Column: A Clue in the Multiple Sclerosis Mystery

by Ralph M. Steinman, M.D.

September 23, 2009

One of the most challenging links between immunology and the nervous system is the disease multiple sclerosis (MS). In people with MS, the immune system attacks myelin, an important material that insulates our nerves and helps conduct electrical signals from cell to cell.

Scientists do not yet understand what triggers the attack on myelin. However, in the last two years a sea change has occurred in our understanding of the nature of the “self” attack after it begins. This new understanding, many of us believe, will lead to new therapies for MS.

In this resurging field, a molecule called interleukin-17, or IL-17, is a fulcrum. IL-17 first came on the scene in 1996 in the lab of Jacques Banchereau, this year’s winner of the American Association of Immunologists–Dana Foundation Award in Human Immunology Research.

The Banchereau team was not, at the time, focused on MS, but rather on molecules that drive inflammation more broadly. They reported in the Journal of Experimental Medicine their discovery of a new molecule—IL-17—which stimulated the production of phagocytes (white blood cells) to defend against infection.

Shortly thereafter, Jay Kolls, now at Louisiana State University, began to identify the helpful roles of IL-17. Kolls was trying to figure out how the body defends against a difficult pneumonia caused by the organism Klebsiella pneumoniae. In 2001, Kolls proved that IL-17 was needed to defend against this bug.

The IL-17 field has taken off in the years since. Scientists identified a major new pathway in which immune T cells—a subtype of white blood cells—commit to making IL-17. These “Th17” cells help our bodies resist not only Klebsiella, but other scourges such as Staphylococcus aureus and the fungus Candida albicans. Th17 cells and IL-17 are important; people with genetic deficiencies in the Th17 pathway suffer from corresponding infections.

That’s the protective role of IL-17. But what about the downside? Thanks to more superb immunology from several quarters, we now realize that Th17 cells bring about certain types of autoimmunity, and MS is a leading example.

Much of current MS research on IL-17 is in a mouse model that has been vital for the development of most existing therapies for human MS. In addition, scientists already are looking for Th17 cells in samples from MS patients.

Notably, immunologists quickly figured out some key molecules that teach T cells to become Th17 in nature. They identified other interleukins, such as IL-6 and IL-23, that drive the Th17 cells.

Furthermore, the intricate genetic program of the Th17 cell is being illuminated. This program allows Th17 cells to make many products in addition to IL-17 whose relevance was previously obscure. Now there is great potential to develop agents to block the elements of the newly discovered Th17 pathway in people with MS and other forms of autoimmunity.

But what about the enigma? How does this Th17 pathway get triggered in the first place, especially to focus on the brain? Federica Sallusto and her colleagues identified a major clue in findings they published in the May Nature Immunology.

This Swiss team knew that Th17 cells had a special receptor called CCR6 that guides the cells’ movement to wherever an attracting molecule, CCL20, is made. Normally, CCR6 and CCL20 work together to direct Th17 cells to body surfaces to fight infections such as K. pneumoniae, S. aureus and C. albicans.

The downside is that parts of the brain, particularly the choroid plexus, are rich in CCL20 and thus also attract Th17 cells. The Nature Immunology research showed that if a mouse has Th17 cells, but these cells cannot get into the choroid plexus, MS is blocked. The step that enables Th17 to enter the brain looks like a pivotal one for figuring out how the autoimmune attack in the brain begins.

Clearly the research community is making significant discoveries in its longstanding commitment to figure out MS and to identify new treatments—beginning with steps toward understanding, once and for all, how it starts.