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81 Cards in this Set
- Front
- Back
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What is rheumatoid arthritis? what are the risk factors? |
Systemic chronic inflammatory disorder, risks include infection and smoking |
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What are the anti-bodies in RA? and which is specific to the disease? |
- Rheumatoid factor - Anti Citrullinated paptide (s) |
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what organs doe RA affect? |
- skin (nodules) - lungs (fibrosis) - kidneys (amyloidosis) - heart (pericarditis) - blood vessels (artherosclerosis) |
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Explain what RF's are? |
- Antibodies of any class - Bind to the Fc region of IgG molecules (including themselves) - Binding of the Fab region of one antibody and the Fc region of another in enhanced by defective glycosylation of the Fc region |
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What is the overall effect of RF's formation of complexes? |
stable and proimflamatory activating compliment - directly proportional to severity |
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What is the normal process for the production of T-cells? |
- In the thymus - Initial development as both CD8 and CD4 - Positive selection for low affinity self interaction with MHC 1 and MHC2 - Unselected cells undergo cell death |
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What happens when the T-cell selection process goes wrong in RA ? |
- lymphopenia - followed by self replication to restore numbers - autoreactive cells |
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What is the significance of Treg in RA? |
- reduced numbers - limited ability to supress antigen presentation - limited TGFb and IL-10 |
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what functional class is a synovial joint? |
diarthroses |
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what are the layers of the synovial joint? |
- articular cartilage - AJ capsule - outer fibrous membrane - inner synovial membrane - synovial fluid |
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What cytokine do T-cells and macrophages contirubute to RA? |
- Il-1/2/6/8/10/17 - TNFa - PDGF - TGFb |
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In RA where are the T-cells activated? what happens to them when activated |
-locally by APC - by IL-6/1/21/22 - where they differenciate into Th-17 CD4+ to produce IL-17 |
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What is the end result of the inflammation of the joint in RA? |
extensive angiogenisis - Pannus development - cartilage and bone destruction |
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What are the subsets of CD4+ T-cells |
- Th1 (INFy and TNFa) - Th2 (IL-4/5/6) - Treg (TGFb and IL-10) - Th17 (IL-17) |
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what is the relative change from healthy treg and th17 cells in RA? |
- treg decreased - Th17 increased |
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what are the functions of - INFy and TNFa - IL-4/5/6 - TGFb and IL-10 - IL-17 |
- activate innate - activate B-cell antibody production - supress t cell response - control inflammatory autoimmune response |
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what is the only cell found in cartilage |
- Chondrocyte |
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what causes the stimulating of PGE2 production by chondrocytes and osteoblasts? |
IL-17 |
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How does IL-17 cause bone destruction? |
- Induces RANK ligand expression to promote osteoclast differentiation - PGE2 production - release of H+ ions cathepsin K enzyme |
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How does PGE2 contribute to RA? |
- reduced collagen synthesis - increase chondrocyte death - increased MMP - increased osteoclast formation - increased angiogenic factor - increased enothelial proliferation and reduced death |
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What enzyme is responible for PGE2 production? |
- COX-2 |
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what is the use of selective COX inhibitors? |
reduces pain, oedema, vasodilation - but little effect on disease progression |
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Name some selective COX-2 inhibitors |
celecoxib and rofecoxib |
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name a DMARD? |
sulfasalazine - broken down to produce 5-amino salicylic acid |
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Name some drugs to treat RA? |
- gold compounds - penicillamine - hydroxychloroquine - immunosupressants - Azathioprine |
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what diseases are good to corticosteriod treatment and which are bad? |
G - RA, asthma B- cystic fibrosis and COPD better for eosinophil inflammation not neutrophil |
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What is the mechanism of glucocorticoids? |
Cause the activation of - anti-inflammatory genes - and beta 2 receptor - IL-10 |
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what was the breakthrough with treatment for RA? |
TNFa inhibitors in the form of anti-bodies - IL-1 antagonist |
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what are the layers of the skin ? |
- epidermis - dermis (papillary and reticular) - subcutaneous |
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What are the major cells of the epidermis? |
- keratinocytes - melenocytes - langerhans cells - mekel cells |
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What are the layers of the epidermis? |
corneum - lucidum - granulosum - spinosum - basale |
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What are the innate denfence of the skin? |
- impermeable barrier - physical barrier - Anti microbial - oil and defensins - Acidic sweat |
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what are the barrier defects in AD? |
-Reduced filaggrin expression - decreased cerimide and sphingosine - decreased antimicrobial production |
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how does stress effect the disease? |
- increased corticotropin releaseing hoermone
- increase adrenocorticotropic hormone - increased cortisol causes - decreased IL-18/1 and ceramide |
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what is the effect of Th2 cell cytokine in AD? |
- decreased AMP's, filaggrin - increased IgE |
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what is the role of staphlococcus areus in AD? |
- Promote the itch- scratch cycle - do not need co-stimulation |
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what are the treatments for AD? |
- emollients - antiseptics - antibiotics - topical corticosteroids |
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what are the immunosupressants for AD? |
- antihistamines - methotrexate - cyclosporine |
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what is the defect in CF? |
Structure and function of CFTR (cystic fibrosis transmmbrane conductance regulator) epressed by all endothelial cells |
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what chromosome is affected in CF? and what is the most common defect? |
-7 - delta-F508 |
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What is the structure of the CFTR membrane? |
- 2 transmembrane spanning regions - 2 nucleotide binding domains - regulatory domain |
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How does CFTR open? |
- protein kinase A - phosphorylates the Regulatory domain - conformational change - chloride ions leave the cell |
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What membrane proteins regulate CFTR? |
- B2 (positivly) - Syntaxin 1A (negativly) |
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What ion channel does CFTR regulate |
ENaC |
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What are the classes of severity of CFTR? |
- 1, no protein production - 2, processing defects - 3, regulation defects - 4, conductance defects |
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What organs are affected? |
- airways - liver - pancreas - small intestine - reproductive tract - skin (sweat glands) |
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How is cystic fibrosis diagnosed? |
- excessivly salty sweat 70mM - failure to thrive + gain weight - persistant chest infection |
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What are the transport systems in a bronchial cell? |
-ENaC - CFTR -Na/K/Cl contransporter - Na/K ATPase (Na leaves the cell through basel membrane) |
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How much greater is sodium re absorption in CF than in healthy cells? |
10X greater |
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Name some bacteria that cause infection on CF? |
- Staphylococcus aureus - Pseudomonas aeruginosa |
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Where is pseudomonas aquired from? |
-water sources |
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What are the events leading to chronic infection? |
- decreased periciliary fluid results in reduced mucocilary transport - mucus hyper secretion creates hypoxic zone - formation of macrocolonies - resistance of secondary defences - increase hypoxic |
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What are the bacteria products of Pseudomonas? |
- alginate (barrier) - P. elastase (cleves antibodies and complement receptors) - Pyocyanin (inhibits lymph proliferation) -Exotoxin A (cytotoxic to macrophages) - Leukocidin (cytotoxic to neutrophils and lymph) |
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What toll like receptor regonises LPS? |
TLR4 |
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what is the function of TNFa and IL-1 in the airways? |
stimulate bronchial epithelium and fibroblasts to produce IL-8 |
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what regulates the production of IL-8? |
IL-10 from macrophages and epithelial cells |
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What are the difference in CF of the response to infection? |
- absence of IL-10 - huge levels of IL-8 - Necrophilia recruitment causes more IL-8 (self amplifying) - CFTR trafficking becomes stuck in the rough ER stimulating inflammation |
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What are the important anti-bacterial molecules of neutrophils? |
- Proteases - Defensins - Bacterial permeability increasing enzyme |
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what generates the super oxide in neutrophils? |
-NADPH oxidase |
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name an inhibitor of neutrophil elastase? |
- alpha1-AT |
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what products protect from oxidant species? and what is its significance |
Vitamin E/A/C - pancreatic problem, no lipase, no fat soluble vitamins taken up -reactive oxygen damages inhibitors of elastase leading to protease imbalance |
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main functions of neutrophil elastase? |
- increases IL-8 - increases mucus secretion - bronchiectasis - c3b and igG clevage - enhance EnaC |
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what is the sequence of event in CF leading to death? |
- defective CF gene - defective/ deficient CFTR - increased Na absorption - dessicated mucus - bronchial obstruction - infection - inflammatin - bronchiectasis, failure, death |
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what is bronchiectasis? |
Perminent enlargement of parts of the lungs (also in COPD) |
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what drugs are used in the treatment of CF? |
- antibiotics (colomycin) - NSAIDS (Ibuprofen) - Corticosteroids (not the best) - bronchodilators - mucolytics (DNase) - anti-proteases |
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What are the bonds in the sputum of inflamed airways? |
- hydrogen bonds - ionic - van der waals - convalent disulfide -physical entanglement - extracellular actin and DNA |
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What are the aims of CF treatment? |
- control infection - reduce obstruction - reduce inflammation - fix basic defect - transplant |
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name a prostaglandin, thromboxane and leukotriene? |
-PGD2, PGE2, PGI2 - TXA2 - LTA4 |
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WHAT IS THE SEQUENCE OF EVENTS THAT LEADS TO PROSTAGLANDIN SYNTHESIS? |
- Phospholipid converted into aa - AA converted to PGG2 - PGG2 converted into PGE2 ect
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WHAT ACTION DO GLUCOCORTICOIDS INHIBIT? |
PLA2 (phospholipase A2) - breaks down phospholipids through ester linkage hydrolysis |
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what are the other sources of eicosanoids? |
- ETE > PGE1 |
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what enzyme makes Leukotriene ? what drugs block LTR and this enzyme? |
- 5-LOX - zafirlukast (R) - Zileuton (E) |
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what is the intracellular mechanism of prostaglandins? name protaglandin receptor? |
- G protein - cAMP - or phosphatidylinositol signal pathway causing increase ca2+ PPARy |
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What are the actions of eicosanoids? |
- pyresis - inflammation - algesia - pro-thrombosis |
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name 5 eicosanoids and give a function? |
-PGE1(vasodilation) -PGE2 (Fever) -PGI2 (algesia) - TXA2 (platelet aggregation) - LTC4 (bronchoconstriction) |
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what are the roles of COX1 and COX2? |
- gastric cytoprotection, haemostasis, regulation of platelet aggregation, renal function - inflammation, allergy states |
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what are the uses of prostanoid mimetics? |
- releif of GI irratation - labour induction - inhibition of platelet aggregation |
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name a selective COX-2 inhibitor? |
- celecoxib |
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Theraputic use of NSAID's>? |
anti inflammatory - analgesic - antipyretic - antiplatlet |
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side effects of aspirin? |
bronchospasm - skin reactions - compensated alkalosis - asthma - hyperthermia increase bleed time |
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what are some of the indications of aspirin? |
fever injury acute gout rheumatoid arthritis myalgia |
