The Chimeric Self

Natural History, June, 2001 by J. Lee Nelson

Cellular traffic between mother and fetus raises questions about the causes of autoimmune disease.

One of the unsolved mysteries of immunology is why the body of a pregnant woman doesn't reject her fetus. After all, our immune system evolved to keep foreigners out, to maintain a clear distinction between self and other. In recent years, the mystery deepened as researchers learned that fetal cells get into the maternal bloodstream during pregnancy and, what's more, may stay there for decades, perhaps indefinitely. What might this mean for how we think about autoimmune disease?

The traditional view of autoimmunity is that it is a case of mistaken identity: a body, often for no apparent reason, fails to recognize some of its own tissues and mounts an attack against itself. There is no evidence, for example, that rheumatoid arthritis sufferers had anything wrong with their joints, or with the tissues lining the joints, that might have led to the onset of the disease; their bodies appear to have simply turned on themselves. The indefinite persistence of fetal cells in a woman's body, however, led me to ask if some so-called autoimmune diseases may be triggered by foreign cells, specifically by fetal cells present in the mother's body. After several years of looking into this question, I recently proposed that what we may be dealing with, in fact, is a kind of chimerism, though on a microscopic scale.

In Greek mythology, the chimera was a fire-breathing creature with the head of a lion, the body of a goat, and the tail of a serpent. In modern medicine, the term "chimerism" refers to an organism whose body contains populations of cells derived from another individual--a less grand but, to researchers like myself, equally compelling notion. Microchimerism is said to exist when the number of nonhost cells is very low (for example, fewer than one foreign cell for every million host cells).

One observation that led me to suggest a connection between microchimerism and autoimmune diseases was that these illnesses--among the most familiar of which are rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis--usually afflict more women than men, sometimes at ratios of greater than ten to one. Furthermore, many of these diseases strike most often in late middle age. Three such examples are thyroiditis (an inflammation of the thyroid gland), primary biliary cirrhosis (inflammation and destruction of the liver), and scleroderma (progressive hardening of the skin and internal organs). If these diseases hit earlier in life, when hormonal differences between men and women are so striking, the logical assumption would be that sex hormones were somehow implicated. But in part because they tend to come on later in life (often not developing until after menopause), I looked for other differences between males and females. Pregnancy was an obvious one, and I was intrigued by the possibility that women are uniquely subject to a kind of reverse inheritance from their children.

Men and children, as well as women who have never been pregnant, also develop autoimmune diseases, but microchimerism could play a role in these populations as well, because there are several ways people may wind up, perhaps indefinitely, with cells that aren't their own. During pregnancy, for instance, the mother's cells can also pass into the developing fetus. In addition, cell transfer can occur between twins in utero. Blood transfusions are another pathway for cell transfer: although the donor's red blood cells--which have no nucleus and are short-lived--are soon cleared from the recipient's circulation, it turns out that the donor's longer-lived, nucleated white blood cells can persist within the recipient.

Further sparking my interest was the knowledge that leukemia and lymphoma patients who undergo bone marrow (stem cell) transplantation often develop a syndrome known as chronic graft-versus-host disease, with symptoms very much like those of certain autoimmune diseases, especially those of scleroderma. This syndrome occurs most often when the donor's cells are not perfectly matched to the recipient's.

Much of my own research--done in collaboration with colleagues at the Fred Hutchinson Cancer Research Center in Seattle and with Diana Bianchi and her team at the New England Medical Center in Boston--has focused on scleroderma. This insidious illness begins with hardening of the skin on the fingers and toes and slowly marches to the arms, legs, face, and trunk. Advanced hardening can result in skin ulcers and the loss of fingers or toes. No treatment exists

to reverse scleroderma, and when it moves to the digestive system, kidneys, heart, and lungs, it is often fatal.

To investigate the possible role of microchimerism in scleroderma, we took blood samples from two groups of women: scleroderma patients and healthy "controls." All the women had previously given birth to a son (mothers of sons were chosen because of the availability of a simple test to detect male DNA in a female host). We found that the amount of male DNA in a tablespoon of blood was significantly greater in the scleroderma patients--equivalent to as many as sixty-one male cells, compared with a maximum of two in the healthy women. The women in our studies had borne their sons many years earlier, yet the levels of male DNA in some of the scleroderma patients exceeded those found in pregnant women carrying a normal male fetus. Working with skin biopsy samples, other investigators subsequently produced similar results.