91av

WHY do our bodies often turn against themselves? It’s not just our genes that
dictate whether we’ll suffer from autoimmune diseases, scientists told the AAAS
meeting this week. Misplaced carbon atoms and human cells that invade our bodies
during pregnancy play a significant role in diseases such as arthritis and at
least one form of diabetes.

Genes influence our susceptibility to autoimmune disease, but this cannot be
the whole story. For example, if one identical twin develops multiple sclerosis,
there is less than a five per cent risk of the other doing so.

Now Denise Faustman of Harvard Medical School in Boston and her colleagues
have shown how different cells manipulate the same DNA to trigger different
autoimmune diseases. Faustman and her team were studying a strain of mice
susceptible to type I diabetes, in which the immune system attacks
insulin-producing cells. Just as in humans, not all siblings get the disease. So
she took the unaffected animals and mated them, and after many generations they
bred healthy mice that did not develop diabetes.

But, to their surprise, they also produced another lineage of mice that got
rheumatoid arthritis. Since Faustman’s team started with an inbred lab strain,
all these animals had the same genes. “It’s remarkable that the same genes can
result in inherited diabetes, arthritis or a healthy animal,” she says.

The team found that the key difference between the mouse strains lay in
carbon tags called “imprints” which are attached to genes in the sperm and egg.
Faustman’s team has evidence that differences in imprinting affects the
production of cytokines, molecules that control the behaviour of immune cells.
She believes that imprinting dictates whether the immune system is predisposed
to attack insulin cells in diabetes or joint cells in arthritis—or none at
all.

J. Lee Nelson of the Fred Hutchinson Research Center in Seattle has found
some intriguing evidence that cells that pass from mother to child and vice
versa during pregnancy could trigger an autoimmune reaction.

Nelson was trying to find out why women get autoimmune diseases three times
as often as men, and why symptoms tend to appear during and after their
reproductive years.

To test the idea that fetal cells trigger autoimmune disease when they get
into the mother’s blood, her team examined mothers with an autoimmune disease
called systemic sclerosis. As she suspected, the women with sclerosis had 20
times more fetal cells in their blood than healthy mothers, and the cells
persisted in the mothers’ blood for decades after the birth.

Her lab looked at fetal cell surface proteins called HLAs, which the immune
system uses to distinguish its own cells from others. She found that if the
mother’s HLAs match some of her child’s, her risk of the disease increases
ninefold. Nelson thinks this similarity allows the fetal cells to escape
immediate immune clearance, only to trigger an autoimmune attack later on.

But Nelson realised that a mother might also harbour cells from her own
mother, setting up a possible three-generation clash of HLA types. In new work
she presented at the AAAS, she has found that if grandmother and child’s HLAs
match closely, the mother’s risk increases even more. This suggests that the two
types of cells somehow cooperate to trigger immune dysfunction. “It’s a war
across generations that takes its toll on the body,” says Nelson.