Pathology and Immunity

Question 1

describe the different cells and molecules involved in injury vs repair

Answer 1

injury
- toxic oxygen metabolites
- proteases
- neutrophil chemotactic factors
- coagulation factors
- nitric oxide
- Arachidonic acid metabolites like prostaglandins

repair
- fibrosis
- growth factors, fibrinogenic cytokines
- angiogenesis factors and remodelling collagenases

M1 and M2 macrophages are vital for this. M1 are proinflammatory and M2 are antiinflammatory

Question 2

describe carcinogenesis and carcinogens

Answer 2

carcinogens, like chemical agents, viruses, physical agents, induce genetic changes that result in neoplastic potential.

chemical carcinogenesis:
- initiation of permanent DNA damage
- promotion by an agent
- includes smoking, diet, drugs, alcohol, asbestos.

physical carcinogenesis
- radiation damages DNA
- UV damages DNA

viral carcinogenesis
- DNA and RNA viruses
- epstein barr virus leads to burketts lymphomas and nasopharyngeal carcinomas
- hep B and C lead to hepatocellular carcinomas
- human papillomavirus leads to cervical and oropharyngeal carcinomas

carcinogenesis
- initiation - carcinogen induces genetic change resulting in neoplastic potential
- promotion: another factor stimulates the initiated cell for division
- progression: additional mutations result in malignancy

Question 3

explain autoimmunity

Answer 3

• specific chronic inflammation
• unwanted response to bodys own cells and tissues
• breach of tolerance to self antigens or commensal bacteria
• sustained immune response generates cells and molecules that destroy tissues

Question 4

explain the vascular changes and mediators released in response to inflammation

Answer 4

• vasodilation
• endothelial cells swell and retract
• vessels become leaky and exudate, allows passage of water, salts and immune cells.
• neutrophil movement is aided by upregulation of adhesions on endothelium
• exudation allows the migration of neutrophils and macrophages into the damaged tissues

exudation leads to oedema due to a build up of fluid, salt, nutrients, complement and fibrin.

histamine, bradykinin and prostaglandins are chemical mediators produced in inflammation that produce vasodilation.

histamines are produced from histidine and are released by degranulation.

prostaglandins are produced from arachidonic acid and COXIII enzyme.

Question 5

list the functions of all the CD4+ t cell subsets

Answer 5

th1 - support macrophages to destroy intracellular mcrobes

th2 - produce cytokines to recruit and activate mast cells and eosinophils. promote barrier immunity at mucosal surfaces

th17 - secrete IL-17 cytokines to induce local non professional immune cells to release cytokines and chemokines

tfh - induce specific b cell responses

treg - suppress t cell activity to prevent autoimmunity

Question 6

list defence cells and their functions and locations

Answer 6

cells of myeloid origin
- neutrophils
- macrophages
- mast cells
- eosinophils
- basophils

cells of lymphoid origin
- t and b cells
- natural killer cells
- innate lymphoid cells

originate in the bone marrow from haemopoetic stem cells

mast cells
- release histamines and heparin
- recruit macrophages and neutrophils
- wounding healing, allergic reactions, defence against pathogens
- found in connective tissues and mucous membranes
- early responders
- granulocytes

macrophages
- phagocytic cell
- consumes foreign pathogens and cancer cells
- stimulates other immune cells
- antigen presentation
- migrates from the blood into tissue

natural killer cells
- kills tumour and viral infected cells
- circulates in blood
- large cells with granules
- hold back viruses until adaptive immunity kicks in

dendritic cells
- can be myeloid and lymphoid in origin
- present antigens to trigger adaptive immunity
- found in skin, lung, intestines. when activated they go to lymph nodes

monocytes
- differentiate into macrophages and dendritic cells when there is inflammation
- stored in the spleen, move through blood to infected tissues

neutrophils
- phagocytic granulocytes - produce NETs
- first responders
- 60% of all leukocytes
- releases toxins that kill or inhibit bacteria and fungi
- recruits other immune cells to the site of infection
- migrate from blood vessels into tissues
- main cellular component in gingival crevicular fluid

basophils
- responsible for defence against parasites
- release histamine during inflammation and allergies
- circulate in the blood

eosinophils
- release toxins that kill bacteria and parasites
- circulate in blood and migrate to tissues

innate lymphoid cells
- non cytotoxic, but part of NKC family
- ILC1, ILC2 and ILC3
- link adaptive and innate immunity

t cells
- give rise to cellular immunity
- recognise peptides being presented by APC via t cell receptor
- undergo thymic education so they do not respond to self peptides
- t helper support other immune cells
- cytotoxic t cells destroy endogenous cells
- t reg suppress other cells in the immune system

b cells
- produce antibodies
- clonal expansion of b cells produces either plasma cells or memory b cells

Question 7

what is innate immunity

Answer 7

first line of non specific defence, occurring within 1-4 days of infection

there is no memory or lasting protective immunity

present from birth

recruits immune cells to the site of infection, and responses are broad spectrum

Question 8

describe degranulation and its role in inflammation and immune responses

Answer 8

granules are vesicles containing preformed mediators like proteinases, antimicrobials and chemical mediators

the main cell types to undergo degranulation are eosinophils, basophils, neutrophils, natural killer cells, and mast cells

mast cells, basophils and eosinophils are associated with allergic, hypersensitivity reactions. basophils and eosinophils also have an important role in antiparasitic immunity.

histamine is amolecule released through degranulation. it has a role in vasodilation, increased vascular permeability, bronchconstriction, smooth muscle contraction, and itching.

neutrophils degranulate to produce NETs, formed from proteins and chromatin.

natural killer cells degranulate to produce perforin and granzymes to kill abnormal cells and microbes.

Question 9

what is acute inflammation

Answer 9

response of living tissue to infection, develops quickly and initiates innate immunity.

there are three processes involved:

• vascular dilation
• increased vascular permeability
• neutrophil activation and migration

there are four main causes:
- microbial infection
- physical agents like trauma, radiation, heat and cold
- irritants and chemicals
- tissue necrosis

leads to rubor, calor, tumour, dolor and loss of function. can lead to abscess formation which leads into chronic inflammation.

whether chronic inflammation will occur depends on the nature of the harmful agent, the severity of the damage and the tissue involved.

the stages:

1 - initiation (microbial recognition by PRRs)
2 - progression (containment by innate immune cells and AMPs)
3 - amplification (recruitment of innate immune cells via chemokine and cytokines and vasodilation)
4 - resolution (healing and repair)

Question 10

what is adaptive immunity

Answer 10

cell mediated and antibody responses in a specific and acquired immune response. occurs after 4-10 days. has immunological memory because antigens are remembered by the b and t cell receptors.

t cells drive the cell mediated immunity, and activate macrophages, natural killer cells, and antigen specific helper and cytotoxic t cells .

b cells produce antibodies.

Question 11

define each of the different abnormalities of growth and outline their main features (developmental and acquired)

Answer 11

developmental disorders of growth:

agenesis
- organ does not develop at all

aplasia
- an organ fails to develop normal structure from the primitive embryonic structure

hypoplasia
- less tissue formed, normal structure
- enamel hypoplasia

hamartoma
- tumour like growth
- only grows when the patient is growing, but the growth is excessive
- eg pigmented naevi, haemangioma and lymphangioma

haemangioma
- type of hamartoma
- present at birth
- if developed later in life, it is a vascular malformation
- sturge weber syndrome

lymphangioma
- mostly cavernous
- cystic hygroma in newborns

pigmented naevi
- moles

ectopia
- normal tissue in abnormal site
- eg meckels diverticulum, ectopic pregnancies and ectopic teeth

acquired disorders of growth (adaptation of cells in response to environmental stresses)

atrophy
- reduced cell size
- occurs by reduced in organelle size, imbalanced cell loss, can involve apoptosis
- can be localised due to ischaemia, pressure, disuse, denervation, idiopathic
- can be generailsed, due to nutrition, hormones or senile

hypertrophy
- increased cell size due to increased production of cellular proteins
- muscle
- often occurs with hyperplasia

hyperplasia
- increase in cell numbers
- increased tissue size and function, regresses when stimulus is removed, only occurs in labile and stable cells
- eg gingival hyperplasia
- mechanism is growth factor driven, and increased output of cells from stem cells.
- eg liver regeneration

hyperplasia and hyperplasia together
- muscle growth
- goitre due to thryoid follicular hypertrophy and hyperplasia as a result of iodine deficiency

metaplasia
- change from one differentiation to another
- adaptive response due to change in environmental demand
- ciliated columnar in smokers becomes squamous
- barretts oesophagus whereby squamous becomes columnar

dysplasia
- disordered growth occuring in metaplastic tissue, severity may indicate malignant change

neoplasia
- abnormal mass of tissue
- persists after stimulus is removed

Question 12

what does anorexia and bulimia do to the mouth

Answer 12

• erosion of tooth enamel
• sensitive teeth
• enlargement of the parotid glands
• sweet breath aroma

Question 13

describe the role of growth factors in healing and repair

Answer 13

promote or inhibit cell growth and differentiation, they bind to receptors on cell surfaces

main functios:
- promomte cell survival
- locomotion
- contractility
- differentiation
- angiogenesis

vascular endothelial growth factor is important for angiogenesis: increases migration and function of endothelial cells as well

Question 14

describe the proceess of somatic hypermutation

Answer 14

initial exposure to antigen
- lag period of 2-5 days
- IgM is produced, as IgM production starts to decrease IgG is produced

second exposure
- IgG is produced in high amounts
- small amounts of IgM is produced as well but not nearly as high as before or as IgG

Question 15

describe mediator release from immune cells following microbial recognition

Answer 15

cytokines are small proteins that coordinate immune responses.

families of cytokines are interleukins, tumour necrosis factor, interferons

they signal through cytokine receptors

chemokines are small signalling proteins that guide immune cells to infection and are involved predominantly in cell recruitment.

Question 16

what are the signs of inflammation

Answer 16

vascular changes
- vasodilation and exudation
- increased blood flow causes heat and redness
- exudation and increased blood flow and lymph flow causes odema, swelling.
- exudate includes fluid salt glucose oxygen soluble mediators fibrin and antibodies and complement proteins
- increased lymph flow allows increased influx of inflammatory infiltrate
- fluid and salts dilute toxins in tissues and allow diffusion of mediators
- glucose and oxygen support growth and function of immune cells
- complement and antibodies allow for opsonisation
- fibrin involved in coagulation for blood clotting

mediator release
- pain caused by stretching of tissues and release of soluble mediators
- histamines, prostaglandins, leukotrienes, seratonin, and bradykinin are chemical
- protein are cytokines and chemokines
- histamine is produced from mast cells and helps with itching, dilation, and activating other immune cells
- bradykinin is involved in coagulation
- serotonin drives inflammatory response, produced from macrophages
- prostaglandins cause cell recruitment, cytokine production, pain, and tissue remodelling. most common is PGE2 and has a role in vasodilation as well

Question 17

describe the difference between passive and active immunity

Answer 17

passive
- we are given the antibodies and immunity without having to work for it
- natural - given to us via milk and pregnancy (IgA and IgG)
- acquired - given antibodies in an antidote ie if poisoned or venom

active
- we have to make the antibodies ourselves
- natural - we are exposed to an antigen and we must produce antibodies against it
- acquired - vaccinations - given weak or dead antigens to produce antibodies against so we are ready for the next exposure

Question 18

describe the process of immune cell recruitment to the site of infection

Answer 18

some immune cells are tissue resident, others must arrive from circulation via chemotaxis.

neutrophils follow a CXCL8 gradient to the site of inflammation

immune cells get into blood vessel walls from circulation via diapedesis via receptors on immune and endothelial cells interacting. these include selectins, integrins and immunoglobin superfamilies.

Question 19

describe phagocytosis and antigen presentation

Answer 19

phagocytes include neutrophils, macrophages and dendritic cells.

used for degrading and removing pathogens, antigen presentation, and disposal of apoptotic cells.

the stages of phagocytosis are recognition, engulfment, phagosome, phagolysosome, cell digestion, residual bodies, and exocytosis.

presenting endogenous proteins: MHC1, found on all nucleated cells, include viral and tumour cells. MHC1 presents to CD8+ t cells

presenting exogenous proteins: MHC2, happens after phagocytosis, found only on dendritic cells, macrophages and b cells. MHC2 presents to CD4+ t cells

antigen presentation links innate and adaptive immunity. leads to cell mediated responses or humoral b cell responses.

Question 20

describe the spread of malignant tumours

Answer 20

can be local, lymphatic, haemotogenous, transcolemic and intraepithelial

metastasis is the spread of malignant cells to distant organs forming secondary tumours

carcinomas pattern of spread
- lymphatics, then blood

sarcomas pattern of spread
- blood, then lymphatics

predictable patterns
- lung - lymph nodes - liver - bone - brain
- tongue - neck - lung - spine

Question 21

describe the receptors involved in adaptive immunity

Answer 21

there are three main receptors:
- t cell receptors
- b cell receptors
- MHC proteins

Question 22

describe the different auto immune diseases

Answer 22

psoriasis
- autoreactive t cells against skin associated antigens
- inflammation of skin, scaly patches

rheumatoid arthritis
- autoreactive t cells against antigens of joint synovium
- joint inflammation and destruction causing arthritis

graves disease
- autoantibodies against thyroid stimulating hormone receptor
- hyperthyroidism

hashimotos thyroiditis
- autoantibodies and autoreactive t cells against thyroid antigens
- destruction of thyroid tissue leading to hypothyroidism

systemic lupus erythematous
- autoantibodies and autoreactive t cells against dna and chromatin proteins
- leads to glomerulonephritis, vasculitis and rashes

sjogrens syndrome
- autoantibodies and autoreactive t cells against ribonucleoprotein antigens
- lymphocyte infiltration of exocrine glands, leading to dry eyes and mouth, can affect other organs

crohns disease
- autoreactive t cells against intestinal flora antigens
- intestinal inflammation and scarring

multiple sclerosis
- autoreactive t cells against brain antigens
- formation of sclerotic plaque in brain with destruction of myelin sheaths around axons
- muscle weakness, ataxia

type 1 diabetes
- autoreactive t cells against pancreatic islet cell antigens
- destruction of beta cells
- non production of insulin

Question 23

describe soft and hard tissue destruction in periodontitis

Answer 23

soft tissue
- regulated by matrix metalloproteinases
- these remodel gingival tissue
- through change in extracellular matrix

hard tissue
- osteoclastogenesis and osteoblastogenesis
- the RANKL/OPG ratio to maintain alveolar bone destruction - if there is too much RANKL being produced then there is too much bone being destroyed

Question 24

what does heart disease do to the mouth

Answer 24

pain radiates to the jaw due to inefficient oxygen to the heart muscle

Question 25

describe the nature, causes and effects of amyloidosis

Answer 25

amyloid is a fibrillar protein produced when there is pathology

amyloid light chain is derived from light chain immunoglobins from plasma cells

amyloid associated is derived from proteins synthesised in the liver

amyloid beta is associated with alzheimers disease

stimulated by chronic inflammation, multiple myeloma, ageing and drug abuse

when it accumulates in the walls of tissues and organs it can compromise their function

Question 26

what are the main effector functions of innate immune cells

Answer 26

• phagocytosis
• degranulation
• antigen presentation
• mediator release

Question 27

describe the responses to blood loss

Answer 27

immediate
- stop the bleeding (haemostasis)
- vascular response - smooth muscle spasms due to trauma, myogenic response and vasoconstrictors. endothelium is involved in platelet adhesion and aggregation
- platelet response - turbulent blood flow allows platelets to adhere collagen in vessel wall and clump together, this releases chemicals to cause further aggregation through positive feedback, then platelet plug forms
- plasma response - coagulation - plasma proteins and tissue components convert fibrinogen to fibrin. requires vitamin K to synthesise clotting factors which are activated in an enzyme cascade.
- common coagulation pathway: factor Xa, calcium, FV, and phospholipids convert prothrombin to thrombin which converts with fibrinogen to make soluble fibrin. factor XIII combines with thrombin to form XIIIa to form insoluble fibrin.
- coagulation: instrinsic pathway: vascular damage, XII, XI, IX, VIII released and work with phospholipid and calcium ions to form factor Xa that then works in the common pathway
- coagulation: extrinsic pathway: tissue damage released VII, tissue thromboplastin, which forms Xa which works in common pathway
- extrinsic is important for initiating clotting, intrinsic maintains the clot
- fibrinolysis removes clot using plasmin

short term
- restore the blood pressure
- lost blood volume reduces BP, so there are arterial baroreceptors that trigger mechanisms to restore BP
- baroreceptors are mediated by SNS, release of adrenaline, angiotensin II and vasopressin
- SNS increases heart rate, ventricular contraction, vasocontriction. increased stroke volume due to increased ventricular contraction and heart rate leads to increased cardiac output. increased arteriole constriction leads to increased TPR. increased MAP.

medium term
- restore the blood volume
- shift interstitial fluid into blood vessels (vasoconstriction increases TPR and there is reduced capillary BP which reduces hydrostatic pressure, more fluid being pulled back into the capillaries)
- decrease fluid loss in kidney (reduced glomerular filtration, increased reabsorption of water and electrolytes due to RAAS and ADH. RAAS releases renin, leads to angiotensin II, leads to aldosterone release, leads to increased reabsorption)
- increase fluid intake - hypothalamus produces desire to drink, due to increase plasma osmorality, reduced ECF, angiotensin II and dry mouth.

long term
- replace the blood constituents
- restored plasma proteins are released in 3-4 days
- RBCs are replaced through erythropoeisis

Question 28

give clear definitions of necrosis and apoptosis and describe the circumstances in which they arise

Answer 28

necrosis is cell death due to pathology, leads to irreversible cell injury. cell contents leak and there is inflammation. cell remains are removed by phagocytosis.

nuclear changes: pyknosis (nucleus shrinks, stains dark) karryorhexis (nucleus fragments), karyolysis (dna digested by endonucleases).

cytoplasmic changes: pale, swollen, eosinophilic

apoptosis:

• genetically programmed, orderly elimination of unwanted cells.
  can be pathological but usually occurs anyway. requires energy, does not cause inflammation.
• pathological triggers include protein misfolding due to ischaemia, viral infection, dna damage triggering p53.
• physiologically it occurs anyway to delete cell populations, maintain constant number of cells, delete inflammatory cells and self reactive t cells.

morphology:

• cell shrinkage, chromatin condenses
• cell membrane is intact
• apoptotic bodies can break off but they are phagocytosed.

Question 29

describe the role of plasma factors in innate immune responses

Answer 29

plasma contains four enzymatic cascades: complement, kinins, coagulation and fibrinolytic.

the complement system drives opsonisation and inflammatory responses, and forms membrane attack complex. complement proteins are produced in the liver and circulate in the blood.

complement has three pathways, classical alternative and mannose binding lectin, and leads to the production of anaphylatoxins.

anaphylatoxins increase vascular permeability, to allow increased fluid leakage and entry of immune cells into the area.

Question 30

what does diabetes do to the mouth

Answer 30

dry mouth
bad breath
burning tongue
inflammation
tooth decay

Question 31

describe the role of epithelium in innate immunity of the oral cavity

Answer 31

epithelium provides antimicrobial peptides, secretory IgA, lactoferrin, lysozyme and cystatins

antimicrobial peptides include beta defensins, human neutrophil peptides, and cathelicidins. they work by membrane disruption, or immune modulation by the activation and attraction of leukocytes

secretory IgA is found in saliva and prevents motility of bacteria and neutralises their toxins.

lactoferrin transports iron ions and has antimicrobial activity. it is produced by neutrophils

lysozyme targets cell walls of bacteria and is produced by both macrophages and neutrophils

cystatins have antiprotease activity and supports remineralisation

Question 32

list the cells involved in healing and repair

Answer 32

can involve regeneration or repair. regeneration is the formation of a functioning tissue, repair is replacement with a fibrous scar.

cells involved are labile, stable and permanent.
labile rapidly regenerate, stable can regenerate if need be, permanent cannot regenerate.

Question 33

describe the three main classes of chronic inflammation and their features

Answer 33

non specific chronic inflammation
- occurs due to failure to resolve acute inflammation
- persistent bouts of acute inflammation
- excessive suppuration
- infiltrate is dominated by macrophages t cells and b cells
- dynamic balance between destruction and repair
- ongoing repair

specific, primary chronic inflammation
- arises de novo
- or due to persistent exposure to agent
- can be granulomatous or not
- excessively activated macrophages
- can be induced by immunological or non immunological agents
- immunological include infective organisms, hypersensitivty, autoimmunity and fungi and parasites
- non immunological include foreign bodies like silic and metal or inert noxious material like asbestos

chronic granulomatous inflammation
- subset of specific chronic inflammation
- predominant cell are modified activated macrophages called epitheloid macrophages fusing to form giant cells
- delayed hypersensitivity type reaction or invading pathogens are immunological causes
- asbestos is non immunological cause.
- macrophages present antigens to lymphocytes which induce formation of epitheloid macrophages whcih contribute to giant cell formation which engulf foreign material
- eg orofacial granulomatosis

Question 34

break down the pathology of periodontitis

Answer 34

aetiology - bacterial origin of plaque
morphology - gingival tissue inflammation
pathogenesis - bacterial protease activity, elevated pro inflammatory response
sequelae - physical debridement of plaque, removal of infected tissue

Question 35

describe the structure of an antibody

Answer 35

Y shaped

two chains joined together

constant region
- attachment point for complement proteins

variable region
- undergo recombination so that every variable region is different for each antibody

two antigen binding sites per antibody

Question 36

outline what is meant by reversible and non reversible cell injury

Answer 36

reversible: cells adapt to changes in environment and return to normal when the stimulus is removed.

reversible morphology: cells can undergo cloudy swelling and fatty change. cloudy due to failure of membrane pumps and influx of fluid into the cell. fatty change is an accumulation of lipid vacuoles due to disrupted fatty acid metabolism. can occur due to alcohol abuse, liver becomes enlarged and pale. organelles can dilate, there is blebbing.

irreversible: permanent, cell death is the consequence.

morphology:
- membrane ruptures, organelles disperse, inflammatory response is activated.

whether the injury is reversible or irreversible depends on type, duration, and severity of the injury. also depends on how susceptible and vulnerable the effected cell is.

can be caused by hypoxia, physical agents, chemicals, drugs, infections, immunological reactions, nutritional imbalance, genetic defects.

immunological reactions include anaphylaxis, autoimmune reactions, and this is due to damage caused from inflammation

Question 37

describe the process of complement

Answer 37

20 proteins produced from the liver, activated during innate immunity to enhance the immune response - to “complement” it.

classical pathway
- antigen on microbial surface
- binds to IgG (if secondary immune response)
- Fc portion of antibody attracts complement proteins - C1 will bind to Fc portion
- C4 binds to C1
- C2, C3 binds
- C3 convertase will cleave C3 into C3a and C3b. C3a breaks off and moves away, C3b allows for the binding of C5b, which then binds C6,7,8,9.
- order of proteins is therefore C1-4-2-3b-5b-6-7-8-9.
- fate of C3a and C5a: mast cells release protease molecules that act on C3a and C5a to activate them, and they become chemotactic agents that guide immune cells to aid in the inflammatory response.
- C5b, 6, 7, 8, 9 form a channel and break off to form a membrane pore that can bind to the bacterial cell membrane and form a pore that allows for entry of water and ions into the cell to lyse the cell.
- C3b is exposed when MAC breaks off, and is an opsonin. there are C3b receptors on macrophages that will bind with C3b to phagocytose the entire complex.

alternative pathway
- bacteria has an antigen on the surface that can bind directly to C3b.
- C5a is released and enhances the inflammatory response, C5b binds to C3b.
- C5b-9 will form MAC
- C3b exposed, opsonisation for macrophages and neutraphils to arrive and phagocytose.

lectin pathway
- bacteria has an antigen on the surface called mannose.
- mannose binding lectin is a protein that binds to mannose.
- not an antibody mediated response, because this binding initiates the lectin pathway.
- C4 binds to mannose binding lectin.
- C2, 3, C3b, C5b, 6,7,8,9
- MAC and opsonisation.

Question 38

describe the hallmarks of cancer

Answer 38

how cancer cells differ from normal cells essentially

• evading apoptosis
• self sufficiency in growth signals
• insensitivity to anti growth signals
• sustained angiogenesis
• limitless replicative potential
• tissue invasion and metastasis

Question 39

describe shock and the common forms

Answer 39

inadequate blood flow to tissues associated with reduced CO and blood volume

can be reversible or irreversible

hypovolaemic shock
- reduced ECF volume

low resistance
- reduced TPR due to widespread vasodilation seen in anaphylactic shock

cardiogenic shock
- heart fails as a pump

Question 40

describe how the immune system recognises tumour cells and why many manage to evade the immune system

Answer 40

tumour associated antigens called neoantigens can be
- products of mutated genes
- overexpressed proteins
- viral proteins
- oncofetal antigens

occurs through elimination, equilibirium and escape

elimination
- cell mediated
- CD8+ t cells and NKCs and macrophages

cells can evade the immune system by:
- altering tumour antigen expression
- activation of immunoregulatory pathways leading to t cell unresponsiveness and apoptosis
- immunosuppressive factors like cytokines can inhibit the t cell response

Question 41

describe the cellular responses by innate immune cells in the oral cavity

Answer 41

microbial recognition leads to cell activation and effector responses.

these responses include phagocytosis, antigen presentation, degranulation, and soluble mediators

microbial recognition occurs by receptors binding to antigens. microbial antigens can be toxins or virulence factors, and this receptor activation causes an immune response

main receptors are toll like receptors, and others include:

• dectin and glucan: fungal recognition
• NOD-like: bacterial recognition
• protease activated receptors: allergen recognition

these are pattern recognition receptors that recognise pathogen associated molecular patterns

Question 42

describe the main features and functions of the toll like receptors of innate immunity

Answer 42

TLR-2
- heterodimer
- ligands that binds are: cell wall beta glucans for bacteria and fungi and zymogsan for fungi
- cells with TLR-2 include monocytes, dendritic cells, mast cells, eosinophils and basophils

TLR-4
- binds LPS for gram neg bacteria and lipoteichoic acid for gram pos bacteria
- found on macrophages, dendritic cells, mast cells and eosinophils

Question 43

describe chronic inflammation

Answer 43

non specific and specific classes exist

non specific arises from persistent bouts of acute inflammation and excessive suppuration. characterised by tissue destruction or repair.

specific arises de novo, due to persistent agent exposure, and can be granulomatous. characterised by excessively activated tissue macrophages.

orofacial granulomatosis is characterised by epitheloid macrophage fusing together to form giant cells. they form in soft tissue.

Question 44

describe the resolution of acute inflammation

Answer 44

requires minimal cell death, damaged tissue must have regenerative capacity, causative agent must be rapidly removed, as well as fluid and debris.

the liver can regenerate and the heart cannot repair in the human body.

Question 45

describe the gell and coombs classification for hypersenstivity

Answer 45

type I
- IgE mediated reaction
- mast cells and basophils involved
- allergen crosslinking IgE bound to mast cells, basophils release vasoactive substances like histamine
- eg cutaneous atopy and anaphylaxis

type II
- cytotoxic responses
- IgG mediated
- natural killer cells, complement and t cells
- eg haemolytic anaemia
- antibody directed against the cell surface antigens mediates cell destruction via complement activation and antibody dependent cellular cytotoxicity

type III
- immune complex responses
- allergen antibody complex deposited in various tissues induces complement activation and ensues an inflammatory response mediated by massive infiltration of neutrophils
- complement and neutrophils involved
- arthus reaction, serum sickness, oral erythema multiforme

type IV
- cell mediated responses
- t cells and macrophages
- tuberculosis and crohns disease
- sensitised th1 cells release cytokines that activate macrophages or direct cellular damage

Question 46

what are acute inflammatory disorders

Answer 46

gingivitis
abscess formation
pericoronitis
cellulitis
angular cheilitis
ludwigs angina

Question 47

describe the four stages of healing of soft tissues

Answer 47

coagulation

• clot formation through coagulation cascade
• in parallel with fibrinolytic system
• involves platelets weaved together by fibrin
• mitosis of labile and stable cells

inflammation

• innate immune cells are recruited, and will phagocytose infectious agents and damaged cells
• stimulation of cells to start to tissue repair and regeneration

proliferation
- formation of granulation tissue
- growth factors and fibroblasts
- growth factors promote or inhibit cell growth and differentiation, aid in cellular proliferation during tissue remodelling
- fibroblasts are involved in deposition of collagen and formation of fibrous connective tissue. occurs in chronic inflammation. macrophages control the function of fibroblasts. M2 macrophages are anti inflammatory and drive fibrosis and angiogenesis.
- angiogenesis and myofibroblasts which brings together the edges of the wound
- vascular phase involves new capillaries forming, which are leaky.
- granulation phase is rich in collagen, capillaries regress and collagen is produced from mature fibroblasts.
- matrix metallaproteinases remodel the ECM, aid in cellular migration and angiogenesis. they are produced from many different immune cells.
- angiogenesis is the formation of new capillaries through sprouting and splitting. sprouting requires vascular endothelial growth factor.

maturation
- granulation tissue is remodelling by remaining cells, the collagen fibres are cross linked
- re epithelialisation and repigmentation
- wound gets stronger, if it is repair then the fibrous scar will remain

Question 48

describe the inflammatory mechanism behind periodontitis

Answer 48

intitiation
- microbes in dental plaque are recognised
- by gingival epithelial cells via PRR

progression
- containment of the microbes
- by innate immune cells and AMPs and IgA

amplification
- recruitment and activation of innate immune cells
- via chemokine and cytokine activity and vascular dilation

resolution
- healing and repair

no resolution
- periodontitis

Question 49

describe the stages of soft tissue healing

Answer 49

clotting
- coagulation, haemostasis
- mitosis of labile and stable cells
- coagulation system

inflammation
- macrophages and neutrophils phagocytose and degrade infectious agents
- stimualtion of certain cells like fibroblasts to start regenerating or repairing tissue

proliferation
- formation of granulation tissue
- fibroblasts are very important
- new connective tissue is formed that is rich in collagen
- angiogenesis
- growth factors are important
- first and second phase
- first is vascular granulation tissue - highly vascularised to allow for flow of immune cells and plasma proteins to rebuild the structure of the tissue
- second phase is fibrous granulation tissue that consists more of fibrous tissue, the mature fibroblasts put together collagen in the granulation tissue. capillaries will regress and the immune cells will return to the blood over time
- fibrosis - extensive deposition of collagen and formation of excess fibrous connective tissue. it is driven by fibroblasts and macrophages and occurs if there is substantial or repeated damage

maturation
- remaining cells will remodel the granulation tissue
- collagen fibres are cross linked along tension lines
- reepithelialisation and regain of tensile strength
- up to 80% of pre injury strength can be regained
- fobrous scar will remain

Question 50

describe the difference between benign and maligant neoplasms

Answer 50

growth pattern
- benign: expands, may be encapsulated, localised
- malignant: invades, no capsule, metastatic (moves elsewhere)

growth rate
- benign is slow
- malignant is rapid, can be aggressive or progressive

histology
- benign: resembles tissue of origin, uniform cell shape and size, few mitotic figures
- malignant: variable resemblance to origin tissue, cellular and nuclear pleomorphism, many mitotic figures

clinical effects
- benign: lump, pressure, or obstruction. can affect hormone production, treated by local excision
- malignant: local pressure, infiltration or destruction. can move. can affect hormone production. treated by removal or radiotherapy or chemotherapy

Question 51

break down pathogenesis of dental caries

Answer 51

aetiology - bacterial origin
morphology - tooth decay
pathogenesis - fermentation of sugars
sequalae - fluoride treatments, removal of infected tissue, fillings, patient advice

Question 52

describe the disease sequalae of acute inflammation

Answer 52

• leads to the cardinal signs of inflammation and suppuration
• whether it becomes chronic depends on tissue involvement, amount of tissue destruction and the nature of the harmful agent

Question 53

describe tumour grading and staging

Answer 53

grading is looking at the biological nature of the tumour - looking at invasion, cellular atypica

staging is looking at the extend of the spread. done through exams, imaging, labs, pathology and surgical reports.

TNM staging is used for oral cancer. T is tumour size, N is the lymph node involvement, M is the presence of metastases.

Question 54

give examples of diseases related to pigmentation and calcification

Answer 54

pathological pigmentation can be endogenous or exogenous

endogenous:
- bruising
- lipofuscin celllular lipid breakdown products like melanin, haemosiderin, bilirubin
- brown

exogenous
- carbon deposition due to inhaled soot and smoke
- tattoos
- heavy metal salts
- pigmentation associated with intravascular drug use

pathological calcification
- deposits of calcium phosphate in necrotic tissue whereby there are normal serum calcium levels, is called dystrophic calcification. occurs in valvular heart disease.
- metastatic calfication is when deposits of calcium salts form in normal tissue due to raised serum calcium levels. can compromise the function of tissues
- raised calcium levels can occur due to increased PTH, bone destruction, excess vitamin D and renal failure.

Question 55

what does kidney failure do to the mouth

Answer 55

retarded tooth development in children
dry mouth
metallic taste
ulcerations on tongue and gums

Question 56

describe the genetic factor of carcinogenesis

Answer 56

important genes in carcinogenesis include:
- oncogenes
- tumour suppressor genes
- DNA repair genes
- miRNA
- chromosomal aberrations
- epigenetic mutations

oncogenes are accelerators of carcingonesis, and can be growth factors, growth factor receptors, signal transducers and controllers of gene expression.

oncogenes work by:
- mutation - increase activity of the product
- excess normal product - duplication of the gene, viral product
- enhanced transcription - translocation, chromosomal rearrangement

tumour suppressor genes
- inhibit cell division
- require loss of both alleles

tp53
- act before restriction point of cell cycle
- main functions are stopping the cell and apoptosis
- inactivated in cancer, through mutation or deletion.

inherited factors
- increased genetic susceptibility
- inherited syndromes through single mutant genes, often tumour suppressor genes
- familial cancer
- defective dna repair ilke xeroderma pigmentosum

Question 57

what does anaemia do to the mouth

Answer 57

burning, red tongue
inflammation of gums

Question 58

describe the three pathways that can arise from tissue damage or necrosis

Answer 58

acute inflammation

• if there is marked neutrophil response and tissue destruction, an abscess forms
• if damage is neutralised and tissue damage is minimal: resolution
• if damage is neutralised and there is tissue damage, there is organisation through phagocytosis and granulation tissue formation: healing by repair
• if the damage is persistent and there is tissue destruction, there is organisation with continued inflammation, this causes chronic inflammation

Question 59

explain the difference between acute and chronic inflammation

Answer 59

acute has rapid onset, involves innate only, is localised, and leads to resolution of disease

acute is caused by microbial infection, physical agents, irritants, and tissue necrosis

chronic is long term, involves innate and adaptive immunity, there is no restoration

Question 60

break down the pathogenesis of oral cancer

Answer 60

aetiology - excessive alcohol consumption
morphology - carcinoma formation
pathogenesis - hyperplasia, dysplasia, carcinoma formation
sequelae - surgery, radiotherapy, remission

Question 61

describe the healing of hard tissues

Answer 61

this is bone remodelling, driven by osteoblastogenesis and osteoclastogenesis.

bone remodelling is constant but there is no net loss because the balance is there.

osteoclastogenesis is bone resorption mediated by osteoclasts. RANK on the osteoclasts must bind to RANKL produced from osteoblasts.

osteoblastogenesis is bone formation mediated by osteoblasts. the osteoblats secrete osteoprotogerin which inhibits RANKL function and controls bone resorption.

when there is a fracture:

formation of a hematoma, which becomes a callus, and eventually normal shape is regained.

coagulation phase
- hamatoma forms (blood clot in bone)

inflammation phase
- recruitment of immune cells
- removal of debris
- soluble mediators produced

proliferation phase
- granulation tissue formed
- becomes fibrocartilage callus
- composed of osteoblasts, fibroblats and chondocytes
- granulation tissue is ossified
- woven bone forms a temporary scaffold for new bone development.

maturation phase
- bone callus is remodelled by osteoclasts and osteoblasts
- woven bone is replaced by cortical bone
- angiogenesis is essential here

Question 62

describe the different antibodies and their function

Answer 62

IgG
- most abundant antibody
- monomeric form, produced from plasma cells
- more abundant during the secondary immune response than the primary
- IgG binds to antigen on cell wall of microbe, can activate the complement system - MAC and opsonisation or enhanced inflammation
- IgG binds to all sites on viral molecules and prevents them from binding to host cell - neutralisation
- can precipitate free antigens ie make them susceptible to phagocytosis
- passed to baby from mother via placenta to give baby passive immunity

IgA
- dimeric form produced from plasma cells
- saliva, sweat, mucosal lining of GIT, milk
- passive immunity to child as they get IgA from mothers milk
- can form a complex due to dimeric form
- destroy bacteria showing up in the mouth, mucosa, and skin via complement - MAC and opsonisation
- high avidity

IgM
- produced from plasma cells in either monomeric or pentameric form
- primary immune response when we are first exposed
- found in ECF and plasma
- activates complement proteins when in monomeric form - MAC and opsonisation
- picks up foreign antigens on mismatched blood transfusions, leads to type 2 hypersensitivity reactions
- 10 different antigen binding sites
- high avidity

IgE
- monomeric
- respiratory tract mucosa for anaphylactic shock - IgE binds to Fc receptor on mast cells and trigger release of vasoactive substances leading to bronchoconstriction and oedema.
- parasites - IgE produced and tagged for eosinophils to produce toxins that destroy the parasites
- found in lymphatics, lamina propria, blood plasma, urogenital structures

IgD
- plasma cells, monomeric antibodies
- isnt secreted, produced in vesicles from Golgi apparatus and fuses with cell membrane
- acts as b cell receptor
- IgM also acts as a b cell receptor

Question 63

there are many disorders in the coagulation system. list them.

Answer 63

von willebrand disease - deficient in von willebrand factor, leads to low levels of factor VIII

haemophilia A - deficiency in VIII

haemophilia B - deficiency in factor IX

warfarin is an anticoagulant drug that inhibits many coagulation factors.

heparin potentiates antithrombin, meaning it is an anticoagulant.

Question 64

describe the plasma factors of inflammation

Answer 64

• complement, with the three pathways, release of anaphylatoxins and membrane attack complex
• kinin, kallikrein generated from hageman factor, production of kinins like bradykinin. kallikrein converts kininogens to kinins. bradykinin functions in activating complement, increasing vascular permeability, stimulating nerves, inducing expression of cytokines and chemokines, and induce the production of chemical mediators.
• coagulation, intrinsic activated when blood contacts tissue outside the blood vessel. extrinsic when human factor 7 leaves the vessel and encounters tissue factors in surrounding tissue. common pathway is when thrombin is produced to produce fibrin clot.
• fibrinolytic system - plasma activated, breaks down fibrin in clots, activates complement via plasmin cleaving C3. products of fibrin degradation promote vascular permeability

Question 65

describe the role of t cells in adaptive immunity

Answer 65

t cells recognise peptides in antigen presentation via the t cell receptor.

CD8+ - CD8 coreceptor, binds to MHC1

CD4+ - CD4 coreceptor, binds to MHC2.

the t cell receptor is usually made up of alpha and beta chains, but some have delta and gamma chains.

the variable region of the t cell receptor is coded by VDJ genes, which are rearranged via somatic recombination.

t cells are educated in the thymus, and undergo positive selection and negative selection. positive is where they must recognise some antigens, negative is where they must not recognise their own antigens.

they reside in the t cell zone of lymph nodes until there is antigen presentation. mature dendritic cells will present antigens and costimulate the t cells to prime them.

the role of t cell subsets are:

TH1 – macrophage, source of interferon gamma
TH2 – allergic responses/plasma cell generation, produce IL 4, 5 and 6 to induce antibody production.
TH17 – epithelium and underlying tissue cell types, clears extracellular bacteria and fungi. produces Il17 and Il22.
TFH – found predominantly in lymph nodes and important for B cell antibody generation. t follicular helper cells, found in the b cell zone of lymph nodes. produce antibodies.
Tregs – control/dampen the immune response. produce Il10. inhibit activation of t cells and dendritic cells.

Question 66

describe the clinical presentation of acute inflammation in dentistry

Answer 66

suppuration is an outcome of acute inflammation. this is the formation of pus arising from infection, neutrophil infilatration is important.

accumulation of pus is surrounded by a pyogenic membrane, the bacteria within pus is inaccessible and this prevents spread.

gingival absesses

periodontal abscesses

periapical abscesses

Question 67

describe the various types of necrosis with appropriate examples

Answer 67

coagulative
- architecture in tact due to no proteolysis
- no nucleus
- grossly firm in texture
- localised coagulative necrosis is called an infarct

liquefactive
- digestion of dead tissues leads to liquid viscous state
- necrotic material is pus
- caused by focal bateria or fungal infection
- CNS necrosis is liquefactive

caseous necrosis
- white friable appearance
- granular debris surrounded by inflammatory cells

gangrenous
- coagulative necrosis
- wet gangrene is liquefactive due to infection

fat necrosis
- focal areas of fat are destroyed and liquefied by activated pancreatic enzymes

fibrinoid necrosis
- occurs in blood vessels due to immmune complexes depositing in the walls

necrotic areas are replaced by a scar, calcium salts can deposit if the remains are not removed