2. The cellular basis of autoimmunity 1 - T cells Flashcards
What is the functional unit of the immune system?
The immune cells
What is the overview of autoimmunity?
- Initiation or reactivation.
- Expansion and trafficking.
- Target organ localisation, activation and damage.
- Amplification, Regulation and systemic and tissue-specific memory generation.
- Remission (or reactivation)
Can autoimmune disease enter remission?
- Yes
- even untreated it can enter remission.
- This is a classic presentation of autoimmunity and makes it difficult to diagnose.
What are spontaneous models of autoimmunity?
- They introduce susceptibility, which leads to the random development of autoimmunity.
- NOD mice
- TCR transgenic animals.
What are induced models of autoimmunity?
- These are models where the disease can be induced by treating them with something that initiates the immune response.
- These can be used to time the disease that you can’t do in spontaneous models.
- Also TCR transgenic animals.
What is the induced autoimmune model for multiple sclerosis?
Experimental autoimmune encephalomyelitis (EAE)
What is the induced autoimmune model for uveitis?
Experimental autoimmune Uveoretinitis (EAU)
When was the concept of autoimmunity thought of?
around 1880s
How was the concept of autoimmunity discovered?
- The Pasteur lab was trying to find a rabies treatment.
- It is a deadly disease so a vaccine or treatment was desperately needed.
- They invented a process for drying and extracting serum from rabbit spinal cords.
- This provoked a protective response. It was a risky vaccine but much better then the disease.
- The immune system confused the rabbit brain with the human brain. This generated an immune response that combats rabies and attacks the brain causing an acute paralytic illness.
- Most people thought the immune system couldn’t do autoimmunity as it’s too dangerous.
When did autoimmunity become a mainstream idea?
1956
What help cemented autoimmunity as a mainstream idea?
- A thyroid disease showed 1000s of lymphocytes present in the tissue.
- 2 scientists came up with the idea this thyroid disease was caused by the immune system and not an infection.
- This was investigating in animal models and human tissues.
- Antibodies were proven to be the cause of this inflammation and disease. They targeted the thyroid specifically.
- This was fortunate, as in the 1950s, only antibodies were understood. T cells, lymphocytes, and other immune cells were unknown.
What can autoantibodies be?
Blocking or stimulating
What do blocking autoantibodies cause?
Under activity, e.g. Hashimoto’s thyroiditis
What do stimulating autoantibodies cause?
Overactivity, e.g. Graves disease
What type of antibodies were present in the thyroid?
IgG
What drives the tissue specificity in autoimmunity?
- Genetics determine MHC (specifically MHC2) association with autoimmune susceptibility.
- Pathogenic antibodies in thyroid autoimmunity are high-affinity IgG.
- These antibodies have been class-switched so T cells are involved.
- MHC2 expression is upregulated in inflamed tissues.
- This shows that CD4 T cells are involved in the disease process.
What was the 1st step in looking for pathogenic lymphocytes?
- in 1960 Mixed lymphocyte populations could transfer EAE.
- this showed that you can transfer disease with cells but not with antibodies.
- This is a complex mix of cells so it is unclear which cells are responsible for disease.
- Cells are required for disease induction.
What was the 2nd step in finding the lymphocytes responsible for autoimmunity?
- in 1969 thoracic duct cells were shown to transfer EAE.
- Thoracic duct cells have a high concentration of lymphocytes from lymphatic drainage.
- This is almost 100% lymphocytes, so it is a more specific test.
What was the 3rd step in finding the lymphocytes responsible for autoimmunity?
- in 1981 antigen-specific T cell lines were isolated and shown to transfer EAE.
- These are T cells that are immunised from animals.
- There is still a mix of different cells
- Something in the cloning process could cause the pathogenicity in the cells.
What was the final step of finding the lymphocytes responsible for mediating autoimmune disease?
- in 1984 TCR were cloned for the 1st time.
- In 1985 Transgenic T cells were cloned for specific receptors.
- This creates uniform cell lines baring a single TCR.
- It was shown that these cells were MHC2 restricted therefore CD4 T cells.
What does encephalitogenic mean?
Cells that cause encephalitis
How were the T-cell clones made in the 1985 experiment to prove MHC2 restriction?
- All cells together and diluted down to a single cell.
- These were then grown up.
- Then, transferred back to the mice to create a mouse with around 90% of the T cells to specific for a single antigen
How was MHC2 restriction proved with blocking antibodies?
- with no antigen expressed, the T cell clone numbers are low.
- With antigen present, there is lots of T cell proliferation and, therefore, disease.
- With antigen present and anti-MHC antibody, T cell numbers reduce again. Not back to 0 but a significant reduction.
- then, specific antibodies for the different MHC2 present in the mice showed the specific for the type of MHC2 that was presenting the antigen.
- A control set of clones was used that were not blockable, showing they were responding to something outside the antigen presentation pathway.
What did the 1985 MHC restriction experiment prove?
To cause autoimmunity, there was MHC-restricted antigen-specific activation of CD4 T cells