Progress Report 2008: Neuroimmunology
The 2008 Progress Report on Brain Research


February, 2008

The immune system employs its large and varied arsenal of interdependent cells and their molecules to protect us from a constant onslaught of disease-causing organisms. If improperly targeted or regulated, however, the cells and molecules of the immune system may themselves cause disease.

Although it is not clear why, the immune system appears to be the aggressor in the neurological disease multiple sclerosis. Immune-mediated damage to the insulating coating of nerve cells’ axons in the brain and spinal cord interferes with transmission of nerve impulses from one cell to another. Multiple sclerosis can cause a variety of symptoms, ranging from vision disturbances to difficulty walking, and it often follows an up-and-down course in which symptoms periodically worsen.

Both genes and the environment affect susceptibility to multiple sclerosis, but it is likely that many different genes and many different environmental influences interact in the development and progression of disease. Research in 2007 provided new evidence of contributions by genetic and environmental factors that work through the immune system.

Converging on the IL-7 Receptor

In 1972, the genetics involved in multiple sclerosis risk were first linked to a group of immune system genes called HLA. Since then there has been relatively little progress in identifying additional specific genetic risk factors. But the publication of the sequence of the human genome (the complete set of DNA instructions in each human cell) in 2001 has allowed for huge advances in genetic analyses. Using new laboratory techniques and powerful computers, researchers can now analyze previously inconceivable amounts of data, looking for the elusive needle in the genomic haystack.

Of the 3 billion base pairs in the human genome, most of the variation is limited to 250,000 to 500,000 segments of DNA. Simultaneous scanning of these many segments is possible with DNA microarrays, or “gene chips.” Genome-wide scans have revealed genes associated with breast cancer, heart disease, and diabetes.1 These scans require large sample numbers to reveal statistically significant associations when multiple genetic factors each have a small effect. (For more on “genome-wide association,” see also Psychiatric, Behavioral, and Addictive Disorders, page 63.)

The results of a genome-wide scan for genes that confer risk for multiple sclerosis were published in the August 30 issue of the New England Journal of Medicine.2 An international consortium of investigators used gene chip technology to examine hundreds of thousands of individual genetic changes in a total of more than 12,000 samples. Without any preconceived ideas of what they would find, the investigators confirmed the link between the HLA region and the disease and teased out two other markers, one in the gene for the interleukin-2 (IL-2) receptor and one for the interleukin-7 (IL-7) receptor. Interleukins are immune system proteins through which cells communicate and affect the function of other cells.

These receptors are important for cell-to-cell signaling in the immune system. Like the proteins associated with the HLA gene, the IL-2 and IL-7 receptors are important regulators of the immune system, so it makes sense that the genes that produce these two interleukin receptors might play a role in multiple sclerosis. However, no attempt was made in this study to show anything beyond a statistical association.

Often, genetic studies will turn up several possible genetic risk factors for a particular disease, none of them very strong. Subsequent efforts to confirm such risk factors often fail. Now, by combining several different experimental approaches in what Michael Hauser of the Center for Human Genetics at Duke University dubbed “genomic convergence,” scientists can home in on the most promising gene candidates.

Affymetrix GeneChip® microarray - Content
Hybridized DNA fragments glow when a laser light is shined on a microarray, which contains many millions of fragments. (Courtesy of Affymetrix) 

A stronger case for a genetic marker can emerge from combining results of studies associating genes with disease within families, analyzing how genes are inherited together and examining which genes are active in affected tissues. This approach has been used to study the genetics of several complex neurological diseases, including Parkinson’s disease and Alzheimer’s disease, as well as multiple sclerosis.

As part of a genomic convergence approach to the last, two studies appearing in the September 2007 issue of Nature Genetics used targeted searches to look at candidate genes, those that had shown promise in previous functional and genetic studies.3, 4 Like the genomic scan, the Nature Genetics studies also implicated the IL-7 receptor. In fact, they identified the same single-base variation (single-nucleotide polymorphism, or SNP) in the gene that produces the IL-7 receptor.

This particular genetic variation was predicted to make it less likely that the receptor will be bound to the cell membrane, where it can perform its signaling function, and more likely to be present in soluble form, where it can bind up IL-7 and keep it from interacting with cells. Indeed, this was the case, both in the laboratory and in people with multiple sclerosis. This change would theoretically reduce the effect of IL-7 in the body. In addition, expression of genes for both IL-7 and the IL-7 receptor were altered in the cerebrospinal fluid of people with the disease.

Evidence continues to accumulate that IL-7 and its receptor play an important role in the disease process, though it is not clear how. The increase in disease risk attributed to the IL-7 receptor gene is small, but the IL-7 receptor is getting harder and harder to ignore. Further study of the IL-7 receptor may reveal its role in multiple sclerosis and provide new approaches to treatment.5

An IL-7-based pathway in the disease process would be but one of many different disease-promoting mechanisms. Analysis of this and other genetic markers may eventually make it possible to pinpoint what occurs in individual patients, improve diagnostic procedures, and customize patients’ treatment plans.

The Sun Sheds Light on Multiple Sclerosis

The risk for developing multiple sclerosis is strongly associated with latitude; living farther from the equator increases the risk. Even people of shared ancestry may differ in susceptibility if they live at different latitudes, especially when they are young. Recent research points to the sun as the reason for this effect.

A study published in Neurology examined the effect of childhood sun exposure in pairs of identical twins in North America.6 The study, led by Thomas Mack of the Keck School of Medicine at the University of Southern California, showed that, within pairs of twins, the one who spent more time outdoors as a child (going to the beach, or playing team sports, for example) had a lower risk of multiple sclerosis. By studying genetically identical twins, the investigators were able to demonstrate the association of environmental factors without the confounding effects of genetic differences.

Another study, conducted in Norway and published in the Journal of Neurology, showed that childhood sun exposure reduced risk of multiple sclerosis.7 The study also showed that a diet rich in fish reduced risk. The authors, led by Margitta Kampman, suggested that the high vitamin D content of fish might be responsible for its protective effect.

Evidence has indicated a direct effect of vitamin D on the brain. Studies have demonstrated that vitamin D reduces stroke risk in animal models. The protective effect of sun exposure could come from a direct effect of exposure to ultraviolet radiation or, indirectly, through the production of vitamin D. We obtain some vitamin D from food, but the majority is produced by the skin through exposure to the sun, which is why vitamin D is sometimes called the sunshine vitamin. In winter, when the days are shorter and the sun is lower in the sky, vitamin D deficiencies are common. In fact, people living in latitudes even with or north of Boston obtain no vitamin D at all from the sun between November and February.

Vitamin D is known to be important for maintaining bone density. Perhaps less well known are the regulatory effects of vitamin D on the immune system. Receptors for vitamin D are present on cells of the immune system, and vitamin D deficiency has been associated with autoimmune or inflammatory diseases, including asthma, rheumatoid arthritis, inflammatory bowel disease, and diabetes. Scientists also are exploring the protective role of vitamin D in mouse models of multiple sclerosis.

Several recent population studies have shown that vitamin D levels in the blood correlate inversely with the risk of being diagnosed with multiple sclerosis. A study conducted in Tasmania, Australia, showed that people with the disease had lower blood levels of vitamin D.8 A study of U.S. military personnel, published December 20, 2006, in the Journal of the American Medical Association, measured vitamin D levels over time and found that decreased levels preceded onset of multiple sclerosis symptoms.

Progress Report 2008, Chapter 5, Image 3, Vitamin D - Content
Research in 2007 indicates that vitamin D, produced in the skin through exposure to the sun, may reduce the risk of multiple sclerosis. (Illustration by William Stilwell) 

This finding supports the interpretation that vitamin D deficiency is a contributing factor to multiple sclerosis, rather than a result of reduced sun exposure due to disability.9 Yet another study, this one from Finland and published in the Journal of Neurology, Neurosurgery, and Psychiatry showed that decreased levels of vitamin D in the blood were associated with worsening of symptoms.10

Because of its potential effects on susceptibility to multiple sclerosis and other diseases, investigators are taking a new look at recommendations for dietary intake of vitamin D. Currently, the Institute of Medicine of the National Academy of Sciences considers 200 International Units (IU), or 5 micrograms, of vitamin D per day to be adequate for most people aged 50 and under. In September 2007, the Canadian Paediatric Society issued a statement recommending that pregnant and nursing women consider vitamin D supplementation up to 2,000 IU per day.11

The group also recommended that babies that are exclusively breastfed get 400 IU of vitamin D and that babies living above 50 degrees latitude (from about as far north as Edmonton, Alberta) receive 800 IU in the winter months. Animal studies suggest that vitamin D can be used to both prevent and treat multiple sclerosis, but more research is needed before these findings can be applied to humans.

Notes

1. Topol EJ, Murray SS, and Frazer KA. The genomics gold rush. Journal of the American Medical Association 2007 298(2):218–221.

2. International Multiple Sclerosis Genetics Consortium. Risk alleles for multiple sclerosis identified by a genomewide study. New England Journal of Medicine 2007 357(9):851–862.

3. Gregory SG, Schmidt S, Seth P, Oksenberg JR, Hart J, Prokop A, Caillier SJ, Ban M, Goris A, Barcellos LF, Lincoln R, McCauley JL, Sawcer SJ, Compston DAS, Dubois B, Hauser SL, Garcia-Blanco MA, Pericak-Vance MA, and Haines JL, for the Multiple Sclerosis Genetics Group. Interleukin 7 receptor  chain (IL7R) shows allelic and functional association with multiple sclerosis. Nature Genetics 2007 39(9):1083–1091.

4. Lundmark F, Duvefelt K, Iacobaeus E, Kockum I, Wallström E, Khademi M, Oturai A, Ryder LP, Saarela J, Harbo HF, Celius EG, Slater H, Olsson T, and Hillert J. Variation in interleukin 7 receptor  chain (IL7R) influences risk of multiple sclerosis. Nature Genetics 2007 39(9):1108–1113.

5. Harley JB. IL-7Rα and multiple sclerosis risk. Nature Genetics 2007 39(9):1053–1054.

6. Islam T, Gauderman WJ, Cozen W, and Mack TM. Childhood sun exposure influences risk of multiple sclerosis in monozygotic twins. Neurology 2007 69(4):381–388.

7. Kampman MT, Wilsgard T, and Mellgren SI. Outdoor activities and diet in childhood and adolescence relate to multiple sclerosis risk above the Arctic Circle. Journal of Neurology 2007 254(4):471–477.

8. Van der Mei IAF, Ponsonby A-L, Dwyer T, Blizzard L, Taylor BV, Kilpatrick T, Butzkueven H, and McMichael AJ. Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia. Journal of Neurology 2007 254(5):581–590.

9. Munger KL, Levin LL, Hollis BW, Howard NS, and Ascherio A. Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. Journal of the American Medical Association 2006 296(23):2832–2838.

10. Soilu-Hänninen M, Laaksonen M, Laitinen I, Erälinna J-P, Lilius E-M, and Mononen I. A longitudinal study of serum 25-hydroxyvitamin D and intact PTH levels indicate the importance of vitamin D and calcium homeostasis regulation in multiple sclerosis. Journal of Neurology, Neurosurgery, and Psychiatry 2007. doi:10.1136/jnnp.2006.105320.

11. Godel JC. Vitamin D supplementation: Recommendations for Canadian mothers and infants. Paediatrics and Child Health 2007 12(7):583–589.

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