lectures Flashcards
1
Q
what is the immune system?
A
A system of cells and molecules designed to fight infection
2
Q
Name some infectious agents
A
Worms: tapeworm Protozoa: malaria Funghi: Aspergilus Candida Bacteria: Staphylococcus Virus: Influenza
3
Q
What are the three layers of defence
A
Physical Barrier- Skin
Innate immune system- primary response
Adaptive Immune system-immunological memory
4
Q
how is the skin protective
A
Impermeable barrier
when damaged- infection more of a problem
prevents bacteria living on skin- done through inhibitory lactic acid and fatty acids in sweat and subaceous secretions
low pH
(sebum secreted from subaceous glands makes skin waterproof and waxy)
5
Q
What is the difference between the innate and adaptive immune system
A
innate system is broadly specific- recognises similar structures in pathogens but reponds the same way everytime it sees the same pathogen
Adaptive immune system- highly antigen specific. Immunological memory much stronger and faster response the second time it meets an antigen
in reality not discrete systems- form a continuum
6
Q
what anti microbal functions do secreted fluids contain?
A
Gastric secretion: acid Semen: Spermine and zinc Milk: Lactoseperoxidase Tears, nasal secretion, saliva: Lysozyme (not part of the immune system)
7
Q
how does mucous protect against infection
A
secreted by lining of inner surface of body
prevents the adhesion of microbes to epithelium preventing colonisation
traps microbes
8
Q
How do physiological bacterial flora protect against infection?
A
they compete with invading microbes for nutrients for growth
produce microbicidal substances
antibiotics that kill bacterial flora make infection more likely
9
Q
What is an antigen
A
an organism or molecule recognised by the immune system
10
Q
what are the cells of the innate immune system?
A
Phagocytes: monocytes macrophages and neutrophils Eosiniphils Mast cells + Basophils Dendritic cells Natural Killer cells
11
Q
what are phagocytes provide 3 examples and where they are derived from?
A
phagocytes use pseudopodium to secure target and engulf them and digest using chemicals
- monocytes (mononuclear phagocytes) found in blood short lived
- macrophages derived from monocytes, leave blood and enter tissue- longer life span
- neutrophils (granules in cytoplasm, lots of cytoplasm, single multilobed nucleus)- fairly short lived produced continuously, found in blood and tissue at site of infection
12
Q
what do eosinophils do?
A
two or three lobed nucleus, lots of cytoplasm
can phagocytose small molecules
release toxic molecules onto surface of organisms too large to phagocytose e.g parasitic worms
(stain with eosin [H and E stain])
secrete major basic proteins, cationic proteins, oxygen metabollites ( e.g. superoxides) and perofins
13
Q
whats the difference between mast cells and basophils
what do they do
A
mast cells found in tissues, basophils found in blood, derived differently
result in inflammation
14
Q
what are dendritic cells
A
-one of the main links between innate and adaptive immune systems
involved in activating immune system- present antigens to t cells through MHC class II
-in skin as immature langerhans cells and lymphoid organs
internalise
-express CD80 and CD86
(CD86 binds to CD 28 on t cells)
activate B cells
required for T cell activation
15
Q
what are NK cells
A
-have a round nucleus with small amount of cytoplasm.
-kill extracellularly
exactly
-kill all cells that don’t express MHC I
16
Q
what molecules are used by the innate immune system
A
Complement
acute phase proteins e.g CRP
interferons- IFN-α IFN-β, IFN-γ - interfere with viral replication
17
Q
what are the cells of the adaptive immune response?
A
T lymphocytes- Th, Tc, Treg
B lymphocytes
antibodies
look similar to NK cells
18
Q
What does Th do
A
helper T cells
19
Q
What does Tc do
A
kills infected cells
20
Q
What does Treg do
A
supress immune system response
21
Q
what do antibodies (Ab) do
A
directly neutralise toxins and viruses
link different parts of immune system
recruit phagocytes, killer cells or complement
22
Q
when is the immune response activated
A
within 0-4 hours of threat- recognition by nonspecific and broadly specific effectors
23
Q
macrophages
A
derived from monocytes- from bone marrow
active in tissues especially spleen and lymph
phagocytes
pathogen recognition receptors induce other receptors- induce oother reactions, produced cytokines
24
Q
what are the two types of Dendritic cells
A
follicular dendritic cells
dendritic cells
25
what is the difference between dendritic cells and follicular dendritic cells
dendritic cells are wide spread,
express: MHC class II, CD80,86
process antigen to T cells
phagocytosis
follicular dendritic cells in germinal centre
dont have MHC class II or CD80,86
do not phagocytose
native antigen to B-cells
26
Follicular dendritic cells
only in secondary lymphoid tissue- spleen and lymph nodes
activate B cells
no MHC II or CD80/86
cant phagocytose
27
how do FDC activate B cells
present native antigen to B Cell
B cell recognises antigen antibody complex
brought to centre of germinal lymphoid tissue
activates B cell which matures
IgG response- highly specific antibodies
28
what % of NK cells circulate
2%
29
what is missing self
```
'missing self' is what NK cells recognise
they kill cells that do not express MHC class I which all of our cells possess therefore they kill if no protein or antibody is recognised- missing self
```
30
give an example of an infection that avoids death missing self
cytomegalovirus
modifies MHC class I so it is still recognised
however it can still be killed by NK cells through many activator molecule being expressed that inhibit the recognition of MHC I causing NK cells to be activated anyway
31
what are Pattern recognition receptors?
found on neutrophils, macrophages, DC
32
where are the acute phase proteins produced
liver
IL 1 IL 6 TNF activate
causes release of C3 (part of complement)
CRP (activates complement)
fibrinogen- cogagulation
33
What are the three ways to activate complement?
Classical pathways
Lectin
Alternative
34
What cleaves c5 and c3
C3: c4b2a, c3bBb
35
What is the membrane attack complex
C3a, c3b, c5a, c6, c7, c8, c9
36
Explain opsinisation
```
TLR recognises microbe
Complement C3b added to microbe
Antibody added in same way
Phagocyte has C3bR and antibody R
Antibody+ complement activates phagocyte
```
37
what is inflammation
```
tissues response to injury or infection
characterised by the increased blood flow and entry of leukocytes into the tissue
results in:
swelling
redness
elevated temp
pain
```
38
what is complement
a set of around 20 proteins that act in an enzymatic amplification cascade to activate components involved in immune response
- perform opsinisation
- cell lysis (membrane attack complex)
- enhance inflammation
travels around blood is inactive soluble proteins
39
what proteins are in the classical pathway?
C1q C1r C1s-> C4b2a- c3 convertase
40
what makes up the MAC
C5b C6 C7 C8 C9 (many C9s)
41
where do T cells develope
Thymus in chest cavity ( from bone marrow)
42
when do T cells express both CD4 and CD8
when immature
43
what T cells are CD4+
T helper
| Treg
44
what cells are CD8+
Tc
45
what are the two forms of TCR
alpha beta
| gamma delta- rare
46
what are the regions of the TCR
V- variable- recognises peptide MHC complex
| C-constant
47
what is the structure of the TCR
```
2 chains ( usually alpha and beta) linked by disulphide bonds
each chain has a variable region, a constant region and a transmembrane region
```
48
what does the the alpha beta TCR recognise?
the antigen presented by MHC on an antigen presenting cell
49
what class of MHC does CD8 bind to
CD8 (cytotoxic Tcells) bind to MHC class 1
50
what class of MHC does CD4 bind to?
CD4 (cytotoxic T cells) binds to MHC class 2
51
what is the co receptor of TCR
CD3 co receptor
made up of 1 gamma, 1 delta, 2 epsilon,
2 zeta
52
how does LCK work
LCK recognises ITAM region of CD3 and zeta chains and phosphorylates a tyrosine group to activate if a pathogen is presented to TCR
53
what is the TCR complex
TCR CD3 + 2 zeta chains
54
how many different types of TCR is on a single T cell
1
55
what are the 2 forms of selection of T cells
positive selection- recognise own MHC
| negative selection- recognises self antigens
56
what is anergy
an unactivated T cell
| TCR + MHC II + CD4 not enough
57
describe the process of T cell activation
xx
58
how many B7 molecules exist on antigen presenting cells
B7.1-CD80
| B7.2-CD86
59
what are the functional activities of T cells
Proliferate (specific for pathogens)
mediate effector response
form memory cells
60
what is the function and what are expressed/produced by Th1
```
help Tc and macrophages
inhibit Th2
IFN gamma
IL-2
TNFbeta
```
61
what is the function and what are expressed/produced by Th2
```
help B cells produce antigens
inhibit Th1
IL-4
IL-5
IL-10
IL-13
```
62
what is the function and what are expressed/produced by Th17
pro inflammation
IL-17
IL-22- more important
63
what is the function and what are expressed/produced by Tfh
help germinal centre B cells
IL-21
ICOS
64
what is the function and what are expressed/produced by
| Treg
suppress immune system
TGFb
IL-10
IL-35
65
what is the function and what are expressed/produced by
| Tc (CD8+)
Perforin
Granzymes
FasL
Cytokines
66
how does Th1 activate macrophages
TCR-MHC
CD40L->CD40R on macrophage
IFN gamma released- super activates
67
how does Th1 activate Tc
-releases IL2 and IL6 to enhance Tc cells- co stimulation
| +MHC I and TCR
68
methods of cytotoxic T cell killing
Granule dependent killing- perforin makes holes
fasL binds to target
caspase activation apoptosis
69
what distinguishes a T cell from a B cell
look the same microscopically
T cells express CD4 or CD8
B cells express antigens
70
What are the five classes of antibodies?
```
IgG
IgA
IgM
IgD
IgE
```
71
where are B cells produced
Bone Marrow
72
what do naive B cells express?
```
IgM and IgD
Ig alpha Ig Beta- not actual antibodies
CD19-marker for B cells
CD20-marker for B cells
CD40
```
73
what is an antibody made up of?
variable region and constant region
| recombination of variable region makes 10^15 different antibodies.
74
what does the variable region do?
recognises antigen
75
what is clonal selection
```
presence of antigen specific for an antigen leads to the reproduction of the antigen
Ig alpha and Ig Beta stimulated
2 types of cells produced:
Plasma cells- secrete antibodies-
Memory cells- express antibodies on surface
(T cells
2 types of cells:
effector cells
memory cells
```
76
how many different constant regions are there ( of antibodies)
3
| Cµ Ckappa Clambda
77
adaptive immune response
qualitatively and quantitatively better
78
how does class switching of antigens happen
```
requires MHC presenting antigen from B cell to Th2 (best at class switch)
Th2->B cell
CD28->B7
D40L->CD40R
cell contact dependent
+cytokines
mutual activation
B cell enters cell cycle
Cytokines direct class switching
```
79
what cytokines direct IgE switch
IL4 and IL12
inhibited by gamma interferon
80
what is somatic hyper mutation
in variable region of antibody, proof reading down regulated
each replication chance of mutation- increases variability but can lead to defunct antibodies- stop codon
can be massively favourable
81
how do FDCs enhance immunomemory
store small amount of antigen for a long time- stops memory cells from dying
82
what MHC class do B cells have
MHC class 2
83
which cells have MHC class II
professional antigen presenting cells
| B cells, DC, macrophage,
84
explain the action of B cells in presenting an antigen to a t cell
Antibody binds antigen
antibody +Ig alpha+ Ig beta (=whole receptor) src family tyrosine kinases phosphorylates tyrosine in ITAM on Ig alp and beta
antigen brought into B cell by endocytosis of antigen antibody complex
antigen degraded
intake of antigen activates B cell
presented in MHC classII
85
T cell independent
```
polysacharide- shape of molecules brings antibodies close together in membrane doesnt require T cell activation
no t cell no class switching
```
86
T cell dependent
need T cell interactions CD40 L, CD28
| cytokines
87
what are the 4 types of receptors in the immune system
```
pattern recognition receptors e.g TLR
MHC class 1: HLA A, HLA B, HLA c
class 2: DP, DQ, DR
TCR
BCR
```
88
what is the structure of an antibody?
2 heavy chains
| 2 light chains
89
what is the complementarity determining region
a part of the antibody that is highly variable and is complementary to an antigen
90
where does the variability of antibodies come from?
recombination of the CDR
91
where is the heavy gene located
Chr 14
92
what are the 2 forms of light chain
Kappa Chr 2
| lambda Chr 22
93
what are the gene segments that make up the heavy chain involved in recombination
Variable (V)- 40 genes
Diversity (D) -27 genes
Joining (J)- 6 genes
constant (C)- 9 genes
94
describe the process of recombination
(randomly) one D put next to a J
| V recombines with DJ splice out introns get a VDJ sequence
95
how many heavy chains do you have
2 copies one from each parent
96
how many light chains
2 kappa 2 lambda
97
which enzyme is responsible for V-D-J recombination
recombinase enzymes encoded by RAG1 RAG2
98
what do RAG1 and RAG2
recognises recombination signal sequence (RSS)
99
what is the 12 23 rule
you can only recombine a gene with 12 space RSS wit hone with 23 space RSS
D- 23
J-12
V-12
can only combine v with D and J with D not J with V or D with D
100
how do you get additional diversity in antibodies
recombinatorial inaccuracies- recombine DNA location of splice
N-nucleotide addition- Terminal deoxynucleotidyl transferase TdT
Chain combinations
Somatic hypermutation- each division of cell is a chance for mutation
101
what does class switching of antibodies involve
```
changing constant recion of heavy chain
IgG- Gamma
IgA- alpha
IgM-mu
IgD-delta
IgE-epsilon
```
102
what are the 4 subclasses of IgG
IgG 1
IgG2
IgG3
IgG4
103
what are the 2 light chains of an antibody
Kappa and lambda
104
what connects the two heavy chains of the antibody
hinge region with disulphide bonds
105
give two examples of antibody monomers
IgM- pentamer in circulation
| IgA dimer in mucosal surface
106
where can antibodies be found
cell surface
| soluble
107
what is an epitope
region of antigen that an antibody can bind to
always a similar size no matter how big an antigen is
a bigger antigen will just have more epitopes
108
what is a discontinuous epitope
amino acids from all over the antigen fold to be close to each other
109
what is a continuous epitope
when aas are next to each other in a sequence (primary sequence)
110
what forces are involved in binding antigen and antibody
H bond
electrostatic forces
hydrophobic interaction
van der waals
111
what is a single arm of an antibody
Fab
112
why do antibodies have 2 arms
more chance to bind to an antigen
113
by how much does the IgM pentamer increase the chance of binding to antigen
10^7 increase in equilibrium constant
114
how can more than 1 antibody bind to a single antigen
different epitopes on a single antigen
115
what is the most common antibody
IgG
116
how does an antibody stay in a membrane
many hydrophobic aas far down stream from CDR
117
how are antibodies secreted
hydrophobic aas removed
118
which antibodies work best alone
IgM and IgG
119
antibodies acting on their own
bacterial toxin- stopped from entering cell by Ab binding
block viruses- binds to receptors on viruses
bacteria- blocked from binding to mucosal surface
120
how do antibodies link to other parts of immune system give 3 examples
RBC -complement receptor (Cr1)- recognise antibody antigen complex
C3b taken to liver and spleen
-FC gamma- receptor on phagocytic cells respond to IgG
IgG opsinises cells for phagocytosis
-IgM and IgG activates MAC
-antibody dependent cell mediated cytotoxicity
FC gamma R on NK cells- release toxic molecules
-IgE causes mast cells to degranulate. FC epsilon R
121
what is the function of IgM
antigen receptor on naive B cells (monomer)
when released from plasma cell- pentamer
first antibody produced in immune response
activate compliment
122
what is the function of IgG1
activates compliment
enhances phagocytosis
can cross the placenta
(in breast milk)
123
what is the function of IgG2
activate compliment
124
what is the function of IgG3
activate compliment
enhance phagocytosis
can cross placenta
125
what is the function of IgG4
can cross placenta
126
what is the function of IgA(1 and 2)
protect mucosal surface
127
what is the function of IgD
antibody on naive B cell
128
what is the function of IgE
release of inflammatory mediators from mast cells
| allergy
129
where are HLA genes expressed
```
HLA genes are the genes of MHC class 1
they are expressed on all nucleated cells
```
130
where are MHC class 2 expressed
professional antigen presenting cells
dendritic cells, B cells, macrophage
(professional antigen presenting cells will express both MHC class 1 and class 2)
131
what is MHC class 3
involved in immune response eg complement
132
what is the function of MHC class 1
alert cytotoxic T cells to intracellular infection
133
what is the function of MHC class 2
specialized for activating helper T cells
134
which HLA (MHC class 1) gene is most polymorphic
HLA-B
| HLA-C is least variable
135
where is there high variation in the population MHC genes
pathogens are constantly changing we need a wide range in the population so the entire population isnt wiped out
136
what is the structure of MHC molecules
2 sausages on a BBQ
5 Beta sheets
2 alpha helices- form the groove in which the peptide sits
137
which chain is more variable in MHC class 1
Alpha
| only 1 Beta variety
138
what is the domain structure of MHC class 1
```
00
o0
/
0=alpha 1/2/3
o=beta 2 microglobulin
/=transmembrane
groove between alpha 1 alpha 2
```
139
what happens if ß2 microglobulin is KOed
the MHC molecule will not reach the cell surface
140
what is the domain structure of MHC class 2
```
0o
0o
/ /
0=alpha 1/2
o=beta 2 microglobulin
/=transmembrane
groove between alpha and beta
```
141
what is the difference between MHC I and MHC II
MHC II can bind larger pieces of antigen as it is not closed at the ends of the groove. open grooves allows larger peices to bind
142
do all regions of the MHC binding groove contribute equally
no anchor positions more important
position 5 Y/F
position 8 L/M/I/V
sequence of aas only important at anchor regions
143
co stimulation of MHC I to TCR
Tc- CD8 recognises non polymorphic part of MHC
| CDR of TCR bind to protein and polymorphic region of MHC
144
what happens to the cell when an infection happens
immunoproteasome formed
switch on of genes associated to the proteasome
immunoproteasome chops up to the correct region for MHC I
145
how big is the region of antigen presented on MHC I and II
endogenous proteins- MHC I- 8-9 aas long
| exogenous MHC II- 15 aas long
146
how does an antigen get presented onto MHC class 1
syntesis of MHC in RER
calnexin binds to alpha chain to make it bind to ß2 microglobulin
calreticulin 57 keeps MHC in correct shape for antigen to bind
Transporters associated with antigen processing (TAP) 1 and 2 pick up protein cleaved by immunoproteasome and takes it to RER (active)
put into MHC
MHC taken to cell surface
147
how does a protein get presented to MHC class 2
antigen phagocytosed binds to proteasome broken down to the correct shape
invariant chain produced by RER and put into MHC groove prevents anything else binding
MHC II moves to endosome containing the correct length protein
most of invariant chain degraded, some remains called CLIP
DO and DM remove CLIP from groove
MHC taken to membrane
148
what is cross presentation
the ability of MHC class 2 to present endogenous peptides and MHC class 1 to present exogenous
149
can an MHC reach the cell surface without a peptide
no
150
which motile system do immune cells use
Blood
| Lymph
151
what lets immune cells into the lymph node
HEV
| high endothelial venules
152
how do lymphocytes/ immune cells reach the inflammed tissue
histamine increases the gaps in the endothelium of blood vessels allows immune cells into the inflammed tissue
histamine acts as chemotactic gradient
153
when does an immune cell stay in the lymph node
if an antigen is present a cell will stay in the lymph node otherwise it leaves
154
what is the structure of the lymph node
cortex- mostly B cells
paracortex mostly T cells
medulla
155
what brings antigen to lymph node
Dendritic cell recognises antigen with PRR (TLR)
moves out of tissue into lymph node
(no longer phagocytic)
upregulates CD80 CD86
156
what happens when an antigen is in a secondary lymphoid tissue
follicle produced
| becomes secondary follicle with germinal centre in the middle
157
what are the structures of germinal centres
```
Mantel zone round the edge- less densely packed
dark zone
basal licht zone
apical light zone
naive B cells move from top to bottom
```
158
what do FDC do
present antigen to naive B cell
| have immune complexes of antigen, antibody and complement
159
what cells are in the germinal centre
```
B cells
T cells (Tfh)
DC
FDC
macrophage
```
160
what happens in germinal centre
B cell class switching
affinity maturation
memory cell generation
plasma precursor generation- plasma cells would cover antigens on FDC
161
what are the similar structures to germinal centre in spleen?
periarteriolar lymphoid sheath
Red pulp
white pulp-b cells
germinal centre in the middle
162
how does the mucosal surface protect against infection
IgA in mucous
dimer joined by joining chain and secretory component derived from poly Ig receptor- binds to polymerised antibodies
secretory part
cleaves receptor bound to secretory part
plasma cells producing IgA underneath mucosa
163
what is the role of IgE
back stop
Mast cells express FC epsilon receptor which is very high affinity for IgE so essentially is coated with IgE
when it binds to an antigen causes degranulation- release of histamine and chemotactic factors that draw neutrophils and eosiniphils into the tissue
164
peyer's patch of gut
m (microfolded) cells at base of villi in lamina propria
antigen transported to it generation of thymine follicle and then secondary follicles with germinal centre
lymphocytes activated leave peyer's patch go to mesenteric lymph nodes where they are fully activated and go back to gut
165
how do lymphocytes home to intestine
mucosal Addressin cell adhesion molecule 1 (MAdCAM1)on blood vessel in endothelium interacts with integrin alpha4 Beta7 on lymphocyte
MAdCAM1 only in gut endothelium brings them back to gut
166
what are the 2 types of communication in immune response
cell-cell contact dependent
| soluble molecule
167
what size are thesecreted molecules
8-80kD
168
what are the functions of diffusable signallling
hematopoesis control
| immune response
169
groups of cytokines
```
Interleukins
colony stimulating factors
chemokines
interferons
tumour necrosis factor
GF
```
170
give an example of pleiotropy in cytokines
IL4
B cell activation and proliferation
Thymocyte and mast cell proliferation
171
give an example of redundency in cytokines
IL 2, IL5, IL4 all cause B cell proliferation
172
give an example of synergy in cytokines
```
IL4 can cause class switching of antibodies
IL4+IL5- much more efficient
```
173
give an example of antagonism in cytokines
```
IL4 causes class switching
IL4+INF gamma- inhibits class switching
```
174
give an example of a cascade involving cytokines
IFN gamma produced by Th cells
| activates macrophages which produce IL12 which stimulates Th cells
175
which cytokines are proinflammation
IL-1 IL-17
176
which cytokines are immunosuppressive
IL-10, TGF ß
177
which cytokines are antiviral
IFN alpha, IFN gamma
178
which cytokines are T cell proliferation
IL-2, IL-12
179
B cell proliferation
IL-2, IL-13
180
Haematopoiesis
M-CSF, GM-CSF
181
Chemotaxis
IL-8 (CXCL8), RANTES (CCL5)
182
therepeutic use of cytokine
IFN alpha for viral infections
rheumatoid arthritis- anti TNF alpha- blocks
genetically engineer soluble TNF receptor works the same as an antibody in RA
183
what is auto immune disease
when auto antibodies are produced and T cells that act on our own cells becoming pathological
184
what is central tolerance
specificity to our own cells in T and B cells in Thymus and Bone marrow
185
explain positive and negative selection in thymus
T cell is double negative
T cell becomes double positive
Positive selection- TCR can recognise our own MHC. binding to MHC I and II in thymic epithelium prevents death of T cell by stoping apoptosis. the default pathway is to die
Negative selection- apoptosis enduced in cells that have high affinity for self MHC + self protein
high affinity for MHC I- CD4 turned off
High affinity for MHCII CD8 turned of
become single +ve T cell
186
what removes dead T cells in thymus
Macrophages
187
how do self antigen reach thymus
hormones in blood
188
how do tissue specific proteins get to thymus?
AIRE (autoimmune regulator) TF causes the thymic expression of tissue specific genes
189
what is peripheral tolerance
the removal of self reactive lymphocytes that escape central tolerance
190
how B cells undergo central tolerance
clonal deletion
| receptor editing- removal of self antibody for an active one
191
what are the two mechanisms of peripheral tolerance
Clonal anergy
| suppression
192
describe anergy
the induced inactivation of a T/b cell
if the only stimulation is CD4 + TCR MHC II cell inactivates
reactivated by IL2
193
how can you increase costimulatory factors?
PRR recognises PAMPs increases transcription of CD80, CD86 to activate CD28 on T cell and cause activation
if self antigen- no PAMPs no stimulation
194
how do Treg cells
express FOXP3 and CD25
(foxp3 can be stimulated through an antigen)
secrete IL10 and TGF ß (immunosuppressive)
release cytotoxic granules
mop up IL2- reduced lymphocyte proliferation and differentiation
removes CD80/86 from antigen presenting cells by using CTLA4
195
what is autoimmune disease
the result of a breakdown of immunological tolerance
196
give 3 examples of tissue specific autoimmune diseases
MS
Hashimoto's disease
Type I diabetes
197
give two examples of non tissue specific autoimmune disease
SLE- antinuclear antibody
dermatomylitis
RA-IgG antibody against IgGFc
198
what causes autoimmune disease
Genes- e.g. MHC, CTLA-4
if 1 identical twin gets an AI disease increases chance of other one to 50%
more common in female than males
environment-stress, infection
199
give 2 examples of MHC genes leading to AI disease
Ankylosing Spondylitis- HLA B27 increases chance of getting disease by 87%
antigen mimickry
Rheumatic fever
streptococcus group A antigen that looks likecadiac myosin
200
WHAT IS HASHIMOTOS THYROIDITIS
anti body against thyroid peroxidase
inflammation of thyroid
Tc cells kill thyroid
enlarged thyroid
201
SLE
antinuclear antibodies
| immune complex trapped in capillaries and glomeruli
202
Graves disease
TSH R overstimulated
203
what is allergy
immune response to what should be harmless
204
What are the 4 types of hypersensitivity
Type 1
type 2
type 3
type 4
205
what is type 1 sensitivity
IgE mediated mast cell degranulation
e.g asthma
IgEs bind to different epitopes of antigen
allergen causes cross linking of Fc epsilon R starts signalling cascade
degranulation of mast cells- histamine + serotonin released
synthesis of TNF alpha and prostaglandins and leukatryins
late phase response (5-12hours) mediated by CD4+ helper T cells
no allergy gene
206
what is type 2 sensitivity
cytotoxic antibody against cell surface antigen
e.g transfusion reaction/ transplant rejection
IgG antibody dependent
Killer cells with Fc receptor +IgG recognises antigen on target causes release of cytotoxic products
Complement mediated cell lysis
macrophage engulf target
207
what is type 3 sensitivity
Immune complex mediated
e.g SLE
antibdoy antigen complex not cleared aggregates attracts complement
C3a and C5a increase inflammation +platelet aggregation+ IL1 and TNF
chemotaxis of neutrophils C5a- tissue damage
208
what is type 4 sensitivity
Delayed type hypersensitivity
T cell mediated
e.g tuberculin skin reaction mycobacterial antigens
contact dermititis to nickel
eosiniphils cause damage to tissue
macrophages enlarge- form multinucleated macrophages- can cause granuloma- seal off area
Tc cells kill target
209
how do you test for allergy
patch test on skin
| patch of pure antigen put on skin
210
treatment of type 1 hypersensitivity
avoid allergen
corticosteriods- block TF of proinflammatory genes
sodium chromoglycate- blocks mediator release from mast caells
antihistamine
montelukast
immunotherapy sublingual immuno treatment (SLIT)
small amount of allergen (not enough to produce response)
anti IgE- reduces IgE and therefore Fc epsilon R
211
hygeine hypothesis
```
clean environment increases Th2 to Th1 causes class switching to IgE
soap removes protective secretions by skin
```
212
Haemolytic disease of the fetus
Type 2 hypersensitivity
rhesus incompatibility
example
mother RhD- father RhD+
child Rhd+
birth only time fetal RBC enters mother. mother makes anti RhD+ antibodies
no problem in first pregnancy
second pregnancy secondary response-> haemolytic disease of the fetus
treatment
after birth mother given IgG anti D- mops up fetal RBC doesnt sensitise mothers B cells
213
innate hypersensitivitytoxic shock caused by stapylococcus aureus
excess release of TNF and IL1 and IL6
| acute respiratory distress syndrome
214
what is an autograft
graft from same individual
| one part of body to another e.g skin graft
215
what is an iso graft
graft between identical individuals
| e.g twins
216
what is an allograft
between different members of same speicies
217
xenograft
from different species
| e.g pig heart
218
explain the a strain and B strain mouse thing
A graft onto A mouse=accepted
B graft onto A mouse=rejected
B graft onto AB mouse= accepted
AB graft onto B mouse rejected
219
T cell transfer
A mouse + B graft-->t cells--> A mouse + B graft- secondary response
A mouse + B graft-->t cells--> A mouse + C graft- primary response
A mouse + C graft-->t cells--> A mouse + B graft- primary reaction
220
recognition of graft antigen: 2 pathways
Direct
| Indirect
221
explain the direct pathway
allo MHC different to host MHC
TCR recognises foreign MHC and peptides
T cell attacks
222
Indirect
donor cell- MHC removed when entering recipient
| broken down and presented as antigen to host
223
what is graft versus host reaction
e.g bone marrow transplant, host immunosuppressed- graft attacks host
224
what tissue does not need to be typed before transplant
cornea- no blood supply
pig heart valves
225
all grafts eventually reject
fact
226
what are the 4 types of rejection
Hyperacute
accelerated
acute
chronic
227
what is responsible for the hyperacute rejection
complement activated
| within hours
228
what is responsible for the accelerated rejection
within days
| memory T cells
229
what is responsible for the acute rejection
days- weeks
| primary response of T cells
230
what is responsible for the chronic rejection
unknown cause
| immune complex, recurrence of disease
231
how do immunosuppressive drugs such as cyclosporine
| tacrobimus and rapamycin work
```
affect TCR MHC recognition
normal TCR signalling
transcription of IL2 feeds back to TOR (target of rapamycin) IL2 R activated TOR
Rapamycin- blocks IL2 production
T cells cant be stimulated
```
232
what is the alpha gal problem
2 linked galactose sugars on pig cell surface
gal alpha 1 3 gal
present on many microbes- lots of IgG against them
KO alpha gal- no rejection
233
what are the two forms of immuno deficiency
primary-genetic
| secondary-effect of external agent
234
in what age group is primary ID more common
children
235
how could a mutation have an effect on a protein
stop codon- truncated protein
| point mutation- misfolding
236
give 3 examples of primary immunodeficiency affecting the innate immune system
Chronic granulomatous disease-
leukocyte adhesion deficiency- ß2 integrin defect affecting neutrophils and monocytes
Complement deficiencies- most profound in C3 as all pathways meet here
-C8- no membrane attack complex
237
chronic granulomatous disease
Nadp oxidase defect affects phagocytic cell- cant produce respirative burst- the release of reactive oxygen species
```
NADPH oxidase makes super oxide (02 -)
NADPH oxidase made up of
P22phox transmembrane
gp91phox- transmembrane- x chromosome
p47phox
p67phox
rac2
p40phox
```
gp91phox x chromosome more likely in men
238
Primary immunodeficiency affecting adaptive immune response
B-cell:
- selective IgA deficiency
- Hyper-IgM syndrome
- X- linked agammaglobulinaemia- Bruton's tyrosine kinase
T-cell:
Wiskott-Aldrich syndromeWASP
DiGeorge syndrome TBX1
severe combined immunodeficiency
239
Hyper IgM
```
CD40 L defect
no class switching as there is no contact between Th and B cell
```
240
selective IgA deficiency
1 in 300
most people dont even realised
covered up by other classes IgM taken to mucosal surface by poly Ig transporter
241
severe combined immunodeficiency
RAG1/2
| involved in recombination
242
DiGeorge
in mice- nude
Tbx1
no T cells- recurrent infection
partially developed Thymus
243
T- B- NK+ SCID
RAG1/2 15%
no T cells so B cells cant produce antibodies
Artemis 15%
244
T- B+ NK-
gamma c Chain
| JAK-3 10%
245
T- B+ NK+
IL-7 R alpha
246
causes of secondary ID
malnutrition- lack of calories, lack of iron/zinc
loss of cells or molecules of immune system through intestine in intestinal Lympangiectasia
nephrotic syndrome
Tumours of immune system- lymphoma, leukemia
cytotoxic drugs/irradiation- affects rapidly dividing cells
infection- malaria
247
how does HIV work
hiv injects CD4+ cells that bind to it (MHC 2, professional antigen presenting cell Th2, macrophage)
CD4 + chemokine coreceptor (CCR5 in macrophage, CXCR4 in T cells)
gp120 binds to CD4. gp120 changes conformation. co recepto binds induces another conformational change which results in the movement of CD4 away and the binding of gp 41 which mediates fusion of HIV and cell through the fusion pore
248
opportunistic infections
Virus cytomegalovirus
bacteria- mycobacterim tuberculosis
funghi pneumocystis jiroveci
protozoa toxoplasma gondii
249
treatment of immunodeficiency
Antibiotics
gamma globulins- Ab for Ab deficiency
cell replacement- hematopoetic stem cell
gene therapy- take out defective gene
250
what principles do vaccines utilise
Memory
| specificity
251
what is injected
Toxoid- non toxic modified toxin with many of the same epitopes
252
what effectors are activated
Tc cells
antibody
Th
253
what is an attenuated organism
an organism that is alive but not capable of causing disease
254
what does an adjuvant do
stimulates dc so that they can activate T cells
| mimicks PAMPs
255
how does a carrier help
has similar epitope to toxoid
256
what does a vaccine have to be?
```
effective
available
safe
stable
affordable
```
257
what does a vaccine consist of
Antigen
carrier
adjuvant
258
smallpox
wiped out in 1979
| work started 1798
259
rinderpest
wiped out in cattle in 2011
260
what were the two types of vaccines used for polio
Salk- inactivated 1956
| Sabin-attenuated mid 1960s
261
what were the problems with wiping polio out?
hard to target the IgA response
oral drops administered- IgA rises in mucous of lungs and nasl butharder to raise intramuscular IgA
hard to reach some areas of the world e.g afghanistan- war zone
262
what is antigenic shift
exchanges of genome between human avian and swine version of bacteria
263
what is antigenic drift
point mutations changes genome
264
why do you need a new influenza jab every year
lots of shift and drift
peoples job around the world to find the most likely next flu bout
done 2 times a year for both hemispheres
265
problems with HIV vaccines
identification of Immunogens
and immunisation stratergy
broad and long lasting CTL immunity
broadly neutralising antibodies
266
where has there been a small break through in HIV vaccine
Thailand
4 infections of recombinant canarypox vector with HIV gag, pol, env genes
2 booster injection
limited protective efficacy
267
where has there been a small break through in HIV vaccine
South africa
| tried the Thai vaccine - similar response
268
malaria
trial in children between 5 and 17 months 50% protective
269
why are conjugate vaccines used
cojugate vacine = polysaccharide+ protein
polysaccharide would produce T independent response, adding protein get T dependent one
example
meningococcus group C
270
who are vaccines given to
'at risk' groups
BCG (TB) under 35
Chickenpox- any age
flu- children/elderly
```
Pneumococcal vaccine( 2-65)
Hep B- birth onwards
```
271
why is yellow fever the holy grail of vaccines
1 shot- lifetime immunity
272
why is a gene gun used
injects genes/ proteins into arm
| gene expressed- activates Tc cells- mimicks immune response
273
what are the potential mechanisms for immune system attacking tumours
antibody + complement
antibody dependent cytotoxicity eosiniphils
direct NK cytotoxicity
Tc recognising tumour derived peptides
274
what are the problems with using the immune system to attack tumours
tumours express our protein- dont have different MHC etc
275
is there a link between virus and tumours
yes some tumours are caused by viruses
primary ID more likely to develop lymphome- EBV
```
immunosuppression- lymphoma-EBV
cervical cancer HPV
skin papilloma
liver Hep b + c
Kaposi's sarcoma- human herpes
```
malaria Burkitts lymphoma EBV
276
EBV can cause
Lymphoma- ID/IS
Burkitt's lymphoma- Malaria
277
micro organisms and cancer
helicobacter pylori- stomach cancer
most not caused by viruses
278
what causes most cases of cancer
multiple mutations
p53 mutation causes tumour specific antigens in colorectal, lung, bladder, head ad neck
279
developmental tumour
usually developmental proteins
MAGE- melanoma associated gene
causes melanoma, colorectal, lung and gastric tumours
280
viral antigens
antigens from tumour expressed by virus
HPV
cervical
281
tumour associated
not just in tumours also in other cells. present in tumour in higher numbers
PSA
prostate
282
overexpressed
very high levels on tumour some on normal cells
her 2
breast cancer
283
why doesnt the immune system attack tumours
tumours have mechanisms that prevent attack
clonal selection of cells that do not express tumours- has a survival advantage
secrete molecules to down regulate dendritic cells
down regulate cytotoxic T lymphocytes
Treg stimulated
284
how do tumours down regulate DCs
T cells need CD 80 86 stimulation simultaneously to activate
PRRs recognise pamps and damps in infection which upregulates CD80 86 on DCs
tumours do not release Pamps and DAMPs
ANERGY
285
how do tumours immunosuppress
VEGF
IL10
are both immunosuppressive
TGF ß- normally from Treg
Tregs usually tumour infiltrating- suppress immune system
286
why has tumour specific or associated proteins not been successfull
Tregs prevent it from killing tumour
| does increase immune response
287
what potential immunotherapies for tumour
Antibody
cell transfer
vaccine
288
antibody
recognise antigen specific or associated activates complement/killer cells
could attach toxin to antibody (only TSA)
289
T cell transfer
take out from patient increase number of T cells and replace
grow dendritic cells
use GMCSF IL4 drive monocyte to DC
tumour antigen and cytokine taken into DC
cytokine helps DC mature
DCs infused into patient present tumour antigen to T cells
290
vaccine
immunise against virus
therapeutic
Induce Tc cell response
