IAH theme 4 Flashcards
(176 cards)
1
Q
What are the aims of tissue and organ transplantation ?
A
transplants have to be physiologically fucntioning
process should not harm the recipient
Should not be rejected by the immune system
2
Q
Is immunosupression selective ?
A
no
3
Q
What type of reaction is hyperacute rejection ?
A
type II hypesensitivity- antibodies to the cell surface
4
Q
What happens in hyperacute rejection ?
A
pre existing antibodies IgG against MHC in vascular endothelium in grAT
5
Q
What causes a hyperacute rejection ?
A
mediated by MHC class I or ABO mismatch
6
Q
Why might a person have antibodies to MHC on hyperacute rejection ?
A
pregnancy
multiple blood transfusion
previsous transplants
7
Q
What happens in hyperacute rejection when antibodies bind to vascular endothelium ?
A
complement activation- endothelial damage
graft haemorrhage
blood clotting- vascular blockage
8
Q
How can we avoid hyperacute rejection ?
A
MHC antigen cross matching
serological testing
9
Q
What type of reactions are graft v host and transplant rejection
A
alloreaction- type IV
10
Q
What is type IV hypersensitivity ?
A
T cell mediated
11
Q
What are alloantigens ?
A
antigens that vary between individuals of the same species- eg. MHC
12
Q
What are alloreactions ?
A
Immune response by one individual to the alloantigen of another causes by alloreactive T cells
13
Q
What happens in transplant rejection ?
A
Kidney is transplanted
recipients T cells attack transplant
14
Q
What happens in graft v host disease ?
A
haemoatopoietic stem cell infusions
stem cells transplanted
T cells in the transplant attack recipients tissues
15
Q
What are the preparations for transplantations ?
A
limit ischaemia limit MHC class i/class II mismatch
16
Q
What is ischaemia and what does it lead to ?
A
inadequate blood supply
leads to tissue damage and inflammation
17
Q
What happens if there is an MHC class I/class II mismatch ?
A
alloreactive CD4 cells to class II alloreactive CD8 cells to class I
18
Q
What happens if alloreactive T cells are produced ?
A
organ is attacked
acute rejection - type IV hypersensitivity
19
Q
What is the gross appearance of an acutely rejected kidney ?
A
read areas of haemorrhage
grey areas of necrosis
20
Q
When are immunosuppression drugs given for transplantation ?
A
before and after surgery
increases likelihood if infections
21
Q
What can acute rejection progress to ?
A
chronic rejection
22
Q
What type of reaction is chronic rejection ?
A
type III hypersensitivity - deposition of immune complexes of antibody/MHC molecules on vascular endothelium of graft
23
Q
What does immune complex deposition lead to in chronic rejection ?
A
monocytes and neutrophils activated
Allograft specific T cells develop leading to chronic allograft vasculopathy
24
Q
What happens in chronic allograft vasculopathy ?
A
arteriosclerosis of graft- hypotension, fibrosis and atrophy
loss of fucntion
fibrotic tissue deposition
25
What are the other causes of chronic rejection ?
ischaemic injury
viral infection - due to immunosupression
relapse of original disorder - leukaemia eg
26
What is the structure of MHC class I ?
alpha 1 2 and 3
B2 microglobulin subunit
present to CD8
27
What is the structure of MHC class II ?
alpha 1 and 2
beta 1 and 2
present to CD4
28
What is significant about MHC ?
lots of polymorphisms distributed differnetly within population
across different regions of the MHC
29
How does MHC relate to survival of transplanted organs ?
More MHC mismatches and the percentage of graft survival decreases
Half life diminshes with increasing mismatches
30
What is graft half life ?
time taken for the amount of viable graft tissue to be reduced in half
31
What is the order of MHC sensitivity of different organs ?
cornea is MHC neutral - easy to transplant
liver
Heart
Kidney
Bone marrow - require strict MHC matching - expresses a lot of MHC class II that can eb attacked by antibodies
32
How does a bone marrow transplant work ?
chemotherapy and irradiation to remove host bone marrow and kill cancer cells and stop immune response
infuse new haemoatopoietic stem cells that are matcheed
remake bone marrow
33
What are the conventional immumosupressive drugs ?
corticosteroids
| cyclosporin and tacrolimus
34
What do corticosteroids do ?
inhibit inflammation by inhibting cyotkine production by macrophages
35
What does cyclosporin do #/
blocks IL-2 production by T cells and stops T cell proliferation as IL-2 is T cell growth factor
36
What are the side effects of cyclosporin ?
lead to gingival overgrowth
kidney damage
hypertension
37
What does the unique specifictity of antibodies allow ?
detection of proteins
38
What is the constant region ?
```
amino acid similarity between antibodies of the same class
different classes have different constant regions
```
39
What is the variable region ?
antigen specificty
| Fab
40
What are the antibodies like that are produced from conventional immunisation ?
```
mixed specificity
mixed isotypes
variability in batches
limited amounts as drawn from the blood
polyclonal
```
41
What are the monoclonal antibodies like ?
single specificity
single isotype made
no variabiltiy between batches- good quality
limitless production quality
42
What are recombinant antibodies like ?
```
single specificity
single isotype
no variability between batches
limitless production quality
genetically altered to be human like- no immune response
```
43
How do we produce monoclonal antibodies ?
Take B cell from mouse immunised with antigen
combine with myeloma cells- B cell cancer cells
kill non hybridomas
select for antigen specific hybridoma
clone hybridoma- make limtless antibodies - monoclonal
44
How can we diagnose immunodeficiencies ?
IgG, IgM , IgE, IgA levels
whole blood cell count
lymohocyte count
flow cytometry- chracterise deficiecy
45
How does flow cytometry work ?
label a mixture of cells with fluorescent antibodies to specific cell surface molecules - distingusih cells by cell surface expression
laser picks up the cells with a particular antibody
numerate them in a plot- see which deficiency
46
What is CD3 ?
cell surface molecule on CD4 and CD8 cells
47
What is CD19 ?
On B cells only -
| plot shows none present in XLA
48
How are autoimmune diseases analysed ?
physiological function- see if it is reduced, eg. hyperthyroidism in Graves disease
look for presence of autoantibodies
49
How do we detect serum autoantibodies ?
with ELISA
50
Describe the presence of ELISA for autoantibody detection ?
antigen in plate
serum added- might contain autoantibody
second antibody added which is enzyme linked
binds to Fc tail of autoantibody if present
enzyme added- colour chamge if binds to secodnary antibody
Quantification of colour change- spectrophometer
51
How can we use immunofluoresence for antigen detection ?
Direct immunoflupresence- antibody added that has F on it - binds to antigen
Indirect immunofluoresence- second antibody that bidns to a primary antibody, Second antibody only has F
52
Which diseases can indirect immunofluoresence be used for ?
bullous pemphigoid- autoantigen in basement membrane, can use direct immunofluoresence to detect
Pemphigus vulgaris- more antigens in epithelial cells connections- immunofluoresence with second antibody
Good pastures syndrome- in glomerulus, immune complexes- detect complexes with antibodies
53
How can we diagnose allergies ?
intradermal skin test
54
Describe the intradermal skin test ?
injection with saline- see if injection causes any response- shouldnt
inject with Histamine- see a normal allergic response
inject with suspected allergen- could be positive
55
What are some agents used to manipulate the immune response ?
adjuvants in vaccines
molecules that inhibit cytokine signalling pathways- Tofacitinib- for rheumatoid arthritis - reduce joint inflammation
56
What do monoclonal antibodies end in ?
mab
57
What are the the types of monoclonal amtibodies ?
murine
chimeric
humanised
human
58
What are the problems with human monoclonal antibodies ?
need to be injected in large amounts
cant be eliminated in glomeruli
Fc receptors- bind to other cells- increase retention
high production costs
59
How does omalizumab work ?
antibody against IgE- anti-IgE
stops IgE in circulation binding to Fc receptors on mast cells upon allergen exposure- no degranulation
used in chronic asthma
60
What is an example of a biologic ?
infliximab in rheumatoid arthritis
61
How does infliximab work ?
anti-TNF alpha
inhivits TNF alpha induced inflamamtion in rheumatoid arthritis
dampens joint inflammation
62
What are the proven effects of infliximab ?
reduced pain and swollen joints
| also reducd CRP
63
What does CRP indicate ?
systemic inflamamtion- acute phase protein sin liver- higher CRp
64
What is an adenoma ?
benign tumour
contained within a site
even when in an important area
65
What is adenocarcinoma ?
malignant tumour
invasive
spreads
66
Where can you find adenomas and adenocarcinomas ?
in glandular/secretory tissuse
67
What are the key features of cancer ?
proliferation and invasion
68
What are cancer cells immunologically similar to ?
self cells
69
Do cancer cells grow slowly or fast ?
slowly
70
How do we know the immune system can recognise ad reject tumours ?
immunodeficient animals- have higher incidence of cancer
immunosupressive therapy- increased cancer rates
cancer incidence increases with age due to immunosunescence
MHC differences can influence tumour survival
71
What are the genetic changes and immune recognition that can happen in tumours ?
```
normal peptide presentation by class I
mutation and becomes cancerous
presentation of mutant peptide from a mutated cellular protein
reactivated embryonic genes
overexpression of normal self protein
```
72
Which viruses are associated with human cancers?
HIV
HPV
EBV
HepB and Hep C
73
Which type of viral infection leads to cancers ?
chronic viral infections
74
How is HPV associated with cancer ?
certain strains - cause warts
| warts are benign that cause cellualr transformation
75
WHich cancers is HPV associated with ?
oral cancer
cervical cancer
cancers of the UGT
head and neck
76
What does Hep B virus do in cancer ?
transforms liver cells into hepatocellular carcinoma
77
What does EBV do in cancer ?
lead to lymphomas
78
What are lymphomas ?
cancer of mature lymphocytes
79
Which cancers does HIV lead to ?
karposis sarcoma
| skin cancer- HHV8
80
How do viruses cause cancer ?
viruses set up chronic infections
interfere with normal division mechanisms leading to hyperplasia
increased cell proliferation and transformation into cancer
81
Which bacterial infections can lead to cancer ?
helicobacter pylori
stomach ulcers
stomach cancer
82
Describe the progression of HPV associated cancer ?
increasingly displastic cells
no longer stratified squamous
invasion into connective tissue- cancerous lesions
dysplasia - cancer transformation
83
What is CIN ?
cervical intraepithelial neoplasia
84
Can HPV related cancer regress ?
yes the cancer can regress
85
Which strains of HPV are associated with cancer ?
HPV 16 and 18
| cancerous transformation
86
What is the cause of 99% of cervical cancer cases ?
HPV
87
What is the immune response like against HPV ?
lesions are cleared within 2 years
good immune response to HPV
immune supression is effective in the majority
88
Why do not all people clear HPV infection ?
the HPV antigen is not recognised
| viruses escape epithelial cells
89
How does HPV cause cancer ?
infect epithelial cells
| inhibit tumour supresssor mechanisms like p53 so cells proliferate above the normal regulatory mechanisms
90
How do tumour supressor mechanisms work ?
p53 delays the cell cycle so
| cells can be repaired and then replicated
91
What does inhibiting p53 lead to ?
mutated cells still proliferate
92
What happens to p53 in cancer ?
inhibited/mutated
93
How many types of HPV are there and what doe sit mean ?
30-40 types
| many multivalent oncognenic vaccines needed
94
What type of cancer due to HPV is increasing ?
head and neck
95
What is suspected to reduce and eliminate cervical cancer rates ?
screening programmes
availability of invasive surgery
vaccination for boys
96
What is preventing us deciding if HPV vaccine elimianates cervical cancer ?
latency period
97
What is predicitve modelling ?
modelling technique that HPV associated cervical cancer will decrease due to spread of vaccine line n australia- also used for boys
98
What are the downsides of predictive modelling ?
some high grade cancers are not caused by HPV
not sure of effectiveness against CIN3 cancers
infections may just regress and the cancers regress randomly
99
How do HPV and HCV spread ?
contaminated blood
blood contaminated instruments
sex
mother to child in childbirth
100
What do HBV and HCV cause ?
hepatitis
liver cirrhosis- scarring, fibrosis and loss of tissue function
hepatocellular carcinoma
both have a long incubation period
101
What is acute hepatitis associated with ?
clearance by the immune system
| sets up chronic infections in immunosupressed patients
102
What does HCV do ?
inhibits activation of dendritic cells
no specific T cells
impaired viral clearance
103
What does Hepatitis C do ?
mutates rapidly
| causes chronic hepatitis
104
Which Hep has an effective vaccine ?
hepatitis B
105
What do Hep B and Hep C do with Tregs ?
promote Tregs
| promote viral infection through supression of antiviral responses
106
Which immunotherapy techniques are used to target specific antigens ?
monoclonal antibodies
107
How can monoclonal antibodies be used in the treatment of cancers ?
target cancer molecules like B cells in lymphoma - ritumixab
target host immune system to boost performance using checkpoint inhibitor drugs l
targeting cancer and using radiotherapy to kill isotypes
108
Why do we get a GVH response in BMT ?
allogenic donor T cells circualte and activate causing tissue damage
interact with dendritic cells
109
What is BMT use dfor ?
rescue haemoatopietic system after chemotherapy and irradiation for leukaemia
110
As well as a GVHR what do you get ?
graft v leukameia response - donor T cells attack leuakaemia cells as well
111
What happens in allogenic HLA matched non self transplantation ?
GVH
| GVL as well
112
What happens in autologous self donors ?
no GVHR
but no GVL effect
relapse
113
What do new BMT regimens involve ?
therpauetic T cells to indice controlled GVL effect
114
Give an example of adoptive T cell therapy ?
chimeric antigen receptors
expressed in T cells
confer anti tumour specificity in lymphocytes
target tumour
115
What percentage of pathogens enter by the nose and mouth ?
70%
116
What is the mucosa lined with ?
glandular epithelium
| bathed in secretions
117
What are some elements of the immune response in the mouth ?
enzymes- lysozyme break cell walla by osmosis and lysis
AMPs- lysis
lactoferrin-enzyme that complexes ion, prevents growth
118
What is the main Ig in the mouth ?
IgA- in the mouth from saliva
119
What is mucin ?
highly glycosylated protein
mixes with water- coagulates bacteria
so they can be swallowed
120
Is the oral mucosa keratinised ?
no except for the masticatory mucosa
121
What do epithelial cells make in defence ?
beta defensins
122
What is the advantage of squamous epithelial cells ?
exfoliate as a defence
| get rid of colonisers and prevent attachment
123
What is the GCF ?
serum exudate
adaptive elemetns- IgM and IgG
cellular elements like neutrophils
AMPs
124
When does GCF increase ?
in inflamamtion and pocket depth- increases
125
What are the salivary glands in the mouth ?
minor- many and widely distributed
| major- parotid, sublingual and submandibular
126
What are flow characteristics ?
GCF pocket/ urine/saliva- flow dislodges bacteria
127
What are the different solubilities of bacteria ?
soluble phase
mucosal phase
tooth surface
plaque biofilm
128
What are AMPs and what do they do ?
defensins/statherin
| disrupt bacterial membranes and enveloped viruses
129
What are adhesive proteins ?
mucin, PRPs, Agglutinin
| bacterial adhesion in fluid phase, promote adhesion to teeth
130
What are metal ion chelators ?
lactoferrin
| scavenge for zinc and iron respectively
131
What are protease inhibitors ?
cystatin
| prevent nutrient acquisition by bacteria
132
What in the interface in the mouth with the systemic immune response ?
GCF
133
Where does GCF originate ?
in the gingival crevice
134
What are the defences of the oral mucosa ?
barrier fucntion- keratinocytes
desquamtion of oral epithelium
AMPs
mucus layer
135
What is the role of the phase 1 natural host defence in the mouth ?
act to inactivate
clear
prevent attachment and prevent invasion
136
What are the components of the host defence ?
```
salivary components
integrity of oral mucosa
acquired enamel pellicle
commensal flora - competition for nutrients
vascualrity- host defences
```
137
What are the components of the gingival epithelium ?
oral epithelium
junctional epithelium
sulcar epithelium
138
What is the role of the junctional epithelium ?
attachment of the gingiva to enamel
139
What are aspects of infection with periodontitis ?
```
migration of JE
loss off attachment
bone loss
plaque development
tissue loss and loss of fucntion
```
140
What is the role of phase 2 in the mouth ?
innate immunity
| containmet, prevention and spread and clearance
141
What are the aspects of innate immunity in the mouth ?
GCF elements
macrophages- signalling and cytokines
neutrophils- phagocytosis
complement- opsinisation, chemotaxis and lyis
142
Why do neutrophils move through the gingiva ?
move through the gingiva in response to commensal flora to IL8
143
What is IL8 ?
a chemokine
144
What do neutrophils do in the gingiva ?
physiological inflamamtion state in the gut
145
What happens to neutrophils in periodontitis ?
neutrophil migration upregulated in respose to pathogenic microflora
IL8 also increases
146
What happens to people with neutrophil defects ?
they have increased susceptibiltiy to periodontitis
147
What type of inflamamtion does HIV lead to ?
necrotising ulcertaive gingivitis
148
Compare the intestinal burden in the intestine and sulcar/JE ?
high amount of flora in the intestine
| variable amount of flora in the SE/JE
149
What are the bacteria like in intestine and the sulcar/JE ?
bacteria in solution in gut
| bacteria in biolfim in sulcar/JE
150
What is the mucus layer like in the intestine and the JE ?
thick mucus in the gut
| no mucin in the JE but in the mouth
151
What are the antibodies in the gut/SE ?
gut- IgA
| crevice- IgG
152
What are the jucntions like in the gut/SE ?
gut- tight jucntions
| JE- porous
153
What are the inflammatory states in the gut/JE ?
gut- stbael physiologial inflamamtion
| JE- difficult to prevent a damaging inflammation
154
What type of Ig is IgA ?
mucosal
155
What is the tole of phase 3 in the mouth ?
enchancement of innate immunity
| long lasting specific immunity
156
What are periodontal antibodies good for ?
enhancing the innate immunity
157
What does phase 2 do to phase 3 ?
broadcast
amplify
enhancement
158
What does phase 3 do to phase 2 ?
regulated by cytokines
| mediated by T cells and antibodies
159
What is salivary IgA secreted from ?
salivary glands
| with S-IgM
160
What does S-IgA do ?
inhibition of adherence and penetrance
neutraliation of viruses and virulence factors
form complexes with mucous - agglutinate and swallowed
161
What are the different types of IgA ?
IgA1- against proteins
| IgA2- agaisnr polysaccharides
162
How is salivary IgA made ?
antigen uptake - phgocytosis and endocytosis
presented to dendritic cells
T cell acitvation and B cell activation
b cells make IgA
B cells migrate to over mucosal sites
IgA secreted via endocytosis acorss basolateral membrane
163
What is the conformation of IgA ?
J chain
| dimeric when secreted
164
What are the characteristics of the sungingival microbiota ?
```
streptococci
actinomyces
biofilm
anerobic
immune response is difficult
```
165
What are some examples of PAMPs ?
```
LPS
lipoteichoic acid (GP_
DNA
fimbriae
Fatty acids like acetic acid
```
166
What happens to PAMPs?
recognised by TLRs and intracellualr signalling pathway
167
Which cells recognise PAMPs ?
dendritic cells
macrophages
epithelial cells
fibroblasts
168
What is the end result of PAMP detection ?
cytokines- reinforce cells
chemokines
AMPs
prostanoids
169
What is the tole of the primary phase?
recognition
170
What is the role of the secondary phase ?
diversification
reinfrocement
amplification
braodcast
171
What is IL-1 beta ?
```
inflamamtroy cytokine
activates neutrophils
activates macropahes - make more IL1
activates capillary endothelium - more neutrophils and macrophages
activate dendritic cells for APC
```
172
What happens to IL-1 id plaque persists ?
chronic activation
173
How can high levels of IL-1 be detected ?
BY ELISA in the GCF
174
What happens in chronic activation of IL-1 ?
activation of osteoclasts- bone resorption
fibroblasts- MMPs= chew up collagen
fibroblasts- collagen in chew up in PDL
neutrophils over stimulated to make IL-1
175
What is in ahigh level in GCF in periodontitis ?
MMP
176
What is doxycycline ?
doxyxline
| inhibit MMP
