Zusammenfassung der Ressource
Autoimmunity
- Autoimmunity
- When the immune system
loses sense of self and
attacks and destroys
healthy body tissue
- A destructive
immune
response
against self
antigens
- Once started,
difficult to stop
- Severity
ranges from
minor to
lethal
- Affects 5-7% of the population
- Can affect any
organ or organ
system in the body
- Autoantibodies can be
passed from mothers
to their babies
- Autoimmunity vs. hypersensitivity
- Immunogen in
hypersensitivity is an
allergen, in autoimmunity it's
an autoantigen
- Hypersensitivity
causes a clinical
allergy,
autoimmunity
causes an immune
disorder
- 10% of the population
experience
hypersensitivity, 5%
experience autoimmunity
- Mortality by
hypersensitivity is
rare, but in
autoimmunity it is
high
- Mechanisms in
hypersensitivity include
type I, II, III and IV, in
autoimmunity type II, III
and IV
- What causes
autoimmunity?
- Failure to maintain
self-tolerance
- Risk factors
- Genetic susceptibility
- Presence of
susceptible genes
- Being female
- Could be due to
imbalance in hormone
levels
- Rise in hormones associated
with pregnancy may cause
abortion of the foetus
- Endometriosis and
preeclampsia are
thought to be
autoimmune in nature
- ORE: oestrogen
response elements
- There isn't a single
pin-pointable gene
- Numerous genes
involved in susceptibility
- Environmental
triggers
- Infections
- Injury
- Drugs, toxins, UV
radiation
- Stress, poor diet, lack of
exercise, lack of sleep,
abuse of alcohol and use
of tobacco
- Exceptions to the rule: simple
genetic autoimmune illnesses
- Autoimmune
polyglandular syndrome
type I (APS-1)
- Gene: AIRE
- Knockout causes decreased expression of
self antigens in the thymus, resulting in
defective selection of self reactive T cells
- Mechanism: decreased
expression of self antigens in
the thymus resulting in a defect
in negative selection
- Immunodysregulation
polyendocrinopathy
enteropathy,X linked (IPEX)
- Gene: FOXP3
- Knockout causes
decreased function of
CD4 CD25 regulatory T
cells
- Decreased
generation of regulatory T cells
- Autoimmune
lymphoproliferative
syndrome (ALPS)
- Gene: FAS
- Knockout causes failure of
apoptotic death of self
reactive B and T cells
- Failure of apoptotic
death of self reactive T
or B cells
- MHC association
- Mechanisms underlying the
association of MHC alleles with various
autoimmune diseases are still not clear
- Association with MHC
class II genes
- MHC may present a self
peptide and activate
pathogenic T cells
- MHC may influence
negative selection of
developing T cells
- Genetics of autoimmunity
- NOD2
- Polymorphism associated with
25% of Crohn's disease
- Microbial sensor
- PTPN22
- Most common
autoimmunity
associated gene
- Phosphatase
- CD25
- Associated with MS
- Role in regulatory T cells
- Injury
- Sympathetic opthalamaia
- Physical trauma in one eye
can initiate autoimmune
response to both eyes
- Eye anterior chamber is
an immune privileged
site
- Normally autoimmune
antigens in this site are
not exposed to the
immune system
- Trauma to one eye results in the release of
sequestered introcular protein antigens
- Released intraocular antigens are carried to the
lymph node and activate T cells
- Effector T cells return via bloodstream and
attack antigen in both eyes
- On occasion this causes blindness in both
damaged and undamaged eyes
- Superantigens
- Several infectious agents
contain antigens with the ability
to polyclonally activate a
subset of CD4+ T cells bearing
particular VB TCR families
- Hypothesis: this may
activate auto antibodies
- This would increase VB
in autoimmune lesions
- Isolated reports in
rheumatoid arthritis and
diabetes
- No strong evidence
- Polyclonal activation
- Viruses and bacteria can induce
non-specific polyclonal B cell
activation leading to
autoantibodies
- Gram negative bacteria,
cytomegalovirus and EBV
are polyclonal activtors
- SLE patients produce
large quantities of IgM
polyclonal antibodies
- Systemic Lupus
Erythematosus (SLE) can
attack any part of the body
resulting in inflammation or
tissue damage
- Local infections
- Induces inflammation which
results in activation of
non-professional APC
- Thyroid cells do not normally express MHC class II
- IFN-gamma produced during infection or
non-specific inflammation induces MHC class
II expression on thyroid cells
- Activated T cells recognise peptides presented by
MHC class II and induce autoimmune thyroid
disease
- Hashimoto thyroiditis
- Follicular cells of the thyroid
- Type I diabetes
- beta cells of islets of Langerhans
- Molecular mimicry
- Some viruses and bacteria possess
antigenic determinants that are identical
or similar to normal host cell components
- The same MHC molecule presents both a
pathogen peptide and a self peptide that
mimics it
- Naive T cell is activated by the pathogen
peptide present by the MHC molecule
- Effector Th1 cells responds to the self peptide
mimic and activates the macrophage causing
inflammation
- Examples
- Rheumatic fever
- Multiple sclerosis
- Type I diabetes
- Systemic Lupus erythematosus
- Post rabies encephalitis
- Used to develop in individuals
that had the rabies vaccine
- Rabies virus was grown in rabbit
cell culture that contained
antigens from rabbit brains
- In vaccinated people these
antigens would induce
formation of antibodies and
activated T cells which would
cross react with the recipient's
own brain cells causing
encephalitis
- Epitope spreading
- Once
autoimmune
diseases begin
they tend to be
progressive with
remissions and
exacerbations
- A mechanism for
chronic progression
- In a persistent microbial infection and tissue
damage, initial response to one self epitope
expands to involve additional epitopes on the
same molecule as well as additional self
proteins
- Explains how one epitope can
mature into full blown
autoimmune response
- Release of sequestered antigen
- APC with cross reacting Ag (molecular mimicry)
- Inappropriate MHC expression on non-APCs
- Activated macrophages from
activated T helper cells cause
inflammation and local Delayed
Type Hypersensitivity (IV)
resulting in tissue damage
- Activated Th cell produces B cells
which produce plasma cells by
polyclonal activation that produce Abs
to self antigens resulting in tissue
damage
- Autoimmunity classification
- Organ specific autoimmune diseases
- Type I diabetes
- Goodpasture's syndrome
- Autoantibodies specific for
antigens in the basement
membranes of the kidney and
the alveoli of the lungs
- Leads to complement activation and
direct cellular damage as well
inflammatory response mediated by
the build up of complement split
products
- Tissue damage leads to
kidney damage and
pulmonary haemorrhage
- Smoking can be the trigger
because it damages alveoli
and exposes collagen
- Multiple sclerosis
- Grave's disease
- Hashimoto's thryoiditis
- Systemic autoimmune diseases
- Rheumatoid arthritis
- Scleroderma
- Systemic lupus erythematosus
- Autoimmune diseases of the endocrine glands
- Insulin dependent diabetes mellitus
- Type 1
- T cells attack and destroy
insulin producing cells
(beta cells) located in the
islets of Langerhans
- The pancreas does not
produce or properly use
insulin and consequently
increased levels of blood
glucose
- Islets of Langerhans contain
several cell types secreting distinct
hormones, each cell expresses
different tissue specific proteins
- In IDDM an effector T cell
recognises peptides from the beta
cell specific protein and kills the
beta cell
- Glucagon and somatostatin are still
produced by the alpha and delta cells
but no insulin can be made
- Treated with daily
insulin injections
- Factors
involves in the
destruction of
beta cells
- Activated CTLs migrate to the
islets and begin to attack the beta
cells
- Cytokine production
released during response:
IFN-y, TNF-a and IL-1
- Coxasckie virus group B-
direct destruction of the beta
cells by the virus as a result of
molecular mimicry
- Chronic thyroiditis: Hasimoto's disease
- Production of autoantibodies and
sensitised to Th1 cells specific for
thyroid antigens
- Intense infiltration of the thyroid
gland by lymphocytes,
macrophages and plasma cells
- Binding of autoantibodies
against thyroid tissue
proteins interferes with the
iodine uptake and leads to
decreased production of
thyroid hormones
- Treatment: oral
administration of thyroid
hormone
- Hyperthyroidism: Graves' disease
- Autoantibodies produced against the thyroid
gland
- Long acting thyroid
stimulating antibody
causes unregulated
overproduction of
thyroid hormones
- Symptoms
- Heat intolerance
- Nervousness
- Irritability
- Warm, most skin
- Thyroid enlargement
- Treatment
- Thyroidectomy
- Destruction of
thyroid by
radioactive 131I
- Autoantibodies
can be passed
from mothers to
their babies
- Mother with Graves disease makes
anti-TSHR antibodies
- During pregnancy antibodies cross
the placenta into the foetus
- Newborn infant also suffers from
Graves' disease
- Plasmapheresis removes maternal
anti-TSHR antibodies and cures the
infant's disease
- Myasthenia Gravis
- Blocks normal binding of acetylcholine and
mediates complement mediated degradation of
receptors
- Binding autoantibodies to the acetylcholine
receptors on the motor end plates of muscles
- Progressive weakening of the skeletal muscles and
loss of muscle control
- Symptoms
- Drooping eyelids
- Inability to retract the corners of the mouth
- Systemic autoimmune diseases
- Defects in immune regulation
- Response is directed
towards a broad range of
target antigens and involves
a number of organs
- Tissue damage is widespread by...
- Cell mediated
immune
responses
- Direct cellular
damage caused by
autoantibodies
- Accumulation of
immune complexes
- Celiac disease
- Wheat flour gluten peptide
specific CD4 T cells
- Gluten is degraded in the gut lumen to
give a resistant fragment
- Gluten fragment enters the gut tissue
and is deaminated by transglutaminase
- Naive CD4 T cells respond to
deaminated peptides presented by MHC
II
- Inflammatory effector T cells cause villous atrophy
- Systemic Lupus Erythematosus (SLE)
- Appears in
women age
20-40
- More
prevalent in
females
- Symptoms
- Low grade fever
- Ulcers
- Aching muscles
- Arthritis
- Fatigue
- Loss of
appetite
- Butterfly rash
on face
- Poor circulation
- Antinuclear antibodies directed
against DNA, nucleoprotein,
histones and nucleolar RNA
- IgG against a wide variety of cellular
constituents (defect in maintenance of B cell
self tolerance
- Binding of antibodies to cell surface
antigens causes inflammatory responses
leading to cell and tissue destructon
- Immune complexes, deposited in blood
vessels, kidney, joints and other tissues
cause tissue inflammation and
destruction
- Damage occurs by...
- Formation of immune complexes
- Type III hypersensitivity
- Antibody mediated injury to
blood cells
- Type II hypersensitivity
- Gene: C1q
- Knockout causes defective
clearance of immune complexes
and apoptotic cells
- Rheumatoid arthritis
- Mostly affects women age 40-60
- Major symptom: chronic
inflammation of joints
- B cells in joints produce IgM
autoantibodies called rheumatoid
factors
- This binds to Fc region of normal circulating IgG,
forming IgM-IgG complexes that are deposited in
the joints and activate the complement cascade
- Type III hypersensitivity reaction which leads to
chronic inflammation of the joints
- Multiple sclerosis
- Autoimmune
neurological
disease
- Symptoms may be
mild such as numbess
in the limbs or severe
such as paralysis and
loss of vision
- Most people
are
diagnosed
between the
ages of 20
and 40
- Autoreactive Th1 cells in the
cerebrospinal fluid induce expression
of chemokines and cytokines that
recruit inflammatory cells
- Inflammatory lesions along the myelin
sheath of nerve fibres
- Treated with immunosuppressive drugs
- Possible
environmental
influence and genetic
infleunce
- Cause unknown,
possibly a virus