Wk2 - Immunology Flashcards
What are the different factors involved in innate immunity
Soluble factors: Antibacterial factors (lysozyme (enzyme present at mucosal surfaces, active in breaking down the gram positive cell wall) and lactoferrin (Protein found at mucosal surfaces, chelates iron and therefore reduces soluble iron in the GI/respiratory tract, Inhibits the growth of bacteria)) Compliment system (Active at mucosal surfaces and also in blood, enzymatic cascade)
Cellular factors: Scavenger phagocytes (mainly macrophages and neutrophils)
The 3 outcomes of the compliment cascade
Recruitment of inflammatory cells
Opsonization of pathogens
Killing of pathogens
How are macrophages able to carry out their function?
When might macrophages not be able to carry out their function?
They express TLR (a pattern recognition receptor)
Pattern recognition receptors:
Recognise molecules found commonly in micro-organisms
Able to recognise extracellular and intracellular threats
Respond to bacteria, fungi and yeasts
May not be able to carry out their function due to highly pathogenic bacteria or due to structural failure (e.g. surgery or injury that allows the bacteria to enter the body)
Macrophages have 2 main functions
Macrophages are involved in…
1) Clearance of micro-organisms
2) Getting help - by releasing hormones e.g. cytokines and neutrophils
Involved in:
Phagocytosis - specialises in destruction of pathogens. Also removes harmless debris e.g. tattoo pigment.
Antigen presentation - processes engulfed particles, travels to draining lymph nodes and presents T cell to MHC II
Cytokine production - M1- inflammatory, TNF alpha; M2- Regulatory, IL10
Inflammation is (in general terms)…
Universal response to tissue damde.
Damage can be caused by infection, necrosis or trauma
Explain how changes in the vasculature and cells occur with inflammation
1) Vascular dilatation - histamine and prostaglandins released –> arterioles dilate increasing blood flow, fluid passes into tissues causing swelling
2) Neutrophil activation - chemotaxis, phagocytosis and bactericidal
3) Endothelial activaiton - 5HT, histamine, bradykinin, C3a, C5a, leukotriene. Activates vascular endothelium; increased cell adhesion molecules; increased leakiness of endothelium; Plasma proteins travel into tissues including immunoglobulins, compliment and fibrinogen
5 cardinal signs of inflammation
Redness - hyperaemia Swelling - fluid exudate and hyperaemia Heat - hyperaemia pain - bradykinin and PGE2 Loss of function - combination. Pain and swelling prevent movement
Types of exudates
Neutrophilic exudate (supportive/purulent) Fibrinous exudate Serous inflammation (in peritoneal cavity or pleural cavity)
Spread of infection
Natural barriers
Air borne
Blood borne
Immune factors
Sequelae of acute inflammation
Abscess, chronic inflammation
Define chronic inflammation
Results from persisting tissue damage and ongoing acute inflammation or de novo (by viral infection).
Associated with a chronic inflammatory cell infiltrate including lymphocytes, macrophages and plasma cells.
Often leads to fibrosis or scarring.
Granulomatous inflammation is a subtype of chronic inflammation with a specific histological appearance (granulomatous inflammation associated with caseous necrosis)
Granulomatous inflammation
Defined by the presence of granulomas, collection of epitheloid macrophages and multinucleate giant cells
Subtypes include necrotising, non-necrotising, foreign body granulomas
Describe the antibacterial (soluble) factors of innate immunity
Lysozyme - enzyme present at mucosal surfaces; Active in breaking down the gram positive cell wall
Lactoferrin - Protein found at mucosal surfaces; Chelates iron and therefore reduces soluble iron in the GI/respiratory tract; Inhibits the growth of bacteria
Describe features of neutrophils
Have a multi-lobed nucleus Release DNA tangles Kills bacteria but also kills the surrounding cells Makes up 60-70% of WBCs Provides a rapid response to infection
The process of neutrophils killing bacteriats
Chemotaxis - migrate towards bacterial products (e.g. LPS), chemokines and ‘danger signals’ (e.g. compliment components)
Phagocytic: Will ingest and destroy pathogens using proteases, reactive oxygen species, lysozymes etc.
Degranulate: Release toxic granules intracellularly
Die locally: producing characteristic pus
Features of eosinophils
Process of eosinophil
Classically respond to parasites
1-6% of WBCs
Pathological role in allergy
Chemotaxis: migrate in response to chemokines e.g. eotaxin
Degranulation: release toxic substances into the surface of parasites e.g. major basic protein, eosinophil cationic protein, eosinophilic peroxidase
Cytokine production: drive inflammation - IL1, IL2, IL4, IL8, TNF alpha
Process of basophils/mast cells
(Have an important role in allergy)
Degranulation: Rapid release in pre-formed granules containing cytokine and mediators e.g. histamine - Wheal and Flare reaction
Cytokine release: store many pre-formed cytokines that are ready for release that attract and drive the subsequent immune response
Innate immunity overview
Capable of containing vast majority of interactions with micro-organisms.
Recognise danger patterns with genetically determined receptors
Capable of inactiviating micro-orgnaisms through combination of secreted factors and phagocytosis
Can activate adaptive immunity if required.
What are the link between the innate and adpative immune system
Dendritic cells:
Derived from the same precursors as macrophages
Prototype Antigen Presenting Cell
Dendritic cells = cells of langerhans
Process of dendritic cells
Phagocytosis: unlike macrophages, dendritic cells are not specialised in destruction of pathogens. Instead they function mainly as antigen presenting cells (APCs)
Migration: sit in tissues constantly sampling environment. When activated will travel to draining lymph nodes.
Antigen presentation: presents to CD4 T cells and can initiate an adaptive immune response
Structure of antibodies
Light chains
Heavy chain
Fab region - antigen binding region
Fc region - binds to Fc receptors on phagocytes; Activates compliment
What are the 3 functions of antibodies?
opsonise for phagocytosis
Activates compliment for lysis
Neutralises toxins and pathogen binding sites
How do the antibody isotypes differ?
They differ in their Fc region
IgM antibody
Main antibody of primary immune system (is produced first)
Low affinity
Activates compliment
IgG antibofy
Main antibody of secondary immune system
High affinity as part of secondary response
Activates compliment, binds Fc gamma receptor on phagocytes (opsonises)
Crosses placenta
IgA antibody
‘antiseptic paint’
Present in secretions and lines epithelial surface
Neutralises by blocking binding of pathogens
Important in nose, lung, gut
IgE antibody
High affinity binding to mast cells through Fce receptor
Role in allergy
optimal B cell response requires T cell help
T cell help: Cloncal expnasion of specific B cells Progression to antibody secreting cells (plasma cells) Progression to memory B cells Isotype switching to IgG, IgA and IgE Affinity maturation
T cell receptor
the receptor is on the surface of T cells and only recognises antigen when it is presented in a MHc molecule
Recognises short peptide lengths, not whole three diensional molecules
T cells can only see antigen in context of MHC. Describe features of class I MHC, and class II
Class I:
Presents to CD8 T cells
Found on all nucelated cells
Presents intra-cellular antigen
Class II:
Presents to CD4 T cells
Presents extra-cellular derived antigen (phagocytosed)
Found on anitgen presenting cells: DC’s, macrophages, B cells
Activated CD4 T cells differentiate into…
Th1 cells - IFN-gamma secretion; host defense against intracellular microbes; inflammation.
Th2 cells- IL-4, Il-5, IL-3 secretion; host defense against helminths; allergic reactions
Th17 cells: IL-7 secretion; host defense against some bacteria; inflammatory disorders
T regulatory cells: Act to regulate function of other immune cells, in particular T cells
Primary and secondary organs of the adaptive immune system
Primary - thymus (T cell education), Bone marrow (B cell education)
Secondary - lymph nodes, spleen, mucosal associated lymphoid tissue of GI tract (MALT) and bronchial tract (BALT)
Overview of adaptive immune system
Provides specific antibodies to the innate immune system to enhance pathogen clearance.
Provides cytokines to the innate immune system to upregulate activity
Finishes off the job of clearing pathogens.
Develops a memory to prevent future infection
Secondary response
Memory B cells and memory T cells already present at high frequency.
Memory lymphocytes have lower threshold for activation and actively patrol the sites of previous pathogen entry.
Preformed antigen specific IgA prevents pathogen binding.
Preformed high affinity IgG rapidly opsonises pathogen for phagocytosis
Features of the 5 types of hypersensitivity
I - immediate, atopic - IgE mediated
II - cytotoxic, antibody dependent - IgM or IgG bound to cell/matrix Ag
III - immune complex - IgM or IgG bound to soluble Ag
IV - cell mediated - T cells (CD4+ & CD8+)
V - receptor mediated - IgM or IgG bound to receptors
Characteristics of type 1 hypersensitivity
Response to challenge occurs immediately.
Tends to increase in severity with repeated challenge.
Predominantly mediated by IgE bound to mast cells.
Responsible for most allergies - asthma, eczema, hayfever
Describe the stages of allergy (type I hypersensitivity)
- Sensitisation
- Mast cells primed with IgE
- Re-exposure to antigen
- Antigen binds to IgE associated with mast cells
- Mast cells degranulate releasing - toxins (i.e. histamine), tryptase, pro-inflammatory cytokines, chemokines, prostaglandins, leukotrienes
- Pro-inflammatory process stimulates and amplifies future responses
Tissue effects to allergy - early effects
Occurs within minutes if exposure to antigen
Occurs largely as a result of histmaine and psotaglandins - casues smooth muscle contraction, increased vascular permeability
Tissue effects to allergy - late phase
Occurs hours to days after exposure to antigen.
Prinicipally mediated through recruitment of T-cells and other immune cells to site.
Results in - sustained asmooth muscle contraciton/hypertrophy & tissue remodellign
What is anaphylaxis?
Sever, systemic type 1 hypersensitivity:
Widespread mast cell degranulation caused by systemic exposure to antigen (i.e. penicillin)
Vascular permeability is prinicple immediate dander: soft tissue swelling threatening airway; loss of circulatory volume causing shock.
Can be rapidly fatal
Describe features of type II hypersensitivity
Causes by binding of antibodies directed against human cells - IgG is usual causes IgM, IgA)
Uncommon causes of allergy - drug associated haemolysis
Common cause of autoimmune disease e.g. bullous pemphigoid (deep blisters on skin)
Process of type II hypersensitivity
- Sensitisation
- Opsonisation of cells - generated antibodies opsonise cells.
- Cytotoxicity - compliment activation, inflammation, tissue destruction
- In some cases - direct biological activation with antigen (i.e. receptor activation, impaired enzyme action) - type V can do stage 4
Describe features of type III hypersensitivity
Mediated by immune complexes bound to soluble antigen.
Cause of autoimmune disease and drug allergy.
Aggregate in small blood vessels: direct occlusion, compliment activation, perivascular inflammation
Example = SLE
Describe features of type IV hypersensitivity
Example of Type V hypersensitivity
Process of Type IV hypersensitivity
Also known as delayed hypersensitivity
Presents several days after exposure
Mediated by the action of lymphocytes infiltrating the area
(type II, III and IV are all delayed hypersensitivity)
Example = DMT1, Allergic Contact Dermatitis
Example of type V = Graves disease
Process of type IV:
Contact-sensitizing agent penetrates the skin and binds to self proteins, which are taken up by Langerhans cells.
Langerhans cells present self peptides haptenated with the contact-sensitizing agent to Th1 cells, which secrete IFNgamma and other cytokines.
Activated keratinocytes secrete cytokines such as IL1 and TNFa and chemokines such as CXCL*, CXCL11, and CXCL9.
The production of keratinocytes and Th1 cells activated macrophages to secrete mediators of inflammation
Define autoimmune disease
harmful inflammatory response directed against ‘self’ tissue by the adaptive immune response.
Divided into:
- organ specific (e.g. T1DM, Myasthenia Gravis, Addison’s disease)
- systemic (e.g. RA, SLE, IBD, connective tissue disease, systemic vasculitis)
Describe T1DM - an organ specific autoimmune disease
Selective, autoimmune destruction of the pancreatic beta cells - often mix of type II and type IV.
Causes profound insulin deficiency and death if not treated with insulin replacement.
Inflammation of the islets of Langerhans precedes symptoms by many years
Describe mysathenia gravis - an example of organ specific autoimmun disease
Syndrome of fatigable muscle weakness - limbs, repsiratory, head and neck.
Causes by IgG against acetylcholine receptor.
antibody blcoks receptor at neuromuscular junction and prevents signal transduction
Give examples of systemic autoimmune disease
Rheumatoid arthritis Systemic lupus erythermatosus inflammatory bowel disease Connective tissue disease Systemic vasculitis
Examples of organ specific autoimmune disease
T1DM
Myasthenia Gravis
Addisons disease
Characteristics/signs and sympotms of RA
Pulmonary nodules and fibrosis Pericarditis and valvular inflammation Small vessel vasculitis Soft tissue nodules Skin inflammation Weight loss, anaemia
pathophysiology of RA
Rheumatoid factor: - IgM and IgA directed against IgG Fc region. Forms large complexes –> high concentration with in synovial fluid.
Inflammation leads to release of PAS from inflammatory cells.
Alters variety of proteins by converting alanine to citrulline
in RA, anti-citullinated protein/peptide antibodies are common.
Stages leading to inflammation in RA
Amplificaition of inflammatory cascade.
Furhter chemoattraction of inflammatory cells into synovium - macrophages, neutrophils, lymphocytes.
osteoclast activation and joint destruction.
Fibroblast activation and synovial hyperplasia.
Systemic inflammation.
Biologic therapy for autoimmune diseases
Infliximab - monoclonal antibody; Target = soluble cytokine
Etanercept - a soluble receptor ; Target - soluble cytokine
Rituximab - monoclonal antibody; Target - surface marker
Effect of biological therapies on autoimmune disease for RA
Reduces joint swelling and pain
Decreases systemic inflammation
Delays and prevents appearance of erosions and one deformity
Cost - increased risk of infection, esp TB
Genetic predispostion to autoimmune disease
Genes involved:
MHC-1 and II (HLA locus)
Cytokine and their receptors, i.e. TNF alpha
Environmental factors for autoimmune disease
Infection - molecular mimicry; tissue damage exposing self-antigens
Geographical factors: Vitamin D mediated through sunlight exposure
Modifiable personal risk factors - smoking
Enzymes and proteins involved with inflammation in RA
Presence of antibodies of citrullinated proteins strongly predicts RA
Citrullinated proteins develop due to action of enzymesinduced during inflammation
Associated with conversion of alanine to citrulline
A bacterium is inoculated into tissue, leukocytes leave the vasculature and migrate to the site of bacterial inoculation. The movement of leukocytes is most likely to be mediated by which of the following substances A) Bradykinin B) Chemokines C) Histamine D) Prostaglandins E) Complement C3a
Chemokines
A patient has a fever, productive cough and O2 sats of 92%. Auscultation demonstrates crackles at the right base. CXR demonstrates consolidation at the right base. Which of the following inflammatory cell types is most likely to be seen in greatly increased numbers in a sputum specimen? A) Macrophages B) Neutrophils C) Mast cells D) Small lymphocytes E) Multinucleate giant cells
Neutrophils
A man dies two weeks following an acute myocardial infarction. At post mortem, a histological section of the infarct shows that the necrotic myocardium has largely been replaced by capillaries, fibroblasts and collagen. Which of the inflammatory cells in this lesion has the most important role in the healing process? A) Macrophages B) Plasma cells C) Neutrophil polymorphs D) Eosinophils E) Lymphocytes
Macrophages
A man develops infective endocarditis. Blood cultures grow Streptococcus viridans. Microbes are opsonised and cleared. Which of the following mediators is the most important in this process? A) Bradykinin B) CRP C) IFN-gamma D) NO E) Complement F) TNF
Complement
A man becomes increasingly breathless. A CXR shows that fluid has accumulated in his right pleural space. A pleural tap shows that the fluid is composed of neutrophil polymorphs in the majority. Which of the following mechanisms contributes to the accumulation of fluid in the pleural space? A) Lymphatic obstruction B) Neutrophil release of lysosomes C) Promotion of platelet adherence D) Arteriolar vasoconstriction E) Endothelial contraction
Endothelial contraction
What could have caused the appendix to perforate? A) Acute necrotising inflammation B) Rupture of a diverticulum C) Vasculitis D) A parasitic infection E) All of the above
All of the above
A 42 year old man presents with a dry cough of several months duration
What is your differential diagnosis?
What simple tests can be performed?
What is your differential diagnosis?
Asthma, COPD, ILD, Sarcoid, Reflux
What investigations will you ask for
Peak flow, PFTs, CXR, CT, HRCT, Serum ACE, Endoscopy
In this granulomatous condition (granulomatous inflammation), what is main cell type involved? A) Neutrophil polymorph B) Macrophage C) Lymphocyte D) Eosinophil E) Basophil
Macrophage
A man injures his finger and it becomes red, hot and swollen.
What process is this?
What are the five cardinal signs
What is your differential diagnosis?
What process is this? Acute inflammation What are the five cardinal signs Pain, heat, redness, swelling, loss of function What is your differential diagnosis? Arthritides, infection, gout, tumour
What mediator permits diapedesis of inflammatory cells A) Serotonin B) VEGF C) Nitric oxide D) Endothelin-1 E) Integrins
integrins
A 66 year old female presents with early morning pain and stiffness in her joints On examination, the following are noted (ulnar deviation of digits) What is this condition A) Osteoarthritis B) Rheumatoid arthritis C) Psoriatic arthritis D) Gout E) Septic arthritis
RA
A biological therapy called anti-TNF alpha is recommended
What is the mechanism of action?
What are the side effects?
What is the mechanism of action?
Apoptosis, cytotoxicity, diminished cell influx or a reduction in chemotatic molecules
What are the side effects?
Mild rash/pain, autoantibody production, TB, skin cancer, lymphoma
Brief steps to forming a protein from DNA
DNA polymerase - causes DNA replication
RNA polymerase - Transcription - forms RNA from DNA.
Translation occurs on the ribosome –> protein
Define Pathology and Disease
Broad tissue types - epithelial
Pathology - study of disease
Disease - abnormality of cell/tissue structure and/or function
Epithelial:
squamous
glandular
solid organs e.g. liver, kidney, thyroid
Broad tissue types - connective
Fibrous Blood vessel Fat Muscle Bone Cartilage
External environmental changes to cells (stresses)
Physical factors
Chemical factors
Infection
Nutrition
Internal environmental changes to cells (stresses)
More or less functional demand
Hormones/metabolic
Immune response etc.
Causes of cell injury (aetiology)
How is cell injury caused by environmental changes (stresses)
Aetiology - physcial agents, chemicals/drugs, infections, hypoxia/ischaemia, immunological reactions, nutritional imbalance, genetic disease
If the stress is more intense, longer-lasting, or of a specific type, or if the cell is very sensitive, then there may be cell injury
Cells directly affected may undergo: Sub-lethal cell injury; Cell death
The body may respond with inflammation, acute or chronic injruy
Possibly after many years, affected cells may undergo neoplasia
Describe the process a cell undergoing environmental stresses goes through
Normal cell Cell with adaptation Cell with reversible injury Cell with irreversible injury Cell death
Physical agents causes stress to cells
Chemicals/drugs - causing stress to cells
Mechanical trauma: stricture, adhesions, hernia, criminal
Temperature extremes: heat or cold
ionising radiation: causes DNA damage
Electric shock
Chemicals: May damage various cell organelles and processes e.g. disruption of cell membranes (osmotic damage), protein production or folding Includes: Drugs e.g. chemotherapy, paracetampol Poisons (cyanide) Environmental (insecticides) Occupational hazards (asbestos)
Cell injury may be reversible or irreversible…
Reversible - Changes due to stress in environment; Return to normal once stimulus removed
Irreversible - Permanent; Cell death, usually necrosis, follows
Needs to pass threshold to become permanent - threshold depends on type, duration and severity of injury
Hypoxia:
Definition
Causes
Deficiency of oxygen
Causes - anaemia, respiratroy failure
Disrupts oxidative respiratory processes (in mitochondria) in cell and so decreases ATP
Ischaemia
Defintion
Causes
Reduction in blood supply to tissue
Caused by blockage of arterial supply or venous drainage e.g. atherosclerosis
DEpletion of not just oxygen (as with hypoxia alone) but also nutrients e.g. glucose
Damage therefore more rapid and severe
Mechanisms of cell injury; oxidative stress
Oxidative stress caused by reactive oxygen species (free radicals)
Normally formed in small amounts as a by-product of respiration
Formed pathologically by absorption of radiation, toxic chemicals, hypoxia etc.
Lack of antioxidants makes damage more likely (lack of antioxidants can be due to poor nutrition)
Reversible cell injury - Nature of changes are same whether reversible or reversible - but reversible are less severe and inclue…
‘Cloudy swelling’ - osmotic disturbance: loss of energy-dependent NA pump leads to Na influx and build up of intracellular metabolites
Cytoplasmic blebs, disrupted microvilli, swollen mitochondria
‘Fatty change’ - accumulation of lipid vacuoles in cytoplasm caused by disruption of fatty acid metabolism, especially in the liver
Irreversible cell damage features
Disrupted membranes
Pyknotic nucleus
Cell death may be as necrosis or apoptosis
Cell death following injury is usually necrosis which is uncontorlled and due to external stimuli - necrosis is always pathological
The other form of cell death is apoptosis which is ‘programmed’ and therefore controlled - apoptosis is usually more physiological e.g. during embryogenesis and development; It can be pahtological e.g. in viral infection
Definition of necrosis
& Histological changes
= unprogrammed cell death
Infarction = necrosis caused by loss of blood supply
Histological changes:
Cell swelling, vacuolation and disruption of membranes of cell and its organelles including mitochondria, lysosomes and ER
Release of cell contents (cell lysis) including enzymes causes adjacent damage and acute inflammation
DNA disruption and hydrolysis
Name and briefly describe the different types of necrosis
Coagulative - firm, tissue outline retained
Subtypes: Haemorrhagic (due to blockage of venous drainge); Gangrenous (larger area especially lower leg)
Colliquitive - tissue becomes liquid and its structure is lost e.g. infective abscess, cerebral infarct
Caseous - combination of coagulative and colliquitive, appearing ‘cheese-like’ (caseous): classical for granulomatous inflammation, especially TB
Fat - due to action of lipase on fatty tissue
Effects of necrosis
Functional - depends on the tissue/organ
Inflammation - release of cell conetnts activates inflammation and causes damage - either acute with removal of stimulus and then hearing and repair; Or chronic with persistence of stimulus and chronic inflammation
Define apoptosis
= genetically programmed/activated cell death
Requires energy and distinct pathways involved
Important physiological role, but can occur in pathological mechanisms
Does not cause inflammation but may be caused by immunological mechanisms
Different morphology from necrosis
Aetiology of apoptosis - physiological and pathological
Physiological:
Examples include:
Embryogenesis - deletion of cell populations
Hormone development involution - uterus, breast, ovary
Cell deletion in proliferating cell populations to maintain constant number o cells: epithelium
Deletion of inflammatory cells after an inflammatory response
Deletion of self-reactive lymphocytes in thymus
Pathological:
Viral infection - cytotoxic T-lymphocytes
DNA damage
Hypoxia/ischaemia
Morphology of apoptosis
Cell shrinkage Chromatin condensation (unlike necrosis): packaging up of nucleus Membranes of cell and mitochondria etc remain intact, unlike necrosis But cytoplasmic blebs form and break off to form apoptotic bodies which are phagocytosed by macrophages
What is the first person in a family to present to a genetics clinic called?
Necrosis vs Apoptosis
Propositus
Indicated in family tree by an arrow pointing to them
Necrosis - Uncontrolled; Always pathological; Causes inflammation; Releases cell contents.
Apoptosis - Programmed/controlled; Usually physiological; Does not cause inflammation; Does not release contents
Depositions =
abnormal accumulation of substances
Location may be: intracellular, or extracellular, in connective tissue
Composition may be of:
Normal endogenous substances e.g. normal products of metabolism, including protein, lipid, and carbohydrate; Pigments (bile, haemosiderin e.g.) (some deposits are both product and pigment)
Exogeneous (foreign) material e.g. pigments (tattoo pigment) of industrial material (asbestos)
Amyloid: Nature
Amyloid is a geneeral pattern/appearance which can be produced by multiple different proteins, due to multiple different causes (cirrhosis)
Amyloid accumulation may be:
Systemic: widespread
Localised: one place
How does amyloid occur?
Excessive production/accumulation of a normal protein or
Production/accumulation of an abnormal protein; and
Tendency of a protein to misfold (i.e. abnormal)
Description of inflammation
Physiological response to tissue injury
Vascular and cellular components
Acute or Chronic
Terminates in resolution, repair or continues
Explain how changes in the vasculature and cells occur in acute inflammation
1) Vasodilation:
Transient vasoconstriction then vasodilation
Starts in arteries
Increased blood flow
Due to histamine, NO & prostaglandins on vascular smooth muscle
Fluid passes into tissues causing swelling
Increased vascular permeability: Contraction of endothelial cells Increased inter-endothelial spaces Mediated by histamine, bradykinin, substance P Endothelial injury in severe injuries Injury can be caused by neutrophils Increased transcytosis Permits escape of protein rich fluid exudate into extravascular tissue
Vascular congestion/stasis:
Slower flow, increased concentration
2) Neutrophil activation:
Chemotaxis, Phagocytosis and bacteriocidal effects
3) Endothelial activation:
By mediators produced during inflammation
Increased levels of adhesion molecules
Types of exudate
Exudate is extra-cellular fluid with a high protein and cellular content. (Transudate is extra-cellular fluid with a low protein and cellular content).
Examples:
Serous –> usually a transudate, found in pleural, pericardial, peritoneal spaces - seen in mild inflammation. Seen in TB
Fibrinous exudate –> fluid rich in fibrin, an exudate due to high protein content, often on serosal surface, meninges. Seen in strep throat and bacterial pneumonia.
Suppurative/purulent (neutrophilic) exudate –> pus forming, an exudate rich in neutrophil polymorphs (abscess)
Haemorrhagic exudate
Membranous exudate
Pseudomembranous (ulceration) e.g. in c.diff
An exudate allows delivery of nutrients, dilution of toxins, entry of antibodies and stimulates the immune response
Sequelae of acute inflammation.
Who performs a post-mortem examination?
Sequelae - Abscess, Resolution, Healing by repair, Chronic inflammation
General pathologists
Describe what post-mortem examination involves
External examination - height, weight, BMI
Skin, hair, eye colour
Iatrogenic - scars, drains, IV lines
Evidence of trauma
Jaundice, cyanosis, finger clubbing, oedema, lymphadenopathy
Internal examination:
1) Evisceration
A single incision from sternal notch to syphysis pubis to removed thoracic, abdominal and pelvic organs
A second incision around posterior part of the skull to reflect the scalp, the skull is opened and the brain removed.
The evisceration is usually performed by anatomical pathology technicians.
2) Organ dissection:
The pathologist inspects each organ and then carefully dissect them - Macroscopic assessment
Pathologist may retain small amount of tissue for microscopic assessment
At the end of the PM examination
All of the organs are returned to the patient’s body cavity (minus the tiny amount of tissue taken for microscopic assessment)
If no death certificate has been issued before the PM, the pathologist will write a death certificate
The report prepared by the pathologist is sent ti the PF, or for ‘consented/hospital’ cases, to the patients GP and the clinician in charge of care.
The patient’s body is reconstructed to permit viewing of the deceased by their family
The patient’s body is released for burial or cremation as specified by the deceased/family
Features of Medical Certificate of Cause of Death (MCCD)
1a) Disease or condition directly leading to death
1b) Due to, or as a consequence of…
1c) Due to or as a consequence of…
1d) Due to, or as a consequence of….
2) Other significant conditions contributing to the death, but not related to the disease or condition causing it
Potential causes of death
Neoplastic e.g. lung and breast cancer Vascular e.g. MI Degenerative e.g. AD Infective e.g. pneumonia Traumatic e.g. RTA Inflammation e.g. COPD Metabolic e.g. diabetes Iatrogenic e.g. intra-operative death
What are the risk factors for DVT?
Vessel wall - inc age, varicose veins, surgery
Blood flow - Obesity, pregnancy, immobilisation, IV catheters, external vein compression
Composition of blood - Thrombophilias (inc family history), inflamm conditions, oestrogen hormones
How do we confirm or exclude the diagnosis of DVT
Clinical decision rule - determine likelihood of DVT
Blood tests - Fibrin D-dimer, a measure of dissolved thrombus
Image Venous system of leg - compression ultrasound, venography
What clinical scoring system is used in A&E for DVT?
Well’s Clinical Scoring System
DVT diagnosis decision algorithm
Well Clinical Score <2 and D-dimer -ve == very unlikely DVT
Wells <2 and D-dimer +ve ==> Treat as DVT (until confirmed or excluded by US)
Well’s score >=2 with D-dimer -ve or +ve ==> treat as DVT (until confirmed or excluded by US)
Outcomes following DVT
Painful swollen leg Pulmonary embolism - 50% of DVT cases will have asymptomatic PE Recurrent VTE Venous insufficiency Post Thrombotic Syndrome
Outcomes following PE
Dyspnoea, chest pain, haemoptysis Collapse (massive PE) Death (fatal PE) Recurrent VTE Chronic Thromboembolic Pulmonary Hypertension
Treatment of DVT
Prevent thrombus extending or embolising - Anticoagulation for 3-6 months:
Heparin (LMWH)
Warfarin (target INR 2.5)
Direct Oral Anti-Coagulant (direct Xa or IIa inhibitor)
Remove risk factors
Pain relief
Graduated elastic compression stockings
Prevention of VTE
Avoid risk factors if possible
Risk assess at hospital admission or surgery
Provide thrombo-prophylaxis when appropriate - Anti-embolism stockings; Heparin (LMWH daily subcut)
Education patients on risks and avoidance measures - early mobilisation
Causes of chest pain?
MSK - rib fracture, muscular, chondritis Cardiac - angina, MI Lung - Pleuritis pain (infection, infarction, malignant) Vascular - PE, aortic dissection Oesophageal - acid reflux, hiatus hernia
Pathology of CAD
Atheramtous arterio-vascular disease:
Development of atheroma/plaques
Progressive narrowing and stenosis of artery:
- plaque rupture
- Acute thrombus - Vascular occlusion; Downstream ischaemia and infarction
Risk factors for arteriosclerotic Cardiovascular Disease
Smoking Hypertension Hyperlipidaemia Diabetes Obesity Family history
Diagnosis of MI or Acute Coronary Syndrome
Suggestive history
Clinical evidence of cardiac dysfunction
ECG findings
Biochemical evidence of myocardial damage (ischaemia) - elevated troponin
Visualisation of coronary arteries - cardiac catherisation
Complications following an MI
Death Arrhythmia Pericarditis Myocardial rupture Mitral valve prolapse Left ventricular aneurysm +/- thrombus Heart Failure
Causes of limb weakness
MSK - Myopathy, Arthropathy
Neurological - peripheral neuropathy, spinal lesion, cerebral lesion (ischaemia, inflammation, malignancy)
Treatment of stroke and AF
Remove thrombus (rarely) - Thrombolysis; Carotid end-arterectomy Remove/correct source of thrombus - Anticoagulation (warfarin or DOAC); Revert to sinus rhythm (cardioversion); Replace defective heart valve Address other CVD risk factors - HBP, hyperlipidaemia
Cellular pathology is composed of
Autopsy (post-mortem examination)
Histopathology (tissues)
Cytopathology
Define chronic inflammation
Results from persisting tissue damage and ongoing acute inflammation or de novo.
Associated with a chronic inflammatory cell infiltrate including lymphocytes, macrophages and plasma cells.
Often leads to fibrosis or scarring.
Granulomatous inflammation (often causes/caused by caseous necrosis) is a subtype of chronic inflammation with a specific histological appearance
Definition of granulomatous inflmmation
Defined by the presence of granulomas, collections of epithelioid macrophages and multinucleate giant cells.
Subtypes include necrotising, non-necrotising, foreign body granulomas
Outcome of acute inflammation
Resolution - back to normal
Healing by fibrosis - after substantial tissue damage; Tissue incapable of regeneration; Abundant fibrin exudate
Progression to chronic inflammation - Persistent stimulus, tissue destruction leading to ongoing inflammation.
Differential diagnosis of a sore leg
Trauma - fractures, dislocation, muscle strain
Non-traumatic - OA, RA, septic arthritis, gout and pseudogout, bursitis
Skin/soft tissue infections - cellulitis, abscesses, necrotising fasciitis
Vascular causes - Venous occlusion (e.g. DVT); Acute ischaemia (Peripheral arterial disease, cardiac thromboembolism); Lymphoedema.
Causing of bilateral leg swelling - Systemic oedema: HF, cirrhosis, nephrotic syndrome, malnutrition, immobility
Risk factors for DVT
Vessel wall - inc. age, varicose veins, surgery
Blood flow - obesity, pregnancy, immobilisation, IV catheters, external vein compression
Composition of blood - Thrombophilias (FHx), inflammatory conditions, oestrogen hormones
How do we confirm or exclude the diagnosis of DVT?
Determine likelihood of DVT
Blood tests - Fibrin D-dimer, a measure of dissolved thrombus
Image Venous system of leg - compression ultrasound, venography
Well’s clinical scoring system is used for DVT
Outcomes following DVT
Painful swollen leg Pulmonary embolism - 50% of cases of DVT will have asymptomatic PE Recurrent VTE Venous insufficiency Post Thrombotic Syndrome
Treatment of DVT
Prevent thrombus extending or embolising - Anticoagulation for 3-6 months: Heparin (LMWH), Warfarin, Direct Oral Anti-Coagulant (direct Xa or IIa inhibitor)
Remove risk factors
Pain relief
Graduated elastic compression stockings
Prevention of VTE
Avoid risk factors is possible
Risk assess at hospital admission or srugery - Anti-embolism stockings; Heprain (LMWH daily sub cut)
Education for patients on risks and avoidance measures - early mobilisation
Causes of chest pain
MSK - rib fracture, muscular, chondritis
Cardiac - angina, MI
Lung - pleuritic pain (infection, infarction, malignant)
Vascular - pulmonary embolism, aortic dissection
Oesophageal - acid reflux, hiatus hernia
Most likely cause of chest pain in 65y male
Angina Heart burn (hiatus hernia) MI Pneumonia (+pleurisy) Pulmonary embolism
Pathophysiology of coronary artery disease
Athermatous aterio-vascualr disease:
Development of atheroma/plaque
Progressive narrowing and stenosis of artery:
-Plaque rupture
- Acute thrombus - Vascular occlusion, Downstream ischaemia and infarction
Risk factors for arteriosclerotic cardiovascular disease
Smoking Hypertension Hyperlipidaemia Diabetes Obesity Family history
Tx of arteriosclerotic cardiovascular disease
Prevent thrombus extension - Anti-platelet agent (aspirin, clopidogrel), Anticoagulant (heparin)
Remove the thrombus - Thrombolysis (alteplase, tenecteplase); Remove clot via catheter (PCI)
Cellular pathology is composed of…
Autopsy (post-mortem examination)
Histopathology (tissues)
Cytopathology (cells)
Types of cytology samples
Exfoliative cytology - scrape, smear and brush cytology (including cervical)
Fine needle aspiration (FNA)
Immunohistochemistry = staining technique which yields …
yields brown staining of specific protein
A developmental anomaly is essentially any…
congenital (present at or before brith) defect that occurs when normal growth and differentiation of the foetus is disturbed.
Caused by genetic mutations, chromosomal aberrations, teratogens and environmental factors (smoking/alcohol)
Congenital anomalies are anomalies that exist at…
at or before birth regardless of the cause and congenital anomalies, may be either:
- Functional/metabolic - how the body works (inborn errors of metabolism, haemophilia, CF) or
- Structural - how the body is made up physically/architecturally
Features of ventricular septal defect
ventricular septal defect is the most common congenital heart anomaly.
Ventricular septal defects often associated with other syndromes, such as Down’s.
Ventricular septal defect (VSD) usually symptomless at birth and usually manifests a few weeks after birth.
Acyanotic congenital heart defect, aka left-to-right shunt, so there are no signs of cyanosis in the early stage but uncorrected VSD can increase pulmonary resistance leading to the reversal of the shunt and corresponding cyanosis
Spina bifida
Defect of the neural tube (i.e. the embryonic structure that develops into the spinal cord and brain) wherein a portion of the neural tube fails to develop or close properly.
Symptoms include:
Muscle weakness or paralysis
Seizures
Bowel and bladder problems
Orthopedic problems e.g. deformed feet, uneven hips and scoliosis
Hydrocephalus
Less severe developmental anomalies =
Syndactyly
Polydactyly
Cleft palate
Hamartoma =
Malformation that may resemble a neoplasm that results from faulty growth in an organ.
Composed of a mixture of mature tissue elements which would normally be found at that site which develop and grow at the same rate at the surrounding tissue
Chondroid hamartoma
Lung lesion which may be seen as a ‘coin lesion’ on x-ray
Can mimic malignancy clinically if endobronchial.
Composed of a mixture of epithelium, cartilage, fat, smooth muscle
Benign
Ectopia =
An abnormal location ro position of an organ or a tissue, most often congenitally but can occur as a result of injury
Ectopia cordis: displacement of heart outside the body
Ectopic thyroid tissue: nodules of mature thyroid tissue located elsewhere in the neck
Ectopic pregnancy: implantation occurring in fallopian tube rather than endometrium
Diverticulum
Circumscribed pouch/sac caused by herniation of lining mucosa of an organ through defect in muscular coat
Classic examples are Meckel’s diverticulum and sigmoid colon diverticula/diverticulum disease
Diverticular disease
Effect include inflammation, bleeding, perforation, fistulation
When there is chronic inflammation
Merckel’s diverticulum
Congenital
Two inches long usually and present at terminal ileum.
Complications include inflammation, bleeding, perforation and obstruction/intussuception
Inflammation mimics appendicitis due to location
Causes of atrophy
Loss of innervation Diminished blood supply Decreased workload Loss of endocrine stimulation Ageing
Metaplasia =
Reversible change from one fully differentiated cell type of another e.g GORD
What is neoplasia?
An abnormal tissue mass the growth of which is excessive (i.e. not an adaptation to physiological demands) and uncoordinated compared to adjacent normal tissue
Persists even after cessation of the stimuli that caused it
Anaplasia -
Lack of differentiation of a tumour (undifferentiated)
Dysplasia =
Disordered growth in which cells fail to differentiate fully, but are contained by the basement membrane i.e. non-invasive.
Recognised by alterations in the appearance of cells:
cell nuclei become hyperchromatic
Nuclear membranes becoem irregular
Nuclear to cytoplasmic ratio increases
Dysplasia may regress, persist or progress
Carcinoma in situ =
Full-thickness epithelial dysplasia extending from the basement membrane to the surface of the epithelium
Metastasis - spread of tumour to distant sites can occur by:
Lymphatic spread - most common pathway fro carcinomas
Haematogenous spread - typical of sarcomas
Seeding of body cavities (transcoelomic spread) - e.g. ovarian carcinoma nad gastric carcinoma
Name 2 inflammatory mediators responsible for Wheal and Flare reaction/Triple reaction.
Name 2 types of cells which release these inflammatory mediators
Histamine
Prostaglandins
Serotonin
Mast cells - histamine, prostaglandins
Platelets - Serotonin
Describe at least on advantage to the body of the Wheal and flare reaction
Attracts neutrophils and other inflammatory cells
Dilutes toxins
Name 2 phagocytic cells involved in acute and/or chronic inflammation
Macrophages
Neutrophils
Compare and contrast the innate and adaptive immune responses. (2m)
Innate - Quick initial response.
Cells -neutrophils and NK cells
No memory
Adaptive - Higher potency, more profound response.
Takes longer to initiate
Has memory
Cells - lymphocytes
Define and give an example of histology
Definition:
The study of a section of tissue which contains the cells in their normal structure, using staining technique such as H&E
Advantage:
Gives overall picture of the tissues structure and function, and can easily identify pathology
Define and give an advantage of cytology
Definition:
The study of individual cells
Advantage:
Cytology is done very quickly, and it is inexpensive
What does the acronym FISH stand for
Fluroescent in-situ hybridisation
What is a translocation?
One part of a chromosome is swapped over from a part of another chromosome
What translocation is associated with follicular lymphoma? How does this translocation help to promote malignancy?
BCL2 between chromosomes 14 & 18
Define atrophy
Wasting/degeneration/decrease in size of cells
Regardless of tissue type, name a common cause of atrophy
Lack of innervation to a particular cell
Provide one clinically important example of atrophy and its specific cause
Paralysis - spinal cord injury - causes wasting of muscle cells
Define hypertrophy
Increase in the size of cells
Regardless of tissue type, name a common cause of hypertrophy
Increased functional deman, due to environmental demands/adaptations
Provide one clinically important example of hypertrophy and its specific cause
Ventricular hypertrophy - due to HF
Define metaplasia
Change from one differentiated cell to another differentiated cell
Regardless of tissue type, name the common cause of metaplasia
Change in environment or stresses
Provide one clinically important example of metaplasia and its specific cause
Barretts oesophagus.
Stratified squamous cells to gastric simple columnar cells
Dysplasia may develop from metaplastic cells. Define dysplasia
Growth of abnormal cells, always pre-cancerous
Dysplasia is well-recognised to occur in the uterine cervix. What is the main cause of cervical dysplasia?
HPV (human papilloma virus)
Name 2 main normal epithelia present in the cervix uteri
Non-keratinised squamous
Simple columnar
The aim of the cervical screening programme is to detect and treat dysplasia in the cervix uteri. What microscopic appearances would suggest a diagnosis of dysplasia, on cytology (1 mark) and on histology (2 marks)
Cytology - smaller/darker/irregular nuclei from pap smear test
Histology - darker, dense and no order of maturation
Name the specific pathological term for the most common form of cervical cancer
Squamous cell carcinoma
