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Miscellaneous Flashcards

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1
Q

What are the two top causes of death globally

A

Ischaemic heart disease and stroke

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2
Q

What did Virchow propose was the basis of disease

A

Cell injury

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3
Q

What cancel injury be inflicted bye

A

Extremes of oxygen tension or pH

Lack of ATP

Exposure to toxins, drugs and chemicals (xenobiotics)

Cold and heat

Prolonged deprivation of vital nutrients

Trauma and ageing

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4
Q

Name some adaptations to stress

A

Hyper Trophy

Hyperplasia

Atrophy

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5
Q

What happens in cell atrophy?

How is this achieved

A

Cell volume diminishes over several hours or days through reduction in the complexity of the cytoplasm
Organelles are encapsulated by intracytoplasmic membranes and digestion by fusion with lysosomes

My digestion of cellular proteins by that proteasome system, backed up by autophagy

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6
Q

True or false

If cells are unable to adapt, they will suffer cell damage that may be reversible or irreversible

A

True

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7
Q

How is reversible injury to cells seen

A

As cell swelling or fatty deposits

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8
Q

What is cell swelling commonly caused by?

A

Sodium/potassium pump shutdown leading to an influx of sodium and hence water into the cell and mitochondria

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9
Q

Describe apoptosis briefly as a death process

A

A death process that requires the cell to retain control over its own energy metabolism

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10
Q

What happens in necrosis

A

There is a loss of cell volume homoeostasis and cellular swelling and rupture of internal and plasma membranes occurs

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11
Q

How can necrosis cause an inflammatory reaction

A

Intra cellular contents leak into extracellular space and can reach the bloodstream

Some components are chemotactic for neutrophils and elicit in acute inflammatory response

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12
Q

Necrosis is poorly controlled and tends to spread

True or false

A

Trim

It involves sheets or groups of adjacent cells

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13
Q

Name six cellular targets of cell injury

A

Mitochondria

Decreased ATP

Membrane damage

Cytoskeletal damage

Increased reactive oxygen species

DNA damage, unfolded protein accumulation

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14
Q

What are free radicals

How can they be created

A

Molecules that have unpaid electrons and nitric oxide

Ionising radiation and xenobiotics
When tissue is re-oxygenated after hyperoxia, free radicals are generated resulting in reperfusion injury

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15
Q

Do free radicals have a long half life

What can they do

A

No but they are highly reactive, causing strand scission in nucleic acid and disruption of protein structure

They also damage lipid membrane is creating additional free radicals

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16
Q

Can free radicals be useful

A

ROS and NO Can be utilised by neutrophils and a macrophages to good effect to kill invading microorganisms

However this may damage host cells

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17
Q

What is reperfusion injury

What happens next

A

A dramatic destruction of the endothelium of small but vessels carrying renewed bloodflow to a previously hypoxic area

The recruitment of neutrophils is encouraged and this may cause further damage.
Platelets are also recruited with thrombin to seal off the blood supply. This is thrombosis

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18
Q

What does decreased ATP need to

A

Reduce activity of the membrane sodium potassium pump

Increased glycolysis

Influx of calcium

Ribosomal detachment and loss of protein synthesis

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19
Q

Why is reduced activity of the sodium/ potassium pump bad

A

Sodium accumulates in the sale and calcium is lost

Water accumulates causing ER dilation and cell swelling

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20
Q

Why is increased glycolysis due to reduced oxygen supply to mitochondria bad

A

Lactic acid is produced and pH is reduced resulting in decreased cellular enzyme activity

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21
Q

Why is an influx of calcium after decreased ATP supply bad?( 3)

A

Increased activity of intracellular proteases, phospholipases, endonucleases and ATPases

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22
Q

Name a response pathway to stress that is common to all living cells

A

The heat shock response

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23
Q

Describe the heat shock response

A

Cytoplasmic HSFs dissociate from HSPs

HSFs trimerise and translocate to the nucleus and suppress transcription of many genes and activate transcription of HSPs

HSPs are responsible for preconditioning (where cells exposed to minor injury become resistant to more major stresses)

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24
Q

Describe the unfolded protein response to stress

A

This response and shows the rate of protein synthesis does not exceed the sales capacity to complete the folding process

The UPR activates signalling cascades that increase synthesis of folding chaperones, enhances presume of protein degradation and slows down protein translation

The UPR is usually reversible and is part of host cell shutdown

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25
Is cell shutdown reversible or irreversible What happens
It is a primitive reversible response to injury and is initiated within minutes RNA and DNA synthesis is suppressed and many enzyme catalysed reactions are inhibited
26
What can the ER protein concentration reach What happens at this concentration
100mg/ml Unwonted precipitation and aggregation of proteins can occur unless proteins are correctly folded and chaperoned
27
Give two important examples of stress kinase pathways
Jun N-terminal Kinase (JNK) / SAPK P53
28
What is the SAPK pathway
The stress activated protein kinase pathway This is the same as Jun N-terminal Kinase pathway
29
What does the blood that leaks into the stomach from a peptic ulcer look like What will emesis look like
Green brown as has been broken down by acid Coffee granules
30
What makes up Pus
Fibrin and neutrophils
31
What makes collagen
Fibroblasts
32
If NSAIDs are mentioned in the question, what should you be thinking
PEPTIC ULCERS
33
How can you test for helicobacter infection
Urease test Helicobacter parasites produce urease not seen in humans normally Therefore if you add urea it will be broken down into NH3 and CO2
34
If the stomach surface looks microscopically like cobblestones, what should you be thinking
Stomach inflammation
35
What does Zollinger Ellison syndrome cause
Gastric tumours (gastrinomas)
36
What must we be tolerant to?
self | innocuous substances
37
What was an antigen be injected with to elicit a strong adaptive response?
adjuvant
38
What do adjuvant's often contain
bacterial products, which stimulate macrophages | or dendritic cells through Pattern Recognition Receptors.
39
What does complete freund's adjuvant contain
ground up mycobacteria
40
What do adjuvants do (2)
cue the immune system that an infection is taking place. convert soluble protein into particulate material, which is ingested by antigen presenting cells such as macrophages
41
What are the 2 types of tolerance?
central - occurs during lymphocyte development peripheral- occurs after the lymphocytes leaves the primary organ
42
Describe clonal selection of T cells
1 - generate TCRs irrespective of specificity 2 - select small number of TCRs that work with self MHC molecules to see foreign antigens positively select clones with some affinity for MHC negatively select clones that bind too strongly to MHC+ peptide
43
What does negative selection in the thymus result in
deletion of thymocytes whose T cell receptors | have ‘high affinity’ for self.
44
Why should B cells not need to be tolerised
they should need T cell help
45
How do self reactive B cells avoid apoptosis
by replacing the light chain via receptor editing
46
What happens to a b cell when it binds to high doses of soluble self antigen
anergy rather than apoptosis
47
Describe an experiment which demonstrates negative selection of self reactive B cells during maturation in the bone marrow
Mice expressed a transgene encoding IgM against the H-2Kk MHC molecule. In Kd mice, and not Kk, the immature B cells did not bind self antigen and a large number of mature B cells in the spleen expressed antiKk as membrane Ig. Conversely, when the mice expressed Kk (as well as Kd), the immature B cells recognised the molecule and were deleted. More detailed analysis of these mice showed that a small number of mature cells expressed the µ chain encoded by the transgene. They had undergone light chain editing and no longer bound to Kk.
48
Name one problem with central tolerance How can this be circumvented
Many antigens are not expressed in the thymus or the bone marrow expression of AIRE which activates peripheral genes in the thymus
49
What is AIRE
A transcription factor which turns on many 'peripheral' genes in the thymus, so that the developing T cells may be exposed to their products.
50
What happens if you lack AIRE
APECED, | autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
51
Describe the four proposed mechanisms for peripheral tolerance
Ignorance Split Tolerance Anergy Suppression
52
Describe the ignorance mechanism of peripheral tolerance
when potentially self-reactive T cells are not activated. This could be because antigens are hidden from the immune system in locations that are not freely exposed to surveillance (eg brain and testes)
53
Name 3 immunologically privileged sites why are they considered to be this
brain eye testes not freely exposed to surveillance from the immune system`
54
What does split tolerance reflect
the notion that, as many pathways in the immune | system are interdependent, they do not all need to be tolerised.
55
What is the most frequent situation of split tolerance
where T cell tolerance has been established but autoreactive B cells are still present. Without T cell help the B cells are 'helpless'. The explanation of this is that it takes 100-1000- times more antigen to tolerise B cells than it does T cells
56
Why is the b cell / t cell split tolerance common for self serum proteins
it takes 100-1000- times more antigen to tolerise B cells than it does T cells
57
What is anergy
a state of non responsiveness
58
How can anergy be induced in a T cell
if the receptor is engaged by the MHC molecule but the second signal is absent
59
What happens to anergised cells
they do not die but biochemical changes take place so it no longer responds
60
How are immature B cells anergised
exposure to soluble antigen in large amounts without cross linking occurring on the surface
61
What is suppression
autoreactive T cells are prevented from reacting by the presence of other T cells, AKA Regulation
62
What T cells are involved in suppression? what do they express? What is the transcription factor?
Treg cells (CD4) high levels of IL2 receptor CD25 FOXP3
63
Where do natural Tregs develop
thymus
64
What is the affinity of Tregs for self antigens in MHC molecules? How is it therefore affected by selection
intermediate not deleted by negative selection.
65
``` What happens to Tregs on contacting self antigen presented by MHC class II molecules ```
suppress the proliferation of naive T cells responding to autoantigens presented on the same antigen presenting cell
66
Name 2 cytokines that aid the downmodulation action of Tregs What are other methods of downregulating T cells
IL-10 TGF-beta induced activation of an enzyme (IDO) by DCs which inhibits T cell growth by depleting tryptophan, inhibition of proinflammatory cytokines, signalling to the APC to decrease B7 co-receptor expression which is recognized by CTLA-4 which is highly expressed by Treg (and activated conventional T cells).
67
Name proposed mechanisms of peripheral induction of Tregs
the cytokine profile upon antigenic stimulation; chronic low-dose antigen exposure; lack of co-stimulation; presentation of antigen by immature DCs
68
Where might presentation of antigen by immune DCs to induce Tregs occur
in the GALT
69
Describe GALT
gut associated lymphatic tissue a microenvironment rich in TGF-β where cells may be exposed to the microbiome and food antigens
70
Why might you not have Tregs What happens to boys this age
IPEX - congenital mutations in FOXP3 die by age 2 due to autoimmunity and lymphoproliferation
71
What is IPEX
Immunodysregulation polyendocrinopathy enteropathy X-linked mutation in FOXP3 and congenital lack of Treg
72
What do scurfy mice lack
FOXP3 Die after 4-6 weeks
73
What happens in both IPEX and Scurfy mice
In both cases, effector T cells undergo | massive proliferation and cause lethal autoimmunity
74
What are the factors that affect tolerance
timing, dose of antigen, amount of co-stimulation location
75
Describe Medawar's neonatal tolerance experiment
Mouse A injected at birth with bone marrow from B 6 months later: A grafted with B's skin and C's skin B graft accepted C graft rejected If repeated but B's marrow injected a week after birth, tolerance is not achieved and both grafts rejected
76
Interpret the experiments of Medawar involving mice B and C
bone marrow stem cells from mouse B establish chimerism in the host. Some of these cells differentiate into antigen presenting cells and migrate to the thymus where they tolerise developing thymocytes by deletion (central tolerance). Lifelong chimerism is needed to maintain tolerance but even a low level of chimerism is sufficient. If the transfer is done later the number and maturity of the peripheral T cell pool of the host is sufficient to destroy the donor stem cells before they can engraft.
77
What are the tolerance mechanisms involved in pregnancy
1. physical barrier 2. lack of MHC class I on trophoblast 3. Immunosuppression
78
Describe how the trophoblast is developed to be tolerated by mum
Trophoblast cells that form the outer layer of the placenta in contact with maternal tissues do not express classical class I molecules and so are not targets for cytotoxic T cells.
79
What immunosuppressive factors are produced to increase tolerance in pregnancy
-fetal protein and IDO (indoleamine 2,3-dioxygenase, a tryptophan catabolising enzyme)
80
What are 2 examples of knowledge of tolerance being used clinically?
cancer | co-receptor blockade
81
Describe co-receptor blockade in tolerance
Block CD28 (which is essential for T cell activation)
82
What drug can be used to increase tolerance via co-receptor blockade What is it Why does this work
abetacept soluble CTLA4 fusion protein CTLA4 binds B7.1 and B7.1 to with greater affinity than does CD28, Injection of Abetacept prevents T cells from receiving their costimulatory signal.
83
When would you use abetacept
to treat rheumatoid arthritis and to prevent graft rejection.
84
The immune system is important in dealing with which cancers eg?
tumours associated with viruses e.g. Kaposi's in immunosuppressed AIDS patients
85
Why can cancers be targeted by the immune system?
``` tumours make altered protein antigens that could be presented by MHC class I. ```
86
Why can tumours that have altered proteins that could be presented by MHC CI molecules continue to grow
``` lost MHC class I expression by mutation or loss of fragments of chromosome. ```
87
What are 2 new cancer therapies targeting tolerance
Ipilimumab - Ab against CTLA4 Anti-PD1 antibody
88
Describe how ipilimumab works
Ipilimumab=antibody against CTLA4 prevents CTLA4 from binding to CD80 or CD86. This breaks mechanism of immune tolerance and enhances signaling via CD28. It works by activating a strong immune response against neoantigens expressed by the cancerous melanocytes
89
What is ipilimumab approved for treatment of
Ipilimumab is approved for | the treatment of metastatic melanoma
90
What are neoantigens
Typically, UV light (from too much exporue to the sun) causes mutations that alter self peptides. These proteins now look “foreign” to the immune system and are hence referred to a neoantigens.
91
What is PD1
expressed by activated T cells, and like CTLA4, delivers a negative signal to the T cells.
92
How does CTLA4 normally work
CTLA4 competes with CD28 and prevents costimulatory signals from being transmitted to the naïve T cells.

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