Notesale: Turn your study into money

Document Preview

Extracts from the notes are below, to see the PDF you'll receive please use the links above

---

Immune responses to infectious disease
Location
Where a pathogen is located influences the immune response
...

Extracellular infections cause the immune system to; activate the complement system,
activate phagocytosis, produce opsonizing antibodies, and produce neutralising antibodies
...

Bacterial evasion mechanisms to host immune responses
A number of gram-negative bacteria express pili which enable them to attach to host target
cells, eg
...
Bacteria such as Bordetella pertussis secrete adhesion molecules that help the
bacteria adhere to ciliated epithelial cells of the upper respiratory tract
...
streptococcus pneumoniae, whose polysaccharide capsule prevents
phagocytosis, and as there are 84 serotypes of s
...
Some pathogenic
staphylococci str able to assemble a protective coat from host blood proteins
...
Mechanisms for interfering with the
complement system help other bacteria survive
...
Pseudomonas secretes an enzyme, elastase, that inactivates
both C3a and C5a anaphylatoxins, thereby diminishing the localised inflammatory reaction
...
Bacteria such as listeria monocytogenes escape from the phagolysosome
to the cytoplasm, a favourable environment for their growth
...

Bacteria such as shigella flexneri, are able to induce apoptosis in macrophages, some
bacteria secrete hyaluronidase which enhances bacterial invasiveness
...
Sepsis is a
systemic response to infection that includes fever, elevated heartbeat and breathing rate,
low blood pressure, and compromised organ function due to circulating defects
...


Sepsis results from septicemia, infections of the blood, in particular those involving
gram-negative bacteria such as salmonella dn e
...
The major cause of sepsis from gram
negative bacteria is the cell wall component LPS (endotoxin)
...
Systemic infections activate PRRs on
monocytes, neutrophils vascular endothelial cells, inducing them to produce cytokines,
chemokines, adhesion molecules, and clotting factors that amplify the inflammatory
response
...
TNF also stimulates the release of clotting factors by vascular endothelial cells,
systemically this result in blood clotting in capillaries
...
High TNF-alpha, and IL-1 beta adversely affect the heart
...

Superantigens
Superantigens are viral or bacterial proteins that bind simultaneously to specific V beta
regions of T cell receptors and to the alpha chain of MHC class II molecules
...
Each superantigen displays a
specificity for one of these V beta versions, which can be expressed by up to 5% of T cells,
regardless of their antigen specificity
...
Superantigen
binding however, does not bypass the need for costimulation, professional antigen
presenting cells are still required for full T cell activation by these microbial proteins
...
Hence
the activation is polyclonal and can result in a massive T cell activation, resulting in over
production if The cell cytokines and systemic toxicity
...

Immune system response to viral infection
Innate response elements commonly engaged by encounter with viral PAMPs, such as
secretion of type 1 interferons, inflammasomes, and NK cell activation, as well as IL-2
production, can help eliminate the virus but also provide crucial instructions for the adaptive
response that will follow
...
When IFN- alpha and beta bind to their receptors,
the JAK-STAT pathway is activated and results in the production of new transcripts, one of
which encodes an enzyme that leads to viral DNA degradation
...
Neutralising
antibodies, especially those at the sites of infection, as well as circulating antibodies that
foster opsonization, complement activation and phagocytosis, protect the host by blocking or

eliminating virus in the extracellular spaces, although they cannot eliminate virally infected
cells
...

Viruses and programmed cell death protein (PD-1)
PD-1 and its ligands play a role in the evasion of tumour cells from antitumour immunity
...
Upregulation of pD-1 and its ligands PD-L1 and PD-L2 is observed during
acute virus infection and after infection with persistent viruses, including HIV, HBVm and
HBC, experimental evidence suggests that insufficient signalling through the PD-1 pathway
promotes immunopathology during chronic infection by exaggerating primary T cell
responses
...
PD-L1 alo mediated inflammation effects in
the acute phase of an immune response
...
PD-1 is a member of the immunoglobulin superfamily and regulates the magnitude and
quality of T cell responses
...
These molecules counterbalance co-stimulatory receptors on T cells
such as CD28
...
PD-1 negatively regulates
the terminal differentiation of naive CD8+ T cells into effector CD8+ T lymphocytes during
acute viral infection
...
Type I
and III IFNs are antiviral cytokines which are induced early in virus infected barrier tissues
...
Although type I IFNs moderately upregulate PD-L1
they increase NK cytotoxicity and allow clonal expansion and memory formation of antiviral
CD8+ \t cells
...
Recognition of viruses by PRRs also upregulates PD-L1
...
IL-10
upregulates the expression of PD-1 and PD-L1 in an STAT=3 dependent manner in dendritic
cells and monocytes
...
Thus, in the late phase of viral infection, PD-L1 is upregulated thereby
downregulating terminal differentiation of CD8+ T cells and preventing excessive tissue
damage due to uncontrolled cytotoxic attack
...
The absence of PD-L1 on hematopoietic cells results in lethal immune
pathologies due to an increase in the number and function of cytotoxic CD8+ T cells
...
immunodominant, virus-deprived epitopes by increasing the threshold
of CD8+ T cell activation
...
In the acute phase of viral

infection, virus specific T cells rapidly up regulate the co inhibitory receptor PD-1 upon
recognition of the antigen
...
Chronic virus infection results
in sustained upregulation of PD-1
...

Blockade of the PD-1/PD-L1 axis reinvigorates antiviral T cell functions and reduced viral
load
...

Cytotoxic T lymphocyte antigen 4 (CTLA 4)
CTLA-4 is expressed on T cells
...
if CTLA-4 binds, it delivers an
inhibitory signal to the T cell
...
lymphoproliferation, or multi organ proliferation
...
Exhaustion is often restricted to CD8+ T
ce;ll responses, although CD4+ T cells have also been reported to be exhausted in certain
chronic infections
...

Regulatory T cells
T cells are polarized to become regulatory T cells (T regs) by the cytokine TGF-beta and
IL-2
...
T reg cells release the cytokines
IL-10 and TGF- beta
...
T reg
cells suppress the activation of effector responses and are critical for regulating homeostasis
and tolerance to self antigens
...
HCV overcomes the antiviral effect of interferons by blocking or inhibiting the action of
PKR, a protein kinase essential to signal transduction
...
HSV produces
a protein that inhibits the human transporter molecule needed for antigen processing (TAP)
...
A
number of viruses escape immune attack by constantly changing their surface antigens, eg
...
Some viruses, such as EBV and HIV, can cause generalised or specific
immunosuppression, which works as a means of evasion
...

Passive evasion mechanisms involve infection of immune privileged sites (sites isolated from
lymphatic circulation, such as the eye,testis, uterus, and placenta), HSV utilises passive
evasion mechanisms by infecting neuronal cells establishing a latent dormant infection
...
Aggressive evasion
mechanisms involve viral infection of immune cells which are essential for immune response
function, thereby causing immunosuppression, viruses such as measles and HIV utilise
aggressive evasion mechanisms
...
A tumour that is not capable of indefinite growth and does not
invade the healthy surrounding tissues is said to be benign
...
Malignant tumours eventually
exhibit metastasis and spread, where small clusters of cancerous cells dislodge from the
original tumour, invade the blood of lymphatic vessels, and are carried to distant sites where
they take up residence and continue to proliferate
...
Carcinomas are tumours that develop
from epithelial origins or the epithelial lining of internal organs and glands, eg
...
Lymphoma, melanoma, and
leukaemia are malignancies arising in one of the many cell types derived from hematopoietic
stem cells
...
Oncogenes are typically DNA sequences that
encode proteins involved in promoting cell growth and proliferation, such as transcription
factors, growth factors, or intracellular signalling molecules
...
When the DNA sequences involved in apoptosis,
or programmed cell death, are not functioning properly they can also aid in cellular
transformation, encouraging the survival and proliferation of neoplastic cells
...
Sustained inflammatory
responses increase cellular stress signals and can lead to genotoxic stress, increasing
mutation rates in cells thus fostering tumorigenesis
...
In this way,
immune cells and the factors they produce can sustain and advanced tumour growth
...
This directs oxygen supplying blood vessels to the site of a solid tumour and aids
tumour cell invasion into surrounding tissues via transport through newly constructed
lymphatic vessels
...
HBV infection which can lead to liver cancer
...
There is an increased incidence of cancer due to inefficiency of
immunosurveillance due to; ageing and consequent immunosenescence, primary/inherited
immunodeficiency such as that caused by lymphoma, secondary/acquired immunodeficiency
such as that caused by several types of cancer, immunosuppression due AIDS, or
immunosuppression due to immunosuppressive drug regimens post transplantation
...
In one multicenter study, the TILs from
patients with metastatic melanoma were collected and expanded in the presence of IL-2 in
vitro to overcome their anergic state
...
half the patients saw significant tumour regression, with 10% of
the patients experiencing remission
...

This divergent response could be influenced by an abundance of Treg cells in
non-responding patients
...
Tumour
specific antigens can be found in some virally induced tumours where sequences from
infecting viruses are recognized by the immune system
...

Tumour associated antigens
Tumour associated antigens are normal cellular proteins that display abnormal expression
patterns and thus are not foregin
...

Immunoediting
Immunoediting describes how the developing tumour-specific immune response eliminates,
maintains equilibrium of, and allos the escape of cancer cells
...
When this is in balance, unhealthy cells are eliminated and
new cells take their place
...
Tumours can arise
...
In phase I (elimination) cancer cells are recognised
by the immune system, eg
...
In phase III (escape) further
mutation in the surviving tumour cells leads to the capacity for immortal growth and
metastasis
...


Tumour immune evasion
Tumours can down regulate MHC class I expression as a mechanism of immune evasion
...
Such
tumour cells also down regulate the expression of ligands that bind activating receptors on
NK cells, allowing these cells to avoid NK cell mediated killing
...
This can arise due to
changes in the extrinsic response system, eg
...
decreases in pro apoptotic signalling components (Bcl-2) or increases in anti
apoptotic signalling components (survival)
...
Tumours may inhibit tumour associated antigen expression or mask
tumour associated antigen with the mucoprotein sialomucin, thus they are hidden from the
immune system, tumours may generate a microenvironment of immune suppression
...
Tumours may also
induce T reg cells
...
Ipilimumab is an example of a
checkpoint inhibitor
...
Two other monoclonal
antibodies specific for another T cell checkpoint molecule, PD-1, have received FDA
approval
...
However, rather than compete for costimulation, this molecule binds
PD-L1 found naturally on dendritic cells and expressed abbrenetly in many tumours, a side
effect of immune checkpoint inhibitors is generalised down regulation of the immune system
...
mAbs can
be conjugated with toxic substances- immunotoxins
...
Examples of mAbs include; pembrolizumab which targets PD-1 and is used
in the treatment of melanoma, non-small cell lung cancer, kidney cancer, and hodgkin's
lymphoma; and atezolizumab which targets PD-L1 and is used in the treatment of bladder
cancer, non-small cell lung cancer and merkel cell carcinoma
...
chimeric antigen receptor (CAR) T
cells begin with autologous T cells isolated from a patient with cancer
...
CAR T cells are then capable of activating T cells
...
Second generation CARs included the same basic design
principles with the addition of one or more costimulatory signals
...
The first CAR T cell therapy was approved by the FDA in 2017
...
In a multicentre preliminary clinical trial, 83% if
patients had complete remission within the first three months of treatment
...
For
example, the adjuvant Bacillus calmette-guerin (BGC), which promotes cytokine release and
dendritic cell activation when injected into bladder tumours, improving prognosis
...

Systemic cytokine therapy is another passive immunotherapy
...
Single cytokine treatments are mildly
effective and can be toxic so they are preferentially used at low concentrations in
combination
...

Therapeutic cancer vaccines are designed to redirect or enhance the anticancer response
and use strategies like infusion of autologous dendritic cells with tumour antigens, in vitro
stimulation and expansion of autologous cells, or presentation of hidden tumour neoantigens
to the immune system
...
Autologous dendritic cells
are isolated from a patient bloods and cultured with a fusion protein consisting of the
prostate cancer specific antigen, PAP, and the APC activating cytokine, GM-CSF
...
Other
anti cancer vaccine strategies under development are exploring the possibility that occult
tumour specific antigens (neoantigens) can be exposed and exploited
...
These neoantigens are thus unique to each individual and
also highly specific to malignant cells
...
Data generated from high
throughput techniques have made bioinformatics a necessity in cancer research
...
The commensal gut microbiota
plays an important role in stimulating the host immune system
...


Another form of cancer immunotherapy involves the utilization immune sensitizing agents
...

Other small molecule inhibitors inhibit anti apoptotic pathway protein such as Bcl-2 family
members
...
Some drugs such as
ReACp53 block p53 inhibition and restore its tumour suppressor activity

---