Women and Lupus: The Inactive X Chromosome Awakens
American College of Rheumatology 2006 Annual Meeting, Plenary Session III, November 14, 2006, Presentation 1972
Women and lupus: The inactive X awakens
Every human (with occasional exceptions) has 23 matched pairs of chromosomes (bundles of genes), and for each of these pairs, one is inherited from the mother, the other from the father. These chromosomes contain the blueprints that guide the production of proteins in the body. Each set of instructions that designate how a protein will look is called a gene. Therefore, it is our genes that determine our basic physical characteristics, and also direct the activities that occur at the most basic levels of our cells.
Twenty two of the 23 inherited chromosomes from each parent are nearly identical in size and structure; not so, however, for the chromosomes that determine which sex a person will be. Women receive two chromosomes of similar length, called the X chromosome, one from their mother, and one from their father. Males inherit an X chromosome from their mother, and a much smaller chromosome, the Y chromosome, from their father. Since (except in some rare instances) each man has one X and one Y chromosome, and each woman has two X chromosomes, it is the father’s contribution that determines what sex the child will be.
Because the X chromosome is larger than the Y chromosome, people with two X chromosomes might have more copies of certain active genes than people with an X and a Y. Usually this does not happen, because in women, certain genes on one of the two X chromosomes become inactive. That insures that men and women will have the same number of genes and produce the same number of proteins for certain cellular functions. The silencing of this X chromosome is achieved through a process called methylation, which means that a chemical modification has been introduced to silence the genetic material. The opposite of this can also occur, which is called demethylation.
A number of studies and findings have suggested that demethylation of particular genes may be involved in lupus. Qianjin Lu, MD, PhD, of the Xiangya Hospital of Central South University in Changsha, China, and a team of researchers led by Bruce Richardson, MD, at the University of Michigan, looked at the effect of demethylation of the X chromosome, and whether that was associated with lupus activity. In particular, Dr. Lu and colleagues focused on CD40-ligand, a molecule that may sometimes be overproduced by immune cells of women with lupus. The gene that directs the production of CD40-ligand is located on the X chromosome.
Their first experiments found that the gene that promotes the production of CD40-ligand was unmethylated in T-cells of men, while in women, half the promoter genes were methylated and half were unmethylated; this was consistent with the understanding that one set of the "double" instructions in women becomes inactivated.
Following that determination, they used a process to demethylate the CD40-promoter gene. That had no effect on the amount of CD-40 ligand produced in T cells from men, but resulted in greater production of this protein by T-cells in women.
They then compared the methylation and expression of the CD40-promoter gene in T cells of women with lupus with those of healthy women. In eight women with lupus, the promoter gene was demethylated to a much greater degree than in the healthy women and the degree of demethylation seemed to be proportional to disease activity.
The research team then compared the level of CD40-ligand produced when they stimulated T cells from men and women who had lupus, and whose lupus disease activity was scored as the same on the SLEDAI test. There was a greater degree of expression of CD40-ligand by the cells from women than from those from men.
Through this step-by-step process, the researchers concluded that demethylation of the inactive X chromosome results in greater expression of the CD40-promoter gene. This, in turn, may be a factor that helps to explain why there is more lupus in women. What causes the demethylation, however, still remains to be determined. And clearly, since men can develop severe lupus, there may be more than one way to get lupus. In fact, it is thought that there are many factors contributing to lupus in both men and women. Each study like this one, however, can contribute to solving this intricate puzzle.
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