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 between the brain and other parts of the body.

In MS, the body’s own defense mechanism, the 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 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. This SNP, the 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 focuses on the development of genetically modified mice that replicate the IL7R protein levels produced by humans who do and do not harbor the SNP. Further, Dr. Gregory and colleagues at University of Texas Medical Branch published a paper  in Cell (2017) that identified an RNA helicase protein (DDX39B) as being important for proper processing of IL7R protein and subsequently as a novel risk factor for MS. 

Experimental autoimmune encephalomyelitis. For many studies of human diseases, it is necessary to use a model organism to test hypotheses and search for pathogenesis. For multiple sclerosis, experimental autoimmune encephalomyelitis (EAE) is a commonly applied animal model, often used in mice.

EAE allows researchers to study specific aspects of the disease that are not feasible in human studies. For instance, Dr. Gregory’s lab is focusing on how the stress of autoimmune disease affects the thymus, causing significant decrease in size, loss of cellularity, and possible infiltration of B cells from the periphery.

Through EAE experimentation, Dr. Gregory’s lab also identified microRNA 149-5p (miR-149) as a gene of interest associated with EAE development and possibly MS. MicroRNA’s are small pieces of RNA that can serve regulatory functions, modifying expression of certain proteins. Ongoing research is attempting to determine the significance of miR-149 in EAE and evaluate its potential role in human biological pathways.

Novel drug that moderates MS severity. Dr. Gregory’s lab, in collaboration with Duke Drs. Eric Benner (Pediatrics) and Mari Shinohara (Immunology), is exploring  the effects of a naturally occurring molecule on autoimmune disease.  Dr. Gregory and colleagues have found that that the molecule moderates the production of pro-inflammatory immune cells and aids in recovery from neuronal damage.

Multiple Sclerosis Study Team

Simon Gregory, PhD

Principal Investigator

Stephanie Arvai

Laboratory Analyst I 

Stephanie Giamberardino

Statistical Analyst

Nava Barman

Undergraduate 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
3101 Industrial Drive, Suite 210
Raleigh, NC 27609