Download autoimmunity

AUTOIMMUNITY
Scores
0
<5
<10
<15
<20
<25
<30
<35
<40
<45
20
<50
<55
<60
<65
<70
<75
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<95
Number of students
Autoimmunity
Midterm 2 distribution
30
25
median 79.5
15
scores
10
5
0
Autoimmunity
•Types of autoimmunity
•Possible mechanisms
•Defects in thymic tolerance, AIRE
•Defects in downregulation of immune responses
•FasL
•CTLA4
•Role of inflammation/adjuvants/ costimulation
•Suppressor/regulatory T cells
•Environmental factors
•Cross reactivity
•Crosslinking
•Role of MHC
"horror autoxicus"
Ehrlich, who was studying the
ability of antibodies and
complement to destroy
xenogeneic red blood cells,
recognized that if antibodies to
self erythrocytes were
produced, the results would be
devastating.
Paul Ehrlich ca. 1890
Autoimmune diseases are tissue and antigen specific
2-5% of the
population
suffers from
autoimmune
disease
Type I juvenile onset (insulin-dependent) diabetes
Type I diabetes is a T cell-mediated disease in which the
islets cells of the pancreas are attacked and killed. The
antigen recognized is not known, but there is a very large
correlation with the expression of the DR3/4 HLA types. The
culprit appears to be a variant of the linked DQ-beta gene
lacking a charged aspartic acid at position 57.
Diabetic autoimmunity is characterized by self-reactive B and T lymphocytes that
target a set of proteins expressed in pancreatic cells. Proinsulin (PI), IA2, GAD65
and 67, and islet cell autoantigen of 69 kDa (ICA69) are the major examples.
These target self-Ags are not islet cell specific, and neither is diabetic
autoimmunity; signs of celiac and thyroid autoimmunity are fairly common in
patients, and diabetes-prone NOD mice develop signs of thyroid and Sjögren’s
disease. Occasional islet-reactive T cells are found in almost 10% of the general
population, but <0.5% of these subjects are likely to develop overt diabetes.
Although it is uncertain what expands autoimmune T cell pools and what
determines their tissue-destructive potential, access to islet target tissue has been
suggested as a critical element in diabetes-prone hosts, despite availability of most
relevant autoantigens in other tissues.
Processive insulitis and islet cell destruction in diabetes-prone NOD strain mice
Healthy islets
Lymphocyte infiltrate
Figure 13-34
Some
autoantibodymediated
diseases
Figure 11-2
Figure 11-14
Figure 11-5
Graves
disease
involves
antibodies
to thyroid
stimulating
hormone
receptor
In some cases, it is clear that antibodies are pathogenic
Figure 11-7 part 2 of 2
System lupus erythematosis
The diagnosis of SLE is made when
other illnesses have been ruled out, and
when a person has 4 of 11 criteria. These
criteria include: discoid rash, malar
(butterfly) rash, photosensitivity, mouth
sores, arthritis, serositis (usually heart or
lung inflammation), kidney disorder,
neurological problems, blood changes,
immune changes, abnormal titre of
antinuclear antibody (ANA). It is
important to remember that 4 or more of
the above need to be present.
Sometimes SLE is suspected with fewer
symptoms present. For example, if a
person has a positive ANA, the diagnosis
may not be confirmed unless other
symptoms are present. It can be
frustrating to not know for sure. The
average time from the onset of
symptoms and diagnosis is about 3
years.
SLE continued
SLE can damage almost any part or organ of the body. Many people are
initially thought to have arthritis because SLE has caused inflammation of
the joints. Kidneys are frequently affected. If SLE affects the brain, for
example, a person might be initially diagnosed as psychotic, epileptic or
suffering from a stroke.
The respiratory system is one of the most frequently involved systems in
SLE. Infections present frequent problems. Certain medications used in
SLE may predispose a person to unusual kinds of infections.The more
serious problems involve lung disease including interstitial lung disease,
pulmonary hemorrhage.
Treatable. Treatment of SLE depends on the severity of the case. Some
people require only anti-inflammatory medicine (i.e. aspirin) to control pain
and swelling. Others may need corticosteroids or cytotoxic medications
including azathioprine or cyclophosphamide. In some cases, medications
may be used to suppress the immune system. Antimalarial medications
are frequently used.
Figure 11-9
Probable mode of antinuclear antibody production in SLE.
Linked recognition allows an autoreactive T helper cell to promote antibody
formation to non-covalently associated epitopes. (In this case, dsDNA acts as a
"hapten" and histone H1 as the autoreactive T cell epitope.)
Epitope spreading in Pemphigus vulgaris
Mechanisms by which autoimmunity might occur
Underlying defect/cause
•
•
•
•
•
Defects in immune tolerance (thymic negative selection)
Defects in the regulation or self-limits of immune reactions
Defects in costimulation (leading to failed peripheral tolerance)
Clonal ignorance and/or microbial crossreactivity
Antigen clearance defects
Proximal causes of disease
• Usually, antigen-driven lymphocytes cause inflammation, cell
death, or tissue damage.
• (Where known) there is a requirement for CD4 T cells reactive
to self peptide (Strong MHC bias)
• High affinity IgG antibodies to self-tissue cause disruption of
normal function, cell death, or C' damage.
Defects in immune tolerance
• AIRE deficiency: failure to
delete autoreactive T cells in
the thymus.
• The protein is a transcription
factor that is believed to turn
on many tissue specific
genes IN THYMIC
MEDULLARY EPITHELIAL
CELLS and plays a role in
negative selection.
Defects in the regulation or self-limits of immune reactions
These proteins are associated with limiting T cell responses
Protein
Expressed by
Phenotype of knockout
Fas
Activated T cells
Lymphoproliferation and
autoimmunity
CTLA4
Activated T cells
Regulatory T cells
Lymphoproliferation,
autoimmunity, death
TGFb
Various, including
Regulatory T cells
Massive inflammation
death
IL10
Th2 cells
Regulatory T cells
Inflammatory bowel
disease
Along with its role in cell killing, FasL is important in eliminating activated T cells
T cell
T cells
T cell
Fas deficiency leads to autoimmune lymphoproliferative syndrome
Fas and FasL deficient mice
•Both types of mice have an identical phenotype
•Lupus erythematosus
•Antinuclear antibodies (histone, dsDNA)
•Immune complex disease
•Glomerulonephritis (kidney inflammation)
•Skin disease
•Proteinuria (leakage of protein into urine)
•Massive T cell accumulation
FasL expression may play a role in "immune privilege"
FasL expression in
brain, eye, placenta,
and reproductive
organs is believed to
contribute to
immunological
privilege.
Aberrant FasL
expression may also
be an adaptation of
tumors to evade
immune surveillance.
Mechanism of Fas Ligand-induced death
Normal costimulation by
signaling through CD28
Appropriate activation
of naïve T cells requires
in addition to a ligand
for the T cell receptor a
second interaction with
CD28. This second
signal is called
"costimulation." Under
many conditions,
dendritic cells provide
this signal during a
primary response.