In lupus, the immune system’s attack on the body begins with a simple molecular act: an antibody twists DNA into a shape it can grab.
The immune system is the ultimate arbiter of which substance is dangerous to the body and which is benign, what is self and what is not- self. But when that judgment goes awry, a biological civil war called autoimmune disease breaks out. Perhaps the most infamous autoimmune disease is systemic lupus erythematosus, which afflicts tens of thousands of Americans (90 percent of them women) and is sometimes fatal. In lupus, the body inexplicably begins to attack its own DNA, setting off a chain reaction that leads to inflammations in the connective tissues of the skin, kidneys, and other organs.
Now researchers at the University of Michigan think they have uncovered an early link in that destructive chain: the means by which the immune system first captures and subdues what it has come to see as its enemy.
In a normal immune response the body detects the presence of some foreign protein or carbohydrate--an antigen--displayed on the membrane of an invading bacterium or virus. It then begins churning out Y-shaped proteins called antibodies that grab onto the invader, tagging it for destruction. But in lupus, for reasons still not understood, the body suddenly begins producing antibodies to attack bits of harmless DNA (some of them released by dead cells) that float around in the bloodstream. The antibody-DNA complex then sticks to, say, the walls of the kidney, initiating a full-scale immune attack on that bit of tissue.
One thing researchers hadn’t figured out was how the antibodies manage to grip DNA, which is so different from their typical targets. Gary Glick, a chemist at Michigan, thought he might have the answer--a phenomenon known as induced fit, which occurs when one molecule literally changes the shape of another so they can fit together more closely. It’s as if you were trying to fit a round peg into a square hole, explains Glick, and you could actually change the shape of the hole to make the peg fit better.
To see if lupus antibodies might be changing the shape of DNA, Glick and his colleagues looked at a type of DNA structure called a hairpin. A hairpin is a single strand of DNA that has folded back on itself, bringing pairs of complementary nucleotides--the building blocks of DNA--into contact. The complementary nucleotides bind to each other, twisting the single strand into the familiar double helix--except at one end, where a single-stranded loop of unpaired nucleotides remains.
Glick’s team synthesized two kinds of hairpin: the natural type, and a second one in which the weak hydrogen bonds that ordinarily link the two strands of the double helix were supplemented by much stronger disulfide bonds (a type of bond usually found only in proteins). The researchers then extracted an anti-DNA antibody from lupus-prone mice, sicced it on both types of hairpin, and watched what happened.
As Glick had expected, the antibody bound quite nicely to the natural DNA--but not to the strengthened pieces. In other words, it could get a secure grip only on what it could deform. Our little disulfide lock prevented the DNA from changing its structure, Glick explains. This showed that the antibody molecule, after touching or sticking to the DNA initially, is grossly changing the shape of the DNA molecule to make a better fit.
The antibody binds initially to where the hairpin is single stranded, he goes on, and then starts unwinding the double helix. But not only is it unwinding it, it’s breaking the double helix, breaking the hydrogen bonds. The hydrogen bonds are so weak, Glick says, that all it takes to break them is a little pushing and pulling by the antibody as it attaches itself securely to the single-stranded loop.
Hairpins are not the only type of DNA floating in the bloodstream. There are other types--for instance, an ordinary double helix with a bubble of unraveled DNA in its center--and in lupus they may be attacked by other antibodies. But Glick suspects that his induced-fit mechanism plays a role in most if not all of these attacks. If researchers can just figure out all the details of how an antibody tightens its grip on DNA, he says, they may be able to find a way to loosen it--or to stop the antibody from getting a grip in the first place. That’s why we’re now trying to generate a real three-dimensional picture of this antibody-DNA complex, says Glick. If you can find precisely where on the DNA the antibody binds, you can perhaps design and synthesize drugs that would block it.
