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AUTOIMMUNITY: AN UNMET CLINICAL CHALLENGE Lauren Johnson with Dr. Pamela Langer Overview What is autoimmunity? Septic Arthritis Narcolepsy Ankylosing Spondylitis Treatment New Direction of Research 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. Molecular Mimicry Naive immune system Sensitized immune system 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 Activation Pathways 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) 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 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 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 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 Damage in Ankylosing Spondylitis Immune system cells attack spine May be molecular mimicry component Klebsiella pneumoniae Causes tissue damage Ossification = new bone formation Risk of spinal fracture in Ankylosing Spondylitis Bamboo spine Normal spine 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 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) Humira Action Future Directions Attempting to treat the source Identify Study autoimmune T cells (Gocke et al., 2009) 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 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. Thank you! Dr. Pamela Langer References Al-Ahaideb, Abdulaziz. "Septic arthritis in patients with rheumatoid arthritis." Journal of Orthopaedic Surgery and Research (2008). Journal of Orthopaedic Surgery and Research. 29 July 2008. Web. 5 Jan. 2010. <http://www.josronline.com/content/3/1/33#B5>. Andrej, Tarkowski. "Infectious arthritis." Best Practice & Research Clinical Rheumatology 20.6 (2006): 1029-044. ScienceDirect. 24 Dec. 2006. Web. 5 Jan. 2010. <http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WBJ-4MDP7DT3&_user=2532480&_coverDate=12%2F31%2F2006&_rdoc=1&_fmt=full&_orig=search&_cdi=6712&_sort=d&_docanch or=&view=c&_acct=C000057783&_version=1&_urlVersion=0&_userid=2532480&md5=06d77d07a7e841a764d1e282 684d1b48#sec5>. Berchtold, P., and M. Seitz. 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