Immune Tolerance Flashcards
Why must immune response be regulated? (3)
- Prevent over-activation of lymphocytes —> tissue damage
- Prevent reactions against self-antigens
What is immune regulation?
Control of the immune response to prevent inappropriate reactions
What can the failure of immune regulation lead to? (4)
- Autoimmune diseases
- Allergies
- Hypercytokinemia
- Sepsis
What varies within different autoimmune diseases?
How organ-specific vs systemic they are
What are 4 examples of autoimmune diseases?
- Rheumatoid Arthritis
- Grave’s
- Lupus
- Psoriasis
What does rheumatoid arthritis affect?
Joints
What does psoriasis affect?
Skin
What does Lupus cause?
Widespread inflammation
What does Grave’s disease affect?
Eyes
What proportion of the UK have an autoimmune disease?
10%
What are the underlying causative factors of autoimmune disease?
Genes and environment
What do autoimmune responses result from? (2)
- Self-antigens
- Microbial antigens —> overreaction
What causes autoimmunity?
- T cells
- Antibodies
Why can immunological diseases often chronic?
Attacking self antigens —> always more antigens in the body (self-perpetuating)
What are allergies?
Harmful immune responses to non-infectious agents
What mediates allergic responses?
- IgE and mast cells —> acute anaphylactic shock
2 T cells —> delayed type hypersensitivity
When does hypercytokinaemia or sepsis occur?
Too much immune response
- Often in positive feedback loop
What are the 2 triggers of sepsis?
- Pathogens enter wrong area
- Failure to regulate response
Which 3 signals are required to activate a T-cell to perform a cell-mediated immune response?
- Antigen recognition
- Co-stimulation (APC and T cell stimulate each other)
- Cytokine release
How does the of the adaptive immune response to a pathogen usually end?
Apoptosis of lymphocytes —> only memory cells survive
What is the principle of cancer immunotherapy?
Use own immune response to target tumour cells (reactivate T cells)
Why does cancer immunotherapy have side effects?
May re-activate all T cells —> auto-immune disease symptoms
What are the 3 outcomes of an immune response?
- Resolution (normal) —> phagocytosis of debris by macrophages
- Repair (healing) —> scar tissue and regeneration via fibroblasts and collagen synthesis
- Chronic inflammation (doesn’t stop) —> damage repair ongoing
What is immune tolerance?
Unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen
Why is immune tolerance important? (2)
- Self-tolerance
- Therapeutic potential (preventing rejection, treat autoimmune/allergy)
What are the 2 types of immune tolerance?
- Central
- Peripheral
When does central immune tolerance occur?
Before T and B cells enter circulation
When does peripheral immune tolerance occur?
When T and B cells are in circulation
What is central immune tolerance?
Destruction/inactivation of self-reactive T and B cells before they enter circulation
Why is central tolerance necessary?
Prevent immune responses to own cells
- Because so many (10^15) TCRs and antibodies —> some will inevitably match self-antigens
How does B-cell central tolerance occur?
Down-selection
- immature B cell in bone marrow meets antigen that binds to IgM of BCR —> apoptosis
How does T-cell central tolerance occur?
AIRE (AutoImmune REgulalator)
Why is T-cell central tolerance more complicated than for B-cells?
Involves MHC
- TCRs should be able to bind to self-MHC
Which 3 checks are made to T-cells during T-cell selection for central tolerance?
- Doesn’t bind to any self-MHC —> death by neglect
- Binds too strongly —> negative selection
- Binds too weakly —> positive selection
Where does positive and negative T cell selection occur?
Thymus
- Further selection outside thymus
How is T-cell selection done for MHC peptides found outside the thymus?
AIRE (transcription factor) —> allows thymus to express genes from other tissue
What do mutations in AIRE lead to?
Multi-organ autoimmunity
How does AIRE promote self tolerance?
Allows thymic expression of genes from other tissues
What is AIRE?
AutoImmune REgulalator
What is peripheral tolerance?
Destruction/control of self-reactive T or B cells that do enter circulation
Why is peripheral tolerance needed? (2)
- Deals with cells escaping central tolerance
- Deals with changes in lymphocytes —> become destructive to self-antigens
What changes occur to B cells after antigen exposure?
Somatic hypermutation —> affinity maturation
What is somatic hypermutation?
B cells changing their antigen-specificity after leaving the bone marrow and becoming exposed to antigens
What are the 3 mechanisms of peripheral tolerance?
- Anergy
- Ignorance
- Deletion (AICD)
How does anergy stimulate peripheral tolerance?
T cell not appropriately co-stimulated by cognate MHC —> less likely to be stimulated in future even if co-stimulation correct
How does ignorance stimulate peripheral tolerance?
Antigen concentration too low —> doesn’t reach threshold to trigger TCR
- eye
How does AICD stimulate peripheral tolerance?
Antigen activates T-cell apoptosis
- Induced expression of death ligand (Fas ligand = CD95 ligand)
What is AICD?
Antigen Induced Cell Death
What type of T cells regulate other T cells?
Treg cells (T regulatory cells)
- Th0
What are the 3 key phenotypes of Treg cells?
- CD4 —> Th cells
- High IL-2 receptor (CD25)
- FoxP3 TF
Which 3 cytokines are secreted by Treg cells?
- TGF-β
- IL-10
- IL-35
What are the 2 mechanisms of Treg cell action?
- FoxP3 expression
- IL-10 secretion
Which transcription factor to Treg cells express?
FoxP3
What do mutations in the FoxP3 TF cause?
IPEX syndrome
- Immune dysregulation
- Polyendocrinopathy
- Enteropathy
- X-linked
What are the 3 functions of IL-10?
Anti-inflammatory:
1. Block pro-inflammatory cytokine synthesis
(TNF, IL-6, IL-8, IFN-γ)
2. Downregulate macrophage functions
3. Viral mimics
Why is IL-10 pleiotropic?
Single molecule with multiple phenotypic (3) effects
Why is IL-10 the master regulator?
Regulates other cytokines
When are Treg cells essential and why?
Pregnancy
- Baby antigens half foreign (from father)
What are the 2 types of Treg cells?
- Natural —> nTreg
- Inducible —> iTreg
What is the function of nTreg cells?
Prevent harmful reactions against self
Where do nTreg cells develop and reside?
- Develop —> thymus
- Reside —> peripheral tissue
What is the function of iTreg cells?
Limit collateral damage of all immune responses
When do iTreg cells develop?
Periphery
∵ develop from mature CD4 T-cells exposed to antigen
What is the function of cytokines?
Tailor immune response to specific type of pathogen
What are the 2 categories of cytokines?
- Inflammatory —> increase response
- Anti-inflammatory —> decrease response
What is the function of chemokines?
Drive immune response to correct place
What changes in chemokines when its cell is activated?
Chemokine receptor profile
What is the difference between antigen-binding in T and B cells?
- T —> MHC on DC/B-cell
- B —> soluble antigens
How do Th and B cells co-stimulate each other?
- Th to B —> Th express CD40L (ligand) and B express CD40
- B to Th —> B express B7
How do Th cells activate themselves?
Express CD28
What is co-stimulation in lymphocytes?
Lymphocytes must be activated by stimulation from…
1. Themselves
2. Other lymphocytes (T vs B)
Which cytokine mainly stimulates T-cell activation?
IL-28
What determines the type of antibody used in an immune response?
Th cell cytokines
What is Ig class switch
Changes in the constant (C) region of an antibody heavy chain
—> Different effector functions
—> Same antigen specificity
What drives Ig class switch?
Th cytokines
