Immune Tolerance

Question 1

Define immune tolerance and why it is needed?

Answer 1

Immune regulation: control of the immune response to prevent inappropriate reaction against self-antigens. Regulation required to avoid excess lymphocyte activation + tissue damage during normal protective response against infection and prevent reaction against self antigen.

Question 2

What is autoimmunity? Provide examples

Answer 2

Autoimmunity: immune response against self-antigens leading to pathologic or damaging disease. Examples: Chronic diseases with prominent inflammation, often caused by failure of tolerance or regulation – Rheumatoid Arthritis, IBS, Multiple Sclerosis, Psoriasis.

Question 3

What is the incidence of autoimmunity and why does it occur?

Answer 3

Can be systemic or organ specific. Affect 2-5% of population, incidence increasing. Fundamental problem is imbalance between immune activation and control. Failure of control mechanisms underpin it and underlying causative factors could be susceptibility genes and environmental factors – more prevalent among women but in cases of infectious disease, sometimes women less affected.

Question 4

What is the mechanism of action of autoimmunity?

Answer 4

May result from immune response against self-antigens (autoimmunity) or microbial antigens (Crohn’s Disease). When the immune response is inappropriately directed or controlled, effector mechanisms of injury are the same as in normal response to microbes. Can be caused by T-cells or antibodies. May be chronic and self-perpetuating as if attacking self-antigens, there will always be more to attack.

Question 5

What is an allergy?

Answer 5

Harmful immune responses to non-infectious antigens that cause tissue damage + disease, mediated by antibody IgE and mast cells in acute anaphylactic shock or T cells in delayed type hypersensitivity

Question 6

What is hypercytokinemia and sepsis?

Answer 6

A cytokine storm where too many cytokines are released too quickly, triggered by a positive feedback loop. Can be triggered by pathogens entering wrong compartment (sepsis) or failure to regulate response to correct level.

Question 7

What are the phases of cell-mediated immunity in brief?

Answer 7

1. Induction happens when dendritic cell collected infected material and loads on MHC molecule and moves into lymph node. Here material presented to T cells and those that recognise peptide sequence on MHC respond and are activated. Effector T-cells then return to site of infection, carrying out a response. Once infected cells cleared, T cells move into a contraction phase, called a memory pool where immune response shut down.

Question 8

What is a key trait immune responses must have?

Answer 8

Self-limitation. Manifested by decline of immune response where principal response is to eliminate the antigen that initiated the response (first signal for lymphocyte activation is eliminated). Once done, immune response needs to shut down.

Question 9

What are the 3 signals needed for an immune response to take place?

Answer 9

1. Antigen recognition, 2. Co-stimulation, 3. Cytokine release. When all 3 activated, T-cell/B-cell activated.

Question 10

Why is antigen important for immune response?

Answer 10

Key sign of survival. Response against pathogen declines as infection is eliminated and key survival signal for lymphocytes is the antigen. Once that’s eliminated, they undergo apoptosis while memory cells are the survivors.

Question 11

What are the outcomes from end of immune response?

Answer 11

1. Resolution: No tissue damage, returns to normal. Phagocytosis of debris by macrophages.
2. Repair: healing with scare tissue and regeneration. Fibroblasts and collagen synthesis.
3. Chronic inflammation: active inflammation and attempts to repair tissue ongoing.

Question 12

What is tolerance?

Answer 12

Tolerance is specific unresponsiveness to antigen, induced by exposure of lymphocytes to that antigen (tolerogen vs immunogen). All individuals tolerant of own antigens and breakdown of this leads to autoimmunity. Restoring tolerance has therapeutic potential as can be used to prevent graft rejection and treat autoimmune + allergic diseases.

Question 13

What is central tolerance?

Answer 13

Destruction of self-reactive T/B cells before they enter circulation and deletion occurs or are made harmless in generative organs as part of maturation process. Need to be removed to prevent autoimmunity.

Question 14

How is central tolerance promoted in B cells?

Answer 14

B-cell down-selection of self reactive in immature cell simple as if immature B-cell in bone marrow encounters antigen in a form that can cross-link their IgM, apoptosis triggered.

Question 15

How is central tolerance promoted in T-cells?

Answer 15

T-cell selection occurs in thymus. T-cell needs to bind peptide in context of self MHC. If it doesn’t bind self MHC at all, it is death by neglect (apoptosis). If it binds MHC too strongly without any peptide there, cells removed by negative selection and apoptosis triggered. If it binds self MHC weakly, receives signal to survive and goes into circulation via positive selection .

Question 16

How are various self-antigens expressed in the thymus?

Answer 16

AIRE is a transcription factor which allows for thymic expression of genes, expressed in peripheral tissue. Promotes self-tolerance as T-cells can be selected for reaction against them before entering circulation. • However, if AIRE mutated, will result in multi-organ autoimmunity in syndrome called Autoimmune Polyendocrinopathy Syndrome Type 1

Question 17

What is peripheral tolerance?

Answer 17

Mechanism by which self-reactive T cells or B cells which escape into circulation are destroyed or inactivated (anergic)

Question 18

How does a B cell mature in circulation?

Answer 18

Once activated, B-cell can become a plasma cell and produce antibody and memory cells. Undergoes a further round of maturation known as affinity maturation where self reactive B cells could be activated as it involves B cell recognising antigen and slightly modifying shape of antibody to better bind it. Unlike T cells, B cells can change specificity after leaving bone marrow (somatic hypermutation) which usually helps improve antibody quality but exposure to environmental/self-antigens can alter outcome e.g. cross-reaction

Question 19

What are the three mechanisms of peripheral tolerance? Describe anergy

Answer 19

Anergy, Ignorance and Deletion (AICD). • Anergy occurs as naïve T-cells need co-stimulatory signals to activate and most cells lack this plus MHC class 2. If naïve T-cell sees peptide + MHC ligand without appropriate co-stimulation, becomes anergic and is less likely to be stimulated in future even if co-stimulation present then.

Question 20

Describe ignorance

Answer 20

Antigen present at too low a concentration to reach threshold for T cells receptor triggering. May be in immunologically privileged sites like eye and brain where T cells don’t really see antigen. Compartmentalisation of cells and antigen control interactions occurs as T cells don’t come into contact with antigen and so don’t react.

Question 21

Describe deletion

Answer 21

Activation through T cell receptor can result in apoptosis. Instead of proliferation, T cell dies. Driven by nature of initial T cell activation events and caused by induction of expression of the death ligand, Fas ligand.

Question 22

How do T regulatory cells suppress immune response?

Answer 22

T regulatory cells inhibit other T cells and other lymphocytes by production of cytokines. Two main mechanisms of action: Block T cell activation or Inhibit effector functions of T cells. Do this by secreting immune-suppressive cytokines (TGF-beta, IL-10, IL-35) or inactivating dendritic cells/responding lymphocytes

Question 23

What can a mutation in a Treg cell cause?

Answer 23

Treg cells express transcription factor FoxP3 and mutation in this results in severe+fatal autoimmune disorder: Immune dysregulation, Polyendocrinopathy Enteropathy X-linked Syndrome

Question 24

What is the significance of IL-10?

Answer 24

Treg cells perform mainly through IL-10 which is a master regulator. Functions include:
• Blocks pro-inflammatory cytokine synthesis including TNF, IL-6, IL-8 and IFN-gamma
• Downregulates macrophage functions
EBV makes a viral mimic of this cytokine

Question 25

Why do Treg cells only exist in mammals?

Answer 25

May be linked to how regulation is imp in pregnancy as exposure to new antigen and hence expressed in context of foreign MHC 1

Question 26

What are the two types of Treg cells?

Answer 26

1. Natural regulatory cells – develop in thymus, require recognition of self antigen during maturation, reside in peripheral tissue to prevent autoimmunity
2. Inducible regulatory T cell – develop from mature CD4 T cells which are exposed to antigen in periphery. May generate in all types of immune responses to limit collateral damage.

Question 27

What is the role of cytokines and chemokines?

Answer 27

Cytokines program immune response and can focus it on right kind of response (pro-inflammatory or anti-inflammatory). Chemokines drive movement around body and ensure molecules reach right place – receptor profiles change with activation state of cells.

Question 28

What two molecules in a T-cell determine its function?

Answer 28

Transcription factors and Cytokines. Diff T-helper cells are programmed by different transcription factors and produce different cytokines so T helper type defined by what transcription factor it produces. T helper cells also cross-regulate so cytokines produced by one class of T helper cell inhibits another.

Question 29

What are the 3 signals used by T cells and B cells to generate immune response.

Answer 29

T-cell stimulant antigen is a peptide presented on a MHC. For co-stimulation, expresses CD40L to activate B-cell and CD28 to be activated itself. Cytokine produced is IL-21 and many others.
B-cell antigen is a soluble one. Expresses CD40 to be activated by T and B7 to activate T as co-stimulation.

Question 30

How do T-cells shape the antibody response?

Answer 30

Constant region of antibody important in function as diff antibody classes have diff constant regions and these differences in function reflect the different types of response required to clear pathogens. Number of gene cassettes which can be swapped around.
T-cells produce cytokines which programme B cells to make different classes of antibodies: T cells go to B cells which then activate a family of gene transcription and gene editing which means they either drop in/out certain constant regions.