Miscellaneous Flashcards
What are the two top causes of death globally
Ischaemic heart disease and stroke
What did Virchow propose was the basis of disease
Cell injury
What cancel injury be inflicted bye
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
Name some adaptations to stress
Hyper Trophy
Hyperplasia
Atrophy
What happens in cell atrophy?
How is this achieved
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
True or false
If cells are unable to adapt, they will suffer cell damage that may be reversible or irreversible
True
How is reversible injury to cells seen
As cell swelling or fatty deposits
What is cell swelling commonly caused by?
Sodium/potassium pump shutdown leading to an influx of sodium and hence water into the cell and mitochondria
Describe apoptosis briefly as a death process
A death process that requires the cell to retain control over its own energy metabolism
What happens in necrosis
There is a loss of cell volume homoeostasis and cellular swelling and rupture of internal and plasma membranes occurs
How can necrosis cause an inflammatory reaction
Intra cellular contents leak into extracellular space and can reach the bloodstream
Some components are chemotactic for neutrophils and elicit in acute inflammatory response
Necrosis is poorly controlled and tends to spread
True or false
Trim
It involves sheets or groups of adjacent cells
Name six cellular targets of cell injury
Mitochondria
Decreased ATP
Membrane damage
Cytoskeletal damage
Increased reactive oxygen species
DNA damage, unfolded protein accumulation
What are free radicals
How can they be created
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
Do free radicals have a long half life
What can they do
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
Can free radicals be useful
ROS and NO Can be utilised by neutrophils and a macrophages to good effect to kill invading microorganisms
However this may damage host cells
What is reperfusion injury
What happens next
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
What does decreased ATP need to
Reduce activity of the membrane sodium potassium pump
Increased glycolysis
Influx of calcium
Ribosomal detachment and loss of protein synthesis
Why is reduced activity of the sodium/ potassium pump bad
Sodium accumulates in the sale and calcium is lost
Water accumulates causing ER dilation and cell swelling
Why is increased glycolysis due to reduced oxygen supply to mitochondria bad
Lactic acid is produced and pH is reduced resulting in decreased cellular enzyme activity
Why is an influx of calcium after decreased ATP supply bad?( 3)
Increased activity of intracellular proteases, phospholipases, endonucleases and ATPases
Name a response pathway to stress that is common to all living cells
The heat shock response
Describe the heat shock response
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)
Describe the unfolded protein response to stress
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
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
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
Give two important examples of stress kinase pathways
Jun N-terminal Kinase (JNK) / SAPK
P53
What is the SAPK pathway
The stress activated protein kinase pathway
This is the same as Jun N-terminal Kinase pathway
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
What makes up Pus
Fibrin and neutrophils
What makes collagen
Fibroblasts
If NSAIDs are mentioned in the question, what should you be thinking
PEPTIC ULCERS
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
If the stomach surface looks microscopically like cobblestones, what should you be thinking
Stomach inflammation
What does Zollinger Ellison syndrome cause
Gastric tumours (gastrinomas)
What must we be tolerant to?
self
innocuous substances
What was an antigen be injected with to elicit a strong adaptive response?
adjuvant
What do adjuvant’s often contain
bacterial products, which stimulate macrophages
or dendritic cells through Pattern Recognition Receptors.
What does complete freund’s adjuvant contain
ground up mycobacteria
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
What are the 2 types of tolerance?
central - occurs during lymphocyte development
peripheral- occurs after the lymphocytes leaves the primary organ
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
What does negative selection in the thymus result in
deletion of thymocytes whose T cell receptors
have ‘high affinity’ for self.
Why should B cells not need to be tolerised
they should need T cell help
How do self reactive B cells avoid apoptosis
by replacing the light chain via receptor editing
What happens to a b cell when it binds to high doses of soluble self antigen
anergy rather than apoptosis
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.
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
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.
What happens if you lack AIRE
APECED,
autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.
Describe the four proposed mechanisms for peripheral tolerance
Ignorance
Split Tolerance
Anergy
Suppression
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)
Name 3 immunologically privileged sites
why are they considered to be this
brain
eye
testes
not freely exposed to surveillance from the immune system`
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.
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
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
What is anergy
a state of non responsiveness
How can anergy be induced in a T cell
if the receptor is engaged by the MHC molecule but the second signal is absent
What happens to anergised cells
they do not die but biochemical changes take place so it no longer responds
How are immature B cells anergised
exposure to soluble antigen in large amounts without cross linking occurring on the surface
What is suppression
autoreactive T cells are prevented from reacting by the presence of other T
cells,
AKA Regulation
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
Where do natural Tregs develop
thymus
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.
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
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).
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
Where might presentation of antigen by immune DCs to induce Tregs occur
in the GALT
Describe GALT
gut associated lymphatic tissue
a microenvironment rich in
TGF-β where cells may be exposed to the
microbiome and food antigens
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
What is IPEX
Immunodysregulation polyendocrinopathy enteropathy X-linked
mutation in FOXP3 and congenital lack of Treg
What do scurfy mice lack
FOXP3
Die after 4-6 weeks
What happens in both IPEX and Scurfy mice
In both cases, effector T cells undergo
massive proliferation and cause lethal autoimmunity
What are the factors that affect tolerance
timing,
dose of antigen,
amount of co-stimulation
location
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
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.
What are the tolerance mechanisms involved in pregnancy
- physical barrier
- lack of MHC class I on trophoblast
- Immunosuppression
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.
What immunosuppressive factors are produced to increase tolerance in pregnancy
-fetal protein and IDO
(indoleamine 2,3-dioxygenase, a tryptophan
catabolising enzyme)
What are 2 examples of knowledge of tolerance being used clinically?
cancer
co-receptor blockade
Describe co-receptor blockade in tolerance
Block CD28 (which is essential for T cell activation)
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.
When would you use abetacept
to treat rheumatoid arthritis and to prevent graft rejection.
The immune system is important in dealing with which cancers
eg?
tumours associated with viruses
e.g.
Kaposi’s in immunosuppressed AIDS patients
Why can cancers be targeted by the immune system?
tumours make altered protein antigens that could be presented by MHC class I.
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.
What are 2 new cancer therapies targeting tolerance
Ipilimumab - Ab against CTLA4
Anti-PD1 antibody
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
What is ipilimumab approved for treatment of
Ipilimumab is approved for
the treatment of metastatic melanoma
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.
What is PD1
expressed by activated T cells, and like CTLA4, delivers a negative signal to the T cells.
How does CTLA4 normally work
CTLA4 competes with CD28 and prevents costimulatory signals from being transmitted to the naïve T cells.
