Haroons notes Flashcards
What is inflammation?
Acute/chronic tissue injury response
What is the difference between acute and chronic inflammation?
Acute - infections, hypersensitivity (neutrophils)
Chronic - think autoimmunity, recurrent infections (macrophages, lymphocytes)
What are neutrophils like?
‘Polymorphs’ - have many lobes (varying number)
May see Barr bodies in female neutrophils (visible silenced X chromosome - lyonisation)
What are the 5 cardinal signs of inflammation?
Rubor, dolor, calor, tumor, loss of function
Redness, pain, heat, swelling
What are the stages of inflammation?m
- Increased vessel calibre - inflamm. cytokines - bradykinin, prostacyclin, NO. Mediate vasodilation
- Fluid exudate - vessel becomes leaky - fluid is forced out of vessel
- Cellular exudate - neutrophils become abundant in this exudate
What is neutrophils action in acute inflammation?
Margination - migrate to edge of BV
Adhesion - (selectins bind neutrophil, cause rolling along BV margin)
Emigration + diapedesis (movement out of BV - through or in between endothelium)
Chemotaxis -> site of inflammation
What occurs at the site of inflammation?
(Neutrophil action)
1. Phagocytosis
2. Phagolysosome + bacterial killing
3. Macrophages clear debris
What are the outcomes of acute inflammation?
Resolution (normal)
Supporation (purforration)
Organisation (granulation tissue + fibrosis) (cardiac tissue + neurons never resolve; most become this)
Progression (excessive recurrent inflammation -> becomes chronic + fibrotic tissue)
What are granulomas?
Aggregates of epitheloid histology (essentially macrophages)
From granulomatous ‘horseshoe’ shape
Central necrosis () -> classically TB
No central necrosis -> sacrolosis, leprosy, vasculitis (GCA,GPA,EGPA), crohns
Granuloma + eosinophil + parasite
Granulomas secrete ACE -> blood marker (increase in Pxw, granulomatous disease)
What are thrombi + emboli?
Thrombosis -> mass of blood constituents (mostly platelets) forming in vessels
- Vasospasm
- Primary platelet plug - vWF binds to exposed collagen and platelets bind to this (gp1b - activation -> discoid -> pseudopoid) - watch other - gp2a/3b - aggregation
- Coagulation cascade
What influences thrombosis?
Virchows triad
Endothelial injury
Decrease in blood flow
Hypercoagulability
What are the types of thrombosis?
Arterial- atherogenesis - other conditions etc
Venous - venous stasis - etc
What are the fates of thrombi?
Resolution - degrades, normal
Organisation - leaves scar tissue behind
Embolism - fragments of thrombi break off + log in distal circulation
What are emboli?
Thrombi fragments
Can be:
- arterial - lodges in systemic circulation (from left heart)
- venous - lodges in pulmonary circulation (from right heart)
Further conditions etc
What is atherosclerosis?
Plaques forming in intima + media of high pressure vessels (arteries)
What’s in a plaque?
Lipid, smooth muscle, macrophages (+foam cells) platelets, fibroblasts
What are foam cells?
Macrophages that phagocyte LDLs
What is the formation of atherosclerosis?
- Fatty streak - precursor to plaque ~ 10 years old
- Lipid accumulation - increase in LDL, macrophages recruited to phagocyte this; foam cells
- Platelet aggregation - plaque protrudes into artery lumen, disrupts laminar flow, so platelets accumulate here. Thinning of media occurs
- Fibrin mesh + RBC trapping - platelet plug forms fibrin mesh over itself (stable 2 clot) + RBCs trapped within this
- Fibrous cap - fibroblasts form smooth muscle cap over the 2 platelet plug -> this is a stable atheroma
What occurs in unstable Atheromas?
-> in unstable atheromas (angina -> ACS); fibrous cap damaged + continuous platelet plug formation over this, lumen narrowed
What occurs in unstable Atheromas?
-> in unstable atheromas (angina -> ACS); fibrous cap damaged + continuous platelet plug formation over this, lumen narrowed
What are risk factors for atherosclerosis?
DM, hypertension, smoking, obesity, increased age, male (all RF for MI!)
What is apoptosis?
Non-inflammatory controlled cell death
Cell shrink organelles retained + csm intact. Chromatin unaltered; fragmented for easy phagocytosis.
What are the mechanisms for apoptosis?
- Intrinsic
- Bax (protein inhibited by Bcl2) acts on mitochondrial membrane to promote cytochrome C release
- activates caspases -> apoptosis - Extrinsic
- Fas-L or TNF-L binds to csm receptors which activate caspases -> apoptosis - Cytotoxic
- CD8+ binding releases granzyme B from CD8+ cell; granzyme B -> perforin -> caspases -> apoptosis
What is necrosis?
Inflammatory traumatic cell death
- cells burst, organelles splurge, csm damaged, chromatin altered - cell is fd
Coagulation (mc, due to organ ischaemia), liquefaction (brain becomes soup), caseous (TB; soft cheese!), gangrene (black due to deposited FeS from Hb)
Define hypertrophy
Cell gets bigger
Define hyperplasia
Number of cells increase in mitosis
Define atrophy
Number or size of cell decreases
Define metaplasia
Change of one cell type to another type
E.g. Barrett’s oesophagus
Define dysplasia
Change of a differentiated cell type -> poorly differentiated type - mostly indicates pre/cancerous change
Define ischemia
Decreased perfusion to tissue without infarction e.g. TIA
Define infarction
Decreased perfusion with infarction e.g. ischemic stroke
What is carcinogenesis?
Transformation of normal -> neoplastic cells through permanent mutation
What is neoplasm?
Neoplasm = autonomous, abnormal, persistent new growth
Can only arise from nucleated cells -> can’t arise from erythrocytes but can from their precursors!
What is a tumour?
Any abnormal swelling
Neoplasm + inflammation, hypertrophy, hyperplasia all included!
What are tumours classified by?
Tumours are classified by: behaviour , histogenesis
What can behaviours be?
Behaviour - benign or malignant
What are benign behaviors?
- localised (no BV invasion)
- slow growing
- well circumscribed
- exophytic (outward growth)
- rare ulceration + necrosis
- close resemblance to normal tissue
What should you still remember by benign behaviours?
BUT can still be very pathological
- hormone secreting e.g. prolactinoma
- pressure on local structures e.g. pituitary -> optic chiasm
- obstruction
- transformation -> malignant
What are malignant behaviours?
- BM invading
- v-fast mitotic growth - hyper dense nuclei (stain dark)
- poor circumscription (metastatic)
- endophytic - inward growing
- common necrosis + ulceration
- poorly differentiated (little normal tissue resemblance)
What are malignant behaviors like?
- pressure on structures
- form 2 tumours
- obstruction
- very painful (often)
- blood loss (often)
- paraneoplastic e.g. SCLC (SIADH, Cushings)
What is histogenesis?
Origin of cell tumours
What is the histogenesis of epithelium?
Epithelium (carcinoma):
- non-glandular benign = papilloma
- non-glandular malignant = carcinoma (Basal cell carcinomas never metastises)
Glandular benign = adenoma
Glandular malignant = adenocarcinoma
What is the histogenesis of connective tissue?
Connective tissue (sarcoma) - adipocytes = lipoma, lipasarcoma
Muscle striated = rhabdomyoma, rhabdomoyosarcoma
Muscle smooth = leiomyoma, leuomyosarcoma
Cartilage = chondroma, choudrosarcoma
Bone = osteoma, osteosarcoma
What is the histogenesis of lymphoid?
Leukemia, lymphoma, (always malignant)
What are some other cancers?
Others: melanoma (melanocyte malignancy)
Mesothelioma (mesothelial malignancy - typically pleural)
What are some named cancers?
Names:
- burkitt’s lymphoma (B cell malignancy caused by EBV)
- Kaposi sarcoma (vascular endothelial malignancy, HIV associated)
- Ewing sarcoma (a bone malignancy)
- Teratoma (cancer of all 3 embryonic germ layers)
What are tumours graded on?
Similarity to parent cell:
1. Well differentiated (>75% cells resemble parent)
2. 10-75%
3. Poorly differentiated (<10% cells resemble parent)
What are characteristics of neoplastic cells?
- Auto crime growth stimulation - overexpression of GF and mutation of tumour suppressor genes e.g. p53 and under expression of growth inhibitors
- Evasion of apoptosis
- telomerase; prevents telomeres shortening with each replication (this normally rate limits the extent of mitosis a single cell can undergo)
- sustained angiogenesis + ability to invade BM
What are characteristics of neoplastic cells?
- Auto crime growth stimulation - overexpression of GF and mutation of tumour suppressor genes e.g. p53 and under expression of growth inhibitors
- Evasion of apoptosis
- telomerase; prevents telomeres shortening with each replication (this normally rate limits the extent of mitosis a single cell can undergo)
- sustained angiogenesis + ability to invade BM
What are the classes of carcinogens (cancer-causing agents)?
- chemical e.g. paints/dyes/rubber/soot
- viruses - EBV (burkitts), HPV (cervical cancer)
- ionising + non ionising radiation - UVB in skin cancer, ionising in lots!
- hormones, parasites, mycotoxins - e.g. increased oestrogen implicated in breast cancer
- misc - e.g. asbestos
Difference between germline and somatic mutations?
Germline vs somatic mutations:
- germline = mutated original germ cell -> will pass onto next gen
- somatic = mutated mitotic copy of germ cell -> wont pass to next gen
What is the pathway of metastasis?
- Detachment (from 1)
- Invasion of other tissue
- Invasation of BV
- Evasion of host defence, adherence to BV wall
- Extravasation to distant site
What are the methods of spread?
Haematogenous -> via blood. Bone, breast, lung, liver
5 main mets to bone = BLTKP; breast, lung, thyroid, kidney, prostate
Lymphatic -> 2 formation in lymph nodes
E.g. lymphoma (rubbery lymphadenopathy)
Transcolemic -> via exudative fluid accumulation, spread through pleural, pericardial + peritoneal effusions
What is the method of spread for sarcomas and carcinomas?
Sarcomas - mostly haematogenous
Carcinomas - mostly lymphatic
What are exceptions to carcinomas mostly lymphatic transmission?
Follicular thyroid
Chanocarcinoma
RCC
HCC
Ft CRH?
What are staging tumours?
- mostly TNM (tumour - node - metastases)
- different for leukemias + lymphomas and CNS cancers e.g. lymphoma -> ann arbour 1-4, A or B
What mutations are involved in colorectal cancer?
Mutation involved in colorectal cancer
- FAP (familial adenomatous polyposis) -> autosomal dominant mutated APC gene (adenomatous polypasis coli), millions of colorectal adeiamas. Inevitable adenonoaroma by 35 y/o overexpression of c-mYC and point mutation in KRAS
- HNPCC (lynch syndrome) -> mutated MSH gene, autosomal dominant; this genes involved in DNA mismatch repair
What is screening?
- method of early detection (essentially 2 prevention, making management easy!)
- cancers screen for in UK = cervical (cervical swab), breast (mammogram), colorectal (fecal occult)
- heel prick test at birth (Sickle cell, CF, hypothyroid)
What are dendritic cell?
- APC
- of mesenchymal origin (not haematopeitic)
What cells are involved in innate immunity?
Eosinophils (parasites)
Basophil (allergy)
Innate immunity:
Neutrophils
Macrophage
What are cells of adaptive immunity?
NK cell
T cell
B cell
Plasma cell
What are lymphoid organs?
1 - bone marrow - all cells originate, B cell mature
Thymes - T cell maturation + ‘thematic tolerance’
2- lymph nodes - APC + T/B cell interactions
Spleen - RBC recycling, encapsulated bacterial killing
(3 = pathological germ line centres of rapidly proliferating lymphocytes)
What is innate immunity?
Non specific, rapid, already active (little activation needed), no memory
Killing usually: complement activation
Neutrophil + macrophage mostly
Physical barriers - skin, mucus, cilia
Chemical barriers - lysozyme in teas, stomach acid
What is the complement system?
Destroy foreign antigens by
- direct lysis -> membrane attach complex formation (MAC)
- organisation -> increased phagocytosis (c3b)
- inflammation -> macrophage chemotaxis (c3a + cSa)
What are the pathways of complement system?
- classical
- lectin
- alternate
What are neutrophils?
70% all WBC, hours-days, express CD66 receptor (common for all granulocytes)
Key mediator of acute inflammation
F -> essentially mini bombs of N.E, MPO and other ROS
“Polymorphs” = variable number lobes of nucleus
What are macrophages?
Months- years. Can be circulating or resident (e.g. kuppfer)
Clear apoptotic debris
Have TLRs, complement receptor and AB’s bound Fc component
What are eosinophils?
Contain MBP, often seen in parasitic infection
What are basophils + mast cell?
IgE binding -> degranulation -> histamine release. T1 hypersensitivism M?
Mast cells = fixed at tissues
Basophil - circulating in body
What are basophils + mast cell?
IgE binding -> degranulation -> histamine release. T1 hypersensitivism M?
Mast cells = fixed at tissues
Basophil - circulating in body
What are NK cells?
Key role in (self cell killing) viral cell killing; activation + malignant cell killing = degranulation -> perforin (perforates viral infected cells)
(Essentially lymphoid cell)
Natural killer - kills natural host cells
What are receptors on these cells (against pathogens?)?
Toll like receptors (vs pathogens?) + nodule like receptors
(Non Cell bound receptors, free in blood = lectins)
These respond to PAMPs - pathogen associated molecular patterns
DAMPs - damage
What are TLRs composed of?
2 - detects growth (+) and TB
3 - intracellular
4 - LPS (-)
5 - flagellin
7 - single strand RNA intracellular
8 - ultra cellular
9 - non-myelinated DNA
Where are TLRs?
3,7,8,9 are intracellular
Rest are on CSM (extracellular)
Give an example of how TLR works?
TLR-4 activated by LPS of gram -ve bacteria (endotoxin)
Lectins in bloodstream bind pathogen
Then trigger immune response
- active complement, stimulate cytokines release (TNF a, IL1, IL6)
Increased phagocytosis
What do antigen presenting cells do?
Interface between innate bad adaptive immunity
Best cells - dendritic cells
They present foreign antigens to Th cells:
- stimulates further Th proliferation
- stimulates B cell production -> antibodies
What forms an immmne synapse?
When dendritic cell and Th cells communicate
What conditions must be met for an immune synapse to function?
- Receptor binding
- Co-stimulation (other molecules bind after primary receptor binding)
- Cytokine release
What conditions must be met for an immune synapse to function?
- Receptor binding
- Co-stimulation (other molecules bind after primary receptor binding)
- Cytokine release
What other cells can be antigen presenting cells?
E.g. macrophage, B cells but dendritic are the best
What is adaptive immunity like?
Specific, slow, need activation, have memory
Killing usually, antibody mediated
Main cells are T + B (+plasma) cell
What are T cells like?
Maturation in thymus (after BM production)
Thymus tolerance chooses which T cells are good
How does thymic tolerance work?
+ve selection -> T cells tested to see if they recognise thymus’ MHC’s 1+2; selected FDR
-ve selection -> if T cells produce immune response = selected against
- allocation - if T cells interacted with MHC 1 -> CD8 + cells (Tc)
MHC2 ->CD4 + cells (TH)
What is a naive T cell?
T cell never encountering antigen (not matured in thymus yet)
What does CD8+ do?
Interacts with MHC1
F = cytotoxic killing
- Perforin secretion (mediated by granzyme B)
- Express Fas L -> activates caspases
What does CD4+ do?
Interacts with MHC2
2 types: TH1 = IFNY - activates NK cells and macrophages ( increased innate response)
TH2 = IL4 -> activate B cells to differentiate into plasma cells (increased adaptive response)
What else is in adaptive immunity?
T regulatory (IL10) - immune tolerance
and TH17 - inflammatory at mucosal membranes
What are B cells like?
Maturation and production in BM (B cells that launch immunity vs self - adaptive here)
CD19 and CD20 receptors
How are B cells activated?
- They are activated by APC binding + MHC 2 interaction (e.g. with dendritic cell)
- TH 2 releases - IL4 which induces B cell proliferation (clonal expansion)
- IL5 which induces B cell differentiation into plasma cell (produce GRAMED Ig’s)
How do Ig’s act?
Ig’s act against specific pathogen present but if need arises:(e.g. pathogen antigens are very strange), AID (activation induced cysteane deamilase) can:
A: produce point mutation in Ig as “evolutionary” measure; somatic hypermutation
B: induce class switching (mutate are GAMED -> another isotype)
Give examples of class switching
IL4 promotes class switching to IgA
IL5 promotes class switching to IgE (e.g. in allergic response
What are the different types of immunoglobulins?
IgA,M,E,D
What is IgG like?
Most abundant immunoglobulin in blood
Key in secondary immune response (this marker of immunological memory), v. Specific
Ig (mc-1)1,2,3,4 subtypes
What is IgA like?
Most abundant Ig in total body
Found on mucosal linings + in colostrum/breast milk
Forms dimer
What is IgM like?
First Ig released in adaptive response, less specific
Forms pentamer
What is IgE like?
Activates mast cell + basophil degranulation in T1 hypersensitivity
(Anaphylaxis)
What is IgD like?
Unknown function, presumed to be B cell receptor components?
What are MHCs?
Major histocompatibility complex, on chromosome 6, aka HLA molecule
What are MHCs?
Major histocompatibility complex, on chromosome 6, aka HLA molecule
What are the key functions of MHCs?
Key functions:
1. interactions with T cells; TH (CD4+) interact with MHC2 (on APCs), TC (CD8+) interact with MHC1 (on all nucleated cells)(therefore not RBC!)
These essentially ensue the T cells confer immunity vs specific antigen while recognising self cells (APCs)
- Confer susceptibility to inherited autoimmune diseases e.g. HLAB27 -> spondyloarthropathies
HLADR2 DQ3 -> TiDM
HLADQ2/DQ8 -> coeliacs
HLAB8 -> SLE
What is Type 1 Hypersensitivity like?
Type 1 Anaphylaxis IgE mediated
- IgE binds to basophil/mast cell->.degranulation -> histamine; vasodilation + increased permeability (H1 receptor), bronchoconstriction, facial flush, purities, swollen tongue + face
E.g. ATOPY - asthma, hayfever, arthritis,
What is Type 2 hYPERSENITIVITY LIKE?
Antigen-antibody complex
- IgG/M binds to antigen + activates MAC (Complement) at site of A-A binding
- e.g. goodpasture’s, AIHA, pernicious anemia, rheumatic fever
What is Type 3 Hypersensitivity like?
Immune complex deposition
- IgG/IgA binds top antigen + activates complement at site of A-A deposition (kidneys = big boy affected)
- e.g. SLE (including lupus nephritis), post strep glomerulonephritis, IgA glomerulonephritis
What is Type 4 hypersensitivity?
T cell mediated
- TH1 activated by APCs -> response
- e.g. DMT1, TB, MS, Guillain barre
What is anaphylaxis?
Acute medical emergency
- may present with anaphylactic shock (sever hypotension, tachycardic + dyspnoea/cannotase, pale, cold extremities, puffed up face = tongue, itching -> purities, central cyanosis)
How do you respond to anaphylaxis?
Tx 1 - ABCDE: asses vitals
Airway - can they breathe (airway patent)
Breathing -> is it rapid, wheezy, SpO2 <92%
Circulation -> are they pale, cold, clammy, decreased BP
Disability -> confused/camatose, movement
Exposure
2- ASAP treat with 500mg IM Adrenaline
- if necessary, consider - antihistamine (Chloratrenamine), cortisol (hydrocortisone)
What is immune tolerance?
= physiological (to prevent frailty T/B cell self response)
- central -> thymic tolerance
- peripheral -> if T/B faulty cell evade central tolerance , they’re dealt with in 2 lymphoid organs (e.g. spleen)
What is autoimmunity?
Pathological response vs self; faulty immune tolerance; or molecular mimicking
Organ specific (affect main organ)
- T1DM -> endocrine pancreas -> B cells
- MS -> oligodendrocytes of CNS
- pernicious anemia -> parental cells of stomach
- Hashimotoy -> anti-TPO Ab; thyroiditis
TSH-R -> graves
Ach-R Ab’s -> MG
What is the Non-organ specific autoimmunity?
Generalised effect
-> affects DNA; ANA in SLE
-> affects cell antigens;
- RBCs -> autoimmune haemolytic anemia
- Platelets -> immune thrombocytic purpura
-> RA
How does one become immunodeficiency?
- can be:
- inherited (defects in T cells) e.g. IgA (Mc in north Europe) deficiency, SCID (death within 2y)
- acquired (HIV)
What are the patterns of immunodeficiency?
- Decreased CD4+ in HIV (these TH = required for cell mediated immunity; for both macrophage priming? and B cell activation)
Therefore increased susceptibility to disease e.g. CMV colitis (owl eyes), TB, pneumocystitis pneumonia, oral candidate, EBVKitt lymphoma’s
- B cells may be deficient (decreased plasma cells = decreased Ab’s)
- neutrophil + macrophage deficiency (required for phagocytosis + acute inflammation)
- complement deficiency (needed for innate immune killing of bacteria associated with SLE)
- Hyposplenism (lack of / decreased function of spleen; RNC recycling + killing encapsulated bacteria -> s.pneumo, N.meningitis, H.influenza)
What are vaccinations?
A form of artificial active immunity - usually 2 doses; prime, then booster
Can be: - live attenuated (GM) organism e.g. MMR
- antigens
- toxins - e.g. tetanus
- CW constituents e.g. HepB
Trigger immune response top mimic natural infection without being symptomatic
1. initial IgM Ab’s made
2. If pathogen encountered again IgG spike seen
What are routes of administration?
Enteral (GIT involved e.g. oral/PO)
Paraentral (non-GIT; IM, IV, SV, SC injections)
With local or systemic effect
(+ inhaled - ICS
Topical - cream
Rectal - enemas, suppository)
What are drug targets?
Mostly receptors
What can ligands be?
Agonists or antagonists
Agonists- full affinity. ( how well it bonds), full efficacy ( how well receptors activated)
Antagonists- full affinity, zero efficacy
Most receptors are g-protein coupled receptors
What is potency?
How well a drug works (strength) - how much drug is needed to elicit response in the body
How do agonists bind?
Direct binding
How do antagonists bind?
Competitively (compete for active site) or non competitively (allosteric) inhibit receptors
Direct binding
Competitive antagonists decreases potency but doesn’t affect efficacy
- ligand co centration is rate limiting
Non-competitive antagonist decreases both potency and+ efficacy
- ligand concentration not rate limiting here
What are other types of receptor ligands?
Other than direct bonding
- allosteric modulators; increase/decrease normal ligand binding e.g. benzodiazepine
What can drugs be?
Selective or non-selective;
- propanalol = non selective beta blocker -> binds both B, (heart) and B2 (lungs)
- verapamil = selective beta blocker -> binds only B1 (heart)
And also Beta-adrenergic agonists;
- isoprenaline = non selective Beta agonist -> both B1 + B2 (increased contractility + bronchoconstriction)
- SAB2A = selective Beta 2 agonist -> only bronchodilation
What are some other drug targets?
Enzymes, transporters, ion channels
How do enzyme drug targets work?
Main examples are cox-1 and ACE-i
- NSAIDs inhibit cox-1; prevent arachidanic acid -> prostaglandins SE-> GI ulcers
- ACE-i inhibit angiotensin 1-> angiotensin 2 (antihypertensive) SE-> hyperkalaemia, dry cough, teratogenic
How do enzyme drug targets work?
Main examples are cox-1 and ACE-i
- NSAIDs inhibit cox-1; prevent arachidanic acid -> prostaglandins SE-> GI ulcers
- ACE-i inhibit angiotensin 1-> angiotensin 2 (antihypertensive) SE-> hyperkalaemia, dry cough, teratogenic
What are transporters like?
(Mostly ATP-dependent)
- PPI’s e.g. omeprazole -> irreversible inhibition of H+ - K+ ATPase pumps therefore decreased gastric pH
- diuretics - loop; inhibits NKCC2 symporter in ascending limb (furosemide)
- thiazides (bendroflumetheziade); inhibits NaCl cotransporter in D T
- spironolactione; K+ spanning diuretic; inhibits aldosterone action
-SSRI’s, TCAs
What is the difference between specific vs selective drugs?
Specific - act on a certain target
Selective - acts on subtype of target e.g. cardioselective Bb inhibit B adrenoreceptors NOT B2
What are pharmokinetics?
What happens to the drug in the body - ADME
1. Administration- route + entry into body
- bioavailability - how fast and to what extent drug reaches systemic circulation
- Iv = always 100%
- other routes compared to IV!
