mcd cram Flashcards
type one interferons
polypeptides
induce antimicrobial state locally
modulate immune responses by promoting antigen presentation but antiinflammatory
activate adaptive
alpha (all cells first induced by irf 3)
plasmacytoid cells produce alpha and irf 7
ifnar is receptor
plasmacytoid cells
produce ifn alpha and express irf 7
irf genes
interferon regulatory factor
type two and three interferon
gamma and lambda
two is t cells and nk ifngr
three is il28r il10beta
resp tract and liver infection
stimulation of ifn production
pamps such as drna for viruses activate prrs - tlrs rlrs nlrs
prrs interferons
rlrs - beta
tlrs alpha
nlrs
how are viruses detected in cell
cGAS = enzyme detects dsDNA in cytoplasm
causes cGAMP production
passes to sting on er which follows same pathway as prrs with pamps
ifn type one signalling
ifnar1 dimerises with ar2 causing jak1 and tyk2 to cross phosphorylate. STAT proteins are activated which cause inflammatory through gas, antiviral through isre and inflammatory repressor through gas
hundreds of antiviral mediators released like pkr mx ifitm3
interferon response
ifitm3 stops virus entering through endosomes
mx1/2 are gtpases that wrap form multimers and wrap around nucelocapsids of viruses
ifitm3
stops virus entering through endosomes by stopping escape so broken down by acidic endosome
mx1
mx2
GTPases that form multimers that wrap around the nucleocapsids of viruses
duration of ifn response?
few hours, can’t last due to negative regulation mediated by suppressor of cytokine signalling SOCS which turns the genes off.
What is viral ifn evasion mediated by
HIBIBAR Hide pamps Interfere with host gene expression Block IFN induction cascades Inhibit ifn signalling directly Block ifn induced antiviral enzymes Activate SOCS Replicate in a manner insensitive to IFN
How does hep c evade ifn
NS3/4 Protease production cleaves MAVS which is the protein on the mitochondria that is activated by RLRs hence ifn beta cant be produced
how does flu evade ifn
NS1 protein binds to rig/trim/rna complex preventing ifn signalling activation
how does pox and herpes evade ifn
pox genome is hugely anti-ifn. soluble cytokine receptors produced that incapacitate immune mediators.
how does ebola evade ifn
VP35, 24, 30
Respectively blcok rig 1 complexes and rnai expression
block rnai expression
block ifn signalling.
Consequences of viral evasion
both the virus and immune system damage the body
hence can be pathalogical or immunopathological.
more ifn is needed for more severe responses like fever than for localised responses like mx induction
cytokine storm if too much ifn is made, worse in healthier people as better at making ifn
uses of viral evasion tactics
live attenuated viruses - can be made if u put viruses that cant control ifn in cells that cant make ifn. lots of replication
anti-virals, ifn used as treatment but with se’s
ifn lambda stimulates antiviral state but not inflammatory or immune response so good for treating flu.
cancercells dficient inifn can be attacked by viruses whilst normal cells produce ifn so they dot get hurt.
staph aureus
gram +ve most common skin infeciton causes scalded skin toxic shock food poisioning necrotising soft tissue infections treat with antibiotics no vaccine
treponema pallidum
syphilis
painless ulcers to rash lymphadenopathy to asymptomatic to lesions on skin bone vascular neuro manifestations
can be vertically transmitted
no vaccine antibiotics
Herpes
simplex 1&2
dna viruses
painful rash, eczema, herpeticum, encephalitis
no vaccine, antivirals
Varicella Zoster
pox, human herpes virus again
fever malaise rash becomes latent after two weeks still there can cause shingles
herpes zoster shingles painful rash
vaccine and antiviral
Trichophytum
superficial fungal infections dermatophyte, affects keratin areas name is tinea and body part yeasts as well like candida scaly rash crumbly nails antifungals like terbinafine
scabies
sarcoptes scabei ite burrows lays eggs faeces delayed type reaction type four eczematous rash can cause secondary bacterial infection topical systemic insecticides
viral evasion of immune response
mhc 1
internal viral proteins dont vary much so good targets.
includes - evading loading to tap
modulation of tapasin function and prevention of loading to mhc
interfering with mhc presentation at cell surface.
viral methods evading mhc
loading to tap
EBV - ebna1 cant be processed by proteasome
HSV icp47 blocks peptide access to tap
CMV US6 stops atp binding to tap and translocation
modulation of tapasin function and prevention of mhc transport
CMV US3 binds to tapasin and prevents peptide loading to mhc
Adenovirus E3-19k prevents recruitment of TAP to tapasin and retains the MHC in ER
interfering with mhc presentation at cell surface
KSHV kK3 protein induces polyubiquitinylation and internalisation of MHC then endosome to lysosome
how does ebv evade mhc
ebna1 cant be processed by proteasome, only processed peptides get put on mhc 1
How does hsv evade mhc
icp47 blocks peptide access to tap
how does cmv evade mhc
US6 stops atp binding to tap and translocation
and
US3 binds to tapasin and prevents peptide loading to mhc
how does adenovirus evade mhc
E3-19k prevents recruitment of TAP to tapasin and retains the MHC in ER
how does KSHV evade mhc
kK3 protein induces polyubiquitinylation and internalisation of MHC then endosome to lysosome
how do viruses evade nk cells
if in cell that doesnt show mhc class one it will be killed encode mhc class one analgoue to prevent this like cmv or upregulate mhc
cmv in the clinic
most infected, only issue in immunocmpromised like during transfusions, needs elimination before procedure
produces protein ul138 that removes mrp1 (removes toxins from cells). treat with toxic drugs to stop this.
antigenic variation methods
drift is mutating to have different antigens
shift is new subtypes from animals
different serotypes are all stable and cocirculate. Polio, dengue, rhinovirus.
can be consequence of vaccine
how does hiv resist abs
gp120 large gaps between spikes so no cross linking of ab glycosylation masks ab epitopes poorly accessible important bits of ag BNABS can control load
dengue
leakage of plasma from capillaries
high haematocrit and rbc count decreased protein count
bleeding and bruising
treat with iv.
dengue ag variation
four serotypes
abs from last response bind dont neutralise so haemorrhagic fever and could lead to shock.
monocytes bound could be used for replication by virus.
evasion of ab response
glycoprotein antigen ab cant access
can make them look like apoptotic bodies so uptaken and hidden
viral filaments mean glps inaccessible in packets
why is measles vaccine important
infection erases immuno memory so raises morbidity and mortality of other diseases.
main bacterial virulence factors
flagella movement attachment pill adherence capsule protect against phagocytes endospores are metabolically dormant biofilms aggregates embedded in polysaccharide so antibiotic resistant
endotoxins exotoxins
exo damage bio systems neurotoxins enterotoxins pyrogenic exotoxins stimulate cytokine release tissue invasive allow bacteria to tunnel can be other
endo lipids gram -ve released steadily so sudden antibiotic and cell death can release loads leading to septic shock
outbreaks
lots of cases short time
need to isolate strain with pcr, surveillance, reporting system
eu communicable resp
Legionnaire amoeba in lakes inhalation type iv secretion tb, extra lipid layer can be dormant treatment good
eu communicable sti
chlamydia trachomatis
neisseria gonorrhoeae
pili antigen variation
eu food waterborne
campylobacteriosis gi uncooke dpultry adhesion, invasion, flagella etc
salmonella tthree secretion
cholera
listeriosis
eu vector borne
plague yersina pestis
q fever coxiella burnetti
smallpox
eu vaccine preventable
clostridium diptheriae haemophilus influenze neisseria meningitides streptococcus pneumnie bordetella pertussis clostridium tetani
hospital acquire
nosocomial
escape
nosocomial causes
catheters intubation chemo prosthetics lines prophylactic antibiotics inappropriate prescribing
dissemination carriers
concentration is density of people
escape
resistant Enterococcus faecium + vancomycin Staoh aureus mrsa + Clostridium difficile + Acinobacter baumanii - Pseudomonas aeruginosa - mdr Enterobacteriacae - mdr
pathogenic e coli
common gram -ve bacteraemia utis
cephalosporin and carbapenem resistance
others nosocmial
klebsiella pneumoniae
pseudomonias aeruginosa
mrsa
clinical significance of nosocomial infection and reistance
morbidity cost clinicians need to use old more toxic drugs to treat
immunity to fungi
phagocytes then nk which give ifn gamma then dendritic which cause t cells to differentiate then th1/17
fungal virulence
candida spores dimorphism so allows for tissue invasion
Cryptococcus capsule evades phagocytosis
aspergillus conidia inhaled invades as hyphae
what required for innate immunity to fungal infection?
Flies is a prr needed
human deficiencies leading to fungal infection
dectin 1, deficiency leads to mucocutaneous infection as impaired macrophage il6 production and binding in response.
card 9 causes chronic mucocutaneous candidiasis
card9 needed for tnf alpha responding to beta glucan and t cell th17 differentiation
tlr4 polymorphism lead to risk of aspergillosis in transplant.
plasminogen mutation
defence against fungus
neutrophils important
throw nets of chromatin to capture spores act as danger molecules to recruit effector cells
fungal morphogenesis can transition between hyphae yeast candida to modulate dendritic cell response confuses immune response
innate - mucosal immunity
treatment - adoptive immunotherapy make lots of fungal t cells in a sample and give to patients needing to fight infection
gene therapy like restoring genes that fight fungal spores. can be ifn gamma
fungal allergy
inhalation and exaggerated response. aspergillus main one can activate all types one - ig e leukotriens histamine minutes two - igg igm complement three- igg igm complement one day four - t cells lymphokines few days
ABPA
allergic bronchopulmonary aspergillosis
need predisposing condition like asthma CF
high serum ige, t-one hypersensitivity skin test, aspergillus specific ige
may also have eosinophilia igg ab and radiologic abnormalities
corticosteroids
itraconazole
omalizumab ige antibodies
endo vs ectoparasite
endo in body ecto on surface
List Endoparasite examples
Protozoa:
Ameobae, gi tract, cysts invade enter gi parasites released cause ulcers in epithelial cells. spread via veins. microscopy of cysts
Coccidia, like malaria, fever, headache, emesis, chills, anaemia, diarrhoea, toxoplasmosis
Flagellates, diarrhoea giardiasis, trichomonas std normal std symptoms.
Ciliates, balantidum coli, other domestic mamals and primates, immunocompromised vomit dysentry
Metazoa:
roundworms, ascaris, asymptomatic, abdo pain, intestine obstruction, peumonia.
flatworms, taenia [tapeworm), asymptomatic
flukes [ schistosoma, rash fever chills myalgia.
ectoparasite
scabies burrows itchy
lice, lice itchy
blood cell time and function
platelet, ten days rbc one twenty days neutrophil, seven ten hours eosinophil less than neutrophil parasites macrophage monocyte few days phagocyte become macrophage in tissue store and release iron basophil allergy lymphocyte
spherocyte
hereditary spherocytosis
less membrane same cytoplasm
irregularly contracted
hyperchromic, no central pallor, weird shape due to oxidant damage to membrane and hb
polychromasia
blue tint as young.
methylene blue is reticulocyte stain.
target cells
accumulation of hb in central pallor
obstructive jaundice liver disease haemglobinopathies and hyposplenism
elliptocytes
elliptic hereditary eliptocytosis iron deficiency
fragments/shistocytes
abnormal stress or abnormal cell
rouleaux
stacks alterations in plasma proteina
agglutinates
clumps abs on rbc surface
howel-jolly
nuclear remnant due to lack of splenic function
left shift
increase in non-segmented neutrophils or neutrophil precursors
toxic granulation
infection inflammation tissue necrosis normal in pregnancy
hypersegmented neutrophils
btewlve folate deficiency
how to interpret bloods
leucocytosis penia why
anaemia mcv history blood count
thrombocytosis/penia history count clues
polycythaemia
high rbc hb hct
splenomegaly abdo mass cyanosis
causes: pseudo is burns
proper is blood doping physiological abnormal bone marrow high erythropoeitin
anaemia mechanisms
reduced roduction, haem iron deficiency, globin thallassaemia
loss of blood
reduced rbc survival
rbc pooling in spleen splenomegaly.
Microcytic
low mcv
iron deficiency chronic disease issue with haem
thalassaemia issue with globin
normocytic
blood loss
rbc production failure
pooling, hypersplenism portal cirrhosis
macrocytic
megaloblastic iron folate deficiency dna synthesis interfering drugs liver disease alcohol major blood loss no iron stores lots of reticulocytes haemolytic anaemia lyses in blood
haemolytic anaemia
short survival
intrinsic = abnormality of rbcs
extrinsic = factors acting on rbcs
inherited = abnormalities in membrane hb rbc enzymes
acquired = microorganisms drugs chemicals
intravascular = acute damage
extravascular = defective rbcs removed by spleen
suspect when unexplainable normochromic normo/macrocytic
morphologically abnormal cells, more rbc breakdown, bone marrow activity increased. irreg conract, hereditary ellipticytosis
poikilocytosis sickle cells gall stones jaundice polychromic anaemia
hereditary spherocytosis
inherited membrane defect. less flexible = spleen removal quickly = extravascular
more ploychromasia in response reticulocytosis = more bilirubin jaundice gall stones. splenectomy
g6p dehydrogenase deficiency
protects rbcs from oxidant damage. severe intravascular haemolyis after infection or exposure to oxidant/
heinz bodies are irreg contracted denatured hb removed by spleen.
autoimmune haemolytic
autoab at rbcs. splenic macrophage removes some membrane so spherocytosis. steroids splenectomy.
ida vs acd
acd: no clear sign, no bone marrow infiltration, deficiency, bleeding
high crp, high eryhtrocyte sedimentation rate, high ferritin factor viii, fibrinogen
chronic infections inflammation and malignancy
due to tnf alpha interleukin release. stop iron flow to rbcs stop flow out of cells by epo. increase ferritin production more rbc death.
fe deficiency: bleeding,
ida: high transferrin low trans sat, low ferritin
acd: normal trans sat high trans low serum fe high ferritin.
iron transport
ferroportin iron cell to blood
hepicidin inhibits ferroportin
transferrin holds fe in plasma
transferrin and iron taken in as a whole. ferritin shell around fe in cell
Thal vs acd vs fe def
Thal: hb low mcv low serum fe normal ferritin normal trans normal trans sat normal
acd: hb low mcv low serum fe low ferritin high normal trans normal sats
fe def: hb low mcv low serum fe low ferritin low trans high trans sat high
b 12 folate deficiency
needed for dna synthesis and immune integrity in al rapidly dividing cells
macrocytic cells megaloblastic anaemia. has nucleus in pink rbc. anisocytosis large rbcs hypersegmented neutrophils giant metamyelocytes.
fe folate tests thyroid function reticulocyte count blood film
folate cases - alcoholics eczema poor diet, spina bifida
b12 cases - motor neuron signs, poor diet absorption infection needs intrinsic factor - low intrinsic factor = pernicious anaemia.
haemostasis issues
vessel constriction
platelet adhesion/aggregation
plug formation
platelet adhesion aggregation
endothelial cells make pgl2 platelets make txa2. prostacyclin synthetase thomboxane synthetase respectively.
txa2/endoperoxidases induce pgg2 pgh2
lab test = platelt count bleeding time platelet aggregation.
haemostasis lab tests
platelet count
bleeding time
platelet aggregation
aptt activated partial thromboplastin time - initiates coagulatiion through F12 to detect intrinsic/common abnormalities.
pt - prothrombin time, uses tissue factor to initiate coagulation for extrinsic and common
tct - thrombin clotting time
abnormalities in fibrinogen to fibrin.
APTT PT for bleeding disorders
APTT for heparin monitoring in thrombosis
PT for warfarin monitoring in thrombosis.
Fibrinolysis
No reaction between plasminogen and tpa, with fibrin plasmin is created to degrade fibrin.
antithrombin and protein c are anticoagulants.
Primary haemostasis
issue with VWF collagen or platelet.
low platelet = thrombocytopenia due to bone marrow failure, accelerated clearance, pooling in splenomegaly.
impaired function due to hereditary absence of glycoproteins or acquired from drugs.
itp, immune thrombocytopenia anti platelet antibodies splenic macrophages.
other thrombocytopenia due to failure of platelet production, shortened half lives increased pooling.
VWF disease prevents binding to collagen and stabilising factor eight.
Collagen issue
teste: menorrhagia, easy brusing, prolonged immediate bleeding. gum bleeding.
PETECHAE BRUSING
vwf assay?
secondary haemostasis
crosslinked fibrin - no thrmbin burst, VIII issue. Thrombin converts fibrinogen to fibrin. Larger vessels no plugging as no cross linking of fibrin.
factor deficiency usually viii haemarthrosis hallmark.
liver disease transfusion anticoagulants
disseminated intravascular coagulation
bleeding = no bleeding superficially, bruising deep bleeding, restarts a lot, delayed but prolonged.
Test PT APTT FBC factor assays NORMAL PT AND TT WEIRD APTT IN HAEMOPHILIA
thallasaemia
beta - autosomal recessive bo b+.
microcytic more rbcs target cells poikilocytosis
transfusion
scarce only from humans aob and d+ d- ab+ can take all oo- can give to all. igm is ab that reacts. delayed haemolytic reaction is d- given d+ then d+ again as antibodies made.
blood components in transfusion
red cells five weeks four degrees
fresh frozen plasma two years minus thirty. no x matching need blood group.
ffp for reversal of warfarin bleeding and abnormal coagulation pt aptt
cryoprecipitate has fibrinogen and fviii so for massive bleeding and hypofibrinogenaemia sotred at minus thirty for two years
platelets stored 22 degrees for five days constantly agitated. bone marrow failure massive bleeding surgery cardiac bypass
fractioned products fviii fix for haemophilia and fviii for vWD.
ig to treat specific illnesses. im for tetanus anti d rabies IV IG for itp or AIHA
Albumin for burns severe liver kidney conditions.
sickle cell
codon six glutamic acid swapped for valine os less charged. insoluble chain. polymerises forming tactoids forming sickle structure.
Sickling stages = rigid adherent dehydrated
haemolysis anaemia gallstones aplastic crisis
blocks microvascular = infarction. pain
lungs pulmonary hypertension correlating wtih severity of haemolysis.
urinary tract haematuria renal failure
stroke cognitive impariment.
give folate penicilin vaccination analgesic
low hb reticulocytes sickles boats targets howel jolly bodies.
diagnose with solubility test
abnormal white cell count
cell development from HPScells
RBC - EPO
Lymphoid - IL2
Myeloid G-CSF M-CSF
eosinophilia, infection.inflammation.cancer
malignant haematopoises
immature cells = leukaemia
both = chronic leukaemia if neutrphils and myelocytes
acute = low hb platelets
neutrophilia, infection stress Adrenaline corticosteroids neoplasia malignancy. viruses dont usually cause this
eosinophilia, parasitic allergic reactionm neoplasm hodgkins. hypereosinophilic syndrome
monocytosis tb sarcoidosis cml
lymphocytisis mature, reactive or primary disorder, immature is primary disorder. secondary = polyclonal response to infection.
primary=monoclonal
mononucleosis, young looking lymphocyte with rbc dump. glandular fever. in elderley is usually CLL. POLYCLONAL KAPPA LAMBDA IS INFECTION, MONOCLONAL CANCER.
test with southern blot analysis [monoclonal or polyclonal]
chem PATH
red -no anticoagulant LFT
yelow- speed clotting, TFT LFT, U&E
grey- poison for glucose testing fluroide oxalate
purple-K EDTA tops clotting HbA1c
lots of liver enzymes like alkaline phosphatase in tissue damage.
Virology LAb
cell culture, electron microscopy pcr ab detection ag detection serotyping quantification genome sequencing
for resp, throat swab, broncheoalveolar lavage, sputum, Endotracheal tube.
serology, test for specific antigens, IGM IS RECENT INFECTION IGG IS LATER
hiv serology = antibody and p24 ag.
antibody avidity tests igM
immunofluorescence for viralantigens
cns disease, stool throat blood
bacteriology
culture, serology, molecular, antimicrobial susceptibility
+ve skin soft tissue
-ve UT GI
staph a form clumps. coagulase test.
strep = chains.
diarrhoea - stool, salmonella shigella e coli c difficile cholera campylobacter.
mic minimum inhibitory conc. minimum ab to stop bacterial growth.
Histopathology cytopathology
biopsies
resectionspecimens
frozen sections
post mortems
smears
antibodies diagnostics
wash with enzyme
fluor probes
magnetic beads
drugs
indirect labelling, anti antibody by patient or artificially
produce antibodies by:
monoclonal with b cell and immortal myeloma cell
recombinant dna = isolate ab segment, display on protein, use library to screen for antigen.
used as prophylactic anti cancer t cell removal
blockcytokine
ELISA is enzyme linked immuno sorbent assay
anti a binds to enzyme reporter and turns colourless subsrate coloured.
paraneoplastic cerebellar degeneration
in cancer tumour produces antigens that can be found elsewehere g breast cancer cdr2 found on cerebellum so ataxia vertigo unintelligible speech.
immune surveillance of cancer
cancer cells produce antigens immune response can respond to it.
evidence is immunosuppression leads to increased risk of malignancy
controlled colonies of cancer cells
transfer of immunity between patients
men more at risk as women have better immune system
Cancer immunity cycle
cancer cells release antigens and apcs take them up. present to t cells in lymph nodes, which migrate to tumours, infiltrate and kill it.
factors affecting immune response to tumours
local inflammation not caused by small tumours often. no costimulation = anergy
only subtle differences between tumour antigens and self ones so hard to distinguish.
cancer immunotherapy
teach immune system to react to cancer in absence of inflammation, costimulation and recognition of antigen.
what are cancer immune responses similar to
viral response. tumour antigens are cytosilic so t cells detect via mhc class one
viruses can cause cancer. can be opportunistic due to immunosuppression, like ebv+ lymphoma/HHV8+ sarcoa in HIV
HPV e6/e7 oncoproteins so we can target these with a vaccine.
tumour specific antigens
tumour associated antigens
tumour specific antigens - viral proteins that cause cancers or mutated cellular proteins
tumour associated antigens - normal proteins aberrantly expressed. for response, tolerance must be overcome like in autoimmune.
tumour associated antigens
HER2, breast
MUC1,
CEA, normal in foetus,
prostate antigens
immunotherapy vs cancers
intolerant to self t cells can be used if they target tumour associated antigens.
tyrosinase is a common one. involved in skin pigmentation. used for melanoma treatment leads to loss of pigmentation.
issues include autoimmune responses and tolerance due to lack of inflammation.
types of cancer immunotherapy
antibody based monoclonal - anti-her2 direct antibody, conjugated antibody with radioactive particle, bispecific to target two things at once.
therapeutic vaccination, provenge for prostate, wbcs treated with protei to stimulate dendritic cell response.
checkpoint blockade- removes t cell inhibition to enhance existing response against tumour
adoptive transfer of cells is removal of tumour by surgery, extract tumour infiltrating lymphocytes and reinfuse. can also induce chimeric antigen receptors to create a new pathway for t cells to kill tumour cells.
inflammatory dermatoses
eczema - can be atopic due to defective barrier of skin allowinf irritant entry. can be seborrhoeic overgrowth of malassezia
psoriasis - t cells move into dermis release cytokines causing epidermis to thicken and neutrophils to infiltrate.
acne, common, due to hyperkeritanisation, loads of dead keritanocytes in folliclem proliferation of acne bacteria and ruture leading to inflammation.
bullous pemphigoid - autoimmune igg against basement membrane leading to skin cleavage and ulcers.
pemphigus vulgaris like bullous due to loss of cell-cell adhesions
hypersensitivity
type 1, IGE, asthma, allergies, sensitisation on first exposure, degranulation on second. inflammation
type 2, antibody dependent, organ specific AI like graves. AI cytopenias. insoluble antibod.
type3 - immune complex, soluble antigen binds to antibody and deposits in tissues causing clotting and damage. SLE
type iv, delayed type, t cell, graft rejection, coeliac, asthma eczema too. TH1,2 and cytotoxic. Lots of antigen leads to t cell activation of macrophages and tnf-a damage.
Allergy
type i
atopy is hereditary
atopic airway
apc presents to t cell
needs sensitisation. apc to t cell th1/2 treg
subsequently eosinophil degranulation and ige plasma cell production
asthma
ti tiv narrowing airway by type i short acting b2 agonist inhaled steroids long acting oral steroids and for attack.
transplantation
store organs for short periods of time cooled and perfused cornea is 96 hours exception.
immunology - abo and hla important
mismatch can be good if remove abs from plasma
HLA, test mismatches for 2x HLA A, 2x HLA B, 2x HLA DR
rejection, t cell or antibody mediated.
t cell, lymphocytes recruited, rupture BM causing local damage.
AB - vs hla and abo
treat with immunosuppressives like anti cd3 and anti b cells.
regime of transplantation medication
pre, induction agent to deplete t cells
after, steroids, signal transuuction blockers, anti-proliferative agents.
tolerance
central - t cell selection
peripheral, anergy, ignorance, suppression by tregs, needed for antigens not expressed in thymus.
autoimmunity breaks tolerance,
infection can cause this
acquired antigen specific active in neonates.
autoimmune diseases
tii goodpastures graves
tiii sle
tiv diabetes
rheumatoid arthritis multiple sclerosis
cancer terms
neoplasia new autonomous abnormal growth unresponsive to control mechanisms
dysplasia abnormal growth features of malignancy
metaplasia reversible cell type change like garrets oesophagus
cell cycle control
checkpoints, metaphase checkpoint makes sure chromosomes are aligned at plate, kinetochore produces cenp e and bub when not attached to microtubule.
g1 check ready to make dna
before M check dna has been replicated correctly
exit G0
EGF bind to RPTK, cross phosphorylation of tyrosine residues as it’s a heterodimer. grb2 binds to these attached to SOS. ras on membrane, sos brought closer so exchanges gdp for gtp, activating ras, causing kinase cascade.
ERK
causes transcription of c-myc
sh3 and sh2
ras mutation v12 and l61
raf mek erk
final kinase activate c-myc transcription factor.s
cyclins and shit
cell cycle control
cdks always present. need cyclin removal of inhib and addition of excit.
c-myc -> cyclin D -> cyclinD-Cdk4/6 -> cyclin E production which activates cell cycle.
CDK2/Cyclin E phosphorylate Rb which releases E2F which promotes transcription. e2f goes for last three cyclins at different concs.
ink4 and CIP/KIP also inhibit cdks.
cyclin b cdk 1 need removal of wee1 inhib and addiditon of cdc25 excitatory phosphate
systemic chemo
alkylating, add alkyl to guanine cross linking strands to prevent uncoiling, chlorambucil
antimetabolites, purine analogues/folate antagonists methotrexate
anthracyclines, inhibit transcription and replication by intercalating nucleotides within the dna/rna strand. doxorubicin
vinca alkaloids taxanes, microtubules
topoisomerase inhibitors, prevent cupercoiling. induce permanent breaks in backbone, topotecan
targeted chemo
monoclonal antibodies, target overexpression of receptor protein tyrosine kinases. bevacizumab targets vegf
small molecule inhibitors bind to kinase domain of rptks to prevent downstream signalling
eg. glivec for CML
lots of resistance
hallmarks of cancer cells
SPINAP DIE U Self-sufficient Pro invasive Insensitive to anti growth signals Non-senescent Anti-apoptotic Pro-angiogenic
Dysregulated metabolism
Inflammation
Evade immune response
Unstable dna
proliferation
anchorage dependency, needed for proliferation. CELL-ECM by integrins. heterodimers of a/b associate at head region. Form focal adhesions or hemi-desmosomes. Used for signalling. Outside-in, type of ECM difference in force and ecm stiffness leads to different type of cell proliferation.
Integrin+GF = strong signal to activate MAPK pathway, weak on their own.
inside-out, eg clotting, internal pathways increase affinity out head to molecules.
Controlled by density dependence , contact inhibition of locomotion
density = competition for growth factors.
contact inhibition of locomotion., non-epithelial.
stable junctions - calcium dependent cadherins inhibit proliferation. cadherin bound to beta catenin when cell-cell junctions present. if not beta catenin binds to lef1 which is a tf.
cell motility and invasion
filopodia, parallel actin, cdc42
lamellopodia, branched and cross linked actin, rac
1) nucleation, actin needs to attach to inner membrane. ARP proteins form a complex actin joins it. rate limiter
2) filament elongates, profilin increases polymerisation, thymosin reduces it.
3) capping and severing, add cap like capz to limit elongation. Sever via gelsolin to speed up growth/shrinkage
crosslinking via fimbrin alpha actinin etc.
branching and stuff allows for different angles of projections for different functions, arp complex
at the back rho regulate stress fibre formation which severs old attachments alongside contractile movements.
regulated via cytoskeleton signalling pathways
apoptosis
CASPASES
effector and initiator
initiator includes 2,9,8,10, have death domains like ded, have card for targeting
initiator just p20 and p10.
intrinsic - apoptosome formation from cell stress, loss of mitochondria potential, cyt c release, etc.
wheel of CARD ATPase WD40, CYT C binds to WD40 allowing card to bind to procaspase 9 and cross phosphorylate, this tgen triggers it. active process
extrinsic, deatn receptor (Fas, DR4), upregulated, allowing death ligands to bind. FADD is death domain adaptor protein. binding to death receptor, procaspase recruitment. procaspase 8 and fadd form DISC which crossphosphorylates procaspase 8 to start cascade.
FLIP is domain that incorporates into trimer but has no proteolytic activity so cant activate procaspase.
BCL 2 modulate it. Anti = bcl2 bcl xl, pro = bid bad bax bak.
EGF binding to RPTK activates MAPK and also P13K which phosphorylates PIP2 to PIP3 which binds to PKB which has anti apoptotic effects - phopshorylate bad
if no gf, bad not phosphorylated by pip3 pathway so can displace bax and bak to form a mitochondrial pore releasing cyt c.
PTEN counteracts p13k signalling so promotes apoptosis
IAPS bind to procaspases to prevent activation and bind to caspases to inhibit them directly.
stages of apoptosis
1) microvilli junction loss
2) cell shirnkage
3) asymmetry lost
4) nuclear condensation
5) fragmentation of dna
6) bleb formation
7) fragmentation of cell in membrane closed bodies.
Oncogenes and tsgs
protoncogenes activated by mutation amplification translocation or insertional mutagenesis.
eg. rptks egfs ras, kinases
tsgs, p53, apc, rb
colonic benign to cancer
apc mutation hyperproliferation
k-ras adenoma
p53 carcinoma
metastasis
angiogenesis
selection of tip cell, sprout grwoth and guidance, fusion and lumen forms, perfusion maturation.
Triggers, hypoxia hypoxia inducible trranscription factor which is controlled by protein von hippel linedlaue tsg.
vegfr2 mediator of vegf causing angiogenesis
tip cell follows vegf gradient, notch signalling selects and causes nearby cells to not be tip cells.
DII4 and notch go against each other. VEGF increases dii4 which increases adjacent notch signalling causing inhibition of vegfr2.
myeloid cells recruited to guide and support. macrophages carve tunnels
barrier forms to stabilise associated with cadherins and ang i
stabilised by pericytes. and vsmcs which are mural cells.
stabilise with ang one and two inhibiting a tie receptor causing anti inflammatory.
anti vegf
therapy not too harsh as more tumour hypoxia releases more vegf signals so vasculature growth can be more eratic and dangerous. need normalised vasculature so increase efficacy of other therapies.
dna damage repair
uv causes pyrimidine dimerisation leading to cancer
p53 senses dna damage. leads to repair
mechanisms: excision, direct reversal
test for damage done by new drugs from bacteria to mammals.
colorectal
4th common2nd death
apc mutation prevents high cell turnover leading to proliferation.
types:
tubular nine/ten, columnar
villous, mucinous
tubulovillous
sessile flat stalk pedunculated
apc, kras, p53
polyps, adenoma, carcinoma.
due to microsatelitte instability
diet = need folates and mthfr both for dna synthesis. also vitamins for oxidant scavenging
grading is dukes, ABC1C2, limited to walls, beyond mucosa, nodes positive, apical nodes positive.
screening: affected relatives, gene trait, crohns uc
leukaemia
acute
chronic
myeloid
lymphoid
ACUTE LYMPHOBLASTIC
CHRONIC LYMPHOCYTIC
ACUTE MYELOID
CHRONIC MYELOID
series of mutations in one stem cell.
AML - CELLS PROLIFERATE BUT DONT MATURE NO MATURE END CELLS
CML - MORE CELLS, BOTH IMMATURE AND MATURE.
ALL - LYMPHOBLASTS AND NO MATURATION
CLL - MATURE AND ABNORMAL
all blood film, anaemia, neutropenia, thrombocytopenia,
fbc with liver and renal function
treat with replacement of other cells chemo. must be systemic.
breast cancer
all about oestrogen, recepotrs only on some luminal cells not myoepithelial cells.
in cancer oestrogen acts as growth factor.
benign is within gland
lobular has resemblance
medullary shows little resemblance
risk factors involve exposure to oestrogen so menstruation menopause pregnancy the pill
or dimerisation leads to c-myc and tgf-alpha
pre-menopause oophorectomy
post- high dose oestrogen downregulation of receptor.s
or expression is good
suppress ovaries with lhrh
tamoxifen or antagonist
aromatase inhibitors useful in post menopause as blocks main path of androgens to oestrone.
progestins
resistance to endocrine therapy
skin cancer
malignant melanoma irregular margin
basal cell carcinoma peely with dilated vessels
UVB worst one. affects pyrimidines. nucleotide excision repair effective here.
p53 mutation stop sthis.
fitzpatrick phenotype is risk white burn white sometimes tan white sometimes burn white tan asian black
melanin protective.
malignant melanoma - lentigo isnt bad, superficial spreading is bad, ABCD diagnosis, nodular malignant is bad and dark, nodular within ssmm is bad
acral lentigious is ok
amelanotic is bad
epidermodysplasia verruciformis is autosomal causes warts.
mostly surgical
hpv can cause squamous cell carcinoma.
prostate cancer
dre psa tests
heterogenous as defects on tsgs and protooncogenes.
gleason grading, two largest areas biopsied and scored then added together.
treatment: surgical
lhrh agonist
anti-androgen
need less testosterone basically.
