Multiple Sclerosis (MS)

Multiple Sclerosis Background

Multiple sclerosis (MS) is a chronic and often progressive disease that affects the fatty substance called myelin that surrounds the nerves in the brain and spinal cord of the central nervous system (CNS). Myelin insulates the nerves and enables them to conduct impulses within the brain and to other parts of the body. In MS, the body’s own immune system attacks the myelin causing scar tissue, nerve damage, and potentially neuronal loss. Because this loss of myelin impedes the nerve’s ability to conduct electrical impulses to and from the brain, nerve signals have difficulty reaching their destinations, leading to various symptoms including weakness, fatigue, vision impairment, difficulty walking, and pain.

Unfortunately, the exact cause of MS is still unknown. It is believed that a variety of environmental factors, such as smoking, Vitamin D deficiency, microbial infection, as well as genetic risk factors play a part in determining who develops MS. Although MS is not considered an inherited disorder in the classic sense, clustering of MS cases within families suggests genetic influences on MS susceptibility, likely through multiple and potentially interacting genes, each with a relatively small contribution to overall risk.

Multiple Sclerosis Research at DMPI

Interleukin-7 receptor alpha. In 2007, Dr. Simon Gregory led a team that identified a genetic association between a single nucleotide polymorphism (SNP) in the Interleukin-7 receptor alpha (Il7rα) gene and MS. The SNP, which is a change in of a single letter in the sequence of the DNA, leads to an alteration of the levels of IL7R protein produced and to increased risk of developing MS.

Ongoing research in Dr. Gregory’s lab, together with colleagues at University of Texas Medical Branch published a paper in Cell  that identified an RNA helicase protein (DDX39B) as being important for regulating IL7R protein and show that the gene is itself a novel risk factor for MS.

Novel drug that moderates MS severity. In collaboration with Drs. Eric Benner (Pediatrics) and Mari Shinohara (Immunology) at Duke, Dr. Gregory’s lab is exploring the effects of a naturally occurring molecule 20-Hydroxycholesterol (20HC) in the context of an animal model of MS. Dr. Gregory and colleagues have found that 20HC not only decreases the production of pro-inflammatory immune cells but it also aids in recovery from neuronal damage by triggering remyelination via special cells in the brain. This exciting ongoing research is the basis of a grant submission currently under review.

Predictors of disease course in Primary Progressive MS patients (PPMS). Dr. Gregory’s lab recently published a paper exploring the use of high sensitivity protein profiling assays to characterize a neuronal scaffolding protein (Neurofilament Light, NfL) that is released when neuronal degeneration happens in the central nervous system of MS patients. The study showed that, unlike Relapsing Remitting MS where NfL has been shown to reflect the efficacy of MS drug treatment, NfL is not a good surrogate for using clinical progression in PPMS.

Predictors of disease progression: Identifying predictors of disease progression provides important information for the clinical management of MS patient’s disease. Dr Gregory’s lab, together with the Immune Tolerance Network, are generating high resolution single cell profiles from the blood of MS patient who are slow or rapid progressors. By identifying cell signatures throughout disease progression, Dr. Gregory’s group hope to develop diagnostic blood tests that can help manage MS patients disease development.

Assessment of quality of life for MS patients. Together with collaborators from the MURDOCK study at Duke, Dr Gregory is collaborating with genetic epidemiologists across the country to identify risk factors and predictors of quality of life assessment tools from 175 MS cases matched to MURDOCK controls. The recent completion of data collection is now giving way to analysis in this important epidemiological study.

Multiple Sclerosis Study Team

Simon Gregory, PhD

Principal Investigator

Stephanie Arvai

Laboratory Analyst I 

Stephanie Giamberardino

Statistical Analyst

James Giarraputo

4th year Duke Medical Student

DMPI MS Publications

Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk.
Galarza-Muñoz G, Briggs FBS, Evsyukova I, Schott-Lerner G, Kennedy EM, Nyanhete T, Wang L, Bergamaschi L, Widen SG, Tomaras GD, Ko DC, Bradrick SS, Barcellos LF, Gregory SG, Garcia-Blanco MA.
Cell. 2017 Mar 23;169(1):72-84.e13. doi: 10.1016/j.cell.2017.03.007.

An interferon-β-resistant and NLRP3 inflammasome-independent subtype of EAE with neuronal damage.
Inoue M, Chen PH, Siecinski S, Li QJ, Liu C, Steinman L, Gregory SG, Benner E, Shinohara ML.
Nat Neurosci. 2016 Dec;19(12):1599-1609. doi: 10.1038/nn.4421. Epub 2016 Nov 7.

Cleavage and polyadenylation specificity factor 1 (CPSF1) regulates alternative splicing of interleukin 7 receptor (IL7R) exon 6.
Evsyukova I, Bradrick SS, Gregory SG, Garcia-Blanco MA.
RNA. 2013 Jan;19(1):103-15. doi: 10.1261/rna.035410.112. Epub 2012 Nov 14.

Alternative splicing in multiple sclerosis and other autoimmune diseases.
Evsyukova I, Somarelli JA, Gregory SG, Garcia-Blanco MA.
RNA Biol. 2010 Jul-Aug;7(4):462-73. Epub 2010 Jul 1. Review.

Follow-up examination of linkage and association to chromosome 1q43 in multiple sclerosis.
McCauley JL, Zuvich RL, Bradford Y, Kenealy SJ, Schnetz-Boutaud N, Gregory SG, Hauser SL, Oksenberg JR, Mortlock DP, Pericak-Vance MA, Haines JL.
Genes Immun. 2009 Oct;10(7):624-30. doi: 10.1038/gene.2009.53. Epub 2009 Jul 23.

SNPs in Multi-species Conserved Sequences (MCS) as useful markers in association studies: a practical approach.
McCauley JL, Kenealy SJ, Margulies EH, Schnetz-Boutaud N, Gregory SG, Hauser SL, Oksenberg JR, Pericak-Vance MA, Haines JL, Mortlock DP.
BMC Genomics. 2007 Aug 6;8:266.

Interleukin 7 receptor alpha chain (IL7R) shows allelic and functional association with multiple sclerosis.
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 DA, Dubois B, Hauser SL, Garcia-Blanco MA, Pericak-Vance MA, Haines JL; Multiple Sclerosis Genetics Group.
Nat Genet. 2007 Sep;39(9):1083-91. Epub 2007 Jul 29.

Risk alleles for multiple sclerosis identified by a genomewide study.
International Multiple Sclerosis Genetics Consortium, Hafler DA, Compston A, Sawcer S, Lander ES, Daly MJ, De Jager PL, de Bakker PI, Gabriel SB, Mirel DB, Ivinson AJ, Pericak-Vance MA, Gregory SG, Rioux JD, McCauley JL, Haines JL, Barcellos LF, Cree B, Oksenberg JR, Hauser SL.
N Engl J Med. 2007 Aug 30;357(9):851-62. Epub 2007 Jul 29.

MS Support Groups and Information Sources

National Multiple Sclerosis Society – Greater Carolinas

TEL: 919-834-0678 FAX: 704-527-0406
EMAIL: NCT@NMSS.ORG
3101 Industrial Drive, Suite 210
Raleigh, NC 27609