Unit 3 Flashcards
most common form SCID
X linked IL2 R gene
Most common mutation CF
delta F 508
What enzyme does newborn screening in CF pick up
Immunoreactive trypsinogen
Testing for lupus which is more sensitive vs specific
Anti nuclear AB - auto AB to nuclei cells.
98% peoplesystemic lupus have a positive ANA test * most sensitive. Also called immunofluorescent antinuclear antibody test.
Anti-double-stranded DNA antibody (anti-dsDNA) = specific ANA antibody found in about 30% of people SLE + less than 1% of healthy individuals * specific.
The presence of anti-dsDNA antibodies suggests more serious lupus, such as lupus nephritis (kidney lupus). When the disease is active, especially in the kidneys, high amounts of anti-DNA antibodies are usually present.
Use enzyme-linked immunosorbent assay (ELISA)
How chronic infection CF leads decreased lung funcion
o Chronic infection – launch Th17 response against extracellular bacteria. Repeating cycle of infection and neutrophilic inflammation develops. Neutrophil releases lysosomal enzymes + peroxidase. Increased vascular permeability + fluid build-up lungs increasing diffusion distance * limiting effective gas exchange. TGF-ß and endothelin, cause smooth muscle proliferation, intimal thickening, interstitial fibrosis.
o Cleavage of complement receptors CR1 and C3bi and immunoglobulin G (IgG) by neutrophil elastase (NE) results in failure of opsonophagocytosis * bacterial persistence. NE leads production (IL)–8 from epithelial cells and elastin degradation * persistence of inflammation and infection, structural damage, impaired gas exchange, and, ultimately, end-stage lung disease and early death. As chronic inflammation gets resolved get formation scar tissue each time * builds up which reduced lung function.
o Airway obstructed due build up mucus * harder exhale air * reduced FEV
o Struggle expel air quickly as airways could collapse during exhalation – breathe out slowly pursed lips positive pressure maintain airway patency.
Warm type haemolytic anemia
patho
Breakdown tolerance -IgG auto AB produced against rhesus antigen rbc
igG coat RBC binding Fc R receptor phagocytes - phagocytosis esp sleen as splenic macrophages best affinity FC region.
Repeated partial pahgocytosis - damages membrane - spherocyte
Cold type haemolytic anemia
patho
Breakdown tolerance- IgM auto AB against polysaccaride 1 antigen.
Form IC peripheries <37 - Igm binds anitgen low affinity. Igm fixes complement classical * when RBC enter warmer region igM detaches leaving complement bound - kupffer cells high affinity C3b extra vascular hemaolysis liver
Warm type haemolytic anemia testing
Blood film - leucoerthroblastic, poly chromatic spherocytes
+ve direct Ab test IgG C3d
postive coombs for IgG
Cold type haemolytic anemia testing
Blood film normocytic, poly chromatic spherocytes
+ve Cooms complement
Folate cycle
dUMP -> thymidylate via thymidylaye synthase. Thymine needed DNA synthesis.
erythropoesis
Multipotent heamatopoetic stem cell common myeloid progenitor pro-erthroblast basilic erthroblast polychromatic erthroblast Orthochromatic eryhtroblast/normoblast poly-chromatic erythrocyte/ reticulocyte erthyrocyte
Causes micro cytic anemia
Microcytic anaemia- > Hypo chromatic -> Iron deficiency, Thalassaemia, anaemia chronic disease, hyperthyroidism + lead poisoning
Clotting diseases with prolonged prothrombin time
Owen parahemophillia (factor 5 deficiency) Liver failure - deficiency gamma carboxylated coagulation factors - II (prothrombin), VII, IX and X.
An essential cofactor for gamma-carboxylation is vitamin K,
Oculomotor n. parasympathetic component
Preganglionic neurons: midbrain (Edinger-Westphal nucleus)
Postganglionic neurons: Ciliary ganglion
Targets: Ciliary muscle & sphincter pupillae
Function: Accommodation of the lens, constriction of pupil
Facial nerve parasympathetic component
Preganglionic neurons: pons (superior salivatory nucleus)
Postganglionic neurons: pterygopalatine & submandibular ganglia
Targets: Lacrimal glands, submandibular gland, sublingual gland
Function: Increased secretion (tears and/or saliva)
Glossopharyngeal n. parasympathetic component
Preganglionic neurons: pons (inferior salivatory nucleus)
Postganglionic neurons: Otic ganglion
Target: Parotid gland
Function: Increased secretion
Vagus n parasympathetic component
Preganglionic neurons: medulla (Dorsal vagal motor nucleus)
Postganglionic neurons: within walls of viscera
E.g. enteric NS!
Target: Thoracic & abdominal viscera (up to the splenic flexure)
Function: Rest & digest
Pelvic splanchnic nerves
Preganglionic neurons: S2-S4
Postganglionic neurons: within walls of viscera
Target: Hindgut & pelvic viscera
Function: Peristalsis, glandular secretion, engorgement of erectile bodies, urination
Obstructive airway disease
Airflow obstruction due narrowing airways. Fev1 decreases much more FVC (same or drop slightly)* ratio drops.
Restrictive airway disease
Restrictive: Decreased lung volume – fibrosis. Not able create as great pressure difference due lack compliance * draw out smaller volume air. Fev1 and FVC drop by the same amount * ratio remains the same.
Pelvic pain line
Pain from viscera ‘above or in contact with inferior layer of parietal peritoneum’ travels via sympathetic splanchnic nerves
Pain from sub-peritoneal organs is conveyed via parasympathetic nerves
Pseudomonas virulence factors
Type 4 pilli
twitching motility + cell adhesion
LPS
Inflam signal + resistance phagocytosis
Type 3 secretion system
Injection toxins into host cells
Alginate
Slime layer + resistance IC + proteins
Flagellum
Motility + inflam signal
Phospholipse
Tissue invasion
Exoenzyme S/A
Inhibit elongation factors - kills
Sidophores
Iron sequesration + cell death
Elastase/protease
Tissue invasion
How siderphores allow iron sequestration
Siderophores are essential to iron sequestration in pseudomonas but in the process, they strip iron from human cells. Host cells need Fe for oxidative phosphorylation, siderophores are released from bacteria to scavenge Fe3+ from host cells – metabolic stress kills cell + iron sequestered into bacterium via transferrin. Neutrophil response – oxidative burst leads peroxide secretion from phagocytes. Fe3+ strips oxygen from peroxide * no damage to bacterium.
How does pseudomonas cause a respiratory tract infection in CF? 4 mark
o Initially pseudomonas adopts a non- mucoid phenotype, no biofilm formation, motile, cytotoxic with immunogenic LPS -> elicits strong IR.
o Normally bacteria eliminated by non-specific barrier defences – ventilation also have mucus trapping, defensin secretion + ciliary action- poor ventilation or entry bacteria increased by external devices infection occurs normally macrophages detect bacteria + drive inflammation. DC recruits Th17 help, neutrophils recruited + pathogen cleared.
o In CF patients produce excess/thick mucus that bacteria can live inside – mucus not removed by ciliary action * colonisation occurs + replication bacteria cannot be controlled.
o Once inside mucus pseudomonas changes its phenotype to a mucoid alginate secreting phenotype. Biofilm formation which is impenetrable to therapy, resorbs flagella, limited toxin production + this limit immune response as IS only encounter organisms if reach edges of mucus.
Risk factors for pseudomonas
o Failure immunity
o Structural defect
o Lack adequate ventilation
o Devices
How does the mucoid phenotype helps evade IS
How does the mucoid phenotype helps evade IS
o Biofilm prevents penetration of immune proteins + compounds. Lipid A of LPS binds less efficiently to TLR4 -reduced inflammation + reduced bacterial clearance leading to chronic infection with repeated flare ups.
o Increased neutrophil mediated damage respiratory epithelium, elastic + connective tissues. Neutrophils undergo NETosis form extracellular traps + neutrophil granule contents released. Wheeze, cough, mucus hyper-production -> bronchitis, bronchiectasis + pulmonary failure inevitable. Need antimicrobial therapy prevent colonisation + eliminate bacteria during flare ups.
How pseudomonas has developed antimicrobial resistance (natural feature of overdose)
o Hydrophobic penicillins (Penicillin V, flucloxacillin) + glycopeptides cannot enter outer membrane channels
o Hydrophilic penicillins (Amoxicillin) + cephalosporins can enter but chromosomally encoded beta-lactamases degrade them
o Constantly expressed outer membrane efflux pumps pump protein synthesis inhibitors + folate antagonists out cell (Macrolides, Tetracyclines, Trimethoprim + Fusidate)
Mucoid phenotype in psedomonas
Alginate secreting Biofilm formation Resorb flagella Limited toxin production limits IR -
Productive cough CF
Lack CFTR reduced chloride secretion increases sodium + water absorption - lowers water content mucus lining respiratory epithelium - isotonic dehydrated mucus
defective mucocilliary action accumulation secretion obstruct bronchi + bronchitis triggering cough reflex
How Pseudomonas acquires resistance
Chromosomal mutation. Activation of existing resistance genes. Uptake of genetic material from other organisms
Acquired resistance Pseudomonas
o De-repression chromosomal ESBL + plasmid-acquired beta-lactamases (NDM1) OR carbapenemases (KPC) degrade ceftazidime, tazobactam + meropenem
o Overexpression multi- drug efflux pumps actively remove fluoroquinolones (ciprofloxacin), aminoglycosides (gentamicin) + carbapenems
o Changes in drug targets (topoisomerases + small ribosomal subunits) prevent fluoroquinolone + aminoglycoside binding -> expression 16s rRNA methylation enzymes + expression altered topoisomerase enzymes.
What is pseudomonas
Pseudomonas aeruginosa is a Gram-negative, oxidase-positive, non-fermenting bacillus
What pseudomonas relations
Acinetobacter, Burkholderia and Stenotrophomonas
atopy
Atopy (genetic tendency to develop allergic disease). 40% in Caucasian populations. Atopic have higher levels IgE + Eosinophils in blood. Due polymorphism of many genes. MHC II -> enhanced presentation of allergen peptides. TRC alpha chain -> enhanced recognition of allergen peptides. Il-4R -> increased Il-4 signalling. Il-4 -> variation Il-4 protein expression. FceRI -> IgE binding. Chromosome 5 genes for Il-4,3,5,9,12,13 + GM-CSF involved isotope switching, eosinophil survival + mast cell proliferation.
Genetic factors asthma
HLA DR/Q
Polymorphisms ADAM33
Chromosome 5q
Atopic asthma
Atopic asthma
Most common type – type 1 hypersensitivity reaction. Allergic sensitisation + patients’ family hx asthma + high serum IgE.
Stress induced asthma
Stress induced Initially At catecholamine -> bronchodilation. Long periods of exposure catecholamines, their receptors become downregulated * effects less severe. Reduction in catecholamine sensitivity reduces immune cell regulation, as T and B lymphocytes possess adrenergic receptors, so catecholamines can regulate IL-4, IL-5 and IL-13 expression, histamine release from mast cells and recruitment + activation of eosinophils.
Cold induced asthma
Cold/ exercise induced Airway cooling - dehydration of the fluid lining respiratory epithelium. Drying of the airways increased blood flow (hyperemia) -> oedema + bronchoconstriction.
Exercise induced asthma, symptomatic 5-15 minutes after exercise, as catecholamine release during exercise helps with bronchodilation.
Drug induced
Drug induced 3-5%, NSAID + Aspirin sensitivity -> Drugs inhibit AA pathway inhibit production prostaglandins. Prostaglandin E inhibits enzymes generate leukotrienes * inhibit this get upregulation leukotrienes -> bronchoconstriction.
Urticaria (hives) + typical asthmatic symptoms.
Early phase asthma
Early phase response - sensitization
o Inhaled allergens get across mucosal layer taken up DC, presented T-helper cells inducing exaggerated Th2 response to harmless environmental antigen.
o Th2 produces Il-4 -> stimulate proliferation + differentiation plasma cells + IgE production. Il-13 -> stim mucus secretion from bronchial submucosal glands + IgE from plasma cells.
o Plasma cell produced IgE binds to Fc on submucosal mast cells BUT by this time the antigen has already been cleared.
o Second exposure to antigen the ready and waiting mast cells react immediately, releasing granule contents with immediate affects. Allergen binds mast cell bound IgE immunoglobins cross linking Fc receptors triggering degranulation + release;
- Leukotrienes -> bronchoconstriction, increased vascular permeability and oedema and increased mucus secretion (B4 recruits immune cells, C4, D4, E4 bronchoconstrict)
- Histamine -> potent bronchoconstrictor
- Prostaglandin D2 -> bronchoconstriction and vasodilation (causing oedema)
Late phase asthma
o Th2 -> IL-5 activates locally recruited eosinophils into airways which bond IgE immunoglobins through Fc receptors which cross linked bound to allergen. Eosinophils release eosinophil cationic protein + major basic protein -> damages cells respiratory tract + leukotrienes -> oedema + further bronchial constriction.
o Chemokines produced T + epithelial cells recruit more T cells, eosinophils + basophils. Epithelial release eotaxin = chemokine for eosinophils.
Chronic inflammation -> bronchial hyperresponsiveness to histamine, cold air, sulphur dioxide and AMP. mediated by high levels IgE * airways more responsive to contractile stimuli.
Epithelial shedding from chronic inflammation exposes subepithelial tissues to inflammatory mediators + sensitises nerves * altered neural control of the airways. Airway obstruction due muscular bronchoconstriction, acute oedema and mucus plugging.
Characteristics early phase asthma
bronchoconstriction, increased mucus production and increased vascular permeability and oedema, leading to symptoms of wheezing, chest tightness and breathlessness.
Mast cell contents activate subepithelial vagal receptors, triggering acetylcholine release from vagal efferents that directly induces smooth muscle contraction through muscarinic receptors.
