autoimmune and inflammation pharmacology Flashcards
define autoimmunity
an immune response against self/autologous antigens resulting from failure of hosts immune system to distinguish self from non-self-cells
how is autoimmunity caused
Develops when multiple layers of self-tolerance are dysfunctional and Can be genetic
two mechanisms of autoimmunity
genetics & infection
how do genetics cause autoimmunity
polygenetic - causes production of self-reactive lymphocytes
how does infection and inflammation cause autoimmunity
inactivation of antigen presenting cells leading to influx and activation of self-reactive lymphocytes into tissues
define immunogen
a substance capable of eliciting an immune response
define tolerogen
antigens that induce tolerance rather than an immune response
what are the two mechanisms of self-tolerance
central and peripheral
what is central self tolerance
limits the development of B/T cells
what is peripheral self tolerance
regulates autoreactive cells in circulation
what happens to T cells in central tolerance
- Exposed to self-antigens (MHC CD4/8 on APC) * Strong response: apoptosis * Intermediate response: Treg * Weak response: positive selection
what happens to B cells in central self tolerance
- Mature in bone marrow and are exposed to self-antigens during development * High avidity: receptor editing and retesting - if still high apoptosis * Low avidity: reduce expression and become anergic
what happens to T cells in peripheral tolerance
Treg cell binds to active T cell causes anergy, apoptosis or suppression
what happens to B cells in peripheral tolerance
- T cell not activated if B cell activated by self-antigen, no cytokines are released so B cell will not become activated Anergy, suppression or apoptosis
what are the three mechanisms of autoimmune damage
circulating antibodies,
T lymphocytes,
non-specific mechanisms
how do circulating antibodies cause autoimmune damage
○ Complement lysis and interaction with receptors ○ Toxic immune complexes ○ Penetration into living cells
how do T lymphocytes cause autoimmune damage
○ CD4 polarised towards TH1 via cytokines ○ CD8 activated to become cytotoxic T cells and cause direct cytolysis
how do is autoimmune damage caused non-specifically
○ Recruitment of inflammatory leucocytes into autoimmune lesions
what are conventional therapies for the treatment of autoimmune diseases
- anti inflammatory drugs - immunosuppressive drugs - IV immunoglobulin - plasmapheresis - organ specific treatments (insulin, etc)
what happens when bacteria enters the skin
- bacteria enters through epithelial layer 2. macrophage recognises bacteria 3. cytokines, chemokines are released 4. IL1 causes a fever in the hypothalamus
what are the steps of the inflammatory response
- vasodilation 2. migration and margination 3. tissue repair
what happens in step 1 of the inflammatory response
- acute phase reaction (IL1/IL6/TNF alpha) -Platelet adhesion
- vasoconstriction /vasodilation= increased heat/blood flow to area - activation of the compliment system
what happens in step 2 of the inflammatory response
- Leukocyte adhesion - caused by chemoattractant on endothelial cell surface allowing transmigration
- Increased vascular permeability and Extravasion of serum proteins (exudate) and leukocytes with resultant tissue swelling
what happens in step 3 of the inflammatory response
- Wound healing and remodelling 6. Anti-inflammatory response - resolution - IL10, soluble adhesion molecules, TIMPS, etc
name some pro inflammatory mediators
acute phase proteins (CRP), compliment system, kinins, cytokines, chemokines, growth factors, adhesion molecules, extracellular matrix proteins, clotting factors, prostaglandins
what are acute phase proteins
they are synthesised in response to pro-inflammatory cytokines and vary in response to injury and infection
name some cytokines
TNF, IL6, IL1, IL12
what does TNF do
inflammation, acute phase proteins (APPs) in the liver, apoptosis induction, neutrophil induction
what does IL6 do
APPS in liver, proliferation and antibody secretion of B cells
what does IL1 do
inflammation, fever, APPs in liver
what does IL12 do
activated NK cells, TH1 promotion
what are chemokines
- > 50 MW proteins that are chemotactic * 4 sub families that bind to GPCRs ○ CC, CXC, C, CXXXC
what does IL8 do
attracts neutrophils
what does monocyte chemotactic protein 1 do
attract monocytes
what does eotaxin do
attracts eosinophils
what are adhesion molecules
transmembrane receptors that bind to cells or the extracellular matrix (integrins/cadherins)
what are extracellular matrix proteins
collagen, laminin, fibronectin
what is NFkB
a family of transcription factors that regulate pro inflammatory mediators
how does NFkB work
attached to IKB, once phosphorylated NFkB is released and travels to the nucleus and binds to promoter regions to activate transcription of pro-inflammatory mediators
name some anti-inflammatory mediators
anti inflammatory cytokines, soluble adhesion molecules, TIMPs, plasmin activation system, opioid peptides, resolvins
what is an anti inflammatory cytokine
IL10
what are soluble adhesin molecules
bind to adhesion molecules to stop other molecules from binding
what do TIMPs do
inhibit MMPs
what does the plasmin activation system do
causes clot to recede
what do opioid peptides do
counteract pain
what are resolvins/protectins
anti-inflammatory lipid mediators
what is acute inflammation
-Necessary part of the immune system but has resolution - If excessive, can lead to organ failure or death
what is chronic inflammation
- Inappropriate, leads to tissue destruction - Leads to disease * Autoimmune * Neurodegenerative * Chronic age-related disorders
define DMARDs
disease modifying anti rheumatic drugs
give 3 examples of DMARDs
methotrexate, ciclosporin and leflunomide
what is methotrexate
- Folic acid antagonist with cytotoxic and immunosuppressive effects
- 1st choice anti-rheumatic
MOA of methotrexate
- MOA is unrelated to its effect on folic acid metabolism, but may be affected by its ability to block uptake
- Main action is to inhibit dihydrofolate reductase
how is methotrexate given
- Given orally, IV, IM or intrathecally * Low lipid solubility - does not cross BBB * Taken up into cells - metabolised to polyglutamate derivatives which are kept within the cell
side effects of methotrexate
- Can cause bone marrow depression, platelet and white blood cell reduction - liver cirrhosis
MOA of ciclosporin
- Potent immunosuppression,
- Decreased IL2 -decreased cytotoxic T cell proliferation/induction
- Reduced function of effector T cells
how is ciclosporin metabolised
CYP450
side effects of ciclosporin
- Accumulates in tissues at concentrations 3-4x than that in plasma
- Nephrotoxicity - unconnected to calcineurin inhibition
- May be contraindicated in patients with hepatotoxicity and hypertension
what is leflunomide used for
- Rheumatoid arthritis and occasionally transplants
MOA of leflunomide
- inhibitory effect on activated T cells
- inhibits de novo synthesis of pyrimidines by inhibiting dihydro-orotate dehydrogenase
side effects of leflunomide
- Side effects include diarrhoea, alopecia, raised liver enzymes and a risk of hepatic failure
what are NSAIDs used for
- Symptomatic relief from fever, pain, swelling in chronic joint diseases and acute inflammatory conditions - Also for post operative, dental and menstrual pain as well as headaches and migraines
what is fatty acid cyclo-oxygenase 1
constitutive - in most cells, produces prostanoids that act mainly as homeostatic regulators
what is fatty acid cyclo-oxygenase 2
involved in inflammation
how do COX enzymes work
- stimulus 2. phospholipase A2 turns phospholipids to arachidonic acid 3. PG2 and PGH24. endoperoxide isomerase or synthase enzymes to prostacyclin, PGE2 and thromboxane
what is the main prostanoid involved in inflammation and how does it work
PGE2- EP1: bronchial and GIT smooth muscle
EP2/EP4: broncho- vaso- dilation, intestinal fluid secretion stimulation EP3: smooth muscle contraction, gastric acid secretion
what does PGD2 do
vascular bed vasodilation, platelet aggregation inhibition, GIT/uterine muscle relaxation
what does PGF2a do
uterine muscle contraction
what does PG12 do
vasodilation, inhibition of platelet aggregation and renin release
what does TXA2 do
- Vasoconstriction, platelet aggregation and bronchoconstriction
how are COX inhibitors anti-inflammatory
decrease in prostaglandin E2 and prostacyclin - reduces vasodilation and oedema
how are COX inhibitors analgesic
decreased prostaglandin generation, less sensitisation of nociceptive nerve endings to inflammatory mediators
how are COX inhibitors antipyretic
prevents to action of IL1 on the hypothalamus
what are the side effects of COX inhibitors
- GI side effects - nausea, dyspepsia - hypertension - skin reactions - reversible renal insufficiency - bronchospasm - analgesic associated nephropathy - liver disorders - bone marrow depression
what causes the side effects of COX inhibitors
COX1 inhibition
which NSAID is as an antithrombotic
aspirin - 75mg OD
which NSAIDs are used for short term analgesia
paracetamol, aspirin, ibuprofen
which NSAIDs are used for long term analgesia
naproxen, piroxicam
which NSAIDs are used for their anti inflammatory properties
ibuprofen, naproxen
which NSAID is used for their anti-pyretic properties
paracetamol
unwanted side effects of aspirin at therapeutic doses
gastric bleeding
side effects of aspirin in large doses
Dizziness, deafness, tinnitus, compensatory respiratory alkalosis may occur
aspirin side effects at toxic doses
uncompensated metabolic acidosis - especially in children
why should aspirin be avoided in children
Rare but serious post viral encephalitis (Reyes)
why does paracetamol overdose cause fatal liver damage
○ Causes drug to be metabolised by mixed function oxidases to n-acetyl-pbenzoquinoneimine ○ If not inactivated by conjugation to glutathione it can react with cellular proteins and cause tissue damage
