Autoimmunity and Transplantation

1
Chapter 14 Autoimmunity and Transplantation

• Autoimmunity is a destructive immune response
  against self antigens (how does this compare to
  hypersensitivities?)
• Once started, autoimmune diseases are hard to
  stop
• Severity ranges from minor to lethal

Ehrlich predicted autoimmunity and called it
horror autotoxicus
2
Some commom autoimmune diseases
3
Some autoimmune diseases may have a genetic
component and are triggered by external factors
(e.g., infection) or injury. Others are probably
strictly caused by external factors (e.g.,
infection) or injury
4
Some tissue-specific antigen can be expresses in
the thymus causing deletion (death) of thymocytes
that recognize those antigens
5
Autoreactive B cells can arise in germinal
centers from cell that are undergoing somatic
mutations (a mutation could change the
specificity of a BCR from anti-foreign to
anti-self). It is excepted that these
autoreactive B cell will bind antigen (signal 1)
but should not find a autoreactive T cell to
provide help (signal 2). Recall, signal 1
without signal2 results in anergy and death.
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Some parts in the body exclude immune responses.
These are immunologically privileged sites. These
tend to be organs that cannot sustain
immunological damage without seriously
jeopardizing reproductive fitness.
Injury to immunologically privileged sites can
lead to autoimmunity
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Autoimmune diseases can be organ-specific or
systemic
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Autoantibodies (IgG) can cross the placenta and
affect the fetus
Graves disease is an autoimmune form of
hyperthroidism
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Autoimmunity can be classified in a manner
similar to hypersensitivities
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Autoimmune hemolytic anemia
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Nucleated cells can resist complement lysis
better than RBCs. However, complement activation
can cause inflammation and destruction of
nucleated cells by the products of the
inflammatory leukocytes
Hashimotos thyroiditis destruction of the
thyroid by thyroid-specific antibody response.
Hashimotos thyroiditis showing thyroid tissue
with leukocyte (mostly lymphocytes) infiltration
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Graves disease (anti-thyroid stimulating hormone
receptor anti-TSHR)
Normal
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Myasthenia gravis (anti-acetylcholine receptors)
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For insulin-dependent diabetes mellitus, CTL kill
the b cells (cells that make insulin)
Insulin is stained brown
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Many autoimmune diseases are associated with
certain HLA types and with gender

• Genetics
• Gender
• Environment
• Chance

Genetics play an important role but other factors
are also important, such as gender, environment
and chance
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Insulin-dependent diabetes melllitus (IDDM)
appears to be associated with certain HLA class
II types
These studies did not look at the DQ genes.
Thus, although associated with DR, the real
culprit may be the linked genes, DQ
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Immune responses to alloantigens and graft
rejection
Major histocompatibility antigens cause graft
rejection in about 10-14 days
1.Graft MHCa to MHCb2. Let graft be rejected3.
Transfer T cells from MHCb sensitized mouse to a
naïve MHCb mouse 4.Graft MHCa on to mouse that
received the T cell
T cells usually mediate graft rejection
Recall, there is an extraordinarily high level of
anti-allo-MHC specific T cells (chapter 5-14)
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Minor histocompatibility antigens (H antigens)
are not MHC proteins but peptides of other
polymorphic cellular proteins presented by MHC
and lead to graft rejection.
Minor histocompatibility antigens cause graft
rejection after several weeks (3-8 weeks)
If no immunosupression, even a perfect MHC match
between donor and recipient will result in graft
rejection if there are minor-antigen differences
Siblings have a 25 chance of having identical
MHC types. However, unless they are identical
twins, they will almost certainly have several
minor antigen differences.
Same as fig 14-39 frame 2 (previous slide), just
a different scale on the horizontal axis
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Minor histocompatibility antigens can also cause
graft rejection
Here, donor and recipient have identical MHC
types but differ at other (minor) genes (and
therefore different proteins).The graft
recipient (blue/yellow) will see the red peptide
as foreign
Same MHC type
T cells usually mediate graft rejection
In addition to the MHC differences that usually
distinguish one person from another, there are
also many other genetic differences, Like MHC
differences, these minor differences are manifest
in proteins that can be recognized by the immune
system and can be the targets of immune responses
and graft rejection
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Any MHC (or minor antigen) the host sees as
foreign will cause rejection
Examples (assume donor and recipient have the
same minor antigens only experimental, not ever
the case for non-identical twin humans)
MHCa skin onto MHCa receipient ? MHCa skin onto
MHCb receipient ? MHCb skin onto MHCa receipient
? MHCb skin onto (MHCaXMHCb)F1 receipient ?
(MHCaXMHCb)F1 skin onto MHCb receipient
? (MHCaXMHCb)F1 skin onto (MHCaXMHCc)F1
receipient ?
accept
Anti-MHCa
reject
Anti-MHCb
reject
accept
Anti-MHCa
reject
reject
Anti-MHCb
Similarly, minor antigens the host sees as
foreign will cause rejection
21
Preexisting antibodies against antigens in the
graft (usually blood type antigen) can cause
rapid graft rejection
Hyperacute graft rejection mediated by antibodies
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Tissue graft survival
These are averages. How well the donor and
recipient are matched for MHC and minors has a
big impact on graft survival.
Most transplants require lifelong
immunosupression with cyclosporin A or
FK506. These drugs have many affects on the
immune system but, overall, are not too toxic
(see chapter 15-3)
23
Cyclosporin A and other immunosupressive drugs
have made tissue grafts possible
24
A fetus is an allograft that may induce an immune
response in the mother but is usually protected
from the mothers immune system.
MHCa/b
MHCc/d
Possible MHC types for the fetus MHCa/c MHCa/d MH
Cb/c MHCb/d All differ from the mother by 1 MHC
type
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Herd immunity If enough individuals in a
population are immune, infectious disease are not
easily maintained or transmitted within the
group. Thus, even individuals that are not
immune are protected from infection
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The End
Final Exam Friday Dec 11 at 300 in Snyder Hall
301orMonday Dec 14 at 730 in BusAd A102 (here)