Tolerance and Autoimmunity Flashcards
What is immune tolerance
(1) It is the discrimination between self and non self (2) Break in immune tolerance leads to autoimmunity
What is toleragenic
Opposite of immunogenic, an antigen that doesn’t elicit an immune response
What are the reasons of antigens being toleragenic
- Lymphocytes can be killed 2. They can remain inactivated 3. There is no reaction, called immune ignorance It is important to know that the same antigen can be immunogenic to toleragenic depending on how it is presented to the immune system
What is central and peripheral tolerance
- Tolerance that develops in the lymphocyte development in the primary lymphoid organs which are bone marrow and thymus is called Central Tolerance 2. Peripheral tolerance develops somewhere other than the primary lymphoid organs, so it can happen in the lymph nodes and also in the peripheral tissue
Explain the process of selection of T cells
- T cells that bind too tightly with the MHC undergo apoptosis, by negative selection 2. T cells that do not bind with MHC undergo apoptosis, it is called death by neglect 3. T cells that bind loosely with MHC undergo positive selection and leave the thymus as mature naive T cells (either CD4 or CD8) 4. Positive and negative selection is not a 100% effective process, some T cells that bind too tightly with MHC survive and develop into Regulatory T cells.
What is the significance of peripheral T cells
They are CD4+ T cells, they express FOXP3, they contribute to peripheral tolerance
How do T cell get selected such that they do not respond to peripheral antigens
In the thymus, the thymic epithelial cells express AIRE gene which makes the AIRE trasncription factor which makes the thymic epithelial cells express peripheral antigens to which the T cells undergo positive/negative selection.
What happens when there are mutations in AIRE
Leads to multi organ autoimmunity reactions called APECED syndrome (Autoimmune Polyendocrinopathy-Cadidiasis-Ectodermal dystrophy syndrome)
What are peripheral antigens
All antigens on the body except for the ones in primary lymphoid organs such as islet antigens, kidney antigens etc
Why do we need Regulatory T cells
Selection is not 100% efficient, need to induce peripheral tolerance
How is peripheral tolerance achieved
- Functional Inactivation which is also called anergy 2. Treg mediated suppression 3. Apoptosis 4. Ignorance
What is anergy
- It is long lived functional inactivation 2. Occurs when naive T cells recognize MHC/peptide complexes in the absence of coreceptor stimulations or when there are inhibitory signals present
What are some of the inhibitory signals
CTLA4 and PD1
What are the functions of Regulatory T cells and how do they achieve it
- Suppresses the function other T cells that were supposed to undergo negative selection but didnt. 2. These cells achieve this function by developing FOXP3 which is found on the X chromosome
- Also these cells express high levels of CD25
What are the 2 kinds of T regs
Natural regulatory T cells (called T regs) and there are also inducible T regs which are induced in the periphery by TGF-beta
How is immune response regulated after infection is cleared
Apoptosis of effector cells which is done by Lymphocyte Activation Induced Cell Death (AICD) This is done by FAS-FASL.
This is possible because FAS is induced upon T cells after activation (it is FAS, not FAS-L, that was her mistake in this slide)
What pathology is associated with this process of Lymphocyte Induced Apoptosis
Autoimmune Lymphoproliferative Syndrome (ALPS)
- Mutations in FAS gene or in their associated signaling pathway
- Leads to autoimmunity since the lymphocytes cant kill themselves
Is B cell negative selection a 100%
Nope, its the same as T cells, but T cells negative selection not being 100% is potentially more dangerous since CD4 T cells mediate the immune response
How is peripheral B cell tolerance achieved
- Anergy
- Death by apoptosis
- Ignorance
The diagram she showed us for peripheal tolerance
So here it illustrates that even when the B cell encounters an antigen, if there is no stimulation of B cell by the T cells then there will be no antibody switching and hence B cell will not make antibodies against the antigen
What is the realtionship between the concentration of Ig and their associated half life
As the concentration increases, the half life of the Ig decreases
What are the 2 kinds of Fc receptors
There are stimulating Fc receptors as well as inhibitory Fc receptors
What is an example of the Fc inhibitory receptors and what is one important clinical use for them
One example is the FC-gamma-RII receptor. It is important to note that it is bound to the antibody and inhibits signaling by blocking the signaling cascade of the accessory molecules associated with BCR (Ig alpha and Ig beta).
One important clinical use is that this mechanism is exploited in treating Rh negative mothers that are pregnant with Rh positive fetus. RHOGAM is given to these pregnant women which turns off maternal B cells by cross linking BCR to FC-gamma-RII receptor
What is the significance of Fc inhibitory receptors on macrophaes
Helps in bringing down the immune resposne by making IL10, TGF-beta and PGE2 (this inhibits lymphocyte proliferation)
What does autoimmunity correspond to in terms of the different types of hypersensitivity reactions
- 3 and 4. None of them falls under type 1 (makes sense)
Explain Graves disease
- Anti-TSH receptor antibodies, but they are aganistic, they stimualte the receptors on the follicle
- Leads to thyroid hyperplasia (goiter) and hyperthyroidism
- All of this happens due to B and T cell infilteration
Expalin Goodpasture Disease
- Antibodies, specifically IgG are made against the basement membrane that bind to it
- Neutrophils are recruited by these antibodies that do the damage
- Strongly related to lungs and kidney basement membrane, that where the symtoms are first seen
What are the clinical symptoms of lupus
- Fever, arthritis, mylagia, skin involvement, photosensitivity and anemia
- Skin, kidney and joint problems reflect immune complex deposition that leads to problems
How do you check lupus
ANA test: Anti Nuclear Antibodies test.
Here a patient’s serum are placed on a a bunch of cells, if the patient has ANA in the serum, these antibodies will bind to the DNA, flourescent antibodies bind to these antibodies in turn and thats how the ANA test determines if it is Lupus or not.
It is not a definitive test however, 15% of the poeple have ANA but they do not have lupus
What is MS example of
Multiple Sclerosis is part of the type IV hypersensitivity.
Myelin sheath gets attacked by the immune cells. The cells that carryout this response are the CD4 cells: Th1 and Th17 cells. They make IFN gamma and IL 17
What is Type 1 diabetes example of in terms of hypersensitivity
- Type IV, since destruction of islet cells is done by the T cells mediated response
- CD4 and CD8 cells do the cytotoxic activity
- Antibodies are also made in this disease but their role is not clear, however they are not the ones that cause cell destruction
What is the proposed mechanism for type 1 diabetes
- There are some genes that code for receptors that are more prone to autoimmune reactions
- Failure of tolerance can develop when there is less than 100% negative selection
- This leads to development of antibodies and destruction of those antigens
What is the gene that is strongly associated with autoimmunity
HLA alleles, but they are not the only cause of disaaese, it is a multi factorial process, mmany people with the same HLA alleles as a diseased individual do not develop the disease
What are some of the other genes involved in Autoimmunity
- PTPN22 (protein tyrosine phosphatase) which is involved in B and T cell signaling. It is associated with lupus, rheumatoid arthritis and type 1 diabetes
- Polymorphisms in NOD2 can also lead to autoimmunity, 25% of the clinical cases of Crohn’s disease are associated with this.
- High affinity IL2 receptors (which are CD25) polymorphisms, since IL2 is required in T regs development
- IL-23 receptor polymorphisms. IL23 is needed for TH17 differntiation
- CTLA4 polymorphisms
What is molecular mimicry
Antigens from a pathogen that are very similar to self antigens, example post streptoccoal rheumatic fever
How do we treat autoimmunity
- GCs
- Abatacept (CTLA4-Ig): it is an actual CTLA 4, it binds with CD80 or CD86 to turn off the immune response
- Anti CD20 antibody - Rituximab
- Anti-TNF antibody: Infliximab, Adalimumab and Certolizumab
- Anti-IL-6 antibody: Tocilizumab
