Autoimmunity
Outline
History
Definition
Disease states
Causes
Immunopathology
Diagnosis
Treatment
Mouse Models of human disease
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.
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.
Autoimmunity
Basically means immunity to self
A condition that occurs when the
immune system mistakenly attacks and
destroys healthy body tissue.
The “Immunology Definition”
Failure of immune
tolerance
Pick an organ, any organ . . .
Autoimmunity can affect ANY organ/organ system in the human body
Autoimmune Uveitis Multiple Sclerosis
Sjogren’s Syndrome
Pemphigus
Rheumatic Fever Goodpasture’s Syndrome
Diabetes
Autoimmune Hepatitis
Addison’s Disease
Autoimmune Oophoritis Ulcerative Colitis
Rheumatoid Arthritis
Autoimmune hemolytic Anemia
Autoimmunity Classification
Can be classified into clusters that are either
organ-specific or systemic
Examples of Organ Specific
Lungs of a
patient with
Goodpasture’s
Hashimoto’s disease
(thyroiditis) Vitiligo
Examples of Systemic Autoimmunity
SLE
Examples of Systemic Autoimmunity
Sjogren’s Syndrome
Causes of Autoimmunity
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
Exceptions to the Rule – Simple
Genetic Autoimmune Illnesses
Disease Gene Mechanism
Decreased expression of
APS-1 AIRE self-antigens in the thymus,
(Autoimmune polyglandular resulting is a defect in
syndrome type 1) negative selection
Decreased generation of
IPEX FOXP3 Tregs
(Immunodysregulation,
polyendocrinopathy, enteropathy,
X-linked)
Failure of apoptotic death of
ALPS FAS, FASL self reactive T or B cells
(autoimmune lymphoproliferative
syndrome )
Complex Disease and Genetics
There have been numerous disease associated genes or
disease “susceptibility” genes linked to autoimmunity
Complex Doesn’t even begin to
describe Autoimmune genetics
Environment
Pathogens, drugs, hormones, and toxins
are just a few ways that the environment
can trigger autoimmunity
Pathogens
Rheumatic
fever is a
classic
example of
molecular
mimicry
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
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
Estrogens and Autoimmunity
Sex
differences in
autoimmunity
Nature Immunology 2, 777 - 780 (2001)
Immune Regulation
A defect in any arm of the immune system can trigger autoimmunity
Complement
T cells B cells
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
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.
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
Myasthenia Gravis
Disease marked by progressive weakness
and loss of muscle control
Classified as a “B cell” Disease
Autoantibodies against nicotinic
acetylcholine receptors
Diabetes
Disease in which
the body does
not produce or
properly use
insulin
“ T cell” Disease
T cells attack and
destroy
pancreatic beta
cells
Multiple Sclerosis
MS patients can have autoantibodies and/or self reactive T
cells which are responsible for the demyelination
Cytokine Dysregulation in Autoimmunity
CD = Crohn’s Disease
IL-17: The Autoimmunity Cytokine?
IL-17 KO mice – less susceptible to autoimmunity – especially
MS and RA
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
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
Treatment
The key to treating
autoimmunity is
immunomodulation
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)
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)
***********Remember***********
Autoimmunity is a failure of tolerance!
Knowing the tolerance mechanisms the
immune system uses, will help you better
understand autoimmune diseases!
Failure of tolerance and disease Outcome
Disease Example
APS-1
MS, Uveitis, Male
infetility
IDDM, Hashimoto’s
IPEX
RA, SLE, Crohn’s
ALPS
