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Date: September 17, 1998
With Auto-Immune Disease, Gender Differences May Be More Than Hormonal
Researcher's Theory on Systemic Lupus Erythematosus May Have Broader Implications
Princeton, N.J.--Scores of diseases affect men and women differently. The obvious reason? Differences in hormones. Yet, the assumption that hormonal differences are behind the discrepancy in the percentage of men or women who have a specific disease has kept researchers from investigating other gender-based causes.
That thinking is the basis of a theory discussed in the August issue of Immunology Today by Jeffrey Stewart, a member of the technical staff in the laboratory of Professor of Molecular Biology Martin Weigert. Stewart's work focuses on systemic lupus erythematosus, but his theory could have implications for other auto-immune diseases.
Women account for up to 90 percent of those who suffer from lupus. For years, research on the disease has focused on estrogen, with good reason: The disease primarily affects women of child-bearing age, and estrogen has been shown to exacerbate the disease in laboratory animals. But there were problems as well. Patients with lupus had normal estrogen levels, and experiments with estrogen-laden birth control pills were inconclusive.
Could something about women, besides their hormones, be the culprit in lupus? Stewart thinks so. His theory starts with a basic tenet of human reproduction--the knowledge that while men have only one X chromosome, received from their mothers, women have two X chromosomes, one from each parent. In each cell in a woman's body, one of those X chromosomes is inactivated. The result is a biological difference between men and women that has nothing to do with hormones. In men, each cell has the same set of active chromosomes, while women are a "mosaic" of two types of sets, one set being cells with functioning X chromosomes from the mother, the other set having a functional X chromosome from the father.
To Stewart, this mosaic could be the root of an auto-immune disease such as lupus. Human immune systems rely on the ability of T cells to recognize foreign cells--or "non-self" cells--in the body, such as cancerous tumors, virally-infected cells or even transplanted organs. But things can go wrong, causing a T cell to react even when there is no invader. The body has a back-up plan for this occurrence: As T cells mature in the thymus, they react with dendritic cells, which screen out the autoreactive T cells. If the troublesome, autoreactive T cells fail to have these encounters with dendritic cells, Stewart reasoned, the T cells in question can wreak havoc, causing the body's immune system to battle normal cells. (Thus, the term auto-immune disease.)
Stewart's theory suggests that if a T cell is reactive only to dendritic cells with an active X chromosome from a woman's mother, a woman who has a lopsided number of cells with active X chromosomes from her father could be a candidate for an auto-immune disease. The reverse would also be true. While the number of active X chromosomes from each parent in the cells of the entire female population is roughly equal, the split can vary greatly among individual women. For some, the share of active X chromosomes from just one parent can be as high as 9 in 10.
In Immunology Today, Stewart pegs his theory to a statistical analysis of a combination of factors; what happens to autoreactive T cells when a woman's dendritic cell makeup includes a highly skewed share of active X chromosomes favoring one parent, and how likely is this scenario? Stewart takes particular note of a series of 1997 experiments led by Tsuyoshi Sakane, which examined the link between certain T-cell clones and B cells in female lupus patients. The link between B cells and lupus had already been established. However, Sakane's research showed that it was the reaction with T cells, not necessarily B cells acting on their own, that caused the production of both anti-foreign antibodies, which would be expected, and anti-self antibodies, which are unexpected. This peculiar autoreactive quality of the T cells caught Stewart's attention, for he felt his theory could explain the cells' behavior.
While Stewart had been thinking about the relationship between the "mosaic" and auto-immune disease for several months, it was the publication of Sakane's results that Stewart said gave him data to confirm his idea. "All the pieces fell into place," said Stewart. "X-chromosome inactivation provided the female mosaic, the low number of dendritic cell precursors provided the skew in the dendritic cell populations, and Sakane provided the auto-immune T cells. I dropped everything and immediately began writing a manuscript."
The theory has implications for diseases besides lupus. Stewart notes the high incidence of autoimmunity in those with X-chromosome aberrations, including those with Klinefeleter's syndrome (males with two X chromosomes) and Turner's syndrome (females with a damaged X chromosome).
Stewart's theory is already being tested in a clinical setting. Dr. Peter K. Gregersen of the New York University School of Medicine, working at North Shore University Hospital on Long Island, is running tests on lupus patients that could lead to a very simple treatment for the disease. If the critical dendritic cells are failing to recognize autoreactive T cells, Stewart said, it is possible to chemically treat a patient's dendritic cells to make the autoreactive T cells aware of the X chromosome they failed to see in development. A patient's blood would be drawn, treated, and replaced, thus boosting the patient's functioning dendritic cells that would carry out the screening duties. Stewart already has a patent pending on this procedure.