Immunology Flashcards
What does immunological tolerance do?
Serves to protect us from self-reactive lymphocytes.
What tissues comprise central tolerance?
Thymus - T cells
Bone marrow - B cells
What tissues comprise peripheral tolerance?
Secondary lymphoid organs
Peripheral tissue
What are the 4 mechanisms used to induce tolerance to self-reactive lymphocytes?
To delete (eliminate the problem)
To anergise (switch off the problem)
To ignore (ignore the trigger)
To regulate (contain the problem)
What mechanisms are used for central B cell tolerance?
Deletion and anergy
What mechanisms are used for peripheral B cell tolerance?
Ignorance/anergy/death - lack of co-stimulation/T cell help
Which is more efficient - T or B cell tolerance?
T cell tolerance is more efficient
What happens in central B cell tolerance when there’s a low-affinity non-cross-linking self molecule?
There’s binding to one arm, but there’s no cross-linking, meaning there’s not enough affinity to trigger the immature B cell. The cell can still mature because it has the antigen receptors on its surface, but because of its low affinity, it is clonally ignorant.
What happens to an immature B cell in central tolerance when it encounters a multivalent self molecule?
There is extensive cross-linking and rather than turning off the cell, the cell death program is initiated in the immature B cell and it apoptoses.
What happens to an immature B cell in central tolerance when it encounters a soluble self molecule, e.g. a serum protein?
B cell is triggered, but because it is immature, it migrates to the periphery, resulting in an anergic B cell.
In peripheral B cell tolerance, which 2 signals are needed for a mature B cell to respond and survive?
- Signals via the surface Ig-Ag interaction
- T cell help – CD40L, and some cytokines
How long is B cell life span in the absence of T cell help?
Short
When does peripheral B cell tolerance also occur?
Post-somatic hypermutation
What will happen when a naïve B cell sees an antigen?
Naïve B cell can see the antigen
Activation of the CD4 compartment simultaneously, providing the ligand.
Initial response will be crosslinking and a commitment to differentiating into a plasma cell
Because the signals from CD4 aren’t there, it will be short lived with a low affinity antibody and won’t be isotype switched in the domain
B cell dies
What happens when a naive B cell sees an antigen as well as CD4?
Cells transition into germinal centre of lymph node
Isotype switching
High affinity antibodies from plasma cells or generation of memory
What does peripheral B cell tolerance rely on?
T cell tolerance working
If a CD4 T cell is not self-reactive then there’s no way a self-reactive B cell is going to be able to get going very well.
In the absence of CD4 T cell help, will there be production of antibody from a naive B cell?
Yes, but it’s transient
The antigen is low affinity and because the plasma cells are terminally differentiated, it dies off.
Why are self-antigens often seen after infection?
There is release of self-antigens from damaged cells and it may trigger self-reactive B cells in the periphery.
Why won’t self antigens released from damaged cells after infection trigger self-reactive B cells in the periphery?
Because there’s no CD4 help that is specific for the self-antigens, there’s no cognate help and therefore no robust response in the domain.
How is antigen recognition different between B and T cells?
B cells see whole proteins (or components of whole proteins/pathogens)
T cells see peptide fragments that are processed and presented in the context of MHC molecules
Why are T cells technically self-reactive?
Because they have to see a self antigen (the MHC complex)
Where do T cells develop?
In the thymus
How do T cells develop in the thymus?
Early T-lineage precursor receives signals and progresses through different stages to DN thymocyte.
DN thymocytes are commited to T cell lineage but don’t express co-receptors like CD8.
Beta chain is rearranged (checkpoint):
If functional, commited to double positive stage (alpha chain of the alpha-beta heterodimer (the receptor) is expressed at cell surface).
If they see MHC I they will commit to CD8, if they see MHC II they will commit to MHC II.
This is called positive selection.
What is positive selection of thymocytes (T cell precursors)?
Double positive (DP) thymocytes undergo 2 selection processes following the expression of a TCR
Thymocytes that express TCRs capable of recognising self-MHC are selected to survive.
Only thymocytes that express TCRs capable of recognising self-MHC are selected to survive.
What is negative selection of thymocytes (T cell precursors)?
Removal of immature lymphocytes that have strong reactivity to self-peptide.
This is the major mechanism by which T cells are deleted if they react too well to self MHC and self-peptides.
Removal of immature lymphocytes that have strong (e.g. too good) reactivity to self peptide.
What is T cell selection dependent on?
Receptor affinity for self pMHC (Goldilocks Theory)
If there’s not enough interaction (not positive selection) or if the TCR sees self and MHC too well, T cells will die. There’s a sweet spot, where positive selection and commitment to a mature T cell occurs.
What is the schamatic for naive lymphocyte circulation in ignorance?
Naive lymphocytes enter lymh nodes from blood
Antigens from sites of infection reach lymph nodes via lymphatics
Lymphocytes and lymph return to blood via the thoracic duct.
What is the two signal theory for activation of naive T cells in anergy?
In the periphery, 2 main signals are needed to induce a mature T cell response:
Stimulation via the TCR on the T cell
Co-stimulation via CD28 and CD80 on the dendritic cell.
Without co-stimulation, T cell becomes anergic
How does CTLA4 work?
CTLA4 also binds B7, but it’s also a competitor for CD28 in that it has higher affinity for the costimulatory molecules. As a consequence, if there are high levels or a high concentration of CTLA4 on the cell surface, it can start to inhibit the ability of naïve T cells to sustain their activation.
What happens in loss of tolerance?
Immature developing lymphocytes in primary lymphoid tissue that react to self antigens are removed (clonal selection)
Failure to remove the auto-reactive lymphocyte leads to generation of loss of tolerance.
What is the difference between autoimmune response and autoimmune disease?
Continued damage promotes lymphocyte activation. There’s inflammation, so there’s secondary signals and there are going to be self-antigens that might otherwise be sequestered.
See image
How do autoimmune diseases begin?
Circulating B cell binds self antigens released from injured cells
B cell is activated by a T cell specific for self peptide
B cells differentiate into plasma cells, secreting large amounts of self-antigen specific antibody
At sites of injury, self-antigen specific antibody initiates an inflammatory response, causing more injury
More B cells bind self antigens, amplifying the cycle of tissue damage
What is the role of infection in initiation of autoimmune disease?
Infection with microorganism
Get exposure of self antigens due to dying cells
Infection can activate DCs (e.g. TLR signalling), providing co-stimulation
What is the role of autoreactive lymphocyte activation in initiation of autoimmune disease?
Molecular mimicry
Antigens from pathogen are similar in shape to autoantigens
Able to cross react with autoreactive T cells/B cells
