ICS: Pathology & Immunology Flashcards
1
Q
Define inflammation
A
local reaction to an injury or infection involving cells such as neutrophils & macrophages
2
Q
Advantages of inflammation (2)
A
- Good during infections & injuries
- Prevents further spread - destroys microorganisms & walls off abscess
3
Q
Disadvantages of inflammation (3)
A
- during autoimmunity & overreaction to stimulus
- disease may still persist & altered function
- swelling, compression & destruction of normal tissue
4
Q
Define exudate
A
Protein rich fluid that leaks out of vessel walls due to increased vascular permeability
5
Q
Characteristic of acute inflammation (3)
A
- sudden onset
- short duration
- usually resolves on its own
6
Q
Example of acute inflammation
A
appendicitis
7
Q
Main type of cells involved in acute inflammation
A
Neutrophil polymorphs (WBC)
8
Q
Main diagnostic characteristic of acute inflammation
A
Presence of neutrophil polymorphs (NP migration)
9
Q
Causes of acute inflammation (6)
A
- microbial infection
- hypersensitivity reaction
- physical agent
- corrosive chemicals
- bacterial toxins
- tissue necrosis
10
Q
Possible resolutions of acute inflammation
A
- resolution
- suppuration (formation of pus)
- organisation (healing by fibrosis - scar formation)
- progression to chronic inflammation
11
Q
Main response components of acute inflammation (2)
A
Vascular: dilation of vessels
Exudative - vascular leakage of protein rich fluid
12
Q
Macroscopic appearance of acute inflammation (5)
A
- redness (rubor)
- heat (calor)
- swelling (tumor)
- pain (dolor)
- loss of function
13
Q
Systemic effects of acute inflammation (5)
A
- pyrexia (fever)
- weight loss
- lymphadenopathy (swelling of ..)
- increased WBC count
- amyloidosis (deposition of protein in tissue)
14
Q
Characteristic of chronic inflammation (3)
A
- slow onset / after acute
- long duration
- may not resolve
15
Q
Examples of chronic inflammation (3)
A
Tuberculosis, myocardial fibrosis post MI, leprosy
16
Q
Main types of cells involved in chronic inflammation (3)
A
macrophages, plasma cells & lymphocytes
17
Q
Causes of chronic inflammation
A
- primary chronic inflammation
- !! transplant rejection
- progression from / recurrent episodes of acute inflammation (most common = from suppurative)
18
Q
Macroscopic appearance of chronic inflammation
A
- Chronic ulcer / abscess cavity
- Thickening of the walls of a hollow organ
- Granulomatous tissue (when walled off but unable to eliminate → forms granuloma)
- Fibrosis (thickening or scarring of connective tissue)
19
Q
Response process of chronic inflammation
A
- Paracrine stimulation of connective tissue proliferation (formation of new blood vessels = angiogenesis & fibroblast proliferation = collagen synthesis, granulomatous inflammation)
20
Q
Define granulomas
A
- lump of macrophages surrounded by lymphocytes // epithelioid histiocytes with little phagocytic activity
- formation of chronic inflammatory cells
21
Q
Define granulation tissue
A
composed of small blood vessels in a connective tissue matrix with myofibroblasts. important in healing and repair.
22
Q
Diagnostic characteristic of granulomas (histological)
A
Ziehl-Neelsen stain (comes up bright red)
23
Q
Diagnostic characteristic of granulomatous disease (enzyme)
A
Angiotensin converting enzyme
24
Q
Treatment of inflammation (5)
A
- ice
- histamine
- steroid, coticosteroid
- NSAIDs
- antibiotics
25
Examples of granulomatous disease
TB, Sarcoidosis, Crohn’s disease
26
Briefly outline the Neutrophil Polymorph Migration as seen in acute inflammation
1. margination of neutrophils: axial to plasmatic flow
2. adhesion of neutrophils: pavementing
3. neutrophil migrate through walls of venules & small veins
4. diapedesis: mvt of neutrophils out of circulatory system to site of damage or infection
27
Normal cell flow in vessels
axial = central zone of blood stream OR laminar flow = cell travel in centre of vessels & do not touch sides
28
Damaged cell flow in vessels
plasmatic = flows towards endothelium
| (mostly due to loss of intravascular fluid & increased plasma velocity)
29
Define pavementing
Neutrophil adherance to vascular endothelium
- in early acute inflam.
- increased adhesion from interact. bet. leukocyte & endo surface
30
Causes of pain associated with acute inflammation
1. Stretching and distortion of tissues due to oedema and pus under high pressure in an abscess cavity.
2. Chemical mediators e.g. bradykinin and prostaglandins, are also known to induce pain.
31
Difference between resolution and repair
Presence of initial factor (repair = present) & ability of tissue to regenerate (repair = unable)
32
Bringing edge of wound together, no infection, nice healing
Healing by 1st intention
33
Skin is lost, gaping wound (e.g. TA or trauma wounds, granulation tissue)
Healing by 2nd intention
34
'Resolution' for repair tissues
- Damaged tissue replaced by fibrous tissue
- Collagen produced by fibroblasts
35
Cells that regenerate
- hepatocytes
- pneumocytes
- all blood cells
- osteocytes
- epithelium - gut & skin
- peripheral nerves
36
Cells that don't regenerate
- myocardial cells
- central neurons
37
Cell types that regenerate (bigger groups!)
labile, stable cell populations, stem cells
38
Cell types that doesn't regenerate (bigger groups)
permanent cells
39
Define apoptosis
Programmed cell death of individual cells without producing harmful products
40
Define necrosis
Unprogrammed traumatic cell death, often in masses, which induces inflammation and repair
41
Triggers for apoptosis
- DNA damage: detected by p53, regulates caspase
- Virus
- Withdrawal of growth factor
42
Protein that switches on apoptosis
P53 protein - detects DNA damage & initiate repair, if beyond repair then apoptose
43
Conductor of apoptosis
Caspase enzyme
44
Protein that promotes apoptosis (Bcl-2 family)
Bax protein
45
Protein that inhibits apoptotic factors (therefore apoptosis)
Bcl-2 protein
46
Activation of these extrinsic receptors can activate caspase & therfore apoptosis
Fas (fas ligand binds here) & Tumor Necrosis Factor Receptor (TNFR) 1
47
Intrinsic activation of apoptosis
Through P53 protein which also mediates the Bcl-2 family of proteins
48
Disease with too little apoptosis
Cancer, mutations in p53 = cell damage undetected
49
Disease with too much apoptosis
HIV
50
Examples leading to necrosis
Spider venom, frostbite, cerebral infarction
51
Differences between apoptosis & necrosis (3)
- programmed vs unprogrammed
- single vs en mass
- DNA (genetics) vs external
52
Define thrombosis
solidification of blood contents formed within vascular system during life; esp when platelet aggregation is activated within an intact vessel
53
Define clot
blood coagulated outside of the vascular system after death
54
Three factors that can cause thrombosis, one or more can precipitate
- change in vessel wall
- change in blood flow
- change in blood constituents
= Virchow's triad
55
Why is thrombosis uncommon (2)
1. Laminar flow.
2. Non sticky endothelial cells.
56
Cause of arterial thrombosis
atheromatous plaque
57
Two drugs to treat thrombosis
Aspirin to prevent;
Warfarin for severe & patients with thrombus history
As: inhibit platelet agg // War: inhibit vitamin K - clotting factor
58
Define embolus
A mass of material (often a thrombus) in the vascular system that is able to become lodged in a vessel and block it.
59
Most common cause of embolism
thrombus (DVT), also air, amniotic fluid etc
60
Which type of embolism cannot travel to the other side of the body under normal conditions?
Pulmonary (venous) embolism
Normally in pulmonary arteries & cannot cross unless perforated lung
61
Define ischaemia
reduction in blood flow caused by constriction or blockage of the supplying blood vessel
62
Define gangrene
When whole regions of a limb or gut have their arterial supply cut off & large areas of mixed tissues die in bulk
63
Difference between wet & dry gangrene
Dry - tissue dies & healing occurs above it, eventually falls off & patient is fine
Wet - bacterial infection occurs & patient dies of sepsis
64
Define infarction
necrosis of part or the whole organ that occurs when the arterial supply becomes blocked
65
Why are tissues with an end arterial supply more susceptible to infarction?
They only have a single arterial supply and so if this vessel is interrupted infarction is likely.
66
Give 3 examples of organs with a dual arterial supply.
1. Lungs (bronchial arteries and pulmonary veins).
2. Liver (hepatic arteries and portal veins).
3. Some areas of the brain around the circle of willis.
67
What can happen if ischaemia is rectified?
Re-perfusion injury can occur due to the release of waste products accumulated during lack of O2
68
Potential consequences of ischaemia
Infarction or gangrene
69
Consequences of arterial embolus?
An arterial embolus can go anywhere! The consequences could be stroke, MI, gangrene etc.
70
What are the consequences of a venous embolus?
An embolus in the venous system will go onto the vena cava and then through the pulmonary arteries and become lodged in the lungs causing a pulmonary embolism. This means there is decreased perfusion to the lungs.
71
Define atherosclerosis
disease characterised by the formation of atherosclerotic plaque in the intima of vessel walls
72
3 main components of atherosclerotic plaque
- Fibrous tissue IN the artery
- Lipid in the form of cholesterol
- Lymphocytes
73
Is atherosclerosis more common in the systemic or pulmonary circulation?
It is more common in the systemic circulation because this is a higher pressure system.
74
Primary cause of atherosclerosis
Endothelial cell damage
75
Give 5 risk factors for atherosclerosis.
1. Cigarette smoking.
2. Hypertension.
3. Hyperlipidaemia.
4. Uncontrolled diabetes mellitus.
5. Lower socioeconomic status.
76
Preventive measures for atherosclerosis?
1. lifestyle changes
2. aspirin: for those within clinical evidence of the illness, inhibits platelet aggression
3. statins: cholesterol reducing drug
77
Why can cigarette smoking lead to atherosclerosis?
Cigarette smoking releases free radicals, nicotine and CO into the body. These all damage endothelial cells
78
Why can hypertension lead to atherosclerosis?
A higher blood pressure means there is a greater force exerted onto the endothelial cells and this can lead to damage.
79
Define hypertrophy
increase in size of a tissue caused by an increase in size of the constituent cells (without the cells dividing)
80
Define hyperplasia
increased in the size of a tissue caused by an increase in number of constituent cells (with division through mitosis)
81
Define atrophy
decrease in size of a tissue caused by either a decrease in cell size or number
82
Give example of a disease that demonstrates atrophy
Dementia - loss of neurons
83
Define metaplasia
Change in differentiation of a cell from one-fully differentiated cell type to another
84
Give example of a disease that demonstrates metaplasia
Barrett's oesophagus - the cells at the lower end of the oesophagus change from stratified squamous cells to columnar
85
Define dysplasia
morphological changes seen in cells in progression to becoming cancer
86
What is a telomere
Random repetitive DNA at the tip of each chromosome, not copied prior to mitosis & shortens with each replication
87
What happens when a telomere becomes too short
The cell cannot replicate anymore as DNA polymerase is unable to engage
88
When are telomeres replicated (exceptions)
In germ cells & embryos
89
Give an example of a dividing and a non-dividing tissue
- Gut or skin tissue can divide.
- Brain tissue is non dividing.
90
When should chemotherapy used over excision?
When the illness is systemic / circulates all over the body
91
Difference between carcinogenic & oncogenic
Carcino-x: cancer causing
Onco-x: tumour causing
92
Define neoplasms
Autonomous abnormal persistent growth; suffix -oma
93
What needs to be done usually for chemical carcinogens before it causes disease?
Metabolic conversion from pro-carcinogens to ultimate carcinogens
94
What 2 types of cancer can polycyclic aromatic hydrocarbons cause?
Lung & Skin cancer
95
What exposes people to polycyclic aromatic hydrocarbons?
Smoking cigarettes and mineral oils.
96
What types of cancer do aromatic amines cause?
Bladder cancer
97
Three reasons behind how alcohol can cause cancer
- ethanol makes it easier for cells in oropharynx to absorb other carcinogens
- ethanol increases oestrogen levels
- alcohol's metabolite, acetaldehyde, is a mutagen
98
What types of people are more susceptible to bladder cancer caused by aromatic amine exposure?
People working in the rubber / dye industry
99
Name 3 biological agents that can cause cancer
1. hormones: oestrogen & anabolic steroids
2. mycotoxins
3. Parasites
100
What type of cancer do nitrosamines cause?
Gut cancer
101
What type of cancer do alkylating agents cause?
Leukaemia but risk is small in humans
102
Host factor which may increase a person's risk of having cancer?
- race
- diet
- constitutional factors - age, gender
- premalignant lesions
- transplacental exposure
103
Give an example of a situation when transplacental exposure lead to an increase in cancer risk.
The daughters of mothers who had taken diethylstiboestrol for morning sickness had an increased risk of vaginal cancer.
104
Composition of a stroma
Neoplastic cells & stroma (supporting network)
105
Describe neoplastic cells
- derived from monoclonal cells
- growth pattern & synthetic activity usually related to parent cell
106
Describe stroma
- Supportive, connective tissue framework for neoplasms, provides nutrition.
- May consist of fibroblasts, fibrous connective tissues & blood vessels
107
Two types of benign neoplasms of epithelial cells?
Papilloma & adenoma
108
Define papilloma
Benign tumour of non-glandular non-secretory epithelium
109
Define adenoma
benign tumour of glandular or secretory epithelium
110
Define carcinoma
malignant epithelial neoplasm
111
Define osteoma
benign tumour of the bone
112
Define chondroma
benign tumour of the cartilage
113
Define lipoma
benign tumour of the adipocytes
114
Define adenocarcinoma \*
malignant tumour of glandular epithelium
115
Define angioma
Benign tumour of the vascular connective tissues
116
Define sarcoma
(general) malignant tumour of the connective tissues
117
How are tumours classified histologically?
Depending on their degree of differentiation
Grade 1 = well differentiated, resembles parent tissue more
Grade 2
Grade 3 = poorly differentiated
118
Define anaplastic
Poorly differentiated to the extent that there are no recognisable histological features
119
5 types of carcinoma that can spread to the bones ( & vice versa)
1. Breast.
2. Kidney.
3. Lung.
4. Prostate.
5. Thyroid.
120
carcinoma that can spread to the lymph nodes
breast carcinoma
121
Adv's & disadv's of conventional chemotherapy
- Advantage: works well for treatment against fast dividing tumours e.g. lymphomas.
- Disadvantage: it is non selective for tumour cells, normal cells are hit too; this results in bad side effects such as diarrhoea and hair loss.
122
Chemotherapy is most effective against what type of carcinomas?
Slower dividing tumours e.g. lung, colon and breast.
123
What kind of drugs can be used in chemotherapy?
Monoclonal antibodies (MAB) and small molecular inhibitors (SMI).
124
Define carcinoma in situ
a malignant epithelial neoplasm that has not yet invaded through the original basement membrane
125
Define invasive carcinoma
a carcinoma that has invaded through the original basement membrane
126
What is required for a carcinoma to become invasive?
- enzymes (e.g. collagenase for invasion of blood stream)
- cell motility
127
Maximum size a tumour can grow to before needing its own blood vessels
~1mm
128
Two promoters of angiogenesis
1. Vascular endothelial growth factors.
2. Fibroblast growth factors.
129
Three inhibitors of angiogenesis
1. Angiostatin.
2. Endostatin.
3. Vasculostatin.
- statin ending!
130
What is the process during which 'a malignant carcinoma breaches through the basement membrane and spread to other parts of the tissue' known as
Invasion
131
What is the entire spread process 'of the tumour where it spreads from its primary site to produce secondary tumours at distant sites' known as
Metastasis
132
What three mechanisms must a tumour have to achieve growth at secondary metastatic site?
1. evasion of host immune defence
2. arrest
3. Extravasation
133
What are three mechanisms a tumour may use to evade host immune defence
- aggregation with platelets
- shedding of surface antigens
- adhesion to other tumour cells
134
Example of tumour that can spread to the lung
Sarcoma (via venae cavae -\> heart -\> pulmonary arteries)
135
Example of tumour that can spread trans-coelomically
colorectal, stomach & pancreas = all can spread to liver via portal venous system
136
What are the two ways in which neoplasms can be classified?
Behavourial & histological
137
How are neoplasms classified bahavourially
Neoplasms can be classified as benign, malignant or borderline. Borderline tumours (e.g. some ovarian lesions) defy precise classification.
138
7 main features of benign neoplasms
1. Localised.
2. Non-invasive.
3. Slow growth, low mitotic activity.
4. Close resemblance to normal tissue.
5. Normal nuclei.
6. Necrosis and ulceration are rare due to slow growth.
7. Exophytic growth.
139
4 consequences of benign neoplasms
1. Pressure on adjacent structures.
2. Obstruction to flow.
3. Transformation into malignant neoplasms.
4. Anxiety.
140
7 main features of malignant neoplasms
1. INVASIVE!
2. Metastases.
3. Rapid growth, high mitotic activity.
4. Resemblance to normal tissue.
5. Poorly defined border due to invasive nature.
6. Necrosis and ulceration are common.
7. Endophytic growth.
141
Consequences of malignant neoplasms
Destroy surrounding tissue, blood loss due to ulceration, pain, anxiety.
142
Define teratoma
neoplasm of germ cell origin that forms cells representing all three germ cell layers of the embryo; ectoderm, mesoderm & endoderm
143
Define carcinosarcoma
mixed malignant tumours showing characteristics of epithelium & connective tissue
144
Define carcinogenesis
A multistep process in which normal cells become neoplastic cells due to mutations.
145
What must the immune system do in order to be effective?
Differentiate self from non-self
146
Define innate immunity
instinctive, non-specific, present from birth. NO lymphocytes YES lysosomes
147
Define adaptive immunity
Specific 'acquired / learned' immunity. Quicker response. Memory. B / T lymphocytes & antibodies
148
Examples of innate defence mechanisms?
- Physical barriers - skin, gut, bronchi, pH
- Phagocytic cells
- blood proteins
149
Examples of adaptive defence mechanisms?
- Antigen presenting cells
- T cells
- Major Histocompatibility Complex (MHC)
- Antigens - intrinsic & extrinsic
150
Lock and key system in detecting microbes
Pathogen Associated Molecular Patters (PAMPs) & Pattern Recognition Receptors (PRRs)
151
Define PAMPs
Pathogen Associated Molecular Patterns - describes general molecular features common to all pathogens, used by innate i.s. to recognise microbes
152
Define PRRs
Pattern Recognition Receptors Family of proteins which recognise & bind to pathogen ligands, thereby increasing likelihood of successful T cell activation
e.g. Toll-like receptor on macrophages, dendritic cells & neutrophils
153
What are the O2 dependent killing mechanisms of the innate immunity system?
Superoxides & nitric oxide
154
What are the O2 independent killing mechanisms of the innate immunity system?
enzymes: defensins, lysozyme, pH, tumor necrosis factor
155
Function of lysozyme
destroys bacteria cell walls
156
3 examples of polymorphonuclear leukocytes
1. Neutrophils.
2. Basophils.
3. Eosinophils.
157
3 examples of mononuclear leukocytes
1. Monocytes.
2. B lymphocytes.
3. T lymphocytes.
158
In which primary lymphoid tissue do T cells mature?
thymus
159
In which primary lymphoid tissue do B cells mature?
Bone marrow
160
What is the main source of histamine within the body?
Mast cells; histamine is stored in granules in their cytoplasm.
161
How are antigens presented to T cells?
Through complex of Antigen Presenting Cell & Major Histocompatibility Complex
162
Marker for activated T Cells?
CD25
163
Three categories of T cells
Naive, effector or memory
164
What type of antigens do T cells respond to
Only intracellular antigens presented via MHC's
Does not respond to soluble antigens!
165
Define T cell selection
Where T cells that recognises itself are killed in the foetal thymus as they mature
166
Function of T helper 1 (CD4)
helps the immune response against intracellular pathogens. Secretes cytokines.
Also
- activate macrophages triggering inflammation
- regulate monocytes & macrophages
167
Function of T helper 2 (CD4)
helps produce antibodies against extracellular pathogens through B cells. Secretes cytokines.
168
Function of T reg
Regulate immune response
169
Function of Cytotoxic T cells (CD8)
kill cells directly by binding to antigens; induce apoptosis
170
What kind of cells respond to soluble antigens?
B cells
171
What kind of cells respond to intracellular presented antigens via APC & MHC's?
T cells
172
What type of antigens do MHC 1 bind to?
Intracellular antigens
173
Which type of cells express MHC 1's
Virtually all cells of the body except erythrocytes
174
Which type of cell binds to MHC 1's
Cytotoxic T cells (CD8)
175
Which MHC would an intracellular antigen (endogenous) lead to the expression of?
MHC 1's
176
Which MHC would an extracellular antigen (exogenous) lead to the expression of?
MHC 2's
177
Which type of cells express MHC 2's
on surfaces of macrophages, B cells & dendritic cells (i.e. antigen presenting cells)
178
Which type of cell binds to MHC 2's
Helper T cells (CD4)
179
What category of T cells do cytotoxic t cells (CD8) eventually evolve to?
Effector or memory cells
180
What do B cells differentiate into?
Plasma cells. The plasma cells then produce antibodies.
181
What does a T helper cell bind to?
A T cell receptor which is bound to an antigen epitope which is bound to MHC2 on an APC
182
Function of B cells
Antibody factory
Plasma & memory cells
Express membrane bound immunoglobulin
183
How many antibodies can each B cell make?
Each B cell can only make 1 antibody. This 1 antibody can only bind to 1 epitope.
184
What happens to B cells that recognise 'self'?
Killed in bone marrow
185
How many antibodies can each B cell make?
1 antibody which can only bind to 1 epitope
186
Process where B cells divide so all new cells will recognise the same antigen
Clonal expansion
187
Briefly outline the activation process of B cells
1. Phagocytosis of pathogen by B cell & present to T helper 2 via MHC !!
2. Macrophage release IL-1: B cell activated
3. T helper 2 binds to MHC II, which release interleukins that induce B cells to divide via clonal expansion
4. B cells differentiates into plasma & memory cells which will produce antibodies. Increased recognition & faster response!
188
Which interleukin activates B cells
IL-1
189
3 functions of antibodies
1. Neutralise toxins.
2. Opsonisation.
3. Activate classical complement system.
190
Function of mast cells
Release histamine (stored in granules in their cytoplasm). Only found in tissues!
191
Function of neutrophils
Innate - phagocytosis. Involved in acute inflammation! (Neutrophil Polymorph Migration!)
192
Function of eosinophils
Neutralises histamine
Combats parasites
193
Function of basophils
Allergic reaction: release histamine
194
Function of natural killer cells
recognise & kill via apoptosis virus infected & tumour cells
195
Function of dendritic cells
- antigen presenting cells
- both innate & adaptive
- detect & chew then present pathogens on surface
- only these cells can induce primary immune response in inactive / resting T lymphocytes
196
Give 3 examples of APC's
Macrophages, dendritic cells, B cells
197
Examples of dendritic cells
Kupffer cells in liver, Langerhans in skin
198
Define complement
20 serum factors secreted by the liver that when activated, will aim to remove or destroy antigen, either by direct lysis or opsonisation
199
How are complement activated
achievable via 3 pathways = classical, alternatives & lectin. main goal is to cleave c3 → c3a & c3b: create membrane attack complex & enhance inflammation
200
Define lysis
using membrane attack complex, create a hole in pathogen → influx of fluids → lysis → destruction
201
Define opsonisation
antigen becomes coated with substances (= complement) making it easier to be engulfed by phagocytic cells as macrophages have special receptors for complement proteins
202
Contrast antibodies & antigens
```
Antibodies = specific protein produced in response to antigen
Antigen = molecule on microbes
```
203
What is the part of antigen that binds to antibody / receptor binding site called
Epitope
204
Define affinity
Measure of binding strength between epitope & antibody binding site - the higher the affinity the better
205
Briefly describe the structure of the antibody
Y shaped with four chains, 'V' area = Fab region: has antigen binding region
'I' area = Fc region, has Fc receptor which bind to complement, phagocytes, natural killer cells & B cells
206
What does the Fab region on the antibody bind to
Specific antigens
207
What does the Fc region on the antibody bind to
complement, phagocytes, natural killer cells & B cells
208
Where are complement system plasma proteins secreted from?
Liver
209
Which immunoglobulin is found in breast milk and other secretions?
IgA
210
What are the 2 most common immunoglobulins (that are also first to respond)?
IgM & IgG
211
Which immunoglobulin is most commonly involved in allergic responses?
IgE
212
Which cells express high affinity IgE receptors?
Mast cells, basophils and eosinophils.
213
What trigger the release of histamine?
Binding between IgE & cells with IgE specific receptor
214
Name the 5 types of cytokines
- Interferons
- Interleukins
- Colony stimulating factors
- Tumour necrosis factors
- Chemokines
215
Function of cytokines
soluble proteins secreted by lymphocytes or macrophage / monocytes that act as stimulatory or inhibitory signals between cells
216
Function of interferons
induce antiviral resistance in uninfected cells & limit spread of viral infections
217
Function of interleukins
cause cell division and differentiation
218
Function of colony stimulating factors
directs division & differentiation of bone marrow stem cells (precursor of leukocytes)
219
Function of TNF's
mediate inflammation and cytotoxic reactions
220
Function of chemokines
Attract & direct leukocytes to sites of infection
221
Contrast the two types of PRR's
Secreted & circulating PRR - soluble & everywhere activates complement, improve phagocytosis
Cell associated PRR - present on cell membrane or cytosol of cells
222
4 receptors that make up the PRR family
1. toll - like receptor (TLR)
2. C-type lectin receptors
3. nod-like receptors (NLR)
4. Rig-like receptors (RLR)
223
Main functions of TLR
Separates bacteria from virus
Monitors endosome
TLR4 also identify damage & signal for initiation of tissue repair; can be used as a vaccine adjuvant
224
Key characteristic that allows TLR to identify damage
hydrophobicity
225
Main function of C-type lectin receptors
may participate in pathogen recognition (specifically fungi) & phagocytosis
226
Main functions of NLR
in cytoplasm - detect intracellular microbial pathogens. release cytokines and can cause apoptosis if the cell is infected
227
Disease where NLR's are nonfunctioning & hyperfunctioning
non: crohn's
hyper: blau syndrome
228
Main function of RLRs
in cytoplasm - detect intracellular double-stranded viral RNA, activation of interferon production, enabling an antiviral response
229
Type of TLR's used in vaccine adjuvants
TLR4 agonists
230
2 examples of intracellular PRR's
NLR's & RLR's
231
example of extracellular PRR
TLR's
232
What happens when a PAMP is recognised by a PRR?
The innate immune response and inflammatory response is triggered.
233
Additional roles of TLR4
used as vaccine adjuvant
recognition of host molecules in autoimmune disease, failure to do so increases inflammatory responses
234
Aim of a perfect vaccine (5)
- safe
- introduce suitable immune response - no booster needed
- t & b cell memory
- stable and easy to transport
- affordable and accessible
235
types of immunisations
passive & active immunisation
236
define inoculation
introduction of viable microorganisms into the subject
237
define passive immunisation
transfer of pre-formed antibodies
238
adv's & disadv's of passive immunisation
- does not activate immunological memory so no long term protection!
- antisera used to neutralise toxins after immune system eliminated the primary infection → possibility of reaction to it!
239
Three major types of passive immunisations
- anti-toxins
- prophylactic use to reduce chance of establishing infection after exposure
- antivenin (venom)
240
Examples of passive immunisations (say if active or passive)
- DTa, rubella, mumps, polio: natural (cross-placenta & milk)
- anti-toxins & anti-venins: artificial
- pathogen with a short incubation time & disease with complications: artificial
241
define active immunisation
manipulating the immune system to generate a persistent protective response against pathogens by safely mimicking natural infection (without risk of actual infection!)
242
steps of active immunisation
1. Engage innate immune system
2. Elicit danger signals that activate immune system
- triggers e.g. molecular fingerprint of infection - Pathogen-associated molecular patterns and engage TLR receptors
3. Activate specialist antigen presenting cells
- e.g. Langerhans cells
4. Engage the adaptive immune system
- generate memory T and B cells
- activate T cell help
243
Cells involved in primary response to active immunisation
innate immune system
- memory T and B cells generated and circulated for years
244
Cells involved in secondary response to active immunisation
- rapid and large scale
- high affinity IgG
- T cell help
245
4 main vaccine designs
1. attenuated (live)
2. dead or inactivated
3. dna vaccines
4. recombinant
246
adv's & disadv's of attenuated / live vaccines
- transient infection so full natural immune response
- memory response in t & b cells
- often only single immunisation required
- imcompromised: may become infected as a result
- complications to death
- occasionally the attenuated organism can revert to virulent form → may lead to potential outbreak!
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examples of attenuated / live vaccines
e.g. Tuberculosis - Bacillus Calmette-Guerin, polio sabin, typhoid, mumps
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subtypes of dead / inactivated vaccines & examples
- inactivated: anthrax, cholera, hepB
- subunit: diptheria & tetanus
- carbohydrate
- conjugated
- synthetic peptides
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adv's of inactivated vaccines
e. g. anthrax, cholera, hepB
- no risk of infection
- less critical storage
- wider range of different antigenic components are presented so good immune response
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adv's of subunit vaccines
e. g. diphtheria, tetanus
- purified molecular components as immunogenic agents
- safe, only part of the pathogen used
- no risk of infection
- easier to store & preserve
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define conjugated vaccines
polysaccharide (weak antigen) linked to a carrier protein to increase its immunogenicity when used as a vaccine
benefit: long term protective response even in infants
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define vaccines of synthetic peptides (new)
novel technique aiming to produce a peptide that includes immunodominant B cell epitopes and stimulate memory T cell development
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what are DNA vaccines
- aims to transiently express genes from pathogens in host cells
- generate immune response similar to natural infections, leading to T and B cell memory responses
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mechanism of DNA vaccines
DNA plasmid vector vaccines carry the genetic info encoding an antigen which is taken up into cells and transcribed into nucleus → allowing the antigen to be produced inside of a host cell → leading to a cell mediated immune response via the MHC I pathway
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example of dna vaccines
covid vaccine
- AZ is viral vector: once inside the body, spike protein is produced and initiates immune response
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adv's & disadv's of dna vaccines
- safe: especially in immunocompromised patients
- may require booster
- no transient infection
- easy store and transport
- drug delivery is simple and adaptable to widespread vaccination programs
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define recombinant vaccines
Aim is to imitate the effect of transient infection with pathogen but using a non-pathogenic microorganism
- viral or bacterial
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adv's & disadv's of recombinant vaccines
- Produce immunological memory
- Safe - relative to live attenuated pathogen
- requires refrigeration for transport
- Immune response to virus in subject can negate effectiveness
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define adjuvants
Any substance that is added to a vaccine to stimulate the immune system to ensure a powerful immune response
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examples of adjuvants
- whole killed organisms
- toxoids
- proteins
- chemicals: Aluminium salts (extend the half life of immunogen in the site of the injection, resulting in a depot effect the slow release of vaccine) & Paraffin oil
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define allergy
abnormal response to harmless foreign material (allergens)
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define atopy
inherited tendency to develop allergies / overproduction of IgE antibodies to common environmental antigens
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Examples of low affinity lgE receptor expressing cells
B cells, T cells, monocytes, platelets & neutrophils
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Functions of low affinity lgE receptor expressing cells
- regulate lgE synthesis
- trigger cytokine release by monocytes
- antigen presentation by cells
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examples of high affinity lgE expressing cells
eosinophils, mast cells & basophils
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Functions of high affinity lgE expressing cells
- involved in host defence against parasites
- eosinophils: express a different range of granule content to mast cells & baso // mast cells only exist in tissues whereas the other two circulate in blood!
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Mast cells
- what are they?
- what is their function?
* main effector for IgE mediated immunity - cause of reaction during anaphylaxis and inflammatory symptoms
* have a primary role in both innate and adaptive immunity
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How are mast cells activated?
Through **Indirect activation**
* allergens via IgE - prior sensitisation required, generally through mucus surface
* bacterial / viral antigens via IgE
Through **phagocytosis**
Through **direct** **activation**
* cold / mechanical deformation i.e. asthma
* aspirin, tartrazin, preservatives, nitric oxide
* complement products, c3a and c5a
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What happens if mast cells are activated? (4)
* they release the **mediators** stored inside them = **degranulation**
They will cause anaphylactic symptoms, e.g.
* skin: swelling, itching, reddening
* airways: excessive mucus production, bronchoconstriction
* GI: abdominal bloating, vomiting, diarrhoea
* Anaphylaxis: airway, breathing, circulation
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What products are released if mast cells are activated and what are their effects?
* **histamine** (increase vascular permeability, smooth musc contract)
* **cytokines**
* **IL4, IL13** - promotes Th2 differentiation, IgE production
* **TNF - alpha** - promotes tissue inflammation
* **lipid mediators** - **leukotrines** and **prostaglandins** - + vasc perm, smooth musc contr, mucus secretion, chemoattractants for T, eosino, mast and baso
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name the mechanisms of activating mast cells
- indirect activation via lgE
- phagocytosis
- direct activation (3)
- cold / mechanical deformation (i.e. asthma)
- aspirin, tartrazine, preservatives, nitric oxide
- complement products - c3a & c5a
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summary of the types of cells involved in allergy (5)
1. Mast cells
2. Lymphocytes (typically Th2)
3. Dendritic cells
4. Neurons
5. Non-immune cells
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What makes an allergen?
- particulate delivery of antigens
- presence of \*\*WEAK pathogen associated molecular patterns (PAMPs)\*\* resulting in a weak innate immunity activation but \*\*NOT adaptive\*\* as it goes into memory and thus wont be an allergen
- nasal / skin delivery
- low doses
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define anaphylaxis
severe and life threatening reaction to an allergen with systemic symptoms, e.g. severe hypotension, vasodilation and bronchoconstriction
involves mast cell or basophil activation through IgE or direct
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6 features of anaphylaxis?
1. rapid onset
2. blotchy rash
3. swelling of face and lips
4 wheeze
5. hypotension
6. cardiac arrest if severe
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4 broad indications of anaphylaxis?
* skin: swelling, itching, reddening
* airways: excessive mucus production, bronchoconstriction
* GI: abdominal bloating, vomiting, diarrhoea
* Anaphylaxis: airway, breathing, circulation
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principles of treatment of anaphylaxis
Airway, Breathing, Circulation, Disability, Exposure (ABCDE)
- ABC = basic life support
- stop infusion of drug
- give adrenaline and anti-histamines!
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examples of allergy diseases
asthma, eczema, allergic rhinitis
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6 principal ways of treating allergy
- desensitisation
- prevent lgE production
- anti-lgE therapy
- anti-cytokine antibodies
- prevent mast cell activation
- inhibit mast cell products
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principle of desensitisation as an allergy treatment
- giving increasing doses of antigen as immunotherapy, can be admitted sub-lingual or sub-cutaneous (SCIT)
- limited use: no benefits for atopic eczema and asthma
- usually for severe allergies only
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principle of desensitisation as an allergy treatment \*\*
- giving increasing doses of antigen as immunotherapy, can be admitted sub-lingual or sub-cutaneous (SCIT)
- limited use: no benefits for atopic eczema and asthma
- usually for severe allergies only
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principle of anti-lgE therapy as an allergy treatment
- xolair (omalizumab) = recombinant humanised IgG1K monoclonal antibody that selectively binds to IgE
- inhibit binding of IgE to high-affinity IgE receptor
- effective for allergic asthma but highly contested
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principle of anti-cytokine antibodies as an allergy treatment
- targeting IL-5 antibody, IL-5 receptor antibody, anti-IL4 / IL-13 receptor antibody
- example: mepolizumab - for adults with severe asthma
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mechanisms through which preventing mast cell activation can act as an allergy treatment \*\*
- mast cell stabiliser: sodium cromoglycate: reduce mediator release
- beta 2 agonist: salmeterol
- increase cAMP
- Glucocorticoids
- inhibit gene transcription
- long term side effects
- calcium channel blockers
- signalling inhibitors
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principle of inhibiting mast cell products as an allergy treatment \*\*
through
- histamine receptor (H1) antagonists (numerous target cells)
- leokotrine antagonists through inhibiting activation of Th2
- tryptase inhibitors: preventing airway smooth muscle activation
- protease - activated receptor (PAR)
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How are lgE related to allergies
- lgEs are made to things we are allergic to
- mast cells are the main effector cells for lgE mediated immunity - have a primary role in both innate and adaptive immunity
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Define hypersensitivity?
Diseases in which immune responses to environmental antigens cause inflammation and damage to the body itself
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give 4 risk factors for hypersensitivity?
1. protein based macromolecules
2. female \> male
3. immunosuppression
4. genetic factors
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define type 1 hypersensitivity reactions according to gell & coombs classification
- lgE primary, also G & A
- allergic & acute reaction
- acute anaphylaxis, hay fever
**IMMEDIATE**
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define type 2 hypersensitivity reactions according to gell & coombs classification
- primarily IgG mediated cytotoxicity
- e.g. transfusion reactions, autoimmune disease, some drug allergies, e.g. penicillin
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What can cause a type 2 hypersensitivity reaction?
- transplant rejection (!)
- transfusion reactions, drug-induced allergies (peniciliin e.g.)
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define type 3 hypersensitivity reactions according to gell & coombs classification
- IgG / IgM dependent immune complex formation - which are not adequately cleared by innate immune cells, give rise to inflammatory response
- e.g. serum sickness, contact dermatitis
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what can cause a type 3 hypersensitivity reaction?
SLE, Post strep glomerulonephritis
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define type 4 hypersensitivity reactions according to gell & coombs classification
delayed type hypersensitivity, DTH (= several days)
- cell dependent Th1 / cytotoxic T / macrophage)
- e.g. TB, contact dermatitis
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what can cause a type 4 hypersensitivity reaction?
TB & contact dermatitis
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role of \*\*T lymphocyte\*\* in complex allergic conditions such as asthma etc
especially Th-2
- releases cytokines IL4 & 13 which stimulate lgE production
- activates lgE
- recruits lgE antibody-producing B cells, mast cells & eosinophils
