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Sex Differences and Gene Expression in Autoimmune Disease
Edward R. Winstead

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"Pregnancy is by far the best therapy, but we are not recommending it."

—Denise L. Faustman of Harvard Medical School explaining that for unknown reasons, rheumatoid arthritis goes into complete remission during pregnancy, and then returns.

Sex differences clearly affect the immune system, and women are more likely than men to develop autoimmune diseases like diabetes, lupus, and rheumatoid arthritis.

No one knows why autoimmune diseases target females, says Denise L. Faustman, who spoke on the topic at the first meeting on Sex and Gene Expression. Hormones are a plausible explanation and, perhaps, the first place to look, but the link between estrogen and disease is not clear. Although rheumatoid arthritis can go away during pregnancy, lupus often worsens during pregnancy. So hormones certainly arenít the whole story. The link between estrogen levels and disease is anything but clear: women in their 20s and 30s, who produce lots of estrogen, have immune disorders, but so do preadolescent and postmenopausal females, who make less estrogen.

A sex difference that matters

Like emotions, some genes are expressed differently by males and females. Small differences in gene expression, says Faustman, can have profound effects on health. Understanding these differences will be important in the diagnosis and treatment of all immune disorders, she predicts.

Faustman postulates a different reason for the vulnerability of the female immune system: certain crucial genes are less active in females than males. She presented research on female mice that suddenly stop producing a protein that plays a key role in the immune system. Without the protein, the mice develop early-onset diabetes.

The proteasome is a garbage disposal that a few years ago became a Cuisinart

Autoimmune diseases are surprisingly alike, Faustman observes, citing recent research by others. The diseases share many of the same genes, some of which have indistinguishable defects. For example, different autoimmune diseases, apparently regulated by the same genes, sometimes strike the same family: the grandmother has multiple sclerosis, while the mother has rheumatoid arthritis, and the daughter has diabetes.

But carrying the susceptibility genes for a disease does not mean that someone is destined to become ill. Faustman cites the fact that identical twins with different autoimmune disorders are relatively common. Since identical twins share the same genes, the discordance cannot be due to a difference in genes. A more likely explanation, she says, is a difference in gene expression, which involves many factors, including environment and sex.

Each cell has many proteasomes floating in the cytoplasm.

A normal gene sequence

The focus of the research Faustman presented was a mouse gene called Lmp2. Both males and females in the study were born with normal Lmp2 genes, but at about six weeks, some females stopped producing the Lmp2 protein.

The lack of protein appeared to be a sex-related problem of gene expression. Faustman and her colleagues donít know the precise cause of the lost Lmp2 activity, but the consequence was an impaired ability to process proteins that disrupted the immune system and initiated disease.

End view of a single proteasome.

The Lmp2 protein is part of a cellular structure called the proteasome, which degrades proteins and helps the immune systemís killer T-cells learn the difference between the body and invaders. "The proteasome is a garbage disposal that a few years ago became a Cuisinart," says Faustman, referring to recent research on its role in immune health. "It chops up proteins, yes. But it is also a very important pathway for T-cell education."

The effects of bad schooling

Cells without the Lmp2 protein have difficulty processing proteins, and this affects the education of T-cells, says Faustman. Poorly educated T-cells tend to attack the body, causing autoimmune disease.

Cross-section of a single proteasome.

Her study also revealed an unexpected role for Lmp2. It is needed for the production and activation of a protein known as KF-kB, a major regulator of immune system function. NF-kB is one of the most important known proteins in the immune system, says Faustman. The protein plays a role in immune and inflammatory responses. But its role in diabetes and other autoimmune diseases needs to be explored.

Future studies will look for a similar deficit of Lmp2 in humans with early-onset diabetes, says Faustman. This research appeared in the December 1999 issue of Molecular and Cellular Biology.

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»Images of Imprinting

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Hayashi, T. & Faustman, D. NOD mice are defective in proteasome production and activation of NF-kappaB. Mol Cell Biol 19, 8646-8659 (December 1999).

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