IMM250 Lecture 11 – Autoimmunity
1/20 people in Western countries suffer, which is higher than developing country
Non-specific (global immunosuppression susceptible to opportunistic infections)
Inconsistent efficacy (unpredictable response)
Multiple Sclerosis become wheelchair bound
Glomerulonephritis requires continual dialysis
Type I Diabetes requires daily injections of insulin
Rheumatoid arthritis requires daily therapies to keep the inflammation in joints under control
Status of treatment for autoimmune diseases
Not very good therapies
High burden to health care system and economy
Steroids are not good enough
Organ-specific autoimmune diseases attacks particular tissues
o Type 1 diabetes mellitus = pancreas
o Multiple sclerosis = CNS
Systemic autoimmune diseases attacks common tissue and multiple organs (diseases have
stronger role for antibodies circulate more effectively target more tissues)
o Rheumatoid arthritis = joints + heart
o Systemic lupus erythematosus = kidney + heart + CNS
Pathogenesis of autoimmune disease
B cells can cause autoimmune diseases as well
Layers of self-tolerance: Central tolerance
Four mechanisms of maintaining T cell tolerance
T cell precursors migrate from the bone marrow to the thymus
T cells precursors in the bone marrow migrate to the thymus to finish development.
B cells develop and finish development in the bone marrow.
At puberty, the thymus involutes and becomes smaller. A lot of the thymic education takes
place in the first decade of life. It continues to take place in adults but not as efficiently.
Cellular organization of the thymus
What does the thymus look like? Like the LN, the thymus is also an organ that has
compartmentalization to facilitate T cell education. In the LN, compartmentalization facilitates T
cell activation. The cells enter the thymus through the sinus. Under the sinus is the cortex.
Under the cortex is the medulla. There are discrete steps that take place in T cell education (T
cell maturation) that take place in discrete locations. As immature thymocytes mature, they go
through the thymus into the medulla and then they leave.
Bone marrow thymus periphery circulation through body
Mature T cells never goes back to the thymus Epithelial cells of the thymus form a 3-D network surrounding developing thymocytes
The thymus is a highly organized structure. Epithelial cells are not cells of the immune system.
Epithelial cells form a scaffold for the thymus. Epithelial cells play an active role in the education
process of thymocytes.
T cell development in the cortex
In the blood, you never find a double-positive T cell. The thymus is the only place where double-
positive happens. CD8+CD4+ undergo positive selection.
T cell development in the medulla
Thymocyte is an immature T cell that has left the bone marrow. When it enters the thymus, it
does not express CD4 or CD8. when it enters the cortex, it expresses both CD4 and CD8 and
undergoes positive selection (cortex) then negative selection (cortex medulla boundary). If they
pass both tests, the thymocyte is considered a T cell that can patrol the host. It is considered a
safe T cell that is not self reactive.
Positive Selection (cortex)
CD4 and CD8 both bind to MHC. The epithelial cells in the thymic cortex express MHC I and MHC
II. The immature thymocyte will see MHC with peptide. In the thymus during positive selection
in the cortex, a thymocyte sees self peptide. The self peptide has very low affinity for the TCR.
You do not want to be selecting thymocytes strongly reactive for self peptides. They need to be
a little reactive so we know those T cell receptors are good at seeing MHC peptide. If they
cannot see it, then they are of no use to the body. When they see foreign antigen in the context
of MHC, the T cell should be able to see it. This is an opportunity to test that the T cell will work.
Self peptide and MHC allows TCR to be slightly activated. If they get positively selected, it will
move to the cortex-medulla boundary to test for autoreactivity.
If there is no peptide interaction, the immature thymocyte does not get a signal. The immature
double-positive thymocyte in the absence of signal will not be positively selected and die by
apoptosis. This is a thymocyte that fails to see self-peptide in the context of MHC. The bone
marrow is making millions of T cells a day. You do not want to pick T cells that cannot recognize
During the process of positive selection developing T cells (thymocytes) interact with thymic
epithelial cells which express MHC class I and II molecules in association with self-peptides.
Thymocytes interacting with no sufficient but not too high affinity with MHC plus peptide
receive survival signals (therefore the use of the word "positive"), proceed in their maturation
steps and then leave the thymus as mature naive T cells to circulate in the (body) periphery.
These are the T cells that will be able to mount an immune response because they have passed
the "positive selection" checkpoint, in other words they have been tested for their ability to
recognize MHC molecules. The cells that are not able to "see" MHC molecules are eliminated
because they do not receive survival signals. Negative Selection (medulla)
Negative selection happens after the thymocyte has been positively selected. This happens at
the boundary of the medulla and cortex. A double positive thymocyte has been positively
selected. Epithelial cells will present self peptide in the context of MHC. If the TCR is good at
seeing the MHC self peptide, then it is going to die by apoptosis. You do not want T cells leaving
the thymus that have strong reactivity to self antigens. This is a chance to test whether your
thymocytes are self reactive. If they are, they get killed off.
If the double positive thymocyte does not have a strong reaction with the self peptide in the
medulla region, the thymocyte will become a single positive T cell. It will leave the thymus and
patrol the body.
Negative selection gets rid of thymocytes interacting too strongly with MHC molecules and/or
self-peptides. This process is called "negative" because the cells are "deliberately" killed. If these
cells were left free to go to the periphery, they would attack self organs and create
T cell selection
Death by neglect because the thymocytes do not get the same survival factors that other
If the TCR has intermediate affinity for the antigen, positively selected and fails to be negatively
selected, then it can leave the thymus and enter the periphery.
What is programmed cell death?
The visualization of apoptosis. Apoptosis is important because the way the cells die does not
cause inflammation. Apoptosis happens in the thymus at high levels. You see the same amount
of apoptosis in the GC. Life and death is an important part of thymocyte selection and the
Apoptosis occurs through a complicated pathway. FAS triggers this pathway and sends a signal
to the cell to die by apoptosis. This method of inducing apoptosis is important in the thymus. If
you mess with this, you end up with an individual that has profound autoimmunity. You want to
preserve death pathway to kill off thymocytes you do not want.
Problem #1: All T cells are to a certain extent “Autoreactive”
To leave the thymus as a mature T cell, you have to be a little autoreactive. To leave the thymus,
you have to undergo successful positive selection in the cortex of the thymus. The T cell leaves
the thymus with the capacity to see self peptide to an extent. All the T cells in the body have
reacted to self peptide at some point. Every foreign antigen specific T cell binds at least to one
cross reactive self peptide that they saw when they were positively selected in the thymus.
Solution #1: Affinity for selecting self peptide is insufficient to trigger full activation of a mature T cell
(ie, Signal 1 is too weak)
A TCR that recognizes MHC in the context of self peptide can get a weak signal 1. It is probably
not going to get signal 2 because you need inflammation. If a DC has a self peptide drains into
the LN and presents it to an autoreactive T cell, if there is no inflammation, this is the end of the
story. The slightly self reactive T cell is not going to do anything. They get a weak or abortive
signal 1. This is the obvious way to prevent massive autoimmunity. Problem #2: How do T cells get negatively selected to not react to ALL peripheral peptides?
How is it that all the self peptides in the body can be seen in the thymus, if you want to teach
thymocytes to not respond to peptides that come from all over the body?
In humans, within the thymus medullary region, the epithelial cells have the capacity to de-
repress gene expression. Normally if you are a cardiac cell, you express cardiac genes. If you are
a big toe cell, you express big toe genes. The thymus medullary epithelial cells have the capacity
to express a whole bunch of different genes that a normal cell would not express.
Your cells express only the genes that dictate their function and not other genes. How can this be
Transcription factors bind to the gene that you want to be expressed. The medullary epithelial
cells express a broad range of genes through an enzyme called AIRE.
Expression of AIRE in a medullary epithelial cell in the thymus
The red is staining for AIRE.
AIRE was mapped to a chromosome region in humans. People who had recessive mutations in
this gene got a disease called APECED. APECED is a rare disease. If you have mutations in both
copies of the AIRE gene, you get APECED. This is a very serious, debilitating disease.
People get APECED because they lack the machinery to express all of these different peptides in
the thymus to achieve negative selection. They end up with a deflective negative selection
In A, a developing thymocyte has entered the thymus. It has undergone positive selection. It is
time for negative selection. It will interact with thymic medullary cells that express AIRE. AIRE
induces the expression of all of these different self peptides. The self peptides get loaded on
MHC and presented to the developing thymocyte. If the developing thymocyte has strong
affinity for self peptides, they will be negatively selected. If the developing thymocyte has no
affinity for self peptides, they will escape negative selection.
In B, they have a thymus medullary epithelial cell where AIRE does function properly. All these
proteins are not expressed. All self-reactive thymocytes escape negative selection and leave the
thymus. They will attack the host. This is why they get autoimmunity.
Individual organs of the body express tissue-specific antigens
This individual has proteins expressed all over the body. Even though they are far from the
thymus, they are expressed in medullary epithelial cells and presented to thymocytes so those
thymocytes can be deleted.
The transcription factor AIRE in the thymus allows the transcription of proteins that function
elsewhere. This expression of "peripheral" proteins in the thymus is necessary to allow their
interaction with developing thymocytes. Thymocytes that interact too strongly with these
proteins are eliminated, because if allowed to go to the periphery they would cause
autoimmunity. An engineered mouse model
These mice do not get diabetes because the virus specific T cells are naïve and will not go to the
pancreas. They go from LN to blood and they will not see the antigen. If it does not see the
antigen, then it will not get activated.
Infection with virus induces autoimmunity
When you infect the mice with virus, you get active draining of antigen from the pancreas.
Because there is inflammation, DC upregulate B7. The virus specific T cell sees antigen and gets
CD28 signal to activated the T cell. The inflammation caused by the virus leads to diabetes.
In the normal state, the mice have no diabetes.
In the inflammation state, the mice have diabetes.
Obviously we do not have virus specific proteins in the pancreas. This is an engineered model.
This indicates that one of the environmental triggers to autoimmune disease could be getting a
virus and you happen to have one of the autoreactive T cells floating around in the wrong place
and wrong time. This is one theory for a potential trigger of autoimmune disease. This explains
why most autoreactive T cells do not respond because they are segregated away from the
Layers of self-tolerance: Peripheral anergy
Another mechanism for preventing autoreactive T cells is anergy. In the thymus, if you
encounter a self antigen and you have a high affinity for the self antigen, then the thymus is
negatively selected. Another outcome can be anergy which happens in the periphery. A T cell
that sees self antigen does not die and does not cause any harm.
T cell activation (Signal 1 + 2 + 3)
In the normal situation where you have an immune response to a pathogen, DC are activated
through inflammation through PAMPs. The DC will upregulate B7 and present peptides on MHC.
The foreign peptide in the context of MHC and inflammation will be good at delivering signal 1
and signal 2 through the expression of B7. You need signal 1 and signal 2 and cytokines to
activate T cells. What are the different effector mechanisms of activated T cells?
T cell activation happens during infection.
T cell tolerance (Signal 1)
This happens most of the time.
T cell tolerance is when there is a self-peptide presented by MHC but there is no PAMPs. In
absence of PAMPs, you do not get signal 2 and you do not get cytokines. You get some T cell
activation but the T cell is crappy and is not going to exert effector functions. It is either going to
die or become anergic (T cell unresponsiveness). There are a lot of thymocytes that escape
negative selection because you cannot display all self-peptides in the thymus. This is a second
check to get rid of self-reactive T cells in the periphery. DC sample antigen all the time and drag
it back into LN. In the absence of inflammation, it does not have an outcome other than to
induce anergy or deletion.
This happens on mature T cells that have been educated in the thymus but not good for us.
DC are not smart. They will pick up antigen no matter what. They do this in the presence and
absence of inflammation. They take in all these antigens all the time and go to the draining LN.
Most of the time, you get DC that pick up self antigen in a non-inflammed tissue, drag to draining LN, if there is a self-reactive T cell that sees antigen, it will get signal 1 but not signal 2.
The T cell will become tolerant (die or anergic).
If there is inflammation, the DC is ready to prime T cells. Hopefully, the antigen is foreign
antigen. This is likely because inflammation was c