Immunology 8- Regulation of Lymphocyte Responses Flashcards
What is the Pathogenesis of autoimmune diseases based on
genetic predisposition + environmental triggers
Two Features of autoimmune disease
FUNDAMENTAL PROBLEM: imbalance between immune activation and control
Many immunological disease are chronic
Define Immune-mediated inflammatory diseases
chronic diseases with prominent inflammation, often caused by failure of tolerance or regulation
What are Immune-mediated inflammatory diseases caused by
May result from pathogens expressing antigens that are very similar to self antigens hence causing autoimmune disease
Can be caused by T cells and antibodies
Can be systemic or organ-specific
Which cells mediate allergic responses
Can be mediated by IgE and mast cells
-When exposed to their antigen, mast cells degranulate and release their histamines causing local inflammation
Can be mediated by T cells - DELAYED TYPE HYPERSENSITIVITY
Describe Hypercytokinemia and Sepsis
TOO MUCH IMMUNE RESPONSE
Positive Feedback - by triggering inflammation you cause damage to local cells leading to the release of more inflammatory mediators
Hypercytokinemia - too many cytokines in the blood - this happens when the response isn’t properly controlled and you get too much immune response
Sepsis - when bacteria crosses from the mucosa into the blood stream - pathogens entering the wrong compartment
Sepsis can cause hypercytokinemia
What is immunological tolerance
DEFINITION: specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen)
Two types of tolerance:
Central Tolerance - destroy self-reactive T or B cells before they enter the circulation
Peripheral Tolerance - destroy any self-reactive T or B cells which do enter the circulation
If they react with self antigens, some B cells may change their specificity (affinity hypermutation) and some T cells will turn into regulatory T cells
If immature B cells in the bone marrow recognise an antigen in a form which can crosslink their IgM - apoptosis is triggered
What are is Autoimmune Regulator (AIRE)
specialised transcription factor
AIRE - allows the thymic expression of genes that are expressed in peripheral tissues - so the thymus can express all the proteins in the human body
If all the proteins are processed and presented on MHC to the developing T cells, you are negatively selecting against the entire peptide library - thus PROMOTING SELF-TOLERANCE
4 main mechanisms in peripheral tolerance
Anergy
Ignorence
Deletion
Regulation
Describe anergy
Naïve T cells need COSTIMULATORY SIGNALS to become activated
If an antigen is presented in the absence of costimulation you get apoptosis or anergy
Anergy = unresponsiveness (sort of like increasing the activation energy)
So the context in which the DC presents the antigen can have an effect on the activation energy.
Describe ignorance
There are some immuneprivileged sites where the risk of inflammation far outweighs the risk of infection
At these sites, T cells CANNOT become activated because there are NO APCs
Describe Deletion
: Antigen Induced Cell Death
Activation through the TCR can lead to APOPTOSIS of the T cell
In peripheral T cells this is often caused by the expression of the death ligand - Fas ligand
Describe regulation
Regulated by T regulatory cells (Treg)
Treg produces cytokines (IL-10) which inhibits other self-reactive T cells
What gene is related with T regulatory cells
The FoxP3 gene drives T regulatory cells
Mechanism of action Treg cells
Secrete immunosuppressive cytokines (TGFb, IL-10 and IL-35)
They engage other effector T cells and turn them off
IL-10 also has a role in shutting down dendritic cells
NOTE: by having IL-10 in the environment, APCs are much more likely to present antigen in the context of anergic or apoptotic presentation
It switches the DCs from saying ‘this is dangerous’ to ‘this is safe’
Individuals who can’t make Treg have broad spectrum autoimmune conditions - it is a failure of peripheral tolerance
Two types of Treg cells
Natural (nTreg)
Develop in the Thymus
Reside in peripheral tissues to prevent harmful reactions against self
Inducible (iTreg)
When they are exposed to APCs they turn from being a T helper activator function to a Treg function
How can tolerance be broken
Exposure to environmental antigens or self antigens in the context of infection can alter the outcome.
EXAMPLE: Streptococcus pyogenes can produce an antigen which looks like heart muscle antigen
Exposure + Inflammation may trigger a lack of tolerance
What is IL-10
Key anti-inflammatory cytokine Multi-functional (pleiotropic) Acts on a range of cells Blocks pro-inflammatory cytokine synthesis incl TNF, IL-6, IL-8, IFNγ Downregulates Macrophages Viral mimics
Summarise T-B cell collaboration
This tightly licences the immune response because both cells react to the same antigen
Specific interaction of antigen-binding B cell with the T cell has bidirectional effects
T cells are induced to express B cell costimulatory molecule CD40 which binds to CD40 on B cells, and secrete cytokines.
T cell derived cytokines drive proliferation and differentiation of B cells into antibody secreting plasma cells
The cytokines direct immunoglobulin class-switching
