Mechanisms of Disease Flashcards
What are the 3 general considerations for cell growth?
- Growth of the cell population
- Growth @ cellular level (cell cycle)
- Loss of cells by programmed cell death (apoptosis)
Characteristics of the growth of a population of cells + what does it depend on?
- Distinguish between increased cell #s (hyperplasia)
- And increased cell size (hypertrophy)
- This depends on the integration of intra + extracellular signals
- Checks on cellular physiology, cell growth + inhibitory factors and cell adhesion
Characteristics of growth @ a cellular level (the cell cycle)
- Cell growth is the increase in size and sometimes the growth to this only + cell division
- Cell cycle phases (G1, S, G2, M)
- Progression is controlled at 3 key checkpoints - which are restriction points
Characteristics of the loss of cells by programmed cell death (apoptosis)
- Coordinated program of cell dismantling, ending in phagocytosis
- This is distinct from necrosis
- This happens during normal development:
• Separation of digits, involution, immune + nervous system development
• + in response to DNA damage and viral infection
Growth factors, cytokines and interleukins characteristics
- These are proteins
- Proteins that stimulate proliferation, which are called mitogens + maintain survival
- This is usually named after originally identified target:
• EGF, FGF, IL2 + IL4, NGF - Stimulate differentiation + inhibit proliferation, like TGFb
- Induce apoptosis:
• TNFa + other members of the TNF family
What are the 3 broad classes of growth factors, cytokines and interleukins
Paracrine
Autocrine
Endocrine
What are the 3 broad classes of growth factors, cytokines and interleukins - paracrine characteristics
- Produced locally.
- To stimulate proliferation of a different cell type that has appropriate cell surface receptor
What are the 3 broad classes of growth factors, cytokines and interleukins - Autocrine characteristics
- Produced by cell that also expresses appropriate cell surface receptor
What are the 3 broad classes of growth factors, cytokines and interleukins - Endocrine characteristics
- Like conventional hormones
- Released systematically for distant effects.
What are proteins that stimulate proliferation called + their role
- Mitogens.
They maintain survival
what are the named 4 steps of DNA replication
- SCR of DNA. Daughter cells get 1xparental, 1xnew strand
- New DNA made, in 5 to 3 prime direction. From deoxynucleotide triphosphate precursors @ a replication fork. By a multienzyme complex, replication machine
- Fidelity determined, by base pairing (GCAT). Presence of proof reading enzyme in DNA polymerase
- Synthesis of a new DNA strand, using RNA primer. Occurs continuously on leading strand + discontinously on the trailing strand.
What are the 4 main stages of mitosis?
- Prophase
- Metaphase
- Anaphase
- Telophase
What happens during prophase?
- nucleus becomes less definite
- microtubular spindle apparatus assembles
- centrioles migrate to poles
What happens during prometaphase?
- Nuclear membrane breaks down
- Kinetochores attach to spindle in nuclear region
What happens during metaphase?
- chromsomes align in the equatorial plane
What happens during anaphase?
- chromatids separate and migrate to opposite poles
What happens during telophase?
- daughter nuclei form
What happens during cytokinesis?
- division of cytoplasma
- chromosomes decondense
Describe the drugs that act on the cell cycle:
S phase active
- 5 Fluoro uracil
- This is an analogue of thymidine. Blocks thymidylate synthesis
- Bromo deoxyuridine
- Another analogue that might be incorporated into DNA + detected by antibodies, to identify cells that have passed through the S phase
Describe the drugs that act on the cell cycle:
- M phase active [PVC]
- Paclitaxel • Taxol, stabilises microtubules • Prevents de polymerisation - Vinca Alkaloids • Similar reaction to colchicine - Colchincine • Stabilises free tubulin • Preventing microtubule polymerisation + arresting the cells in mitosis - used in karyotype analysis
5 fluorouracil, paclitaxel, the vinca alkaloids + tamoxifen are used in cancer treatment
What are the cell cycle checkpoints?
- There are controls that involve specific protein kinases + phosphatases
- These ensure strict alteration of mitosis + DNA replication
> DNA completely repicatied, DNA not damaged
Chromosomes aligned on splindle
Cells responsive to growth factors - this is the main site of control of cell growth
Restriction point - DNA not damaged, cell size, metabolite/nutrient stress
Cyclin dependent kinase activity controls cell cycle progression : describe the regulation of cyclin CDK activity
- Cyclical synthesis (gene expression) + destruction (by proteasome)
- Post translational modification, by phosphorylation
○ Depending on the modification site might result in:
§ Activation, inhibition or destruction - Dephosphorylation
- Binding of cyclin dependent kinase inhibitors.
Describe the characteristics of the retinoblastoma protein
- It is a key substrate of G1 + G1/S cyclin dependent kinases
- Unphosphorylated RB binds E2F.
○ Prevents its stimulation of S-phase protein expression - Released E2F stimulates expression of more cyclin E + S phase proteins
DNA polymerase, thymidine kinase, PCNA etc. DNA replication will start
Describe the characteristics of cyclin dependent kinase inhibitors
(There are 2 families) - describe Family 1 of cyclin dependent kinases [CDKN1]
- CDK inhibitory protein / kinase inhibitory protein (CIP / KIP )family - aka . CDKN1
- Expression of members of this family are stimulated weakly by TGFb + strongly by DNA damage, involving TP53
- Inhibit all other CDK - cyclin complexes : late G1, G2, M
- Gradually sequestered by G1 CDKs thus allowing activation of later CDKs
Describe the characteristics of cyclin dependent kinase inhibitors
(There are 2 families) - describe Family 2 of cyclin dependent kinases [CDKN2]
- Old name INK4. Expression is stimulated by TGFb
- Specifically inhibit G1, CDKs
- e.g. CDK4 the kinase activated by growth factors
List the sequence of events that are triggered by growth factors
- Growth factor signalling activates early gene expression
- Transcription factors: FOS, JUN, MYC. - Early gene products stimulate delayed gene expression,
- Cyclin D, CDK2/4, E2F transcription factors - E2F sequestered by binding to unphosphorylated retinoblastoma protein (RB)
- G1 cyclin CDK complexes will hyperphosphorylate RB + then G1/S cyclin - CDK complexes will hyperphosphorlate RB which will release E2F
- E2F will stimulate expression of more Cyclin E and S phase proteins
- DNA polymerase, thymidine kinase, proliferating cell nuclear antigen
- S phase cyclin CDK and G2/M cyclin CDK complexes build up, in INACTIVE forms- These switches are activated by post translational modification or removal of inhibitors
- This will drive the cell through S phase and mitosis
- These switches are activated by post translational modification or removal of inhibitors
Summary of the key steps that precede apoptosis
- Growth factors binding to receptors. Induces gene expression
- G1 and G1/S Cyclin-CDK complexes phosphorylate RB in the absence of inhibition by CKIs (expression of these is regulated by TP53 or TGFb)
- E2F released, stimulating expression of genes required for S-phase
- Cell replicates DNA (expression of S-phase Cyclin-CDK complexes)
- If all DNA replicated, G2/M Cyclin-CDK complexes cause cell to enter mitosis. If chromosomes aligned on spindle, exit from mitosis is triggered
- If process fails, TP53 initiates apoptosis
Causes/ mechanisms of cell damage + DNA - Genetic problems
- Abnormal number of chromosmes (aneuploidy)
- Abnormal chromosomes (deletions + translocations )
- Increased frailty (fanconis anaemia)
- Failure of repair (Xeroderma pigmentosa)
- Inborn errors (storage disorders i.e. Tay Sachs disease)
Causes/ mechanisms of cell damage + DNA - Traumatic damage
- Blood flow interruption
- Direction cell rupture
Entry of foreign agents
Causes/ mechanisms of cell damage + DNA - Inflammation
- Vasculitis
- Atherosclerosis
- Trauma
- Thrombo embolism
Causes/ mechanisms of cell damage + DNA - Infection
- Toxic agents
- Competition for nutrients, intracellular replication
- Viruses/mycobacteria provoking immune response
Causes/ mechanisms of cell damage + DNA - Physical
Irradiation, heat, cold, barotrauma
Causes/ mechanisms of cell damage + DNA - Chemical
- Acids + corrosives
- Specific actions like enzymes
- Interference with metabolism like alcohol
What are the 3 basic mechanisms that cell death is caused by
- Necrosis
- Apoptosis
- Autophagic cell death
What are the characteristics of necrosis
- Most common cause of cell death. Occurs after stresses like:
• Ischaemia, trauma, chemical injury
What are the characteristics of apoptosis
- Programmed cell death
- Designed to get rid of unwanted host cells through activation of coordinated + internally programmed series of events
- Effected by a dedicated set of gene products
What are the characteristics of autophagic cell death?
- Degradation of normal proteins that are involved in cellular remodelling that are found during:
Metamorphosis, Ageing, Differentiation + digestion and removal of abnormal proteins, that would have accumulated after toxin exposure, cancer, or disease
What induces the death of breast cancer cells?
- Autophagic cell death. These is degradation of the normal proteins that are involved in cellular remodelling.
What are the causes of necrosis
- Lack of blood supply to cells or tissues. Like injury, infection, cancer, infarction + inflammation.
Describe the characteristics of necrosis
- Whole groups of cells are affected
- This leads to injurious agent or event
- Reversible events will proceed irreversible
- Energy deprivation will cause changes
- e.g. cell unable to make ATP because of oxygen deprivation
- Cells will swell because of water influx - ATP needed for ion pumps to work
- There is haphazard destruction of the organelles, and nuclear material by enzymes from ruptured lysosomes
- Cellular debris stimulates inflammatory cell response
What is the microscopic appearance of necrosis : the nuclear changes
- Pyknosis
- Chromatin condensation + shrinkage - Karyorrhexis
- Fragmentation of the nucleus - Karyolysis
- Chromatin dissolution by DNAse. Causes fading in basophilia of the chromatin
Describe the microscopic appearance of necrosis : describe cytoplasmic changes
- Opacification
- Denaturation of the proteins, with aggregation - Eosiniphilia
- Exposure of basic amino acids - Complete digestion of cells by enzymes
- Causes the cell to liquefy - liquefactive necrosis
Describe the microscopic appearance of necrosis : describe biochemical changes
- Release of enzymes like creatine kinase, or lac dehydrogenase
Release of proteins like myoglobin
Describe the clinical investigations that are associated with cell death - Muscular dystrophy
- Damaged muscles will release creatine kinase + lac dehydrogenase
- M3 and M3H isoforms
Describe the clinical investigations that are associated with cell death - Heart attack
- Damaged muscle cells release lactate dehydrogenase
H3 + H3M isoforms
Describe the clinical investigations that are associated with cell death - bone + liver disease
- Damaged tissues. Release alkaline phosphatase + lactate dehydrogenase isoforms
- Different isoforms are specific to various tissues
What are the 5 types of necrosis
Coagulative necrosis
Liquefactive necrosis
Caseous necrosis
Fatty necrosis
Fibrinoid necrosis
Coagulative necrosis characteristics
- Hypoxic environments
- Cell outlines remain after cell death + can be observed by light microscopy
- Myocardial infarction, infarct of the spleen
Liquefactive necrosis characteristics
- Associated with cellular destruction + pus formation
- Like pneumonia
Caseous necrosis characteristics
- Mix of coagulative necrosis + liquefactive necrosis
- e.g. Tuberculosis
Fatty necrosis characteristics
- Results from actions of lipases on fatty tissues
- Acute pancreatitis
Fibrinoid necrosis characteristics
- Caused by immune mediated vascular damage
- Marked by deposition of fibrin like proteinaceous material in arterial walls
Appears smudgy + acidophilic on light microscopy
What are the functions of necrosis
- Removes damaged cells from organism: failure to do so might lead to chronic inflammation
What are the functions of apoptosis?
- Selective process for deletion of 1. Superfluous 2. Infected 3. Transformed cells
What processes are apoptosis involved in?
- Embryogenesis, metamorphosis, normal tissue turnover, endocrine dependent tissue atrophy, variety of pathological conditions
Give 8 examples of apoptosis.
- Cell death in embryonic hand to make individual fingers
- Apoptosis that is induced by growth factor deprivation (neuronal death from lack of NGF
- DNA damage mediated apoptosis - if the DNA is damaged due to radiation or chemo therapeutic agents: there is an accumulation of p53 (which is a tumour suppressor gene product).
- This arrests cell cycle and enables the cell to repair damage
- If repair process fails, p53 will trigger apoptosis
- Cell death in tumours, causing regression
- Cell death in viral diseases like viral hepatitis
- Cell death that is induced by cytotoxic T cells
- Like cellular immune rejection or graft vs. host disease
- Death of neutrophils during actue inflammatory response
- Death of immune cells (both T and B lymphocytes) after depletion of cytokines as well as death of autoreactive T cells in the developing thymus.
Apoptosis role in frog development
- Apoptosis helps to eliminate the tail during the metamorphosis of a tadpole into a frog
Apoptosis role in mouse development
- There is apoptotic cell death during the development of mouse paws
What are the factors that influence the balance of life and death at the cellular level?
- growth factors
- cytokines
- Death domain ligands
- DNA damaging agents
- lack of growth factors
- disruption of cell-cell and or cell-matrix contacts
- cell-cell and or cell-matrix contacts
What are the 2 types of apoptosis
Intrinsic or extrinsic
Describe the intrinsic pathway for apoptosis?
- Withdrawal of growth factors, like IL3
- There are extracellular signals e.g. TNF
- T cell or NK (natural killer) like granzyme.
What are caspases
- Cysteine aspartate specific proteases
What do caspases do (cysteine aspartate specific proteases)
- Cysteine proteases that play a central role in initiation of apoptosis
- Most proteases are synthesised as inactive precursors that need activation - usually partial digestion by another protease.
What happens when there is caspase activation
- Caspase activation leads to characteristic morphological changes of the cell like shrinkage, chromatin condensation, DNA fragmentation + plasma membrane blebbing
What are the 7 steps of apoptosis
- Single, or few cells selected
- Programmed cell death
- Irreversible once initiated
- Events are energy driven
- Cells will shrink, as the cytoskeleton is disassembled
- There is orderly packaging of organelles + nuclear fragments in membrane bound vesicles
- New molecules expressed on vesicle membranes stimulate phagocytosis - no inflammatory response.
What microscopic changes do you see in apoptosis
- Nuclear changes 2. Cytoplasmic changes 3. Biochemical changes
What microscopic changes do you see in apoptosis - the nuclear changes
- Nuclear chromatin condenses on nuclear membrane
2. DNA cleavage
What microscopic changes do you see in apoptosis - the cytoplasmic changes
- Cell shrinkage, organelles are packaged into membrane vesicles
- Cell fragmentation, membrane bound vesicles bud off
- Phagocytosis of cell fragments by macrophage + adjacent cell
- No leakage of the cytosolic components
What microscopic changes do you see in apoptosis - the biochemical changes
- Expression of charged sugar molecules on outer + inner surface of membranes (recognised by macrophage + enhances phagocytosis)
- Expression of phosphatidylserine on extracellular leaflet of apoptotic cell
- Protein cleavage by proteases, caspases
How do we activate the initiator caspases
- By induced proximity, for example:
- In response to receptor dimerisation upon ligand binding
- Cytochromc C release from the mitochondria
What are the characteristics of Cytochrome C
- Mitochondrial matrix protein
- Released in response to oxidative stress by a permeability transition
- Any inducers of the permeability transition also eventually induce apoptosis
How is the release of cytochrome c regulated?
BCL-2 family
- BCL-2 is a member of a multi gene family in mammals
- The BCL-2 family members form dimers
How is the release of cytochrome c regulated?
BCL-2 family (Anti-apoptotic)
- BCL-2
- BCL-XL
- Others
How is the release of cytochrome c regulated?
BCL-2 family (Pro apoptotic )
- Bax
- Bad
- Bid
P53 and apoptosis - describe the link
- Mutations in p53 gene are the most common mutations in cancer
- Some mutations can destroy ability of p53 to induce apoptosis
Give a definition of pathogens
Ø Disease causing microorganisms
Ø Opportunistic pathogens
• Will only infect the immunocompromised
• Local/systemic, like Staph Epidermis IV line Pneumocystis in HIV infection
Ø Virulence
• Capacity to cause disease
• e.g. virulent strains of commensal bacteria
Describe “Koch Posulates” - what the microorganism has to do
- Be present in every case of the infection
- Be cultured from cases in vitro
- Reproduce disease in an animal
- Be isolated from the infected animal
How to study pathogenesis - use of Virulence factors
- Identify factor / gene in virulent vs. non virulent strains
• Biochemical / molecular genetic studies
Pathogenity islands - can get groups of virulence genes
- Test the hypothesis in animal model, or in vitro
Compare the effects of removing / blocking virulence factor
What are the 4 stages of pathogenesis
- Adherence +/- entry
- Multiplication
Ø Local / general spread - Evasion of host defences
Ø Each stage - Tissue damage
Not all microbes need all 4 stages
Describe Stage 1 Adherence
he bacterial "adhesins" will attached to the surface, e.g. the: • Skin • Urogenital • GI • Respiratory tracts
E coli “P” fimbrae “Pili US”
- Bind P blood group of the uroepithelial cells
Neisseria Gonnorrhoeae fimbrae
- Attach to mucosal cells
- Non fimbriated mutants are less pathogenic
Vibrio cholera fimbriae - Bind intestinal epithelial cell receptors
Strep pyogenes - Lipoteichoic acid binds to fibronectin receptors in pharynx.
describe tears as a non immunological host defence
- cleansing action
- also contains antibacterial substances, e.g. lysosome
describe mucus as non immunological host defence
- barrier to contact of organisms + cell surfaces. May block carb ligand-receptor interactions
describe defensins as non immunological host defence
- antibacterial peptides produced by certain epithelial cells, e.g. intestinal epithelium
- and of potential importance in the control of colonisation
describe intestinal peristalsis as non immunological host defence
- propels microorganisms that do not have a mechanism for colonising the small or large bowel
describe ciliated epithelium as non immunological host defence
- component of the mucocilary ladder which encases upper respiratory pathogens in bronchial mucus
- moves them to the posterior pharynx, where they can be swallowed + disposed of
describe gastric acid as non immunological host defence
- lethal to micro organisms without protective mechanisms
describe microbial flora as non immunological host defence
- on skin + certain mucosal membranes
- able to occupy niches + produce metabolic products that regulate other organisms e.g. antimicrobial substances such as colcins
Describe the process of multiplication (stage 2)
Local surface infection only
- Vibrio cholera
- Some strains of N gonorrhoeae
Local Invasion
- Shigella
- Some Staph Aureus
Wider Invasion
- Through blood, lymph, (nerves)
- S typhi, N meningitidis, Staph aureus
May be critical for transmission
- Respiratory
- Faeco oral + sexual content
Describe the process of evasion of host defences (stage 3)
- Each step in specific & non specific immunity
• Antigenic variation (e.g. N meningitidis)
• Capsules can stop contact with the phagocyte
Ø S Penumoniae B anthracis
• Inhibit phagolysosome formation
Ø M tuberculosi, Listeria monocytogenes
• Immunosuppress host (some of the toxins will act as superantigens)
Describe anti phagocytic actions
Ø Toxin release Ø Opsonisation prevented Ø Contact with phagocyte prevented Ø Phagolysosome fusion inhibited Ø Escape into the cytoplasm Ø Resistance to killing
Describe anti phagocytic actions - 1. Toxin release
- The organism will release the toxin
- The phagocyte is killed by this toxin
Describe anti phagocytic actions - Opsonisation prevented
- Organism makes protein. This prevents contact with the phagocyte
• e.g. streptococcus penumoniae
• Haemophilus
Bacillus anthracis
Describe anti phagocytic actions - contact with phagocyte prevented
- Organism possesses a capsule
- Which prevents contact with the phagocyte
• Streptococcus pneumoniae
• Haemophilus
Bacilus anthracis
Describe anti phagocytic actions - phagolysosome fusion inhibited
- There is fusion of phagosome + lysosome inhibited by organism
• e.g. Mycobacterium Tuberculosis
• Toxoplasma
Chlamydia
Describe anti phagocytic actions - escape into the cytoplasm
- The organism escapes from the phagolysosome ==> into the cytoplasm
- & replicates within the phagocyte
• e.g. leishmania, T cruzi
Describe anti phagocytic actions - 6. Resistance to killing
- The organism will resist killing by producing antioxidants
• e.g. by catalase in Staphylococci, or by scavenging free radials
By phenolic glycolipid of M. Leprae
What can virulence factors do? - Pilus
Ø Aid attachment to human mucosal epithelium. Contains constant + hypervariable regions - analogous to immunoglobulins (Igs), that contribute to antigenic diversity in gonococci
What can virulence factors do? - Por proteins
Ø Forms pores through the outer membrane
Ø Antigenic
Ø Specific serotypes associated with virulence
What can virulence factors do? - opa proteins
Ø Assist binding to epithelial cells
What can virulence factors do? - LOS
Ø Lipo oligo saccharide
Ø Endotoxin activity
What can virulence factors do? - Rmp proteins
Ø Inhibits cidal activity of serum
What can virulence factors do? - IgA protease
Ø Core contains enzyme
Ø Released by cell to destroy IgA1
What can virulence factors do? - capsule
Ø Resists phagocytosis
Stage 4. Damage to host : describe what occurs
- Direct damage by microbe or toxins
- Locally
○ Enzymes : Staph aureus
○ Toxins : Clostridium perfringens, V cholera
- Systemically
○ Exotoxins C diptheriae C tetani - Caused by hosts immune response
- Immunopathology
What are the types and consequences of host damage, as a result of bacterial infection
- Acute inflammatory changes
- Damage by bacterial enzymes
- Exotoxins
- Endotoxin & other causes of sepsis
- Superantigen mediated, e.g. toxic shock syndrome
- Immunopathology:
Ø Immune complex disease (Type 3 hypersensitivity)
Ø Molecular mimicry
Ø Cellular immune response (Type 4 hypersensitivity)
Acute inflammatory changes: symptoms of infections (Local symptoms)
Ø Inflammation
- Redness, swelling, warmth, pain, loss of function
- Pus - pyogenic infection
Acute inflammatory changes: symptoms of infections (systemic symptoms)
Ø Fever, rigors, chills, tachycardia, tachypnoea
Acute inflammatory changes: causes of local symptoms
- Mainly secondary to response of the local small blood vessels with:
• Increased blood flow
• Increased permeability to fluid & plasma proteins
• Increased stickiness of vascular endothelium
• Emigration of phagocytes to site of infection
Acute inflammatory changes: causes of inflammatory response
- Inflammatory response = triggered by release of products from the bacteria, e.g. toxins & enzymes
- & amplified by release of products from host cells
• Histamine, prostaglandins, leukotreines, kinins
Describe acute inflammatory changes
- Results in accumulation of: phagocytes - mainly neutrophils (pus cells) + some monocytes, complement and other factors & exudate at the site of infection
- Pyogenic infection
- Pyogenic organisms include staphylococci + streptococci & meningococci
Acute inflammatory changes characteristics
- Host fights the bacterium
- Inflammation = weapon of the host
- Damage to the hosts tissues may be as a result of the weapons of the bacterium, such toxic products
• e.g. leukocidin from staphylococci - Results in dead & dying neutrophils - pus
- Or damage may be due to inflammation itself
Bacterial enzyme profile:
Hyaluronidase
Origin of hyaluronidase
Ø Streptococci
• e.g. streptococcus pyogenes
Action of hyaluronidase
Ø Will break down hyaluronic acid
Result
Ø Disruption of tissue mosaic
Ø Allowing bacteria & inflammatory exudate to travel deeper and further
Bacterial enzyme profile:
Alpha-Lecithinase
Source of alpha-lecithinase
Ø Clostridium perfringens
Action of alpha-lecithinase
Ø Splits lecithin
Ø Found on the surface of many cells
Result
Ø Major tissue damage caused
Describe the characteristics of bacterial exotoxins
Ø Most exotoxins = proteins that are secreted by the bacterium
The ways that bacterial exotoxins behave
Ø Enzymatic lysis (e.g. alpha-lecithinase)
Ø Pore formation
Ø Inhibition of protein synthesis
Ø Hyperactivation
Ø Effects on nerve-muscle transmission
How else can bacterial exotoxins be classified
- Molecular structure e.g. subunits
- Site of actions e.g. enterotoxins
Ø Exotoxins are made by many bacteria including gram positive and gram negative species
What is an endotoxin
- An integral part of the bacterial cell
- Found only in gram-negative bacteria
- Usually only released when the bacterial cell is damaged
- Evoke a variety of effects at many different sites
Give examples of endotoxin mediated disease
Ø Neisseria meningitidis • Meningococcal meningitis • Meningococcemia Ø Escherichia coli Ø Klebsiella Ø Pseduomonas aeruginosa
What are the actions of endotoxin?
- Activation of the macrophage/monocyte cells.
- These macrophage/monocyte cells will release:
• IL-1
• IL-6
• IL-8
• Platelet activating factor
• Tumour necrosis factor (TNF-alpha) - These also stimulate production of prostaglandins & leukotrienes.
- Cytokines act at various sites, including the endothelium, liver, clotting cascade.
- Results in:
Ø Increased vascular permeability
Ø Hypotension; which leads to shock, fever, disseminated intravascular coagulation (DIC), multiple organ failure
What is bacteraemia?
Ø Bacteria in the blood
What is septicaemia?
Ø Bacteria in the blood; with symptoms
Sepsis: systemic inflammatory response syndrome (SIRS) characteristics
- Gram positive organisms, e.g. Ø Staphylococcus Aureus Ø Streptococcus Pyogenes Ø Streptococcus Pneumoniae ○ May also cause septicaemia/SIRS
What is Toxic Shock Syndrome caused by
- Toxins, that are produced by certain strains of:
Ø Staphylococcus aureus: toxic shock syndrome toxin (TSST)
Ø Streptococcus pyogenes: Streptococcal pyrogenic exotoxin (SPE) - These toxins might act as superantigens
Describe the actions of superantigens?
- They are able to act simultaneous with MHC class 2 antigens, on
• Antigen presenting cells and
• Specific Vbeta regions, of T lymphocytes - This will activate macrophages/monocytes to elicit IL-1, IL-6, TNF-alpha and interferon-y
Multiorgan pathology: immunopathology
Humoral immunity
Ø Production of antibodies by B-lymphocytes
Cellular immunity
Ø T-lymphocytes
What are the characteristics of immune complex disease
- Type 3 hypersenstivity reaction Stretococcus pyogenes & glomerulonephritis
- Host produces antibodies against streptococcal antigens
- Antibodies bind to antigens to form immune complexes
- Immune complexes are deposited in glomerular capillary walls, in diffuse, irregular (lumpy bumpy) distribution
- Activation of complement, influx of inflammatory cells and release of tissue damaging enzymes etc.
Describe the characteristics of molecular mimicry
- Throat infection with Streptococcus pyogenes
- Antibodies against streptococcal antigens (cell wall) are produced
- These antibodies will cross-react with antigens of the host, (similar molecular structure)
- Sites of cross reactivity:
• Myocardium
• Synovium
• Brain
Examples of molecular mimicry?
- Rheumatic heart disease/ rheumatic fever
- Cross reactions demonstrated between
Ø Group A carbohydrate of streptococcus & structural glycoprotein of heart valve
Ø M-protein of streptococcus and cardiac muscle - Binding of antibodies, to host antigen will activate complement and will lead to inflammatory response
- Cell mediated response, also probaly will occur
- Granulomas form in the tissue - Aschoffs nodules
- Cross reacting antibodies in synovium lead to inflammation of joints - arthritis
- Antibodies may also cross react with neurons in the caudate & subthalamic nuclei, leading to involuntary movement:
Ø Syndenhams Chorea
Ø St. Vitus’s dance
Cellular immune responses
- Type 4 hypersensitivity reactions.
• T helper cells react to specific antigens. e.g. Mycobacterium Tuberculosis
• T cells will release cytokines including (TNF-alpha) that activate macrophages
• These + other toxic products might cause tissue damage
• In chronic infections, degree of tissue damage may be extensive
Cellular immune responses
- Characteristic response is the granuloma containing epitheliod & giant
- In TB, necrosis is characteristic
- Macroscopically, granulomas form “tubercules”
- Necrosis is described as caseous (cheesy)
Granulomas characteristics
- May form with other infections e.g. leprosy syphilis (gummas) and schistosomiasis
- Necrosis may be absent in these conditions
- This may reflect different spectrum of cytokine release and cellular activation
How does the immune system defend against bacteria?
- Recognises bacteria. Attaches/ invades
- Finds bacteria + ensures recruitment of defence measures to that site.
- Kills bacteria or cells containing bacteria
- Mops up released toxins that still damage after bacteria are killed - defuse
- Mechanism to remember the bacteria - if they invade again our defences can be mobilised rapidly - memory
Describe the balance between the microbe and the host - properties of the microbe - pathogenic mechanisms)
- adhesins, toxins, capsules
Describe the balance between the microbe and the host - properties of the host : defensive mechanisms
- natural barriers, defensive cells, complement, immune response
What are the stages of infection?
- Acquisition
- Colonisation - adherence
- Penetration
- Spread
- Immune evasion
- Damage
- Transmission
- Resolution
Immune response:
Ø Site of infection, stage, prior exposure
Ø Damage limitation, clearance
Ø Immune protection
What are the types of infection?
Local
- Surface infection; wound
Invasive
- Penetrates barriers, spread
Systemic
- Via blood to other sites
- Effects at different site from colonisation: toxins and endotoxins
Immunopathology
Ø Inflammation
Ø Cross reaction antigens (rheumatic heart disease)
Ø Autoimmunity
Ø Granuloma
How to design an immune system to defend self against bacteria? When bacteria are on the epithelial surfaces
• If not attaching, or signalling there is no harm done.
How to design an immune system to defend self against bacteria? When bacteria are Free living, in the blood, EC
• As plantonic growth, or biofilms
How to design an immune system to defend self against bacteria? When bacteria are inside cells
• Cytoplasmic and vacuolar
Surface defences: mucosal and epithelial surfaces
Act as watchdog
- Cells + signalling
Shedding
- Removal and threat of rapid rep
Normal flora
- Microbial antagonism & microbiome balance
- There are 3 examples of this:
○ Immunological - innative and adaptive
○ Physical barriers
○ Vascularity
Defences of the tissue & blood - - Usually involves tissue damage + controlled by feedback mechanisms
(Non-specific feedback mechanisms)
- Transferrin
- Complement
- Acute phase proteins (released by the liver)
- Phagocytes - monocytes and macrophages
- PMNs - neutrophils
Defences of the tissue & blood - - Usually involves tissue damage + controlled by feedback mechanisms
(Adaptive feedback mechanisms)
- Antibodies
- Macrophage activation
T cells
Recognition, danger and signalling: orchestration of innate and adaptive immune defences
- There is orchestration of innate and adaptive immune defences
Continuous, active, seamless, regulated
What are the characteristics of inflammation
- Response to tissue injury. The functions are to bring serum molecules and cells, to the site of infection
Ø Increases blood supply
Ø Increases capillary permeability
Ø Migration of cells from the blood to the tissue (PMNs, Mps,) - This is an ordered, regulated proecss.
- The cardinal signs of inflammation are heat, pain, redness and swelling (calor, dolor, rubor, tumour)
- Vasodilation, oedema, complement activation
- Mast cell degrannulation, PMNs recruitment, clotting
the virulence factors actions
- Promote colonisation and adhesion, to establish infections (e.g. adhesins)
- Promote tissue damage
- Transmission, e.g. toxins
- Subvert immune defences
Immune response against these might protect from disease
The roles of complement in non-adaptive (innate) immunity
- Induces inflammatory response
- Promotes chemotaxis
- Increases phagocytosis by opsonisation
- Increases vascular permeability
- Mast cell degranulation
- Lysis of cell membranes
• Pro inflammatory and antibacterial
Describe the complement pathways + bacterial capsules
- There are many ways that bacteria can interact with complement
- Mannose binding lectin, is an acute phase protein.
• Will bind MBL associated serine protease (MSP)
Describe the process of opsonisation and phagocytosis
- Uncoated (by antibody) bacteria, are phagocytosed poorly
- On coating with antibody, adherence to phagocytes is enhanced. And will increase complement fixing.
Actions of macrophages and neutrophils (PMNs)
Phagocytose free bacteria
