week 1 Flashcards
Describe the main features of natural killer cells
Recognise stressed or infected cells
express cytotoxic enzymes
produce IFN-Y
10% of lymphocytes
collaborate with macrophages (via IL-12) to enhance killing ability.
Explain the mechanisms underlying target cell recognition by natural killer cells
have inhibitory and activating receptors.
stimulation of inhibitory by ligands on healthy cells causes cascade and blocks activating receptors
if no inhibit, or recognition of foreign then the activating cascade is greater causing degranulation.
MHC1 can present the protein but downregulated in virus or cancer.
Describe the main molecules and steps involved in target cell killing by natural killer cells
Cytoplasmic tails of inhibitory receptors contain ITIM motif
* ITIMs engage molecules (phosphatases) that block the
signalling pathways triggered by activating receptors
* Activating receptors contain ITAM motif
* ITAMs engage protein tyrosine kinase-mediated signalling
events (→ promote target cell killing and cytokine secretion
by NK cells)
* ITAMs are often located not in activating receptors but in
cytosolic portion of adaptor molecules (e.g. DAP 12)
Perforin: forms pores → delivery of granzymes
Granzymes A, B, C: initiate apoptosis (B- mitochondrial)
→ prevents killing of neighbouring healthy cells
Delivered at the site of contact between NK cell & target
Give some examples of lymphocytes with limited antigen recognition capacity
Combine features of T/B lymphocytes and innate cells
γδ (gamma/delta) T cells
NK-T cells
Marginal zone B cells
Mucosa-Associated Invariant T (MAIT) cells
B-1 B cells
Describe defects in various components of the innate immune response and explain the mechanisms by which they cause disease
Quantitative (dec number)
- Qualitative (dec function)
Chronic granulomatous disease
mutation in NADPH component
defect in oxidative burst
Chediak-Higashi syndrome- rare + genetic
defective phagosome-lysosome fusion
Defective neutrophil chemotaxis Defect in B2-chain integrins (LFA-1, Mac-1)
Deficiencies in complement proteins:C3 deficiency → frequent serious infections with pyogenic bacteria (e.g. Staphylococcus aureus, etc.)
C2, C4, C1q deficiency → SLE-like syndrome
outline the clinical utility of H1 and H2 receptor antagonists and their major side effects
H1 antagonists- treat acute inflammation
1st gen (meptramine, promethazine, diphenhydramine) - sedatives/ motion sickness
2&3 Gen- Fexofenadine = active, non-toxic metabolite of terfenadine (can cause arrhythmia)
H2 antagonists- cimetadine, ranitidine- dec gastric acid production- can cause gynocomastia, confusion, dizziness, diarrhoea
Describe the role of histamine in inflammation
Histamine - A local hormone (amino acid based)
released from mast cells, basophils, nrueons, histaminergic cells in gut.
dec TPR, inc permeability of post capillary venules. H2 inc HR.
pain (H1)
Lewis triple response- Red-Flare-wheal
Define the terms prostanoid, leukotriene and eicosanoid
Prostanoids are lipid mediators that regulate the inflammatory response
Leukotrienes are a family of eicosanoid inflammatory mediators produced in leukocytes by the oxidation of arachidonic acid
Eicosanoid- family of molecules derived from polyunsaturated fats- arachidonic acid.
Describe the major enzymatic pathways leading to the formation of prostaglandins and leukotrienes, with special reference to areas where drug therapy can be applied
Cyclooxygenases (COX) convert AA to Prostanoids
COX 1 constitutionally active.
COX 2 needs activation (IL-1, TNFA) COX2 inhibitors prevent this.
Aspirin prevents Thromboaxane prod
Outline the main effects of eicosanoids with special reference to their roles in inflammation, haemostasis and gastric cytoprotection
Present an overview of the development of innate and adaptive immune cells
Lymphoid lineage (not pic)
common progenitor–> pro B or T/NK cells. –> NK or Pro T cells
Describe the main stages of T and B lymphocyte maturation and selection
Immature T cells enter thymus- tested to recognise MHC1/2 and small response to self antibodies
B Cells remain in the bone marrow, again tested for small but not overwhelming self antigen response.
Understand the concept of self/immunological tolerance
If too much reaction to own antibodies- will cause autoimmune disease.
If no reaction at all then cell will die due to lack of signals.
Describe the main mechanisms of central tolerance induction in T and B lymphocytes
If weak or no recognition then death by neglect
if significant reaction then negative selection- death by apoptosis.
antigens are presented to the developing cells by epithelial cells in the thymus/ bone marrow.
positive selection is the process of selecting T cells that recognise MHC and self antigens but not significantly.
Describe the main mechanisms of peripheral tolerance induction in T and B cells
Anergy- where there is no reaction- cell gets no signals and dies
suppression- where the response is suppressed by T reg cells
Deletion- by apoptosis (negative selection)
B cells can gene switch and alter their antibody binding site to change the level of response.
Describe the natural history of tuberculosis infection
give pathological features of tuberculosis
Ghon focus leading to a Gohn complex (when engages with lymph node).
usually infects a peripheral mid zone lung area.
caseous necrotic tissue.
waxy coat, immune system cannot destroy it- inhibits phagolysosome fusion and acidificaiton. can escape into phagocyte.
body ‘contains’ it in calcified nodule- liquefied interior builds pressure and can burst.
Demonstrate an appreciation of the global health burden of disease caused by respiratory infections
Outline and differentiate between the clinical presentations of common upper and lower respiratory tract bacterial and viral infections
many similar prodromes - cough, sore throat, fever.
Flu has sudden onset of symptoms (myalgia, fever)
croup- barking cough, insp stridor, significant distress.
acute epiglotitis- short illness- drooling, stridor, fever, wont lie down, silent chest.
List organisms that commonly cause: community acquired pneumonia, croup, epiglottis, tonsillitis, pharyngitis (sore throat)
CAP- S Pneumoniae (35-40%) H Influenzae (9%)
S aureius and legionells higher for ICU admissions.
Croup- parainfluenza virus
acute epiglotitis- Haemophiluis influenzae
tonsilitis- strep pyogenes
pharyngitis- group A strep/ viruses
Outline the principles of laboratory investigation and diagnosis of respiratory tract infections
culture bacteria
blood results
spirometry
chest x-ray
PCR test if viral, sometimes no diagnosis and treat clnically
Explain how COPD may be exacerbated by respiratory infections
chronic colonisation by Pneumococcus
Haemophilus influenzae
Moraxella catarrhalis
can exacerbate if host defences weaken temporarily.
sputum cultures only useful lab invesitigation, blood cultures useless.
Describe symptoms and signs found in people affected with pulmonary tuberculosis
The classic clinical features of pulmonary TB include chronic cough, sputum production, appetite loss, weight loss, fever, night sweats, and hemoptysis (Lawn and Zumla 2011).
Outline the investigation of a patient with suspected TB
chest x-ray to look for nodes.
3x sputum samples- deep cough, one in the morning.
Demonstrate an understanding of the mechanisms that control cell proliferation and cell death.
depends on combination of intra and extra cellular components.
controlled by checkpoints
growth can only be stimulated in G1 phase, can be stopped at checkpoints.
Relate these mechanisms to the loss of growth regulation in neoplasia.
TGF -B stimulates many inhibitor pathways
also stimulates differentiation of cells to specialise
summarise the key steps in growth
Rb- retinoblastoma a tumor suppressor protein. phosphorylated to allow cell growth
What is TP53 role in DNA repair/ checking
TP53 facilitates a pause in cell cycle to allow repairs. also impacts DNA repair enzymes.
It can also promote transcription of pro apoptotic factors, inducing cell death
Describe the biochemical and morphological differences between cells undergoing necrosis
Necrosis- whole groups of cells affected
result of injurious event or agent
reversible events proceed irreversible
results in an inflammatory response.
haphazard destruction by released lysosozomes
Demonstrate an understanding of the normal and pathological processes that result in cell death and tissue damage.
Outline the endogenous and exogenous initiators of apoptosis.
Detail the different mechanisms of apoptotic cell death. - Caspases
Caspase cascades- most produced in ineffective form. once activated go onto activate more
Describe the morphological and biochemical differences between cells undergoing apoptosis.
Detail the different mechanisms of apoptotic cell death. - cytochrome C
mitochondrial matrix protein.
BCL-2 usually blocks channels keeping it contained
If BAD proteins phosphorylated they can from dimers with BCL-2- opening channels.
OR p53 transcription inserts open channels into the membrane.
Detail the different mechanisms of apoptotic cell death. - TNF
Initially all separate.
come together to form a super killing complex
Describe testing for ABO blood group
Define myeloma and its typical symptoms and clinical presentation
B Cell malignancy derived from antiboy producing plasma cells in bone marrow
Understand the tests required to make a diagnosis of myeloma
hypercalcemia, renal failure, anemia, and bone disease
S for 60% plasma cells, Li for light chains, and M for MRI lesions
Understand the pathology of myeloma associated bone disease
increased action of osteoclasts.
decreased regulation of OPG (osteoprotegrin)
increased regulation Rank ligand
Understand the possible causes of renal failure in myeloma
hypercalcaemia from increased bone breakdown
focus on cast injury- leads to inflamatory response –> scarring and failure
Describe the microbiological investigation of a case of bacterial lobar pneumonia
Describe the mechanism of action and uses of non-steroidal anti-inflammatory drugs
Rx pain
fever
inflammation
Outline and compare the mechanisms of other anti-inflammatory agents used to treat gout, ulcerative colitis and inflammatory diseases of joints
Naproxen- COX 1 and 2 inhibitor.
Describe the major metabolic, cardiovascular, haematological, neuro- and immunological effects of endogenous and synthetic glucocorticoids
Breakdown of protein and fats. Decreased utility of glucose and promotes gluconeogenesis.
CVS: HTN, decreased vasodilation, permeability
CNS: mood changes
Outline the major therapeutic uses of glucocorticoids
Describe the mechanisms of action of steroids, with reference to changes in gene regulation
steroid receptor complexes prevent transcription - stops inflam mediators being produced.
induction of IkBa (inhibitor of NF-κB) which causes NF
-κB repression
describe mechanism of IkBa action and its inflammatory effects
NF-kB is a transcription factor
inhibition of this causes reduction of inflammaroty mediations being created.
it is triggered by TNF-a IL-1b
