Download Autoimmunity: An Unmet Clinical Challenge

AUTOIMMUNITY: AN UNMET
CLINICAL CHALLENGE
Lauren Johnson with Dr. Pamela Langer
Overview

What is autoimmunity?

Septic Arthritis
Narcolepsy
Ankylosing Spondylitis
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Treatment
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New Direction of Research
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What is autoimmunity?

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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

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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
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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

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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
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