Week 8 Flashcards
important general features of immune responses to microbes?
response is mediated by both innate and adaptive effector mechanisms
response is distinct and specialized to effectively combat specific infectious agents
the ability to evade and resist the effector mechanisms that enable the microbe to survive
tissue injury and disease may be caused by the host response to the microbe
what are some ways of direct host damage?
exotoxin secreted by bacteria
endotoxins wall of gram negative bacteria
direct killing of host cells (pathogen replication lyses host cell)
physical blockage
secrete toxins that directly damage host cell
interfere with synthesis of protein metabolism, change signalling pathways in the host cell, produce enzymes that damage host cell
some examples of exotoxins?
clostridium tetani = tetanus (interferes with inhibitory neutrons)
staphylococcus aureus = toxic shock syndrome (release of toxins that act as super antigens = non specific T cell cytokine release)
streptococcus pyogenes = tonsillitis
some examples of endotoxins?
escherichia coli = gram neg sepsis
haemophilus influenzae = meningitis pneumonia
salmonella type = typhoid fever
examples of pathogens that cause direct cytopathic effect:
variola = smallpox varicella-zoster= chickenpox/shingles hepatitis B virus polio virus = poliomyelitis measles virus influenza virus herpes simplex virus = cold sores
what are some ways of indirect host damage?
immune complexes (HepB, malaria)
molecular mimicry
aberrant immune responses (T cells)
immune response against pathogen can lead to tissue damage in the host = granulomatous inflammation
what is a chemoattract for Th17 cells?
CCL20
what is a chemoattractant for monocytes?
CCL2 (produced by Th1)
what are some bacterial strategies for avoiding and manipulating host immune responses:
escape epithelial defences - degrade mucous
escape from phagocytes and innate immunity - capsules, Ig binding, opsonization
evade adaptive immunity - resistance to Ab via capsules
what are some ways that bacteria resist innate immune responses?
prevention of lysosome-phagosome fusion
escape into the cytoplasm from phagosome
resistance to lysosomal enzymes
what are the different serogroups of neisseria meningitides?
A, B, C, X, Z, W135
which Neisseria meningitides serogroups have the capsular polysarccharides?
A, C, W135 and Y
capsule used as a conjugate in vaccine
why is Nm serogroup B poorly immunogenic?
B capsular polysaccharide is poorly immunogenic because identical to the polysialic acid present in many human glycoproteins
group B vaccine is protein antigen based
hydroxyurea?
antimetabolite- urea analogue
- inhibits ribonucleotide reductase, thus interfering with the conversion of ribonucleotides to deoxy ribonucleotides
what phase do antimetabolites work at?
S phase
pharmacokinetics of alkylating agents?
cyclophosphamide- needs P450 metabolism in liver for activity
what phase do alkylating agents work?
not cell specific but predominantly S phase
cell cycle block at G2
adverse effects of platinum compounds?
myelosuppression, CINV
cisplatin = nephrotoxic, ototoxic
indication for platinum compounds?
primary tx for ovarian and testicular cancer
what phase do vinca alkaloids work?
M phase
what phase do taxanes work at?
G2-M phase
difference between vinca alkaloids and taxanes?
vinca alkaloids binds b tubulin and block polymerization with a-tubulin into MT = prevents spindle formation in dividing cells and causes arrest at M phase
taxanes: stabilize MT in non-functional polymerized state and thus can’t pull part for cell division
indications for taxanes?
ovarian cancer
at which phase do topoisomerase 1 inhibitors work at?
S phase
adverse effect of anthracylcines?
long term therapy can lead to cardiomyopathy
which drug is used as a chemical carceration in sex offenders?
cyproterone (anti-androgen) - has prosgestogenic effects that decrease production of testosterone
actions of mTOR1?
protein synthesis ribosome biogenesis cell survival proliferation angiogenesis invasion migration/ metastases
actions of mTOR2?
cell survival
cell cycle progression
actin remodelling
indications for nivolumab?
NSCLC, melanoma
indications for ipilimumab?
metastatic melanoma
mechanism of cytotoxic drug resistance: transport?
decreased accumulation of cytotoxic drugs in the cells due to increased expression of drug transport efflux pumps (P-glycoprotein)
decreased amount of drug uptake in cell
mechanism of cytotoxic drug resistance: metabolic?
decreased metabolic activation of drug (5-FU)
increased inactivation of the drug (anti-metabolites)
increased concentration of target enzymes (methotrexate - DHFR)
decreased requirement for substrates/ utilization of alternative metabolic pathways
mechanism of cytotoxic drug resistance: targets?
mutations leads to altered/ resistant target molecules
increased repair of drug induced dNA damage
inhibition of apoptosis
difference between cocaine and methamphetamines?
cocaine: shorter duration of action; blocks reuptake of DA
meth: longer duration of action; blocks reuptake of DA and stimulates the release of DA from VMAT2
what are some physical harms with stimulants?
OD renal failure cardiac failure seizure MI rhabdomyolosis malnutrition
long term effects of amphetamine use
chronic insomnia
psychosis - lasting up to weeks
HTN, abnormal HB, MI risk
self medication with psycho depressants
malnutrition, less resistant to infections (BBV)
brain damage: memory impairment, cognitive/ motor impairment, impaired thinking
violent, aggressive behaviour
what are the 3 phases of amphetamine withdrawal and what is the onset and durations?
crash phase: 12-24 hrs after use, subsides 2-4 days
withdrawal phase: 2-4 days after use; subsides over 2-4 weeks
extinction phase: weeks to months
what are some characteristics of the crash phase of amphetamine withdrawal?
low cravings
fluctuations in mood
disturbed sleep, exhaustion, fatigue
generalized aches and pain
what are some characteristics of withdrawal phase of amphetamine withdrawal?
strong cravings
increased appetite
fluctuating mood
disturbed sleep, vivid dreams, insomnia,
poor concentration/ attention
disturbed thoughts/ perceptions that can re-emerge but were masked in crash phase
what are some characteristics of extinction phase of amphetamine withdrawal?
gradual resumption to normal mood with periodic episodes of mood changes
disturbed sleep
episodic cravings
more prominent effects of cocaine when compared to amphetmaines?
hyperthermia
pulmonary edema
seizures
muscle rigidity
the effects of GHB?
seizures, resp depression, coma, N&V, aggression
hypnotic with narrow therapeutic window so ID is common
what is the safe level of caffeine for adults?
<400mg/day for adults
specific opiate withdrawal symptoms?
goosebumps, yawning, runny nose, abdo cramps, diarrhea
specific withdrawal symptoms for alcohol?
tremors, confusion (seizures, delirium, hallucination), fever
onset and duration of alcohol withdrawal?
3-24 hours
4-10days
mechanism of dependance and withdrawal for cocaine?
increase expression of DAT
increased presynaptic DA receptors
presynaptic DA is depleted
what is the safe level of caffeine per day?
<400mg/day
Th1 functions in IC bacteria:
IL3 and GM-CSF?
IL3 and GMCSF= stimulate production of monocytes in BM
Th1 functions in IC bacteria:
TNFa and LTa
act on local BV, activates endothelium to induce macrophage binding and exit from BV at the site of infection
what is the chemoattractant for monocytes and where does it come from?
CCL2 made from Th1 cells
how does escaping epithelial defences help -bacteria avoid immune response?
interfere with physical barrier - degrade mucus
attachment and colonization
evasion of immune recognition (antigenic variation and LPS)
how do bacteria escape from phagocytes and innate immunity?
capsules, Ig binding, opsonization, complement
interfere with phagocytosis and phagocyte recruitment (degrades chemokine)
how do bacteria evade adaptive immunity?
resistance to bacteria
interfere with cytokine secretion, Ag presentation
what is the characteristic pathological feature tb?
tb cavity formed when caseated and liquefied centre of tubercular pulmonary lesion is discharged into a bronchus
how is dx of tb made?
chest x ray
sputum is stained with stain for acid and alcohol fast bacilli
immune based tests (mantoux test)
prevalence of lynch syndrome?
1:660 - 1:2000
prevalence of hereditary breast and ovarian cancer?
1:1600
prevalence of familial adenomatous polyposis?
1:8000
prevalence of cowed syndrome?
1: 20 000
very rare
prevalence of li-fraumeni syndrome?
very rare
prevalence of von-hippel lindau syndrome?
1: 36 000
difference between septic shock and toxic shock syndrome?
septic shock = mediated by macrophages and endotoxin (LPS)
toxic shock syndrome = mediated by T cell cytokines and endotoxin (staph aureus)
What is the consequence of the immune suppression seen in severe sepsis?
The cytokine storm seen in sepsis can cause activation-induced cell death (T cells, dendritic cells, etc.) and suppression of antigen presentation leading to the loss of adaptive immune responses. Immunosuppressed patients are then at increased risk of opportunistic infection. Anti-inflammatory cytokines (e.g. IL-10) released to allow return to homeostasis also impair APC/T cell function.
Immunosuppression in severe sepsis predisposes patients to secondary infection that can delay recovery of organ function following the initial pro-inflammatory response. It also has important implications in the care of the elderly septic patients, as elderly patients exhibit increased susceptibility to both infection and septic shock.
septic shock?
Septic shock: sepsis is the presence of an infection in the bloodstream that results in the excessive release of TNF-alpha from macrophages throughout the body. The systemic release of TNF-alpha into the blood causes vasodilation and increased vascular permeability, this, in turn, leads to loss of plasma volume and eventual shock, also known as septic shock. This damage to capillary endothelium and vessel wall vasodilation which may also lead to multiple organ failure due to ischaemia.
how does neisseria meningitides evade immune response?
polysaccharide capsule
changes surface proteins (evade adaptive immunity)
This pathogen also produces IgA1 proteases which serve as a virulence factor by overriding mucosal immunity
how does meningococcal present? (Nm)
septecemia and meningitis
what class of bacteria is TB?
classified as acid fast bacteria due to their impermeability by certain dyes and stains.
how does Tb spread?
M. tuberculosis primarily infects alveolar macrophages but can infect other cell types. It then transits to lung parenchyma where it can infect resident macrophages or other phagocytes like neutrophils. Have the ability to replicate inside macrophages. Immune signals produced by infected macrophages provide additional target for infection. Bacteria can also be taken up by DCs to circulate to thoracic lymph node, where they activate T cells. These T cells return to the infectious site and organise around infected macrophages to form granulomas, which serves as a reservoir for bacteria.
Anti-TB drug resistance is a major public health problem that threatens TB care and control worldwide. Why has TB drug resistance emerged?
Spontaneous gene mutations in TB render the bacteria resistant to anti-TB drugs thereby increasing their chance of survival and consequent transmission to other people when not adequately treated. Because the standard treatment for TB calls for a strict six-month drug regime, compliance with the treatment is very often very challenging and rates of non-compliance or premature treatment interruption can be high, allowing for the development of drug-resistant bacteria that can then be transmitted to other people.
