What Schering-Plough Biopharma?• Pharmaceutical Company

– What kind of research is performed at the facility?

What Schering-Plough Biopharma?• Pharmaceutical Company

– What kind of research is performed at the facility?

• Is there a conflict of interest? – They all work for Schering-Plough

Biopharma– Merged with Merck in 2009

What is an Autoimmune disease?• Is defined as an immune response against self

antigens. • What are some of the major autoimmune

diseases?

-Crohn’s Disease-Lupus -Scleroderma

- Rheumatoid arthritis - Multiple Sclerosis- Totaling about 50

Symptoms

Multiple SclerosisProgressive-relapsing

Secondary Progressive

Primary Progressive

Relapsing-Remitting

http://upload.wikimedia.org/wikipedia/commons/3/3c/Ms_progression_types.svg

• Two major classes– Relapsing

• 85-90% start this way• 65% remain

– Progressive• 10-15% Primary• 20-25% Secondary

Environmental Factors

• More common in people that live farther from the equator

• Sunlight link to MS risk (Vitamin D) – Related?

• Virus connection? (HHV-6 and EBV)

Environmental Factor

Per 100,000 individuals in the population

What are the different genetic factors?

• Human leukocyte antigen (HLA) system– Genes that serve as the major histocompatibility

complex (MHC)

What is a MHC?

MHC I and II• MHC I

– All nucleated cells– Three polymorphic classes– 6 possible combinations in the population– How many can you have?

• MHC II– Mainly dendritic cells, macrophages, and B

lymphocytes– A heterozygote can inherit six or eight alleles– These are one DQ and DP and one or two DR’s

MHC II

MHC II

α1

α2

β1

β2

membrane

Peptide-binding cleft•There are two alleles associated

with MS•DR15 •DQ6

•There are two protective alleles •HLA-C554 •HLA-DRB1*11

MHC II and T cell Interaction

Macrophage

T cell

T cells or lymphocytes• Four classes

– Cytotoxic, Regulatory, Memory, Helper

• T-helper cells (TH cells)– Secrete small proteins (cytokines, interleukins) – Several subtypes to create unique immune response– This differentiation is unknown, but believed to be

through the MHC and peptide sequence recognition

Interleukins• A group of cytokines released by lymphocytes

– Most are produced in CD4+ cells – They are believe to promote differentiation

• The paper mentions– 4, 6, 10, 17, 22, 23, 25, 27

• However, the large focus is on – 6, 10, 17, 23

So, what is so bad about Interleukin 17?

• Myelinated Schwann Cells– Composed of 80% lipid and 20% protein– Myelin Basic Protein, Myelin oligodendrocyte

glycoprotein, and?

• Proteolipid Protein– May assist in compaction, stabilization, and

maintenance of myelin sheaths

http://www.google.com/imgres?imgurl=http://www.signaling-gateway.org/update/images/updates_thumbs/nri2325.jpg&imgrefurl=http://www.signaling-gateway.org/update/updates/200805/index.html&usg=__CDzMs7VIzAxllHFTQG85ytleaWY=&h=80&w=80&sz=3&hl=en&start=13&um=1&itbs=1&tbnid=PXKQovmvAyZWWM:&tbnh=74&tbnw=74&prev=/images%3Fq%3Dinterleukin%2B17%26um%3D1%26hl%3Den%26sa%3DN%26tbs%3Disch:1

Cell Body

Myelin Sheath

Dendrites

Axon

Myelinated Schwann CellProteolipid

Protein

Axon

Now what happens in MS• Proteolipid

Protein• TH-17 cells

• Axon• Myelin

Now what happens in MS

• Proteolipid Protein

• TH-17 cells

Why is this bad?• Sodium Channels along

axon are exposed (lose Nodes of Ranvier)

• Demyelination causes a loss of action potential in the cell.

• Neurons cannot send signals or signals are sent at a very slow rate

Other information you may need to know

• Experimental Autoimmune Encephalomyelitis– EAE model – Equivalent model in mice

• Transforming growth factor Beta (TGF-β)– Development of TH-17 cells

– Development of Regulatory T cells– Blocks the activation of lymphocytes and

monocytes

Where are we going?

• The paper wants to show if TGF-β promotes pathogenic function of TH-17 cells

• Or, does the immunoregulatory effects of TGF-β play in TH-17 cells sensitivity and suppression

• Here, they look at responses of activated myelin-reactive T cells with treatments of IL-23 or TGF-β and IL-6

ReferencesMcGeachy, M. J., K. S. Bak-Jensen, Y. Chen, C. M. Tato, W. Blumenschein, T.

McClanahan, and D. J. Cua. 2007. TGF-β and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated patholgy. Nature Immuno. 8: 1390-97.

Langrish, C. L. et al. 2005. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J. Exp. Med. 201: 233-240.

Abbas, A. K. and A. H. Litchman. 2006. Basic Immunology: 3rd edition. Saunders. Victor, M., Ropper, A. H., and R. D. Adams. 2000. Adams & Victor’s Principles of

Neurology: 7th Edition. McGraw-Hill Professional.