Basic Science Improving MS Care, a Clinical Context Report

JOHN GEVER: I’m John Gever with MedPage Today, here to do a clinical context expert commentary on multiple sclerosis with Dr. Lawrence Steinman of Stanford University, a preeminent neuroimmunologist.

Dr. Steinman, there are a number of questions that, you know, really have been with us as long as we have known about MS. Some of them may have become more prominent recently. I think one of the most puzzling is the female predominance of the disease. I mean because we don’t really know what the triggers of MS are, it seemed like it would be a window into the disease. And yet really it hasn’t worked out that way too well so far. And of course the female predominance has increased over the last decades. So talk a little bit about that, if you would.

LAWRENCE STEINMAN, MD: Yes. Well, one of the most striking things about MS is that over the past 20 years the ratio of females to males has increased from about 2 to 1 to over 3 to 1. So I don’t think that females have evolved that quickly. There must be something going on in the environment that has changed the situation.

Alternatively, one could argue that maybe we are reporting the disease better or that females are more vocal and are being ascertained in a more prevalent way. But this isn’t happening, as best we can tell. The ratio really is increasing dramatically.

So we set out in the laboratory to attempt to begin to answer the question about what might be differences between males and females. And the work I am describing was done first at my lab at Stanford by a very brilliant postdoc, Dr. Shannon Dunn, who moved to the University of Toronto after finishing her postdoc with me.

So, what she found: first of all, beginning in mice, we have an animal model of multiple sclerosis in mice. It’s a model that was first described about 80 years ago called, for want of a better term, EAE, experimental autoimmune encephalomyelitis. And in that model, females are much more susceptible [than] males.

So we were looking at various gene families that are under the control of androgens and estrogens. And one of the genes that was of most interest to us are a group of genes called the PPARs [peroxisome proliferator-activated receptors]. And they come in various varieties, and they are very sensitive to steroid hormones. So when we knocked out a particular member of the PPAR family — PPAR-alpha — it turned out that the susceptibility in males shot way up.

So what we learned from her studies in mice — and they are very elaborate, and they were published in top journals — was that PPAR, particularly PPAR-alpha and also PPAR-delta and -gamma, serve as brakes on the immune system.

So is it the case, at least in a mouse, that female mouse have, say, a smaller amount of the brake, if you will, than a male mouse? And the answer is yes. And it turns out that in the liver and on their T cells and in other places we look, that the males have much more of PPAR-alpha than females. If we castrate the males — and that’s a horrible experiment — the PPAR level drops.

We also noticed that in a cage, the alpha male, the dominant male, has the highest level of PPAR. So it’s exquisitely sensitive to testosterone. If we give testosterone to females, they’ll grow a moustache in a mouse — I’m saying that facetiously — but they will also increase their level of PPARs.