Limits of Optimism

Traditional understanding of MS

A chronic inflammatory disease of the central nervous system marked by localized autoreactive components of the adaptive immune system (T-cells and macrophages) that lead to the destruction of myelin, as well as axonal and neuronal loss.

Multiple sclerosis (MS) is an autoimmune disease wherein one’s immune system attacks attacks their central nervous system comprised of the brain and spinal cord. As a result of nervous system damage, patients suffer from a broad range of neurological disorders including cognitive impairment, depression, visual problems, muscle weakness and spasms that lead to immobility, etc.

MS patients often suffer involuntary eye movements called nystagmus.

The damage to the central nervous system in MS patients is characterized by the deterioration of the myelin sheath that surrounds each nerve fiber. Myelin is made up of 80% lipid and 20% protein, and it’s white appearance gives name “white matter” to regions of the brain where it’s abundant. Myelin acts as a dielectric layer that speeds up electrical signals as they travel through the nervous system. When this layer is lost, the body can no longer propagate signals in an intended or timely manner. In addition to MS, the destruction of myelin can lead to an assortment of diseases depending on which portion of the central nervous system is attacked by the immune system:
- transverse myelitis: spinal cord
- Devic’s disease: optic nerves and spinal cord
- progressive multifocal leukoencephalopathy: brain (viral based)
- Optic neuritis: optic nerve

While a variety of therapeutics exist for MS, currently approved therapies have little effect in progressive stages. The pitfall of current therapies may be that they are primarily designed for anti-inflammatory effects that target the adaptive immune system.

New perspectives on MS
The traditional understanding is challenged by mounting evidence and has lead to the hypothesis that the dysregulation of the innate immune system may be a key factor in the shift toward irreversible neurodegeneration and MS progression. This hypothesis implies that components of the immune system previously thought to be uninvolved may be contributing to disease progression. These include dendritic cells, natural killer T cells, and resident microglia. This newly realized complexity of MS progression explains the previously limited ability to provide accurate prognosis for a significant number of patients, as well as the limited efficacy of FDA approved therapies.

The overall perspective has shifted to MS being a constitutive diffuse syndrome rather than the classical notion of a multifocal disease with periodic heightened immune activation.

Novel therapeutics
The evolving perspectives on MS disease progression has led scientists toward novel therapeutics for this multifaceted adversary:
- Natalizumab: prevents T-cells from passing through the blood-brain barrier and suppresses disease progression.
- Daclizumab: inhibits the activation and proliferation of T-cells.
- Rituximab: modulation of the immune system toward anti-inflammation (inhibition of B-cell activation and function).
- Alemtuzumab: targets multiple immune system components ( T-cells, B-cells, and monocytes) to reduc autoreactivity.
- Laquinimod: an orally administered immunomodulator.
- Fingolimod (FTY720): an orally administered immunosupressant for MS.

* ‘-zumab’ = humanized monoclonal antibody

Lifestyle considerationsThe prevalence of MS directly correlates with distance from the equator (increase in latitude). Experts have explained this trend in the context of decreased exposure to sunlight and seasonal vitamin D deficiencies. This explanation is affirmed by studies showing that risk of MS is reduced in populations who are exposed to increased sunlight/UV, as well as in those who take vitamin supplements. Vitamin D has potent immunoregulatory properties and in disease models, vitamin D3 prevents autoimmune-based inflammation of the brain and spinal cord that leads to myelin damage. Alarmingly, reports indicate that 40-50% of Americans are deficient in Vitamin D.

Therapeutic foods
- Celery (luteolin): blocks the inflammatory response of the brain’s immune system (reduces microglia production)
- Turmuric (curcuming): Anti-inflammatory (dampens macrophage function)

References:
Novel therapeutic strategies for multiple sclerosis–a multifaceted adversary.
Lopez-Diego RS, Weiner HL.
Nat Rev Drug Discov. 2008 Nov;7(11):909-25.

Luteolin reduces IL-6 production in microglia by inhibiting JNK phosphorylation and activation of AP-1.
Jang S, Kelley KW, Johnson RW.
Proc Natl Acad Sci U S A. 2008 May 27;105(21):7534-9. Epub 2008 May 19.

Inhibition of interleukin-12 production in lipopolysaccharide-activated macrophages by curcumin.
Kang BY, Chung SW, Chung W, Im S, Hwang SY, Kim TS.
Eur J Pharmacol. 1999 Nov 19;384(2-3):191-5.

Tags: autoimmune, central nervous system, D3, drug discovery, immune system, Multiple Sclerosis, myelin, therapy, treatments, vitamin D

This entry was posted on Saturday, January 17th, 2009 at 4:11 am and is filed under 1. Science of Health. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.