFYING SELF-CELLS T-cells of the immune system have receptors that bind to antigens, proteins in other cells or organisms. T-cells that would react to self-antigen do not normally mature, but some may escape this filtering, attacking self-cells or tissue. IDENTIFYING INTRUDERS Infected cells display the intruder's antigen on their surfaces. T-cells bind to these cells and signal the cell for destruction. Some viruses and other organisms mimic self-antigens. If the immune system responds to them, it may also inadvertently attack the body's own cells. (Sources: National Institute of Allergy and Infectious Disease; American Autoimmune Related Diseases Association.) (pg. F1)