L3 - Cellular basis of autoimmunity (I) Flashcards
- to review evidence for the role of CD4+ T cells in the pathogenesis of organ-specific autoimmunity - To understand current hypotheses for the initiation of autoimmunity at the level of immune recognition - To learn about cellular mechanisms underlying common patterns of disease (93 cards)
Overview of autoimmunity
A. You get initiation of disease
B. this results in the expansion and trafficking of cells
C. there is localisation to a target organ e.g. eye, joint or brain where there is activation and damage
D. There is amplification, regulation and establishment of immunological memory (+ tissue-resident memory)
E. In the “wild” if left untreated, these conditions often remit but then there can be reactivation and the cycle starts again.
what is a classic presentation of autoimmunity
the cycle of people getting ill and then getting better ( why it is often difficult to diagnose)
When looking at autoimmunity and how the cells are responding what do we use
animal modules which can have spontaneous or induced autoimmunity
what are some spontaneous autoimmune animal models
- type I diabetes = Non obese diabetic (NOD) mouse
- TCR transgenic animals (have had a susceptibility element introduced e.g a T cell receptor introduced as a transgene)
what are some induced autoimmune animal models
Involves immunising the animals to initiate an immune response
- Multiple Sclerosis: Experimental Autoimmune Encephalomyelitis (EAE).
- Uveitis: Experimental Autoimmune Uveoretinitis (EAU).
- Other models: TCR transgenic animals to mimic specific autoimmune conditions (mimics TCR which we know are dangerous)
what is the advantage of inducing a model to have autoimmunity
allows scientists to time the disease in a way which is impossible in a stochastic situation
When did autoimmunity become recognised
in the late 1800s (1885) through work from Pasteur’s lab while developing a treatment for rabies. They prepared extracts from rabbit spinal cords to immunise people, which triggered a protective response against rabies but also provided early insights into the immune system’s ability to attack self-tissues.
How potent is rabies disease
Very potent and is almost always fatal once symptoms appear
What was the side efffect rate for the rabies treatment
1:1000 with patients deeloping acute paralytic illness ( although is high, the risk is better than the fatal outcomes of rabies)
What was happening in people who develop the paralytic disease after rabies treatment
The immune system in the human was confusing rabbit brain and human brain tissue. While they generated an immune response that protected them from the rabies, they were getting a cross reaction that targeted brain tissue causing paralytic effects. This showed how the immune system could also damage the body.
When did autoimmunity become a governing / mainstream idea
1956
Which organ was one that established an important medical concept for autoimmunity
the thyroid ( can see slides where e.g. lymphocytes have infiltrated the organ demonstrating it is a disease of immunity / antibodies rather than the gland itself)
What causes Grave’s disease
Autoantiboes (predominantly IgG1 which are T-helper dependent) which stimulate the TSHR. thyroid grows and secretes too much thyroid hormones
What are Grave’s disease symtoms
increased metabolic rate with rapid or irregular heartbeat, bulging eyes, goiter ( enlarged thyroid gland) and skin disease
What is Grave’s Disease a subset of
Hasmimotis thyroiditis
What does genetics demonstrate about assocation with increased susceptibility to autoimmune diseases
MHC ( Class II in specific over class I)
what implies that T cell help is associated with the pathogenicity of thyroid autoimmunity
the fact that pathogenic immunoglobulins in the thyroid are high affinity IgGs and that Class II expression is upregulated in inflamed tissues (CD4 T cells)
History of CD4+ T Cells as Key Mediators in Specificity **
1960: Mixed lymphocyte populations were transferred between animal models to test for pathogenicity. This revealed that autoimmune encephalomyelitis (EAE) could be transferred with cells but not with antibodies.
1969: Thoracic duct lymphocytes were shown to transfer EAE. These lymphocytes are highly concentrated as they return through the lymphatic drainage system.
1981: Antigen-specific T cell lines were developed to transfer EAE from immunised animals. Researchers expanded these lines to demonstrate that they were responsible for disease transfer.
1984: T cell receptors (TCRs) were cloned molecularly for the first time.
1985: MHC class II-restricted, antigen-specific T cell clones were confirmed to transfer EAE. Uniform cell lines with a single T cell receptor were found to be MHC class II restricted.
1990: The immunodominant class II-restricted T cell epitope of myelin basic protein (MBP) was identified in humans.
1993: TCR transgenic mice were observed to develop spontaneous EAE.
2000: CD4-activating peptide analogues of MBP were shown to precipitate relapses in multiple sclerosis.
How can one measure (T) cell growth experimentally
by measuring how much radiolabeled thymidine is incorporated into the DNA of dividing T cells - a measure of DNA replication and cell growth.
What happens to T-cell proliferation in encephalitogenic clones when an anti-MHC class II antibody is applied?
T-cell proliferation is significantly inhibited, with levels reduced by 1 to 2 orders of magnitude, demonstrating the crucial role of MHC class II in T-cell activation.
How did blocking antibodies help identify the role of specific MHC molecules in T-cell activation? ( looking at EAE in mice)
Blocking antibodies targeting specific MHC molecules (e.g., I-A𝑢 and I-E𝑠/𝑢) revealed that T-cell activation is MHC-restricted and depends on a single MHC molecule, confirming its role in antigen-specific responses.
Why do encephalitogenic T-cell clones cause auto-inflammation in the brain?
These T-cells recognise an antigen from the brain and are activated in the brain. In other organs like the liver or spleen, they don’t encounter this antigen and remain inactive.
What is the purpose of using different antibodies in this experiment?
Different antibodies were used to determine which MHC molecule (e.g., I-A𝑢u or I-E𝑠/𝑢s /u) mediates the antigen-specific activation of T-cells in this mouse strain.
What does the table show about T-cell proliferation in response to anti-I-A𝑢u and anti-I-E𝑠/𝑢s/u?
Proliferation is reduced significantly with anti-I-A 𝑢 u , suggesting dependency on this MHC molecule for activation, whereas anti-I-E𝑠/𝑢s /u does not block activation as effectively.
