Investigating Multiple Sclerosis

An Introduction

Multiple Sclerosis (MS) is the most prevalent autoimmune disease among young people, affecting between 2 and 150 people per 100,000.

It is a condition that attacks and destroys myelin, an insulating substance that aids neural transmission in the Central Nervous System (CNS).

Aetiology of MS

The aetiology of Multiple Sclerosis (MS) is largely unknown; however, the predominant theory today is that the disease is autoimmune in nature.

Both environmental and genetic factors contribute to the vulnerability and pathogenesis of the disease and its suggested triggers of exacerbation include physical injury, bacterial or viral infections, stressful life events, and genetic susceptibility.

Considerable research suggests an inflammatory cycle

Winquist, R.J, Kwong, A, Ramachandran, R, Jain, J (2007). The Complex Etiology of Multiple Sclerosis. Biochemical Pharmacology 74:1321-1329.

Trigger of the immune system

Inflammatory acute damage of axons and glia

Structural repair and revival of function

Post-inflammatory gliosis

Neurodegeneration

Genetic insights into Multiple Sclerosis Pathogenesis

Aaron Sparshott

An Introduction

• The pathogenesis of MS is the result of complex interactions between genes and the environment.

• ~50% of MS cases can be explained by the heritable component.– Certain human leukocyte antigen (HLA) factors belonging to

the major histocompatibility complex (MHC) on chromosome 6 were shown in the 1970s to have strong associations with MS and other autoimmune diseases (e.g. diabetes).

– To date HLA Factors have shown the strongest correlations to MS pathogenesis

– Genetic MS susceptibility however is not limited to one gene, but is rather the sum of a number of variant genes exerting small contributory effects.

MS associated genes

A list of 17 single nucleotide polymorphisms (SNPs) in 13 different gene loci was established by the IMSGC* in 2007, with an association (P<6x10-3) with MS susceptibility.

Two significant non-HLA MS linked gene loci based on statistical evidence and function where; IL2Rα and IL7Rα

HAFLER ET AL. (2007) Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study. N Engl J Med. 357(9):851-62.

* International Multiple Sclerosis Genetics Consortium

• HLA-DRα• IL2Rα (2)

• IL7Rα• CBLB

• DBC1• CD58

• KLRB1 • PDE4B

Level of significance of genetic region with MS susceptibility

• ALK• FAM69α (2)

• KIAA0350• RPL5

• ANKRD15• EV15 (2)

Non-HLA Genes

A number of other gene loci on chromosome 1p22 have also shown links to MS pathogenesis.

The discovery of new linked genes opens new avenues for pharmacological targets and therapeutic strategies.

Both cytokines are of central importance in promoting the growth and differentiation of T and B cells.

IL2Rα’s Role in pathogenesis

• Proposed Mechanism– Regulatory T cells are crucial for the maintenance of

immunological tolerance.– SNPs in IL2Rα cause a loss in regulatory T cell function, thus

limiting the body’s ability to control auto-reactive T cells that have escaped the process of negative selection in the thymus.

– T cells which subsequently assist in the autoimmune reaction.

• Pharmacological Targets & Therapeutic Strategies– In support of this association stage 2 trials of Daclizumab

(Zenapax®) a monoclonal antibody targeting the IL2Rα chain have shown clinical efficacy.

Importance of Genetic Research

• Current Research– Refined the knowledge of MS pathogenesis

• Provided supporting evidence for the scientific community’s consensus that MS is an autoimmune inflammatory disorder

– Led to the development of new pharmacological targets and therapeutic strategies for MS.

• Future Research– Biomarkers for early diagnosis– Preventative strategies– Treatments and therapies designed

specifically for the individual