Immunology 8- Regulation of Lymphocyte Responses

Question 1

What is the Pathogenesis of autoimmune diseases based on

Answer 1

genetic predisposition + environmental triggers

Question 2

Two Features of autoimmune disease

Answer 2

FUNDAMENTAL PROBLEM: imbalance between immune activation and control

Many immunological disease are chronic

Question 3

Define Immune-mediated inflammatory diseases

Answer 3

chronic diseases with prominent inflammation, often caused by failure of tolerance or regulation

Question 4

What are Immune-mediated inflammatory diseases caused by

Answer 4

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

Question 5

Which cells mediate allergic responses

Answer 5

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

Question 6

Describe Hypercytokinemia and Sepsis

Answer 6

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

Question 7

What is immunological tolerance

Answer 7

DEFINITION: specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen)

Question 8

Two types of tolerance:

Answer 8

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

Question 9

What are is Autoimmune Regulator (AIRE)

Answer 9

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

Question 10

4 main mechanisms in peripheral tolerance

Answer 10

Anergy

Ignorence

Deletion

Regulation

Question 11

Describe anergy

Answer 11

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.

Question 12

Describe ignorance

Answer 12

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

Question 13

Describe Deletion

Answer 13

: 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

Question 14

Describe regulation

Answer 14

Regulated by T regulatory cells (Treg)

Treg produces cytokines (IL-10) which inhibits other self-reactive T cells

Question 15

What gene is related with T regulatory cells

Answer 15

The FoxP3 gene drives T regulatory cells

Question 16

Mechanism of action Treg cells

Answer 16

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

Question 17

Two types of Treg cells

Answer 17

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

Question 18

How can tolerance be broken

Answer 18

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

Question 19

What is IL-10

Answer 19

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

Question 20

Summarise T-B cell collaboration

Answer 20

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