Autoimmunity

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undergrad Pharmacology Flashcards on Autoimmunity, created by tanitia.dooley on 22/05/2013.
tanitia.dooley
Flashcards by tanitia.dooley, updated more than 1 year ago
tanitia.dooley
Created by tanitia.dooley over 11 years ago
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Question Answer
What are the effects of histamine at H1 receptors? Give an example of a drug that is used to treat inflammation? vasodilation, increased vascular permeability, contraction of smooth muscle in lung. Fexofenadine
What is 12-HETE? a chemokine eicosanoid
Which prostaglandins are vasodilators? PGI2, PGE2, PGD2 (also inhibits platelet aggregation)
What prostaglandins are vasoconstrictors? PGF2A
What is the effect of thromboxane A2? vasoconstriction
What is the effects of LTC4, LTD4 and LTE4? vasoconstrictor and increased vascular permeability. LTC4 and LTD4 are metabolised to LTE4 and eliminated from the body
What is the effect of LTB4? chemotaxin
Which prostaglandin predominates? PGE2
Describe the synthesis of PAF? Acyl PAF is converted to lyso-glycerl phosphorylchloride by phospholipase A2 which is then converted to PAF by acetyl transferase
What is the role of PAF in asthma? lung chemotaxin in monocytes, neutrophils and eosinophils
How are glucocorticoids linked to PAF? they have anti inflammatory effect by inhibiting PAF formation
How is bradykinin formed? by the cleavage of kininogens by killikrein
Describe B1 and B2 bradykinin receptors B1 expressed at low levels-expression induced with stress/inflammation. B2= constitutively expressed in many normal cells. Causes vasodilation and increased vascular permeability and stimulation of pain nerve endings
What is the effect of NO? What happens when present in high levels? vasodilation, enhances prostaglandin production, increased vascular permeability. It degrades into reactive nitrogen oxide species which damage invading pathogens and potentially host cells
What is sulfasalazine? an antirheumatoid drug which produces remission of the disease by reducing phagocytosis by scavenging ROS and NO
What are gold compounds? antirheumatoid drugs which reduce joiny pain and swelling-mech unknown may be due to inhibiting cytokine release by phagocytes
what is anti cytokine therapy? What are the disadvantages? greatest break conceptual breakthrough in treatment of chronic inflammatory disease. It is biopharmaceutical- recombinantly enginerred Ab specific for human protein- therefore difficult to produce and expensive
What is infliximab? Ab against TNFa- binds to it and prevents its action
What is basiliximab? Monoclonal Ab against IL-2 receptor- binds to the receptor and prevents effective T cell proliferation
What is anakinara? IL-1b receptor antagonist
What is azathioprine? interferes with purine synthesis and is cytotoxic- DNA synthesis required for T cell proliferation therefore inhibits cell-mediated immune reaction. Metabolised to mercaptopurine
What is copaxone? It is a future drug- found to supress experimental models of MS and slows progression of disease in humans- competes with myelin Ag for TCR and binds with high affinity preventing native binding
What is peptide based immunotherapy? aim is to develop a peptide which can form a complex with MHC, can be administered as a drug, can be recognised by TCR but not send signals for activation of the T cell, must prevent native peptide from coordinating with TCR
Describe CD80 blocking drugs? at preliminary stage in clinical trials- experimental models have found that antiCD80abs can decrease disease severity and antiCD86 can increase it- however only successful at treating primary disease before symptoms=not possible
What is histamine synthesised from? histidine using histadine decarboxylase
Where is histamine stored? in high concs in mast cells and basophils in granules which bind acidic proteins and macroheparin to remain inactive
How is histamine releaed? Ag binds to IgE associated Fc receptors, Following reexposure to Ag= cross linking of IgE=increased cytoplasmic Ca2+=mast cell degranulation and release of mediators such as histamine
Give an example of a glucocorticoid hydrocortisone
What do COX2 inhibitors reduce? vasodilation, oedema and pain not accumulation of inflammatory cells
What happens in the COX enzyme in the absence of an inhibitor? arachidonic acid travels down the channel to the catalytic site where it is converted to prostaglandin E2 which binds with lower affinity and is therefore released
What is the role of CD80 and CD86 on APCs? CD80 binds to CD28 on T cells and has positive regulation, CD86 binds CTLA-4 on T cells=negative regulation
How do NSAID work? Bind channel of COX enzyme and prevents arachidonic acid from reaching the catalytic centre so it is not converted to prostaglandin E2
How does MHC interact with the T cell receptor? MHC pockets which AA side chains fit in binding through hydrophobic bonds. certain AA side chains are exposed from the MHC cleft and recognised by the T cell receptor. The peptide provides signals controlling fine specificity of interaction. T cell also interacts with MHC itself and binding of CD4/CD8 to MHC stabilises the structure
What two signals are required for the initiating of T cell activation? 1. peptide antigen cross linking MHC & TCR 2. additional receptor signals from APCs (CD80 & CD86)
What is the difference between the COX 1 and COX2 enzyme? COX 2 has larger channel and additional binding site
Describe delayed type hypersensitivity? CD4 secretes IFN-y which activates macrophages and neutrophils causing the release of NO, ROS and cytokines which causes tissue injury
How are COX 2 selective drugs different to non selective ones? They have increased molecular weight but retained interaction with binding site so too big to pass down COX1. Increase potency by identifying the additional binding site
Describe how insulin-dependent diabetes mellitus is caused? IFN-y secreting T cells around islet of langerhans cause tissue injury of beta cells causing decreased insulin production.
What is the susceptibility factor for diabetetes mellitus? HLA DR3 and DR4-95% susceptible individuals express it compared to 40% healthy individuals. Viral infection
What is the symptoms of diabetes mellitus? ketoacidosis, hyperglycemia
What are the common side effects of NSAIDs? gastric irritation, effects on renal blood flow, tendency to prolong bleeding by inhibiting platelet function, increased liklihood of thrombotic events eg myocardial infarction (exspecially COX2 selective by inhibiting PGI2)
What is cyclosporin and what is its effect? immunosupressant drug, decreases proliferation of T cells by inhibiting IL-2 release= decreased function of effector T cells that secrete cytokines and mediate autoimmune reactions
How does cyclosporin inhibit IL-2 release? binds to the cytosolic protein cyclophilin in T cells which inhibits transcription factor activation and synthesis of IL-2
Describe the disease mechanism of multiple sclerosis? T cells are activated by myelin/myelin related proteins and migrate into the CNS where they secrete IFN-y. They then cause tissue damage to CNS cells causing myelin destruction which released more myelin related proteins causing the release of more cytokines
What are the symptoms of multiple sclerosis? weakness, paralysis, ocular symptoms
What are the susceptibility factors for MS? HLA-DR2 & viral infection
what are the effects of glucocorticoids? decreased production of NO, histamine and prostaglandin, decreased action of helper T cells by decreasing T cell proliferation, decreased cytokine productiong involved in inflammation and reduced activity of macrophages by decreasing gene txn of IL-2, IFNy and TNFa
What is the mechanism of action for glucocorticoids? Bind intracellular receptors which dimerise, conformation change exposing DNA binding domain- move to the nucleus and interact with glucocorticoid response elemment and/or NFkB, Fos/ Jun to modify gene expression
What causes rheumatoid arthritis? Antigen unknown but activates T cells which secrete IFNy which phagocyte activation and secrete TNFa and IL-1B which acts on synovial cells to produce proteolytic enzymes which cause tissue damage of synovial tissue causing inflammation
what are the susceptibility factors in rheumatoid arthritis? HLA DR1 and 4, viral infection
How do infections contribute towards autoimmunity? by up regulating expression of co-stimulatory molecules on antigen presenting cells thus enhancing antigen presentation
describe the Genetic susceptibility of autoimmune diseases? MHC class II gene HLA DR- corresponds with observation that CD4+ cells involved in disease progression
Describe what happens in T cell mediated cytolysis? viral infected cells cause clonal expansion and then cell killing by perforin/fas
Why do T-cells kill all infected cells? they cant discriminate between latent and destructive viruses
Give an example of virally infected cytolysis? hepatitis, myocarditis
what are the effects of prostaglandin? vasodilation, decreased blood flow
What is the difference between the expression of COX1 and COX2? COX1 is expressed in most tissues and has a housekeeping role in homeostasis. COX2 expression is induced by activated inflammatory cells. When immune cells are activated= increased IL-1 and TNFa which leads to the expression of COX2
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