1. AUTOIMMUNITY: AN UNMET CLINICAL CHALLENGE Lauren Johnson with Dr. Pamela Langer

2. Overview  What is autoimmunity?  Septic Arthritis  Narcolepsy  Ankylosing Spondylitis  Treatment  New Direction of Research

3. What is autoimmunity?  Affects 5-8% of individuals in Western countries  Over 80 autoimmune conditions  Rheumatoid Arthritis, Diabetes Mellitus, Multiple Sclerosis  One of the least understood conditions in medicine  Among the leading causes of death in young and middle aged women in the U.S.  Results from immune cells recognizing “self” as foreign.  Cause is unknown, but thought to occur one of two ways.

4. Molecular Mimicry  Naive immune system Sensitized immune system

5. Error in T Cell Selection  T cells must undergo “positive” and “negative” selection  Occurs before they are released into the body  Test cells against a piece of “self”  Strong reaction = deletion / cell death Not perfect

6. Activation Pathways

7. Septic Arthritis  Caused by microbial infection  Septic = whole body infection ; presence of pathogens in the bloodstream  Arthritis = joint inflammation  Easier to diagnose, usually only 1-2 joints involved  Strong immune reaction, many cells activated  Influx of cells to joint = inflammation  Leads to cartilage damage  Risk of septic shock because of high inflammation (blood leaks out of capillaries, get decreased blood supply to organs)

8. Risks in Septic Arthritis  Higher risk if individual has pre-existing joint disease  Taking drugs that suppress immune system  Also risk of molecular mimicry  May lead to more permanent arthritic complications  Borrelia burgdorferi is similar to our own cells  Transmitted by ticks

9. Narcolepsy  Chronic neurological disorder  1/2000 people  Results from inability to regulate sleep-wake cycles  Irresistible bouts of sleep throughout the day, length varies  Only recently shown to be autoimmune  2009

10. Reaction Against Protein in Narcolepsy  Lack of hypocretin = hormone that promotes wakefulness  Narcolepsy patients lack cells that produce hypocretin  Destroyed in autoimmune reaction  Certain variation of immune response gene is present http://upload.wikimedia.org/wikipedia/commons/2/2d/1R02_crystallography.png

11. Ankylosing Spondylitis  Affects 1.3% of adults 25 years and older = 2.4 million people  Angkylos = bent  Spondylos = spine  Belongs to subset of autoimmunity called the spondyloarthropathies  Joint diseases of the spine associated with presence of a specific variant of an immune response gene

12. Damage in Ankylosing Spondylitis  Immune system cells attack spine  May be molecular mimicry component  Klebsiella pneumoniae  Causes tissue damage  Ossification = new bone formation

13. Risk of spinal fracture in Ankylosing Spondylitis Bamboo spine Normal spine

14. Current Treatment for Autoimmune Disease  Manage symptoms  Methotrexate, Prednisone, Plaquenil, Arava Therapeutic targets Inhibit T cell activity Induce T cell death Eliminate certain subsets of T cells Inhibit cytokine activity (anti-inflammatory) * Modulate gene expression

15. Humira  Used for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease  Slows joints damage, provides pain relief  Bind to cytokine from macrophage, relieves inflammation and pain  Tumor Necrosis Factor- α (TNF- α )

16. Humira Action

17. Future Directions  Attempting to treat the source  Identify autoimmune T cells (Gocke et al., 2009) Study structure; synthetic molecules could bind and inactivate  Track the development of the disease in hopes of preventing it (Zangini et al., 2009)  Gene Therapy  Introduce anti-inflammatory genes into cells  Introduce TNF- α receptor genes into cells Need long term expression or repeated administration

18. Conclusions  Many factors affect immune system  Stress, environment, genetics, diet, sleep  Factors push cells one way or another.  Sometimes results in autoimmunity.  Need to be able to recognize autoimmunity in patients.  Research  The more we understand regulation and factors, the more treatment options will be available.

19. Thank you!  Dr. Pamela Langer

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