MS

5 main cell types in the CNS

- Neurons (50% of neural cells)

- Neuroglia (50% of neural cells)

- Astrocytes (~80%)

- Oligodendrocytes (~5%)

- Microglia (~10-15%)

- Ependymal cells (~5%)

which cell makes myelin

oligodendrocytes

are there immune cells in the CNS under normal conditions

no

what molecules can easily pass from the blood to the CNS

small lipophilic molecules

importance of BBB

barrier between blood and CNS tissue that regulates the entry of substances and cells to the CNS

prevent the passage of many harmful substances such as toxins, antibiotics and chemicals from the blood to the nervous tissue

Components of BBB / BSB

Tight junctions between the endothelial cells of the capillaries in the nervous tissue primarily form BBB or BSB.

´Astrocytic end-feet “vascular feet” surround and ensheath these capillaries, are partly involved in the formation and maintenance of BBB or BSB

what limit the migration of immune cells from the blood into the CNS

The BBB and the glia limitans together

what is multiple sclerosis

immune mediated demyelination disease of the central nervous system

MS occurs when activated immune cells infiltrate the CNS and attack myelin

BBB becomes leaky, cells penetrate CNS tissue, recruits astrocytes and microglia - leading to inflammation

Target is myelin

what are the most common symptoms of MS

numbness, tingling

walking difficulty

fatigue

pain

muscle spasms

predisposing factors (triggers) of MS

• Genetic : 200 genes have been associated with MS

• Identical twins show 30% chance

• Siblings 2-5% chance

• Sex biased: Female > Male (3:1)

• Pollutants

• Vitamin D deficiency

• Smoking (increases progression rate)

• Excessive salt intake

• Viruses (Epstein Barr Virus, Varicella zoster virus)

which virus is thought to be the possible cause f MS

Epstein-Barr virus

MS Diagnosis

Blood tests, to check for specific biomarkers associated with MS and rule out other conditions

Spinal tap (lumbar puncture), to check abnormalities in antibodies that are associated with MS and also rule out infections and other conditions with symptoms similar to MS.

Neurological and evoked potential tests, visual or electrical stimuli, a moving visual pattern, or short electrical impulses are applied to nerves in legs or arms.

Magnetic resonance imaging (MRI), to check for MS (lesions) in the brain and spinal cord. Normally, intravenous injection of a contrast agent identify active lesions.

clinical classification of MS

progressive relapsing (PRMS)

steady progression since onset with super-imposed attacks

Secondary progressive (SPMS)

Initial RRMS that suddenly begins to decline without periods of remission and relapses

Relapsing Remitting (RRMS)

Unpredictable attacks which may or may not leave permanent deficits followed by periods of remission (the most common)

Primary Progressive (PPMS)

Gradual progression of the disease from its onset with no relapses or remissions

what is the most common type of MS

Relapsing Remitting (RRMS)

MS mainly affects

younger adults

Does MS involves both immune responses

yes, MS involves both innate and adaptive immune response peripherally and in the CNS

what two immune cells are involved in MS

astrocytes and microglia

where does the MS start from

periphery

Immune response in the pathogenesis of MS

1) Autoreactive T cells recognize a specific autoantigen presented by MHC class II molecules on the cell surface of antigen presenting cells (APCs), such as macrophages, in the systemic immune compartment

2) Activated T cells can cross the BBB in order to enter the CNS. Within the CNS, T cells activate microglia cells/macrophages. Then these cells produce proinflammatory cytokines, release toxic mediators, and increase their myelin phagocytosis and propagating demyelination

3) B cells produce antibodies crossing the BBB or locally produced by infiltrating B cells into the CNS contribute to this process. Autoantibodies activate the complement cascade resulting in the formation of the membrane-attack complex and subsequent lysis of myelin sheath

4) Axon degeneration: The upregulation of Na+ and Ca2+ channels on the axon as well as mitochondrial dysfunction and loss of trophic support contribute to axonal disintegration and degeneration

5) The inflammatory response is regulated by anti-inflammatory cytokines, such as IL-10 or TGF-β, as well as IL-2 inducing programmed cell death (apoptosis) in immunoreactive T lymphocytes

T regulatory cells

good cells

TH 17 cells

breakdown of BBB

Inflammation is dominant in

RRMS

Neurodegeneration is dominant in

SPMS

TNF blocker

inhibits TNF from activated microglia and oligodendrocytes

pathological consequences of immune mediated attacks in MS

Demyelination and neurodegeneration

Progressive MS is associated with axon degeneration causing irreversible and permanent deficits. Without myelin and oligodendrocyte support systems, axons degenerate permanently resulting in permanent neurological impairments

How is MS treated

currently no treatment but disease modifying treatments that reduces immune attacks slowing disease progression and managing MS symptoms

Examples of disease modifying treatments to reduce immune attacks in MS

Corticosteroids, such as oral prednisone and intravenous methylprednisolone, are prescribed to reduce inflammation

Plasma exchange, plasma is removed and separated from blood cells. The blood cells are then mixed with albumin and put back into the body. Plasma exchange may be used if symptoms are new, severe and have not responded to steroids. This will remove proteins that are harmful.

Immunosuppressants: methotrexate, Azathioprine.

why are corticosteroids not that helpful

they suppress T cells including T regulatory cells (which are needed)

Drugs for primary-progressive MS

ocrelizumab (Ocrevus) is the only approved drug in Canada

drugs for relapsing-remitting MS

Interferon beta has been the earliest approved medication for MS

MS attacks often recur when these medicines are stopped

why is myelin repair important

Myelin repair is essential for restoration of structure, conduction of neural signals along axons, and protection of axons from degeneration

Effective treatment to promote remyelination will protect axons from permanent degeneration in progressive MS

Initially in the course of MS, remyelination happens successfully resulting in remission. But as MS progresses, relapses are longer as remyelination becomes challenging

Generation of oligodendrocytes and myelin is a complex process that requires proper differentiation and maturation of OPCs to myelinating cells

Remyelination becomes challenging as in chronic MS microenvironment is not supportive

Vitamin D and MS

• Deficiency in VitD3 is a risk factor for MS

• VitD3 Promotes the Differentiation of Immunosuppressive Regulatory T Cells

• The incidence of MS is increased in northern climates with colder temperature, where vitamin D deficiency is common. Since exposure of the skin to ultraviolet light aids in the conversion of inactive vitamin D to the active form (VitD3), the short days, low UV intensity, and lack of exposed skin common to winter months, decrease the amount of active VitD3 that can be produced

is exercise important for MS

yes, exercise can inhibit inflammation

Medications that have been tested in clinical trials for remyelination

Anti-LINGO

rHIgM22

Clemastine

Domperidone

how does Lingo works

LINGO-1 suppresses oligodendrocyte precursor cell (OPC) maturation and myelination and its inhibition by opicinumab has been tested in clinical trials