Pathology and Immunity Flashcards
describe the different cells and molecules involved in injury vs repair
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
describe carcinogenesis and carcinogens
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
explain autoimmunity
- 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
explain the vascular changes and mediators released in response to inflammation
- 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.
list the functions of all the CD4+ t cell subsets
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
list defence cells and their functions and locations
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
what is innate immunity
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
describe degranulation and its role in inflammation and immune responses
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.
what is acute inflammation
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)
what is adaptive immunity
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.
define each of the different abnormalities of growth and outline their main features (developmental and acquired)
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
what does anorexia and bulimia do to the mouth
- erosion of tooth enamel
- sensitive teeth
- enlargement of the parotid glands
- sweet breath aroma
describe the role of growth factors in healing and repair
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
describe the proceess of somatic hypermutation
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
describe mediator release from immune cells following microbial recognition
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.
what are the signs of inflammation
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
describe the difference between passive and active immunity
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
describe the process of immune cell recruitment to the site of infection
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.
describe phagocytosis and antigen presentation
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.
describe the spread of malignant tumours
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
describe the receptors involved in adaptive immunity
there are three main receptors:
- t cell receptors
- b cell receptors
- MHC proteins
describe the different auto immune diseases
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
describe soft and hard tissue destruction in periodontitis
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
what does heart disease do to the mouth
pain radiates to the jaw due to inefficient oxygen to the heart muscle
describe the nature, causes and effects of amyloidosis
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
what are the main effector functions of innate immune cells
- phagocytosis
- degranulation
- antigen presentation
- mediator release
describe the responses to blood loss
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
give clear definitions of necrosis and apoptosis and describe the circumstances in which they arise
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.
describe the role of plasma factors in innate immune responses
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.
what does diabetes do to the mouth
dry mouth
bad breath
burning tongue
inflammation
tooth decay
describe the role of epithelium in innate immunity of the oral cavity
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
list the cells involved in healing and repair
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.
describe the three main classes of chronic inflammation and their features
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
break down the pathology of periodontitis
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
describe the structure of an antibody
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
outline what is meant by reversible and non reversible cell injury
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
describe the process of complement
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.
describe the hallmarks of cancer
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
describe shock and the common forms
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
describe how the immune system recognises tumour cells and why many manage to evade the immune system
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
describe the cellular responses by innate immune cells in the oral cavity
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
describe the main features and functions of the toll like receptors of innate immunity
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
describe chronic inflammation
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.
describe the resolution of acute inflammation
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.
describe the gell and coombs classification for hypersenstivity
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
what are acute inflammatory disorders
gingivitis
abscess formation
pericoronitis
cellulitis
angular cheilitis
ludwigs angina
describe the four stages of healing of soft tissues
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
describe the inflammatory mechanism behind periodontitis
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
describe the stages of soft tissue healing
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
describe the difference between benign and maligant neoplasms
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
break down pathogenesis of dental caries
aetiology - bacterial origin
morphology - tooth decay
pathogenesis - fermentation of sugars
sequalae - fluoride treatments, removal of infected tissue, fillings, patient advice
describe the disease sequalae of acute inflammation
- 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
describe tumour grading and staging
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.
give examples of diseases related to pigmentation and calcification
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.
what does kidney failure do to the mouth
retarded tooth development in children
dry mouth
metallic taste
ulcerations on tongue and gums
describe the genetic factor of carcinogenesis
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
what does anaemia do to the mouth
burning, red tongue
inflammation of gums
describe the three pathways that can arise from tissue damage or necrosis
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
explain the difference between acute and chronic inflammation
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
break down the pathogenesis of oral cancer
aetiology - excessive alcohol consumption
morphology - carcinoma formation
pathogenesis - hyperplasia, dysplasia, carcinoma formation
sequelae - surgery, radiotherapy, remission
describe the healing of hard tissues
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
describe the different antibodies and their function
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
there are many disorders in the coagulation system. list them.
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.
describe the plasma factors of inflammation
- 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
describe the role of t cells in adaptive immunity
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.
describe the clinical presentation of acute inflammation in dentistry
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
describe the various types of necrosis with appropriate examples
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
