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
What are non-specific conventional therapies for autoimmune diseases?
-IV Immunoglobulin IV-IG (MOA is not clear)
-Plasmapheresis - this removes circulating antibodies, this is a short term effect
example - Organ specific -
-Insulin in diabetes
-Acetylcholinesterase inhibitors for Myasthenia Gravis
What causes a fever?
1) Macrophage ingests a gram (-) bacterium
2) Bacterium is degraded in a vacuole and releases endotoxins this induces the macrophage to produce IL-1
3) IL-1 is released by the macrophage into the bloodstream, through which it travels to the hypothalamus of the brain
4) IL-1 induces the hypothalamus to produce prostaglandins, which reset’s the body’s thermostat to a higher temperature, producing a fever.
FEVER
What is the sequence of an inflammatory response?
1) Trauma = Acute phase reaction
2) Platelet adhesion, transient vasoconstriction of efferent vessels
3) Cytokine-induced vasodilation of afferent vessels - (increased heat/blood flow to area)
4) Activation of complement, coagulation, fibrinolytic and kinin systems
5) Leukocyte adhesion
6) Increase vascular permeability and extravasation of serum proteins, (exudate) and leukocytes (neutrophils, macrophages, lymphocytes) with resultant tissue swelling.
7) Phagocytosis = PUS formation
8) Wound healing and remodelling
What pro-inflammatory mediators are involved in an inflammatory response?
*Complement system
*Acute phase proteins
*Interferons
*Cytokines
-Pro-inflammatory TNF, IL-1, IL6
*Chemokines (CXCL-8, CCL2, CCL5)
*Adhesion molecules etc…
*Prostaglandins, and leukotrienes
*Histamine
*Kinins (bradykinin - pain)
*Matrix Metalloproteinases - MMP-1, 2, 9
*Clotting factors
*Prostaglandins - local
What are the two stages of vasodilation?
1) Vasodilation - triggered by histamine, kinin, prostaglandin and leukotrienes
2) Migration and margination - diapedesis (emigration) - phagocytes force themselves between the endothelium cells of the blood vessel and migrate into the tissue.
What does MARGINATION mean?
The binding of phagocytes to the blood vessel
What is the role of an Acute phase protein?
To fluctuate in response to tissue injury and infections, these are made of hepatocytes, and synthesized in response to pro-inflammatory cytokines.
What is the function of acute phase protein C Reactive Protein?
Opsonin - labels pathogens to be killed
What is the function of acute phase protein Fibrinogen?
Coagulation factors
What is the function of acute phase protein Serum Amyloid A?
Cell recruitment and MMP inducer
What is the function of acute phase protein Complement factors?
Opsonin, lysis, clumping, chemotaxis
What is the function of acute phase proteins Haptoglobin and ferritin?
Bind haemoglobin or Fe
What is the function of cytokine TNF alpha?
Vasculature (inflammation)
Liver (induction of APP)
Induction of cell death
Neutrophil activation
Cachexia
What is the function of IL-1 ? CYTOKINE
Vasculature (inflammation)
Hypothalamus (fever)
Liver (Induces APP)
What is the function of IL-12? CYTOKINE
NK cells, Promotes TH1 subset of T lymphocytes (pro-inflammatory)
What is the function of IL-6? CYTOKINE
Liver - induces APP
Influences adaptive immunity - proliferation and antibody secretion by B cells
What is the function of Interferon alpha and beta? CYTOKINES
Induces antiviral state, activates NK cells
What do adhesion molecules do?
Transmembrane receptors that bind either to other cells or to the extracellular matric, they move to the tissue once attached.
What are the four main classes of adhesion molecules?
1) Ig superfamily (VCAM-1, ICAM-1, LFA-2)
2) Cadherins (E, P, N (cell-cell adhesion)
3) Selectins (E, P, L - recognise carbohydrates)
4) Integrins - 8 subfamilies (a4B1 (ECM and cell-cell))
How are metalloproteinases involved in inflammation?
Matrix metalloproteinases
-Degrade and remodel extracellular matrix
-Create chemokine gradients
ADAMS
-Cleave cytokine and adhesion molecule receptors from cell surface
ADAMTs
-Cleave receptors also
-Degrade proteoglycans
What are extracellular matrix proteins (ECM)?
Collagen,
-Laminin, Elastin, Proteoglycans, Aggrecan, Fibronectin, Matrillin, Nidogen (Layer on top of cells, and the cells interact)
What does NF-kB produce?
-Cytokines (TNF, IL1, IL6)
-Chemokines and their receptors (IL-8, MCP-1, MIP-1s, eotaxin, CCL5, CCL23, Gros)
-Adhesion molecules
-MMP’s (MMP-3, MMP-9)
-Growth factors (GM-CSF, M-CSF)
-Acute phase proteins (SAA)
What does activated NF-kB do?
1) NF-kB is bound to IkB the inhibitor of Kb, NF-kb is inactivate
2) Ikb is phosphorylated
3) It means NF-kB is released and enters the nucleus, this binds to kB
4) This drives to the transcription of proinflammatory chemokines (DNA can be changed to RNA)
What is acute inflammation?
-Part of immune response
-If excessive can lead to organ failure and death
What is chronic inflammation?
-Leads to disease, such as autoimmune disease, can be neurogenerative, and can cause chronic age-related disorders.
-Can cause inappropriate tissue destruction
-Chronic is bad
What are the immunosuppressive effects of Ciclosporin?
*Decreased clonal proliferation of T cells, by inhibiting IL-2 synthesis and possibly decreasing expression of IL-2 receptors
*Reduced induction and clonal proliferation of cytotoxic T cells rom CD8+ precursor T cells
*Reduced function of the effector T cells responsible for cell-mediated responses (Decreased delayed (type hypersensitivity)
*Some reduction of T cell-dependent B-cell responses
Ciclosporin is poorly absorbed by mouth T/F
TRUE
Ciclosporin remains in lympho-myeloid tissue and fat even after administration has stopped T/F
True
What is the most common serious unwanted side effect of ciclosporin?
Nephrotxoicity
Does ciclosporin have any effects on bone marrow depression?
No
What is the MOA of Leflunomide?
Inhibitory effect on activated T cells, as it is transformed to a metabolite that inhibits from scratch synthesis of pyrimidines by inhibiting dihydro-orotate dehydrogenase
What are the unwanted side effects of Leflunomide?
Diarrhoea, alopecia, raised liver enzymes and risk of hepatic failure
What does the long half-life of leflunomide increase the risk of?
Cumulative toxicity
What do NSAIDS inhibit
COX enzyme
How are inflammatory mediators produced?
1) Stimulus (injury)
2) Activates Phospholipase A2 which enables production of Arachidonic acid <– COX inhibits here
3) 2 things happen now
-Lipoxygenases make LTB4 for example
-Prostaglandins PGH2 then make more, like PGD2, PGE2
Which COX is present in most cells?
COX-1
Which COX is present in inflammation?
COX-2
What prostaglandins are produced in acute inflammation?
PGE2 and PGI2 - generated by the local tissues and blood vessels while mast cells release mainly PGD2
What prostaglandins are present in chronic inflammation?
Cells of the monocyte/macrophage series also release PGE2 and TXA2. Together, the prostanoid’s exert a sort of yin-yang effect in inflammation, stimulating some responses and decreasing others
How do COX inhibitors have an anti-inflammatory effect?
Through the decrease in prostaglandin E2 an prostacyclin reduces vasodilation and indirectly oedema. Accumulation of inflammatory cells is not directly reduced.
How do COX inhibitors have an analgesic effect?
Decreased prostaglandin generation means less sensation of noiceptive nerve endings to inflammatory mediators such as bradykinin and 5-hydroxytrptamine. Relief of headaches is a result of decreased prostaglandin mediated vasodilation.
How do COX inhibitors have an antipyretic effect?
Interleukin 1 releases prostaglandins in the CNS, where they elevate the hypothalamic set point for temperature control, this causes fever. NON-steroidal anti-inflammatory drugs prevent this.
What drug can you not give with aspirin?
Warfarin!
Where is Aspirin metabolised?
75% in the liver
