Lecture 5 Flashcards
What is immunological tolerance?
Prevention of an immune response against a specific antigen
What is self-tolerance?
All individuals are tolerant to self-antigens.
What happens when self-tolerance does not work?
Autoimmunity- a reaction against its own cells
Negative selection of self-reactive T-lymphocytes in the thymus is perfect/not perfect
not perfect
Does our body undergo auto-reactivity?
Yes. Our body has to have a low level of auto-reactivity for normal function
What is central tolerance?
Central tolerance is induced in immature self-reactive lymphocytes in the primary lymphoid organs.
It destroys the cells, changes the receptors of B cells, or creates T-reg cells to make sure that mature lymphocytes are not reactive to self.
What is peripheral tolerance?
Peripheral tolerance is induced in mature self-reactive lymphocytes at peripheral sites.
These cells will be inactivated (anergy), deleted (apoptosis) or supressed by T-reg cells
to prevent them from activating in tissues.
Central tolerance occurs in the ____. Here, what type of thymocytes are deleted by apoptosis.
Thymus
- Strongly self-reactive thymocytes
- Nonfunctional thymocytes with no affinity.
What thymocytes are positively selected and migrate into the periphery as mature T-cells?
What happens next?
Those that are activated by a MHC self complex below a certain threshold.
They will then become effector CD4+ and CD8+ T-cells. A small percentage will develop into natural T-reg cells.
Another name for T-reg cells?
CD4+ CD25+ CTLA4+
In peripheral tolerance, we said that mature self-reactive lymphocytes will under inactivation (anergy), apoptosis, or be supressed by T-reg cells. How does anergy occur? (2)
- Naive T cell recognizes self-antigen–> however, no co-stimulation occurs–> anergy is induced.
- Naive T cell recognizes self-antigen–> uses inhibitory receptors (CTLA4 or PD1) to block activation
Sometimes cancer is treated with anti-CTLA4 and anti PD1 that block these receptors leading to?
Checkpoint bloackade–> enhanced antitumor immune responses and tumor ression.
What does checkpoint blockade develop due to inhibition of CTLA4 and PD1?
Leads to autoimmune reactions
T-reg cells develop in the thymus.
How are T-reg cells positvely selected?
T-reg cells are positively selected due to strong TCR interactions with self-antigens. This does not cause apoptosis, as it usually would because they create anti-apoptotic molecules, while protects them from negative selection
Generating T-reg cells requires ____
T-reg cells usually express high levels of _____
TGF-B
CTLA-4
What is CRITICAL for the survival and function of T-reg cells?
IL-2
What is the purpose of T-reg cells?
They are endogenous LONG-LIVED self-Ag specific T cells. They prevent autoimmune reactions.
Natural immature Tregs are made in the ______
Where are inducible Treg (iTreg) cells made?
Natural immature Treg cells–> Thymus
Indubible T-reg cells are made in the LN and GI tract.
Development and survival of T-cells require what?
IL2
FOXP3
In peripheral tissues, Treg cells do what?
Supress self-reactive lymphocytes from activation.
How are iTeg cells made?
- Naive CD4+ cells invitro are presented with an antigen, in the prescense of TGF-B, IL2 and retinoic acid.
*Retinoic acid inhibits formation of Th17, but promotes FoxP3–> Treg cells.
The same naive T-cell invitro that made iTreg cells can make TH17. How?
Naive T-cells recognize an antigen in the presence [TGF-B and IL-6]. This prevents FoxP3 expression.
IL6–> induces RORyt–> induces IL-17
Antigen recognition in the presence of TGF-B induces FoxP3 expression if ______ is not expressed.
IL-6
CD4+CD25+CTLA4+FOXP3+ T reg cells are key mediators of peripheral tolerance. They can inhibit what? (3)
- T-cell activation by APCs
- Inhibit T-cell differentiation –> CTLs
- Inhibit T-cell from helping B cells make antibodies.
How do Treg cells work?
- APC binds to a Treg
- Treg releases IL4, IL10, and TGFB to the APC.
- The APC then has a decrease in expression of CD40, CD80/86 and IL 12
- APC will express IL10, resulting in the loss of ability of APC to induce effectors.
What are the four mechanisms by which a Treg cell can work?
- Inhibitory cytokines (IL-10 and TGF-B)
- Cytolysis (Granzyme A/B, perforin)
- Metabolic disruption
- Inhibit DC maturation and function
Metabolic disruption by Treg cells includes what? (3)
- Apoptosis due to deprivation of CD25 (IL2RA)
- Inhibition by cAMP
- Immunosupression due to A2AR (adenosine receptor 2A)
How does Treg cells prevent DCs from maturation?
- Uses CTLA4- CD80/86
- IDO (indolamine 2,3 dioxygenase) , an enzyme that degrades tryptophan
What two mechanisms can we get rid of self-reactive T- lymphocytes?
- Mitochondrial pathway (intrinsic pathway)
- Death receptor pathway (extrensic pathway)
Cell death is caused when a mature T cell binds a self APC with self Ag. This reaction does not produce IL2 due to no costimulation. This leads to ? (intrinsic)
Apoptosis.
- IL2 starvation, leads to decreased expression of antiapoptotic gene BCL2
- Leads to release of apoptotic proteins from the mT,
- Caspase 9
- Caspase 3 –> CAD –> degredation
Cell death is also cause when a mature T cell binds a self APC, activating its death receptors, such as? (extrinsic pathway)
- Fas receptor is expressed on T cell,
- Binds to FasL on other T cell,
- Caspase 8 activated
- Caspase 3 –> CAD –> degredation
Central B cell tolerance :
**Immature** B cells that recognize self Ags in BM with high avidity:
- die by apoptosis (clonal deletion)
- Undergo receptor editing and change their BCRs. What is receptor editing
Further rearrangement of the IgL chain genes that ocurs until nonself recognizing receptors are made or the cell dies
In central tolerance:
Low avidity interactions of immature B cells with self Ags in BM leads to?
Anergy (functional inactivation) of the B cells.
They can go into the periphery but cannot enter the follicle and they have a reduced life span
BCR editing uses RAG1/2 to rearrange IgLchain when pre- B cells are self reactive.
This recombination can either result in apoptosis due to another self reacting receptor or can lead to?
Innocuous receptor, lacking self reactivity
Mature B cells who recognize self ags in the periphery in the absence of Th cells are rendered
- unresponsive
- die by apoptosis.
- Can also be fixed by CD22 inhibitory receptor.
How does #3 occur?
- CD22 is phosphorylated by Lyn and recruits SHP-1–> which inactivates the B cell signaling.
SO IF THERE IS A DEFECT IN LYN, SHIP OR CD22 inhibitory receptor it can lead to ______
autoimmunity
It is said there are genes that interefere with pathways of self tolerance lead to the persistence of self-reactive T and B lymphocytes.
Infections and other inflammation promote influx of lymphocytes into tissues and activate APCs. What can APCs then do?
APCs will then activate these self reactive lymphocytes resulting in generation of effector T cells and autoantibodies that cause autoimmune diseases
AIRE: autoimmune regulator,
Deficiency causes destruction of endocrine organs by antibodies, leading to the failure of central tolerance.
What human disease is caused by this?
Autoimmune polyendocrine syndrome (APS)
Impaired production of T regulatory cells due to FOXP3 deficiency can cause multi-organ lymphocytic infiltrates and wasting, causing what human disease?
IPEX: immune dysregulation polyendocrinopathy
When there is a mutation in C4 and Clq complement proteins, it leads to defective clearance of immune complexes and impaired tolerance induction by apoptotic cells, causing what human disease?
SLE
Lupus
When there is deficiency in CTLA4, causes uncontrolled proliferation of T cells, causing failure of anergy in CD4+ T-cells. What human disease is this?
CTLA4 polymorphisms associated with several autoimmune diseases
AIRE deficiency
Leads to an incomplete induction of tolerance in the thymus.
This causes autoimmune polyendocrine syndrome
FoxP3 deficiency
FoxP3 deficiency leads to an impaired production of regulatory T-cells, causing IPEX syndrome
Deficiencies of C1q and C4
Causes decrease clearance and impaired induction of tolerance
leading to SLE
What is AIRE?
AIRE is a transcription factor that is expressed on medullary thymic epithelial cells, an APC.
AIRE produces self- TRAs (tissue restricted antigens) on these cells so that they can present them to immature Ag- specific T-cells and kill self-reactive T-cells
A mutation in AIRE would cause what?
Decreased expression of self-ags in the thymus. Thus, self-reactive T-cells cannot be eliminated and enter tissues where the antigen is produced and start killing the cells!
Thus, this leads to an incomplete induction of tolerance in the thymus, causing autoimmune polyendocrine syndrome
When T cells recognize self Ags, they may engage inhibitory receptors of the CD28 family, whose function are to?
terminate T cell responses
Best inhibitory receptors are
CTLA4
CTLA (cytotoxic T-lymphocyte antigen 4) is a homolog of CD28. It causes contraction (inhibition) of T cells (death) while CD28 causes expansion upon Ag recognition
In the absence of CTLA4, what is seen?
- Uncontrolled lymphocyte activation with enlarged spleen and LN.
- Enhances autoimmune disease
Polymorphisms in humans in CTLA-4
- Type 1 DB
- Graves DZ
What are two important properties of CTLA-4?
- Resting T cells have low CTLA-4 expression. Increases with activation
- When expressed, it stops continued activation of T-cells (to help balance signaling)
CTLA-4 is expressed on _____
Treg cells
What are the modes of CTLA-4 action?
- Intrinsic action: CTLA-4 is expressed on a T-cell and causes inhibtion
- Extrinsic action: CTLA-4 on Treg cells or responding T cells bind to B7 on APCs or make it unavailable to CD28. This causes reduced B7 costimulation.
Soluble or sCTLA4 activates CTLA4 fucntion, blocking autoimmunity when there is a lack of CTLA4 , leading to T cell proliferation/differntiation.
Anti-CTLA4 Abs bind to B7(CD80/86) and CTLA4, stimulating?
Anti-tumor immunity
About 5% (12-15million) people have autoimmune diseases. There are about 60-70 different kinds, all of which have no cures and are treated symptomatically. Most are treated _________
symptomatically.
The autoimmune diseases says: the body both is and is not iself
Is there a stuctural difference between self-ag and non-self ags?
No, because all atigens are made of proteins.
Immune response against self-antigens is clinically manifested as what?
Immune-mediated inflammatory disease that is caused by the activation of T/B cells without an ongoing infection.
This is a result of a hypersensitive immune system that causes ones immune system to attack itself.
What are 4 ways autoimmunity is prevented?
- immunologic ignorance, meaning there is an anatomical barrier between self Ag and T cell
- FasL + Fas (deletion)
- CD152(CTLA4) leading to no activation (inhibition)
- Treg releasing IL10/TGFB so T cell doesnt activate (supression)
General features of autoimmune disorders
- Can be systemic or organ specific
- Different effector mechanisms cause different autoimmune diseases
- Chronic, progressive, self-perpetuating.
- Failure of self-tolerance underlies all autoimmunr diseases
Genetics of autoimmune diseases
Autoimmune diseases are complex polygenic traits+ environmental factors. People who have them inherit multuple genetic polymorphims, especially in MHC genes.
Etiology of autoimmunity
Genetic susceptibility causes a failure of self tolerance, producing self-reactive lymphocytes. Add an environmental trigger and you get
–> activation of self-reactive lymphocytes–> immune response against self
Microbial antigens can intiate autoimmune disorder through what 3 ways?
- Molecular Mimicry
2, Polyclonal (bystander) activation
3, Release of previously sequestered Ags
Molecular Mimicry
APC presents a microbial antigen–> self-reactive T cell that can also recognize microbial peptides
This leads to the activation of T cells that recognize self antigens and autimmune disorders
Example of molecular mimicry
Rheumatic fever, is triggered by streptococcal infection and mediated by cross-reactivity between
Ags and cardiac myosin
Example of molecular mimicry
Multiple sclerosis: T cells react with myelin basic proteins and peptides from EBV, influencez virus type A and?
HPV
What is polyclonal activation
MIcrobial infection can cause polyclonal activation of autoreactive lymphocytes (cytokine field)
How can the release of previously sequestered antigens cause autoimmune disorders
Microbes that kill cells can cause inflammation, the release of sequestered Ags and autoimmunity
Autoimmune diseases are more common in women than men for SLE becuase why
estrogens exacerbate systemic lupus erythematosus (SLE) by altering B cell repertoire in the absence of inflammation
Drugs can also alter our immune system. How?
Pencilicin and cephalosporins can bind to the membrane of a RBC and create a neonatigen, which causes auti-antigens that cause hemolytic anemia
The blockade of TNF-alpha (ENBREL) can induce antinuclear Abs, lupus and MS due to its?
inhibitory effects on activated T cells
What does retanoic acid do?
It is produced by DC cells and creates Foxp3+ Treg cells from naive CD4+CD25+ T reg cells
Clearance of immune complexes: Small Ag-Ab complexes form in circulation, C3b are added to the complex, then what happens?
Complement receptor CR1 on erythrocytes bind the complex via C3b in the spleen and liver, phagocytic cells remove complexes from erythrocyte surface via CR1 and FcR
What are the sites where immune priviledge (skin grafts that survive for a long time) occurs?
Eye
brain
pregnant uterus
ovary
testis
hair follicles
adrenal cortex
Mechanical breaking of the barriers due to a trauma results in generation of autoimmune response
MHC genes have the strongest associations with autoimmune disorders, what is the disease for each MHC allele and relative risk?
HLA B27 Class I RR:90 HLA
DRB1 Class II RR: 4-12
HLA DRB1 Class II RR: 35
HLA DR4 Class II RR: 14
- Ankylosing spondylitis 2. Rheumatoid arthritis 3. Type 1 diabetes 4. Pemphigus vulgaris
