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 AIRE?
Autoimmune regulator of expression.
Some tissue specific antigens are expressed in thymic medullary epithelial cells under control of the AIRE (autoimmune regulator of expression) transcription factor
AIRE randomly distributes itself wherever DNA is accessible or open and can turn on gene expression non-specifically.
What does AIRE do?
AIRE randomly distributes itself wherever DNA is accessible or open and can turn on gene expression non-specifically. Two things happen here:
Gene expression that is not normally associated with the thymus, e.g. pancreatic tissue, in the medullary epithelial cells. As a consequence, there is processing of the proteins and presentation by MHC class I and if an immature thymocytes sees it, it will be deleted.
Because there’s a massive deregulation of transcription in these cells, death will often be induced. Resident dendritic cells will then pick up the dead cells/debris and present them to an auto-reactive T cell and then there will be deletion.
What happens if there’s a defect in AIRE?
A defect in AIRE is a defect in the ability to present antigens that would be used to delete T cells, which is why carriers of the mutation present with multisystem/multiorgan autoimmune disease.
What does central T cell tolerance involve?
Immature/developing lymphocytes and occurs in primary lymphoid organs:
Deletion
Selection of Tregs
What does peripheral T cell tolerance involve?
Mature lymphocytes and occurs in secondary lymphoid organs and peripheral tissues:
Deletion
Anergy
Ignorance
Regulation
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
What do Treg cells express?
High levels of IL-2 receptor alpha
TGF-beta
IL-10
Expression associated with FOX-P3 transcription
What is a key identifier of Treg cells?
FOX-P3 (transcription factor)
What can Tregs do?
Suppress all manner of helper T cell and CD8 cell responses.
It’s not just in terms of tolerance that they’re important but also to help attenuate inflammatory responses against viral infections.
What are the most prominent suppressors of immune suppression?
Tregs
What are the 2 different types of Tregs?
nTregs (natural) – derived from the thymus during T cell development
iTregs (induced) – derived following activation of naïve CD4 T cells in the presence of TGF-beta
What do iTregs do?
Secrete immunosuppressive cytokines – IL-10 and TGF-beta
Express CTLA4 and inhibit co-stimulation
Release molecules that create a suppressive environment
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 is autoimmunity?
Loss of the tolerance mechanism
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.
Which 3 key components are needed in the pathogenesis of autoimmune disease?
Genetic susceptibility: especially for T cell autoimmune diseases, like diabetes or MS.
Environmental: e.g. stress or malnutrition
**Loss of self-tolerance: **Can be induced by either of the two above
Why are circulating autoreactive lymphocytes not always activated?
Antigen is not available
Absence of signal 2 - To get immune response need danger signal to activate DCs, supply co-stimulation - might get T cell help from somewhere else
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
Do autoimmune responses always result in autoimmune diseases?
No
Do all autoimmune diseases involve autoimmune responses?
Yes
What does autoimmunity result from?
Chronic (ongoing) autoimmune responses with ongoing tissue damage.
What are the 2 classifications of autoimmune diseases?
Organ-specific and systemic
What is organ-specific autoimmune disease?
Confined to particular organs or cell types and the antigens recognized are organ specific.
E.g. thyroid, ovarian, islet cells, gastric parietal cell (pernicious anaemia); neurological: MS, myasthenia gravis
What is systemic autoimmune disease?
Multiple tissues of the body are targeted and the antigens recognised are more ubiquitous.
E.g. rheumatoid arthritis, systemic lupus erythematosus (SLE)
What are the normal effector mechanisms in response to self antigens?
B cells – production of auto-antibodies:
Type II (including ligand mediated reactions), immune complex deposition (Type III)
**CD4 and CD8 T cells: **
DTH responses (TH1 activation of macrophages, cytokine production, pro-inflammatory mediator release)
CTL killing of stromal cells
Provision of B cell help
Macrophages
Nitric oxide, proteases, oxidative radicals
What can loss of central self tolerance be due to?
Autoimmune polyendocrinopathy-candiadiasis ectodermal dystrophy
Defect in the AIRE gene
Decreased central tolerance
Multi-system autoimmunity
What can loss of peripheral tolerance be due to?
Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked
Defect in the Foxp3 gene
Loss of Tregs and peripheral tolerance mechanism
Multi-system autoimmunity
What are some diseases resulting from B cell mediated autoimmunity?
Grave’s disease (stimulating Ab)
Myasthenia Gravis (inhibitory Ab)
SLE (immune complex deposition)
What are some diseases resulting from T cell mediated autoimmunity?
Insulin dependent diabetes mellitus (IDDM)
Multiple sclerosis
What happens in Type 1 insulin dependent diabetes mellitus (IDDM) Juvenile onset diabetes?
Organ specific, T cell mediated (both CD4 and CD8)
Autoimmune destruction of pancreatic β-cells (insulin producing)
Characterised by infiltration of lymphocytes, weak autoantibody response, T cell reactivity to islet proteins
Gradual loss of insulin secretion, and resultant insulin dependence
Occurs more frequently in people with HLA DR3-DQ2 and DR4-DQ8
What happens in multiple sclerosis?
Polygenic degenerative disorder of the CNS that results in episodes of paralysis during formative disease, with chronic paralysis in the latter stages
CD4 T cells specific for myelin antigens promote an inflammatory response and degrade the myelin sheaths covering nerve axons
Th1 and Th17 responses are detrimental
Th2 responses associated with remission
Dysregulation of Tregs has been associated with MS
HLA-DR15 and HLA-DQ6 associated with disease
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
