5. Investigating the human immune system Flashcards
1. Discuss the knowledge we gain through human immunology and animal models. 2. The range of techniques to investigate the human immune responses. 3. The main methods to investigate human antigen-specific T cell responses. 4. In vivo human challenge models and how they advance medicine and immunology.
What was the birth point of immunology?
Edward Jenner and his vaccination for smallpox. This was the first demonstration that vaccination could protect against infectious diseases.
How did Edward Jenner create the first vaccination?
- He observed that diary maids that had been in contact with cow pox were protected from small pox.
- He proves this by taking material from cox pox lesions and putting them into a small boy.
- The boy develops a mild illness and recovers quickly.
- 6 weeks later, he injects the boy with small pox. He did this up to 20 times.
- The boy didn’t develop small pox.
- This showed injection with an attenuated pathogen can provide protection.
How is immunological research in humans (in vitro/ex vivo) used?
- This involves taking calls or tissues from patients to under stand the mechanisms of disease.
- Insights into the functions of immune cells and some mechanistic studies.
- It has been boosted by major technological advances in the last decades
How is immunological research in animal models used?
- These are important for basic and mechanistic understanding of the immune system.
How is immunological research in human challenge studies used?
To accelerate vaccine development against pathogens of global impact
What was an important human in vitro studies that gave us mechanistic insights?
A study from 1985 that showed how B cells and T cells interact.
1985 B cell/T cell study: What model antigen was used?
An inactivated tetanus toxin called tetanus toxoid.
1985 B cell/T cell study: What cell populations were used?
- B and T cell populations from a person who had been vaccinated using tetanus toxoid.
- The B and T cell clones are specific to the tetanus toxoid.
1985 B cell/T cell study: How did they determine that T cells were aiding B cell function?
- The T and B cells specific for tetanus toxoid are co-cultured with the native tetanus toxoid antigen.
- T cell proliferation is measured and an increasing T cell population was observed despite not being able to recognise the native antigen.
- The B cells efficiently present the antigen on MHC to the T cells.
How do T and B cells recognise antigens?
T cells: fragments of antigens presented on MHC
B cells: native antigens
1985 B cell/T cell study: What is important about T and B cell specificity?
The T and B cells must recognise the same antigen to interact with each other.
1985 B cell/T cell study: What is the role of the BCR in antigen presentation to T cells?
The BCR enables the uptake and presentation of very small amounts of antigens to specific CD4+ T cells.
1985 B cell/T cell study: How does antigen presentation occur?
- The T and B cell clones must come from the same person - suggests recognition of self.
- When a MHC1 inhibitor is introduced antigen presentation still occurs.
- This shows that antigen presentation to T cells is MHC2 restricted therefore it is CD4 T cells interacting and aiding B cells.
What is the B cells MHC2 presentation pathway?
- The antigen binds with the BCR by the epitope.
- The whole pathogen is internalised, degraded and some peptide fragments (T cell epitopes) enters the MHC2 pathway.
- Peptides from the pathogen proteasome are presented to the T cell which activates the B cell.
- The activated T cell produces cytokines to aid the B cell.
- The activated B cell produces antibodies specific to the pathogen b cell epitope.
Why are animal models important?
- They are often used for immunology studies and to determine how the immune system works.
- The immune cells work together within tissues so studying them in isolation is not always accurate.
What are some major immunological discoveries that animal models supported?
- Discovery of phagocytes and their role.
- Discovery of immunological tolerance.
- Discovery of major histocompatibility genes and the MHC complex’s role in mediating the detection and killing of virally infected cells.
- Discovery of dendritic cells.
- Discovery of cancer immunotherapy by inhibition of negative immune regulation.
What are the problems with animal models?
Some therapies or discoveries failed to translate into humans due to:
1. Limited life spans
2. Living in sterile conditions with limited exposure to microorganisms
3. Genetically identical due to inbreeding.
4. Ultimately, they don’t represent human complexity and heterogeneity.
Why are animal models used?
To have an environment where different components of the immune system and body can interact without the ethical problems of doing the same studies on humans.
What is an example of differences in genetic diversity between humans and animal models?
- Just for HLA class 1 humans have 6 different genes with almost every person having a unique combination of gene variants.
- The mice animal models have 3 MHC genes with 1 or few variants.
- As the HLA are fundamental for T cell studies, having limited version effects the results and the ability to present the antigens needed.
Technology used to study human immunity: Flow cytometry and CyTOF
Use to identify different cell populations through the markers they express.