Imflammation Flashcards
What is an immunogen?
A substance capable of eliciting an immune response.
What is a tolerogen?
Antigens that incdude tolerance rather than immune reactivity.
What is central tolerance?
Limits the development of T&B cells, to stop them from attacking ourselves.
What is peripheral tolerance?
Regulates autoreative cells thats already in circulation.
Where does central tolerance of T-lymphocytes occur?
Thymus
Where does central tolerance of B-Lymphoctes occur?
Bone marrow
What occurs during central tolerance of T-lymphocytes?
Exposure to self antigens can lead to 4 out comes depending on the binding:
Strong - Negative Selection
Intermediate - T-regulator Cells
Weak - Positive selection
None - Apoptosis
What occurs during central tolerance of B-lymphocytes?
Recognise self antigens with high avidity - undergo receptor editing, if this fails then cells undergoes apoptosis.
Recognise self antigens with low avidity - Receptor expressin is reduced and cells become anergic.
What occurs during peripheral tolerance of T-lymphocytes?
Anergy
Become suppressed because of T regulatory cells.
What occurs during peripheral tolerance of B-lymphocttes
If recognises self antigen without T-cell activated, goes either into anergy or apoptosis or becomes suppressed.
How does autoimmune diabetes arise?
Autoantibodies against nicotinic acetylcholine receptor are made.
The antibodies mimic a ligand, which causes continual stimulation of the thyroid cells.
Ion channels in muscle receives input from motor neurons at NMS -> induce muscle contraction.
Autoantibodies are directed against receptor for TSH.
Autoantibodies prevent binding of ACh to receptor and induce internalization and degradation of receptor.
Cell mediated attack on the islets of langerhans in endocrine pancreas results in the death of insulin B-cells -> severe muscle weakness.
How does inflammation and fever.
A macrophage ingest a gram-negative bacterium.
Bacterium is degraded in vacuole, releasing endotoxins that induce the macrophage to produce IL-1
IL-1 is released by the macrophage into the blood stream, through which it travels to the hypothalamus of the brain.
IL-1 induces the hypothalamus to produce prostaglandins, reset the body’s thermostat to a higher temp, prod fever.
Inflammation main symptoms?
1 - Rubor - Redness
2 - Dolour - Pain
3 - Calor - heat, fever
4 - Tumour - Swelling
5 - Function Laesa - LOF
What are the sequence of inflammation response
Insult by trauma pathogen causes acute phase reaction
Platelet adhesion, transient vasoconstriction of efferent vessels.
Cytokine-induced vasodilation of afferent vessels
Activation of complement, coagulation, fibrinolytic and kinin systems.
Leukocyte adhesion.
Increase vascular permeability and extravasation of serum proteins and leukocytes with resultant tissue swelling.
Phagocytosis of foreign materials with pus formation.
Wound healing and remodelling.
Stage of 1 inflammation?
Vasodilation -
Triggered by cells parts - Histamine, Kinin, prostaglandin, leukocytrienes.
Migration & margination - margination describes the binding of phagocytes to the blood vessel.
Pro-inflammation mediators
Acute phases proteins.
Complement
Kinins.
Cytokines -
Pro-inflammatory - TNF, IL-1, IL-6
Adhesion Molecules - VCAM-1, ICAM-1
Growth Factors - M-CSF, GM-CSF
Matrix Metalloproteinase - MMP-1,2,9
Clotting factors
Acute phase proteins
CRP - Opsonin
Fibrinogen - Coagulation factors
Serum Amyloid A - Cell recruitment and MMP inducer.
Complement Factors - Opsonin, Lysis clumping, Chemotaxins.
Haptoglobin & Ferritin - Bind haemoglobin / Fe
IL - 1
Vasculature (Inflammation), Hypothalamus (Fever), Liver (Induces APP)
TNF-a
Vasculature, Liver, Induction of cell death, Neutrophil activation, Cachexia
IL - 12
NK cells, promotes TH1 subset T lymphocytes
IL - 6
liver, influences adaptive immunity.
IFN-a/B
Induces antiviral state, activates NK cells .
What are adhesion molecules
Transmembrane receptors that bind either to other cells or to the extracellular matrix.
What are the 4 main classes
Ig Superfamily - VCAM1, ICAM-1, LFA-2
Cadherins - E,P,N
Selectins - E,P,L
Integrins - 8 Subfamilies - a4B1
What Metalloproteinases involved in inflammation?
MMPS - Degrade and remodel extracellular matrix. Create chemokine gradient.
ADAMS - Cleave cytokine and adhesion molecules receptors from cell surface.
ADAMTs = Cleave receptors, degrade proteoglycans
ECM
Collagen Type 1, 2, 3 fibrillar found in bone, skin and cartilage
Collagen Type 4 - Basement membrane.
Laminin, elastin, Proteoglycan, aggrecan, fibronectin, martrilin, nidogen.
NF-kB
Family of transcription factors that regulate hundreds of pro-inflammatory mediators.
What are the NF-kB mediators?
Cytokines
Chemokines
Adhesion molecules
MMPs
Growth Factors
acute phase proteins
Stage 2 of inflammation
Tissue repair - Dead and damaged cells are rebuild.
Name some anti-inflammatory mediators.
Cytokines - IL-10
Soluble adhesion molecules
TIMPs - –| MMP
Plasmin peptides - counteract pain.
Resolvins / Protectins - anti-inflammatory lipid mediators.
What is acute inflammation?
Necessary part of immune response
Excessive inflammation leads to organ failure.
What is chronic inflammation?
Excessive inflammation that is not resolved which leads to tissue destruction, Autoimmune,
What is MTX?
Folic acid antagonist, with immunosuppressant activity. Can cause bone marrow suppression. Interferes with thymidylate synthesis.
What ways can MTX be administered?
IM, Oraly, Intravenously, Intrathecally.
What is ciclosporin?
Cyclic peptide with potent immunosupressove activity.
What does ciclosporin do?
Decreased clonal proliferation of T cells, primarily by -| IL-2 synthesis.
Decreased induction and clonal proliferation of cytotoxic T cells.
Reduces function of the effector T cells.
What are some of the side effects of Ciclosporin?
Nephrotoxicity most common. Can also cause hepatotoxicity and hypertension can also occur.
What is lefunamide?
Drug mainly used to treat RA & occasionally to prevent transplant rejecition.
How does leflunamide work?
–| effect on activated T cells.
–| synthesis of pyrimidines by –| dihydro-orotate dehydrogenase.
What are the s/e of leflunomide?
Diarrhoea, alopecia, raised liver enzymes and increase risk of hepatic failure.
What does COX stand for?
cyclo-oxygenase
What does COX do?
2 main forms,COX-1 & COX-2.
Highly homologous enzymes but are regulated in different and tissue specific ways.
How is inflammatory mediators produced?
Stimulus causes Phospholipase A2 to convert Phospholipids to Arachidonicacid.
Arachidonicacid is the converted into Inflammatory mediators in COX-1/COX-2.
It is converted to PGH2 which is then converted into PGD2, PGE2, PGF2a, PGI2.
What does COX-1 do?
Produced prostanoids that act mainly as homeostatic regulators.
What does COX-2 do?
Is strongly induced by inflammatory stimuli and is beleived to be more relevant as a target for anti-inflammatory drugs.
What does PGD2 do?
Causes vasodilation, inhibition of platelet aggregation, relaxation of GI & uterine muscle & modification of release of hypothalamic/pituitary hormones.
What does PGF2a do?
Causes uterine contraction in humans.
What does PGI2 do?
Vasodilation, –| of platelet aggregation, renin release and natruresis.
What does TXA2 do?
Vasoconstriction, platelet aggregation and bronchoconstriction.
What does PGE2 do?
Inflammatory prostanoid.
What prostanoids are released during acute inflammation?
PGE2 & PG12 are genereated by the local tissues & blood vessels, while most cells release maily PGD2
What prostanoids are released during chronic inflammation?
Cells of the monocyte / macrophage secrete and release PGE2 & TXA2
What are the therapeutic effects of COX –|?
Antiinflammatory.
Analgesic effects.
Antipyretic effects.
What are some of the unwated COX-1
Dyspepsia
Adverse cardiovascular effects
Skin reactions.
Reversible renal insufficincies.
Bronchospasms.
Liver disorders, bone marrow suppresion
What is Aspirin?
Irriversbibly binds to COX-1/2
Strongly –| platelet aggregation - used in CVD.
What are some of the side effects of asiprin?
Common - GI symptoms, gastric bleeding.
Larger doses - Dizziness, deafness, tinnits.
What is paracetamol?
Analgesic & antipyretic, weak antinflammatory.
What can toxic doses of paracetamol cause?
Nausea, vomiting, potentially fatal liver dmg.