Pharmacology: Inflammation Flashcards
Failure
What is autoimmunity?
Autoimmunity results from some failure of the host’s immune system to distinguish self from non-self.
What is a Immunogen?
A substance which causes an immune response
What is a Tolerogen?
An Antigen that the immune system identifies but has no response to
What does central tolerance do?
Limits the development of autoreactive B and T cells.
What does Peripheral tolerance do?
Regulates autoreactive cells in the circulation.
Why do we have both central and peripheral tolerance?
*Not all self-antigens are expressed in central lymphoid organs where the negative selection occurs
*There is a threshold requirement for affinity to self-antigens before deletion is triggered, some of the weakly self-reactive survive.
Central tolerance - If there is a strong interaction with self antigens in the immature T lymphocytes in the thymus, what happens?
Negative selection and then the cell undergoes apoptosis.
If immature b lymphocytes have high avidity what happens?
*Receptor editing
*New light chain in the antibody = not specific anymore
What happens if editing fails in the B lymphocytes in the bone marrow?
Negative selection - Apoptosis
What happens when their is low avidity in central tolerance?
The antigen receptor expression is reduced and cells become anergic (functionally unresponsive)
Central tolerance - In the T lymphocytes in the thymus, what happens when there is a intermediate reaction?
*Some immature T cells recognise self-antigens with high affinity they develop into TREGs and enter the Peripheral phase.
Peripheral tolerance: What must be activated to get a response?
T Cells.
Peripheral tolerance: What is the role of Mature T Lymphocytes?
*Anergy without co-stimulation or cell death
*Sensitive to suppression by TREGS
Peripheral Tolerance: What is the role of the Mature B Lymphocytes?
*Anergy
*Apoptosis
*Suppressed by engagement of inhibitory receptors
What mechanism does Central tolerance do? and where is the site of action?
Mechanism: Deletion editing
Site of action: Thymus and bone marrow
What mechanism does Antigen segregation do? and where is the site of action?
Mechanism: Physically barrier to self-antigen access to lymphoid system
Site of action: Peripheral organs (Thyroid, pancreas)
What mechanism does Peripheral anergy do? and where is the site of action?
Mechanism: Cellular inactivation by weak signalling without co-stimulus.
Site of action: Secondary lymphoid tissue
What mechanism does Regulatory cells do? and where is the site of action?
Mechanism: Suppression by cytokines, intercellular signals
Site: Secondary lymphoid tissue and sites of inflammation
What mechanism does Cytokine deviation do? and where is the site of action?
Mechanism: Differentiation to Th2 cells, limiting inflammatory cytokine secretion
Site: Secondary lymphoid tissue and sites of inflammation
What mechanism does Clonal deletion do? and where is the site of action?
Mechanism: Apoptosis post-activation
Site: Secondary lymphoid tissue and sites of inflammation
What are the stages that build up to the generation of an autoimmune disease?
1) The development of multiple layers of self tolerance which are dysfunctional
2) Anti-self lymphocytes are deleted by apoptosis (- selection)
3) There is a leakage of anti-self lymphocytes to periphery which is controlled by peripheral tolerance
4) Tolerance fails - wrong environment and genes
5) This causes an autoimmune disease
What do people with autoimmune diseases have high circulating levels of?
Auto antibodies
What are the challenges associated with the genetics of autoimmunity?
-Understanding pathogenesis is difficult due to complex genotypes
- Disease specific polymorphisms have a little effect and little predictive value
-Small effects makes this hard to target the genes, which therapeutically is unlikely to have a benefit
How can an infection trigger autoimmune reactions?
-Can occur once an infection is eradicated
-Can be prevented by infections - this is unknown to how it works
example - Asthma ‘Hygiene hypothesis’ - more exposure to allergies, the body can identify self/non self better
What is the mechanism of circulating autoantibodies within autoimmune damage?
-Complement lysis (haemolytic diseases)
-Interaction with cell receptors (Myasthenia gravis)
-Toxic immune complexes (lupus)
-Antibody dependent cellular cytotoxicity (organ specific)
What is the mechanism of T Lymphocytes within autoimmune damage?
-CD4 cell are polarised towards Th1 responses via cytokines (RA, MS, T1DM)
-CD8 cells are activated to become cytotoxic T cells and cause direct cytolysis
What is the mechanism of non-specific within autoimmune damage?
-Recruitment of inflammatory leucocytes into autoimmune lesions (as in synovitis)
What are conventional therapies for Autoimmune diseases?
Anti-inflammatory drugs
-Aspirin, Ibuprofen
-Corticosteroids (can block TNF and IL-1 production)
Immunosuppressive drugs
-Inhibit lymphocyte proliferation
-Ciclosporin A