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Autoimmunity
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Outline
History
Definition
Disease states
Causes
Immunopathology
Diagnosis
Treatment
Mouse Models of human disease
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Autoimmunity Origins
Horror autotoxicus:
Literally, the horror of
self-toxicity.
A term coined by the
German immunologist
Paul Ehrlich (1854-
1915) to describe the
body's innate
aversion to
immunological self-
destruction.
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History Continued
This concept of autoimmunity as the cause
of human illness is relatively new, and it
was not accepted into the mainstream of
medical thinking until the 1950s and
1960s.
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Autoimmunity
Basically means immunity to self
A condition that occurs when the immune system mistakenly attacks and destroys healthy body tissue.
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The “Immunology Definition”
Failure of immune
tolerance
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Pick an organ, any organ . . .Autoimmunity can affect ANY organ/organ system in the human body
Pemphigus
Multiple Sclerosis
Sjogren’s Syndrome
Rheumatic Fever
Autoimmune Hepatitis
Ulcerative Colitis
Goodpasture’s Syndrome
Diabetes
Autoimmune Uveitis
Autoimmune hemolytic Anemia
Addison’s Disease
Rheumatoid Arthritis
Autoimmune Oophoritis
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Autoimmunity Classification
Can be classified into clusters that are either
organ-specific or systemic
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Examples of Organ Specific
Lungs of a
patient with
Goodpasture’s
VitiligoHashimoto’s disease
(thyroiditis)
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Examples of Systemic Autoimmunity
SLE
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Examples of Systemic Autoimmunity
Sjogren’s Syndrome
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Causes of Autoimmunity
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Genes and Autoimmunity
The concept that a single gene mutation leads to a single autoimmune disease is the EXCEPTION not the rule.
Because of this autoimmune diseases are generally classified as complex diseases as there is not a single “pinpoint-able” gene
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Exceptions to the Rule – Simple
Genetic Autoimmune IllnessesDisease Gene Mechanism
APS-1(Autoimmune polyglandular
syndrome type 1)
AIRE Decreased expression of
self-antigens in the thymus,
resulting is a defect in
negative selection
IPEX(Immunodysregulation,
polyendocrinopathy, enteropathy,
X-linked)
FOXP3 Decreased generation of
Tregs
ALPS(autoimmune lymphoproliferative
syndrome )
FAS, FASL Failure of apoptotic death of
self reactive T or B cells
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Complex Disease and GeneticsThere have been numerous disease associated genes or
disease “susceptibility” genes linked to autoimmunity
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Complex Doesn’t even begin to
describe Autoimmune genetics
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Environment
Pathogens, drugs, hormones, and toxins
are just a few ways that the environment
can trigger autoimmunity
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Pathogens
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Rheumatic
fever is a
classic
example of
molecular
mimicry
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Drugs and Toxins
Drugs Examples: Procainamide (Pronestyl)
Drug induced lupus
Toxins Examples: Toxic Oil Syndrome
Occurred in Spain in 1981 after people ate contaminated olive oil.
People developed unique illness marked by lung disease, eosinophilia, and excessive IgE
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Hormones
Females are much more likely to develop autoimmune illness
Rise in hormones associated with pregnancy may even cause abortion of the fetus (RSA)
Endometriosis and preeclampsia are both thought to be autoimmune in nature
Hypothesis: estrogen response elements (EREs) in several genes
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Estrogens and Autoimmunity
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Nature Immunology 2, 777 - 780 (2001)
Sex
differences in
autoimmunity
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Immune Regulation
A defect in any arm of the immune system can trigger autoimmunity
Complement
T cells B cells
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Complement Deficiencies
CD59 or CD55 – Paroxysmal nocturnal
hemoglobinuria
autoimmune hemolytic anemia
autoimmune thrombocytopenia
lupus lymphopenia
Deficiencies in the classical complement pathway renders pts more likely to develop immune complex diseases SLE
RA
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The Complement See-Saw
The complement system is a mediator in both the
pathogenesis and prevention of immune complex
diseases
It has a protective effect when functioning in
moderation against pathogens; at the same time,
the inflammation promoted by complement
activation can result in cellular damage when not
kept in check.
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B or T? That is the question?
Autoimmunity is hard to classify as strictly a
B cell or T cell mediated disease as
multiple arms of the immune system are
involved
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Myasthenia Gravis
Disease marked by progressive weakness
and loss of muscle control
Classified as a “B cell” Disease
Autoantibodies against nicotinic
acetylcholine receptors
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Diabetes
Disease in which
the body does
not produce or
properly use
insulin
“ T cell” Disease
T cells attack and
destroy
pancreatic beta
cells
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Multiple Sclerosis
MS patients can have autoantibodies and/or self reactive T
cells which are responsible for the demyelination
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Cytokine Dysregulation in Autoimmunity
CD = Crohn’s Disease
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IL-17: The Autoimmunity Cytokine?IL-17 KO mice – less susceptible to autoimmunity – especially
MS and RA
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Symptoms
Initial diagnosis may be missed in patients as diseases present with general symptoms
Fever, muscle ache, fatigue, joint pain
Disease specific manifests
SLE – rash
Sjogren’s – dry mouth, dry eyes
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Diagnosis
General tests
C Reactive Protein
Autoantibody titers (anti DNA, anti phospholipids, etc)
Presence of Rheumatoid Factor
Disease specific tests
Neurological exam – MS
Fasting glucose - Diabetes
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Treatment
The key to treating
autoimmunity is
immunomodulation
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Treatment Options
• Anti-inflammatory drugs• NSAIDS, Corticosteroids
• Immunosuppressant drugs• Methotrexate
• Radiation
• Plamapheresis
• Cell Blocking Reagents• aCD20 (Rituxan)
• aCD3 (Teplizumab)
• Cytokine Blocking Reagents• TNF (Humira, Enbrel)
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Mouse Models
Human Disease Mouse Model
RA Collagen Induced Arthritis
(CIA)
MS Experimental Autoimmune
Encephalitis (EAE)
Ulcerative Colitis (UC) Dextran Sodium Sulfate
induced Colitis (DSS)
Diabetes Non Obese Diabetic
(NOD)
Lupus MRLlpr (Lpr = lupus prone)
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***********Remember***********
Autoimmunity is a failure of tolerance!
Knowing the tolerance mechanisms the
immune system uses, will help you better
understand autoimmune diseases!
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Failure of tolerance and disease Outcome
Disease Example
APS-1
MS, Uveitis, Male
infetility
IDDM, Hashimoto’s
IPEX
ALPS
RA, SLE, Crohn’s