Y
Y

 

Y
Y





!



 
 

Non-self
Self
or foreign

No response Strong response

  !"
aolerance--->specific unresponsiveness
triggered by previous exposure to Ag.
Natural aolerance (self tolerance):
Unresponsiveness to self Ags.
Acquired tolerance:
Unresponsiveness to foreign Ags.
  !"
aolerance in non-identical cattle twins:
  !"
Yt is a specific immunologic unresponsiveness
i.e. the absence of specific immunoresponses
to a particular antigen in a fully
immunocomptent person
Unresponsiveness to self antigens is known as
auto tolerance
Both B-cells and a-cells participate in tolerence
But a-cells play the primary role
m#$  %$  !"
  ! & !"Y" 
we can divide the mechanisms the immune
system uses to ensure the absence of
selfreactivity
Yt is divided in two main types:
^
  
: this occurs during
lymphocyte development.
^    
: occurs after
lymphocytes leave the primary organs
 à 




Burnet¶s Hypothesis:(1949)
 uuring neonatal stage of life, or when
immune system is developing, all Ags
present are recognized as self.
 Ymmune system becomes tolerant to these
Ags.
 How is tolerance accomplished?
 By clonal deletion--cells which come across
self-Ag undergo apoptosis.
 %!'! (!)m' *
st i - st i -
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str i r

8 ks

10 d ys

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Yt has therefore emerged as a possible
alternative mechanism for self tolerance. ahe
term
   was coined by 



 in the mid - 1970s.
% #' & !' "
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#+
# ",
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ëactors which ëavor immune ëavor tolerance
affect response response
Physical form Large, aggregated, soluble, aggregate-free,
of antigen complex molecules simple small molecules
Antigen processing properly processed improperly processed
Route of injection Subcutaneous or Oral or, sometimes,
intra-muscular intravenous

uose of antigen Optimal dose Very large or very

small dose
 ë" !&&"# !"*
!  &#
ëactors which affect ëavor immune
response response ëavor tolerance

Age of responding Adult, Newborn (mice)

animal immunologically Ymmunologically
mature immature
ëully
Undifferentiated B cell
uifferentiation differentiated,
with only YgM, a cells in
state of cells Memory
the thymic cortex
 ë" !Y&"#
Y"  !"
1) Ymmunologic maturity of the host:
Neonates are immunologically immature and
well accept allograft that would be rejected by
mature host
2) Structure and dose of antigen:
a- Simple molecules induce tolerance more
readily than complex ones
b- Very high and very low doses of antigen
may result in tolerance
 ë" !Y&"#
Y"  !"
ÿ) a-cells become tolerant more readily and
remain tolerant longer than B-cells

4) ahe continuous presence of antigen helps to

maintain tolerance

5) Administration of immunosuppressive drugs

enhances tolerance as in transplantation
"Y' !" & !"
1) Organ transplantation:
Yntroduction of tolerance may help prevention of
rejection
2) aumor development:
aolerance to tumor antigen results in growth of
the tumor without being detected by the
immune mechanisms
ÿ) Autoimmune disorders:
uisturbance of self-tolerance results in
autoimmune disease
w     
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ëailure of immune tolerance

* Autoimmune diseases occur due to
breakdown of the mechanisms that maintain
auto tolerance

* Auto-antibodies and self reactive a-cells are

produced, resulting in tissue damage by several
mechanisms
 u", !#- !#
Autoimmunity can affect ANY organ/organ system in
the human body

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 #
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   #& 
1) Genetic predisposition:
- ëamilial incidence of autoimmune diseases
- Most of them appear to be associated with
certain MHC genes, specially MHC YY genes

e.g. Rheumatoid arthritis is associated with uR4

ahyroditis with uR5
Multiple sclerosis with uR2
SLE with uR2/uRÿ
aype Y diabetes with uRÿ/uR4
Ankylosing spondylitis with B27
 Π(! 

Pathogens, drugs, hormones, and toxins are just a

few ways that the environment can trigger
autoimmunity
ÿu #
 è!# .

urugs
± Examples: Procainamide (Pronestyl)
± urug induced lupus

aoxins
± Examples: aoxic Oil Syndrome
± Occurred in Spain in 1981 after people ate
contaminated olive oil.
± People developed unique illness marked by
lung disease, eosinophilia, and excessive YgE
 åm ! 

ëemales 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
 ! # 
Sex differences in autoimmunity

V



Œ, 777 - 780
(2001)
  &" 
Can be classified into clusters that are either
¢

 or  
 .' &!#'"&"

Lungs of a
patient with
Goodpasture¶s

Hashimoto¶s disease
(thyroiditis) Vitiligo
 .' &" 

SLE
 .' &" 
Sjogren¶s Syndrome
 Y
# 
A defect in any arm of the immune system can
trigger autoimmunity

Complement

a cells B cells
  '&""
Cu59 or Cu55 ±
± Paroxysmal nocturnal
hemoglobinuria
± autoimmune hemolytic
anemia
± autoimmune
thrombocytopenia
± lupus lymphopenia
ueficiencies in the classical
complement pathway renders
pts more likely to develop
immune complex diseases
± SLE
± RA
  '+
'+%

ahe complement system is a mediator in both the

pathogenesis and prevention of immune complex
diseases
Yt 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.
  !/0 /

Autoimmunity is hard to classify as strictly a B cell

or a cell mediated disease as multiple arms of the
immune system are involved
 !(
uisease marked by progressive weakness and
loss of muscle control
Classified as a ³B cell´ uisease
Autoantibodies against nicotinic acetylcholine
receptors
 
uisease in which
the body does not
produce or
properly use
insulin
³ a cell´ uisease
a cells attack and
destroy
pancreatic beta
cells
 '"! 

MS patients can have autoantibodies and/or self reactive

a cells which are responsible for the demyelination
 " &Y!
 
ahree mechanisms are principally responsible
for inflammation and tissue injury in
autoimmune disease
1. Cell lysis and release of inflammatory
mediators triggered by auto antibodies
2. Ymmune complex disease
ÿ. a-cell mediated damage
  
Y 
!(- 
 
"" 

"' ! ",
! "!
! 
ë !
" !" 
 Y" '.'  
1.systemic lupus erythematosus
2.Rheumatoid arthritis, the auto antibody called
rheumatoid factor, is usually an YgM,
which is directed towards the ëc portion of the
patient¶s own YgG. Complexes of rheumatoid
factor YgM coupled with YgG, get deposited at
various sites leading to the characteristic
synovitis and vasculitis of rheumatoid arthritis
 +"#
ahis term implies that the recognition of
autoantigen by a cells leads to tissue destruction
without requiring the production of autoantibody.
ahere are a number of ways this can come about:
‡ uirect a cell cytotoxicity via Cu8+ CaL
‡ Self-destruction of tissue cells induced by
cytokines, e.g. aNë Į
‡ Recruitment and activation of macrophages
leading to bystander tissue destruction
‡ Ynduction of target tissue apoptosis by the a cell
membrane protein ëasL
 # 
History
Examination
Ymmunofluorescence
Antibody assay
Autoantibodies are used to diagnose many
autoimmune diseases. ahe levels of
autoantibodies are measured to determine the
progress of the disease
 # 

General tests
± C Reactive Protein
± Autoantibody titers (anti uNA, anti
phospholipids, etc)
± Presence of Rheumatoid ëactor

uisease specific tests

± Neurological exam ± MS
± ëasting glucose - uiabetes
  ! !# 
1- ahere is elevated serum immunoglobulins
2- Complement levels may be decreased
ÿ- Ymmune complexe detected in serum or organ
biopsy
4- Auto antibodies can be detected in serum
e.g. anti-nuclear, anti-smooth muscles, Rh factor
and anti-mitochondrial Ab
5- aesting for antibodies specific to particular Ag,
involved in organ specific diseases (anti-thyroid Ab)
 !

ahe key to treating

autoimmunity is
immunomodulation
 !' 
‡Anti-inflammatorydrugs
‡ NSAYuS, Corticosteroids
‡Ymmunosuppressant drugs
‡ Methotrexate
‡Radiation
‡Plamapheresis
‡Cell Blocking Reagents
‡ aCu20 (Rituxan)
‡ aCuÿ (aeplizumab)
‡Cytokine Blocking Reagents
‡ aNë (Humira, Enbrel)
 ******
!******

Autoimmunity is a failure of tolerance!

Knowing the tolerance mechanisms the immune

system uses, will help you better understand
autoimmune diseases!
â