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Vaccinations
Vaccination is the intentional exposure to modified forms or parts of a pathogen that do not
cause disease
...
So that it can rapidly mobilize its forms to fight infection when
required
...
However, many people die each year
from vaccine preventable diseases due to lack of access to the vaccine or poor vaccine
uptake due to scientific ignorance within a society
...
Passive immunity can be acquired naturally, eg
...

Active immunity
Active immunity triggers the host's immune system, resulting in the production of antibodies
by the host as well as memory cells, thus active immunity is long lasting
...
Active immunity can be
achieved by natural exposure to the infectious agent, or it can be acquired artificially by
administration of a vaccine
...
Due to the development of the smallpox
vaccine, not a single naturally acquired smallpox case has been reported anywhere since
1977
...
The danger of contracting the disease must be significantly worse than the
danger posed by a potential vaccine
...

Problems with safety of non-living vaccines include; contamination by toxins or chemicals,
allergic reactions, and the induction of autoimmunity
...
Factors determining
vaccine safety include; the incidence of disease, the incidence of adverse events of vaccine,
immunisation rates, and the availability and affordability of alternative vaccines
...
The chance of a susceptible individual
contacting an infected individual is low
...

Measles, mumps, and rubella vaccine
The measles, mumps, and rubella (MMR) vaccine is a live attenuated vaccine
...
Children should be given two doses of the vaccine, as the first
dose fails to induce immunity in 5% of those vaccinated
...
Vaccine induced
immunity to measles is long lived
...
However the number
of measles cases increased in the UK post 2001, following reduced vaccine uptake
...
However, the paper reporting this claim used an extremely small
sample size of 12 patients, and was later retracted, additionally further studies have failed to
show an increased risk of autism after the MMR vaccine
...
It is
important to maintain the structure of key epitopes on surface antigens during inactivation
...
Chemical
inactivation with formaldehyde or various alkylating agents is more successful
...

Inactivated vaccines require repeated boosters to achieve a protective immune status
...
Even though the pathogens they contain are
killed, inactivated vaccines still carry risks due to failure to follow proper inactivation
procedures
...
Additional
advantages of inactivated vaccines include; stability and ease of storage and transport
...
influenza,
hepatitis A, cholera, and polio
...
This exposes the immune system to the live
pathogen
...
Attenuation can be achieved by growing a
pathogenic bacterium or virus for prolonged periods under abnormal culture conditions
...
Attenuates vaccines have obvious advantages
...
This
results in increased immunogenicity and more efficient production of highly effective memory
cells
...
The ability of
live vaccines to replicate within host cells makes them particularly suitable for inducing
cell-mediated responses
...
The
major disadvantage of attenuated vaccines is that these live forms can sometimes mutate
and revert back to a more virulent form in the host
...
Additionally, live
vaccines may be more biochemically, genetically, and biologically unstable than inactivated
vaccines
...
One example of a live attenuated vaccine is the Sabin oral polio
vaccine (OPV)
...
The attenuated viruses
colonize the intestine and induce production of secretory immunoglobulin A, a defense
against naturally acquired polio virus
...
Unlike other attenuated vaccines, OPV requires boosters, because the
three strains of attenuated polio virus can interfere with each others replication in the
intestine, although subsequently developed mono- and divalent OPV don't have this
drawback
...
The rate of reversion of the OPV to a virulent form is extremely
low; 1 in 2
...
This is considered an acceptable risk in areas
where the danger from wild type polio is high, so risk of paralysis is high
...

Subunit vaccine
Subunit vaccines use only specific, purified macromolecules derived from the pathogen
...
Subunit vaccines are developed using recombinant DNA technology and
high resolution biochemical methods
...
A number of genes encoding
surface antigens from viral, bacterial, and protozoan pathogens have also been successfully
cloned into cellular expression systems for use in vaccine development
...
One limitation of some
subunit vaccines, especially polysaccharide vaccines, is their inability to activate T helper
cells
...
This can be avoided in vaccines that conjugate a
polysaccharide antigen ti a protein carrier, which induces T helper cell responses against
both the protein and polysaccharide
...
Some bacterial pathogens, including those that cause diphtheria and tetanus,
produce exotoxins that account for all of the disease symptoms resulting from infection
...
Vaccination with the toxoid induces
anti-toxoid antibodies capable of binding the toxin and neutralising its effects
...

Passive immunity can be used to provide temporary protection in unvaccinated individuals
exposed to organisms that express these exotoxins
...
Coating the capsule with antibodies and/or complement greatly increases the ability
of macrophages and neutrophils of phagocytose such pathogens, thus providing the
rationale for vaccines consisting of purified capsular polysaccharides
...

The vaccine induces formation of opsonizing antibodies
...
Individual genes that encode key
antigens of especially virulent pathogens can be introduced into safe attenuated viruses or
bacteria that are used as live carriers
...
Since most of the genome of the pathogen is missing, reversion potential
is eliminated
...
This large complex virus, with a
genome of about 200 genes can be engineered to carry several dozen foreign genes without
impairing its capacity to infect host cells and replicate
...
hen tissue culture cells are incubated
simultaneously with vaccinia virus and the recombinant plasmid, DNA encoding the antigen
is inserted into the vaccinia virus genome by homologous recombination at the site of
nonessential TK gene, resulting in a TK- recombinant virus
...
Another vaccine
vector is an attenuated strain of the vesicular stomatitis virus (VSV), which has been
engineered with genes encoding the surface proteins of the Ebola virus
...

Adjuvants
Adjuvants are substances that are added to vaccine preparations to enhance
immunogenicity
...
When mixed with the
pathogen- associated antigens, adjuvants can also aid delivery of the vaccine to the immune
system and enhance general immune responsiveness
...
Alum is a good enhancer of Th2 responses but a
weaker stimulator of Th1 pathways
...
Recently developed adjuvants include virosome, a reconstituted virus envelope
containing phospholipids and virus glycoproteins but without any genetic information
...
Virisome
may elicit a much greater cell-mediated immune response than alum alone
...

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
...
An alloantibody is an antibody formed to foregin antigens, but within the same
species
...
Of
the 347 blood groups specificities recognised by the international society for blood group
transfusion, 303 belong to one of 36 systems
...
Some blood group antigens, including those of the ABO, P1PK, Lewis, H and I

systems, are carbohydrate structures on glycoproteins and glycolipids
...

The ABO system consists of two antigens, A and B, indirectly encoded by two alleles, A and
B, of the ABO gene
...
these three alleles combine to
effect four phenotypes; A, B, AB, and O
...
The product of the B allele catalyses the transfer of Gal from UDP-Gal to
the fucosylated Gal residue of the H antigen
...
The O allele produces no transferase, so the H
antigen remains unmodified
...
The A
and B alleles differ by four nucleotides in exon 7 encoding amino acid substitutions
...

H antigen is the biochemical precursor of A and B
...
Without this fucosylation, neither A nor B
antigens can be made
...
Homozygosity for
inactivating mutations in FUT1 leads to an absence of H from red cells and, therefore, an
absence of A and B antigens
...
Very rare individuals who have H-deficient red and are also H
non-secretors (Bombay phenotype) produce anti-H together with anti-A and anti-B and can
cause a severe transfusion problem
...

Everyone, with the exception of newborns, have ABO antibodies directed against any ABO
and H antigens they themselves lack
...
A patient can be transfused with blood bags that do not contain antigens
that will react with the patient’s antibodies
...
Rh locus on chromosome 1
p36
...
3
...
The D antigen is highly
immunogenic, as the D antigen comprises numerous epitopes of the external domains of the
D protein
...
Numerous variants of D exist and are split into
two types; partial D and weak D
...
If
an individual with a partial D phenotype is immunised by red cells with complete D antigen,
they might make antibodies to those epitopes they lack
...
Weak D antigens appear to express
all epitopes of D, but at a lower site density than normal D
...
anti-D is produced in D negative individuals due

to transfusion of D positive red cells
...
Anti-D is a common cause of severe haemolytic disease of the fetus or
newborn (HDFN)
...
Anti-C, anti-E, and anti-e rarely
cause HDFN and when they do the disease is generally mild
...

All blood groups can be transfused with O Rh D negative blood, thus it is used in emergency
situations
...
Agglutination is the formation of cross-linkages between red
blood cell antigens and corresponding antibodies
...
Factors
affecting in vitro detection of agglutination reactions include; the number of antigen sites, as
the more antigen sites available to bind results in more antibodies binding forming
cross-linkages, thus a greater agglutination reaction results; the size of the antibody, as
larger antibodies such as pentameric IgM can cross-link antigens on adjacent cells causing
direct agglutination of red cells, whereas IgG antibodies are monomeric and the distance
between the Fab regions on a single IgG molecule is insufficient to permit the Fab regions of
two IgG molecules to span the distance between two adjacent red cells and cause direct
agglutination, thus IgM antibodies result in a stronger agglutination reaction; the distance
between cells, as positive charge on sodium ions in saline creates an overall positive charge
and red blood cells repel one another (zeta potential), lower ionic strength saline has a lower
sodium concentration, thus a lower positive charge, thus red blood cells agglutinate easier;
and the antigen-antibody ratio
...
Synthetic gel mixtures
of glass microbeads configured into vertical columns on small cards from density barriers,
retaining agglutinated red cells and allowing passage of the non agglutinated cells
...

Samples may consist of patient red blood cells and reagent antisera (monoclonal antibody
reagent)- forward grouping, or samples may consist of reagent red blood cells and patient
serum/plasma- reverse grouping
...
Donor whole blood samples are tested; to
determine ABO group, to determine D type, and to detect and identify antibodies present
...
Octopress divides whole blood into different components; plasma, platelets, and
red blood cells
...
Packed red blood cell
donations are tested to determine ABO and Rh D type and to ensure absence of antibodies
...
Packed red blood cell
donations can be stored at 2-6 degrees celsius for 35 days
...
The british
society of haematology recommend red blood cell transfusion when Hb<70g/L or when the
patient is symptomatic and Hb is 80-100g/L
...
ABO and D compatible platelets are preferable but when these are not
available, ABO and D incompatible platelets may be used in adults
...
Plasma must be
ABO compatible with the recipient, but AB plasma is the universal plasma donor group
...
Fresh frozen plasma is stored at minus 25
degrees celsius for up to 36 months
...
Fresh frozen
plasma transfusions are used in the treatment of coagulation disorders with bleeding due to
reduced levels of several clotting factors
...
Cryoprecipitate can be stored at minus 25 degree celsius for up to 36
months, and is thawed at 37 degrees celsius
...

Adverse effects of transfusions
Haemolytic disease of the fetus or newborn (HDFN) is the result if red cell alloimmunization
in which IgG antibodies passage from the maternal circulation across the placenta into the
circulation of the fetus where they react with fetal red cells and lead to their destruction
...
Although antibodies against the ABO blood group
system are the most common cause of HDFN this is usually mild
...
During
pregnancy, fetal red blood cells are separated from the mother's circulation by a layer of
cells in the placenta called the trophoblast
...
However, at the time of delivery, separation of the
placenta from the uterine wall allows larger amounts of fetal umbilical cord blood to enter the
mother's circulation
...
The secreted IgM antibody clears the Rh positive fetal red cells from the
mother’s circulation, but memory cells remain, a threat to any subsequent pregnancy with an
Rh positive fetus
...
However, activation of
IgG-expressing memory cells in a subsequent pregnancy results in the formation of IgG

anti-Rh antibodies which can cross the placenta and damage fetal red blood cells
...
In moderate HDFN the baby is born
with anaemia and jaundice and may show pallor, tachycardia, oedema, and
hepatosplenomegaly
...
Kernicterus can be treated with ultraviolet light exposure
...
Investigations will reveal
variable anaemia with a high reticulocyte count, the baby is Rh D positive, the direct
antiglobulin test is positive and the serum bilirubin is raised in moderate and severe cases
many erythroblasts are seen in the blood film- erythroblastosis fetalis
...
Anti-Rh antibodies are also administered to pregnant
women after amniocentesis
...
In a subsequent pregnancy with an Rh
positive fetus, a mother who has been treated with anti-Rh is unlikely to produce IgG anti-Rh
antibodies, thus, the fetus is protected from the damage that would occur when these
antibodies cross the placenta
...
Acute HTRs (AHTRs) are defined as fever and
other symptoms/signs of haemolysis within 24 hours of transfusion, confirmed by one or
more of the following; a fall in haemoglobin concentration, rise in lactate dehydrogenase,
positive direct antiglobulin test, positive cross-match
...

Delayed HRTs (DHRTs) are defined as fever and other symptoms/signs of haemolysis more
than 24 hours after transfusion, confirmed by one or more of the following; a fall in
haemoglobin concentration of failure of increment, rise in bilirubin, incompatible crossmatch
not detectable before transfusion
...

Haemovigilance
The goal of haemovigilance movement is to improve patient and donor safety and
transfusion outcomes
...
Human error
is the greatest potential risk associated with blood transfusion in the UK
...

SHOT collects and analyses anonymised information on adverse events and reactions in
blood transfusion from all healthcare organisations that are involved in the transfusion of
blood and blood components in the UK
...
SHOT also monitors the effect of the
implementations of its recommendations
...
The medicines and healthcare regulatory agency is a statutory body that determines
laboratory and hospital conformance to the blood safety and quality regulations
...

Transfusion of incorrect blood components is the most common cause of transfusion
adverse effects
...

Immediate hypersensitivity reactions result in symptoms that manifest themselves within very
short time periods after the immune stimulus
...
Delayed-type hypersensitivity (DTH) reactions take 1-3
days to manifest themselves, and are caused by T-cell reactions
...
Type I hypersensitivity reactions are mediated by IgE antibodies that bind
to mast cells or basophils
...
These reactions include
the most common responses to respiratory allergens such as pollen and dust mites, and to
food allergens, such as peanuts and shellfish
...


Type II hypersensitivity reactions (antibody-mediated hypersensitivity) results from the
binding of IgG or IgM to the surface of host cells which mediates cell destruction via
complement activation or antibody dependent cell-mediated cytotoxicity
...
Typical manifestations include; blood transfusion reactions, erythroblastosis fetalis,
autoimmune haemolytic anaemia, acute and chronic rejection following transplantation, and
graft versus host disease
...
In type III reactions
antigen-antibody complexes are deposited on host cells or tissues and induce complement
activation and an ensuing inflammatory response mediated by massive infiltration of
neutrophils
...

Type IV hypersensitivity reactions result from excessive and sometimes inappropriate T-cell
activation
...
Typical manifestations include; contact dermatitis, tubercular
lesions, and graft rejection
...
type I hypersensitivity reactions
are a type of immediate hypersensitivity reaction
...
Individuals without allergies generate IgE antibodies only in response to parasitic
infections
...
Allergens are highly soluble proteins or glycoproteins, usually with
multiple epitopes
...
Many allergens have
intrinsic enzymatic activity that contributes to the allergic response, for example the
production of protease
...
Many allergens enter the host via mucosal
tissues at very low concentrations, which tend to induce Th2 responses, the IL-4 and IL-13
produced by Th2 cells induce heavy-chain class switching to IgE
...
Allergenicity is the potential
of a material to cause sensitization and allergic reactions
...
2-0
...
IgE
has an additional constant region which changes the conformation of the molecule and
enables it to bind to receptors on mast cells and basophils
...
The activity of IgE depends on its ability to bind to a receptor specific for the Fc

region of the heavy chain
...

Exposure to an allergen activates Th2 cells that stimulate B cells to proliferate, undergo
heavy-chain class switching to IgE, and differentiate into IgE-secreting plasma cells and
memory B cells expressing membrane IgE B-cell receptors
...
A second
exposure to the allergen leads to cross-linking of the bound IgE
...
Adaptor molecules then latch
onto the phosphorylated tyrosine kinase residues and initiate signaling cascades culminating
in enzyme and/or transcription factor activation
...
Also phospholipase A
initiates metabolism of the lipid arachidonic acid, producing inflammatory lipid mediators
...
These mediators cause numerous effects; smooth muscle contraction,
increased vascular permeability, vasodilation, granulocyte chemotaxis, and extraversion
...
Effects of mast cell activation on the airways include decreased
diameter and increased mucus secretion resulting in congestion of airways and swelling and
mucus secretion in nasal passages
...
Mast cells are most common near epithelial surfaces
...
Binding of IgE to its low affinity FcERII receptor helps to regulate IgE
responses, transports IgE across the intestinal epithelium, and induces inflammatory
cytokine production by macrophages
...
Secondary mediators are either synthesized after target cell
activation or released by the breakdown of membrane phospholipids during the
degranulation process, examples of secondary mediators include; platelet activating factor,
leukotrienes, prostaglandins, bradykinin, cytokines and chemokines
...
Its biological effects
are observed within minutes of mast cell activation
...
binding of

histamine to the H1 receptor induces contraction of intestinal and bronchial smooth muscles,
increased vascular permeability of venules, and increased mucus secretion
...
Binding of histamine to
H2 receptors on mast cells and basophi;s decreased/suppresses degradation, thus,
histamine exerts negative feedback on the further release of mediators
...
H3 is less involved in type I hypersensitivity reactions
...

Mast cells, basophils, and eosinophils secrete cytokines, including IL-4, IL-5, IL-8, IL-9,
IL-13, GM-CSF and TNF alpha
...
IL-4 and IL-13 stimulate a Th2
response and thus increase IgE production by B cells
...
IL-8 activates neutrophils, monocytes, mast cells, and basophils to the site of
the hypersensitive response
...
TNF-alpha
contributes to shock in systemic anaphylaxis
...

Leukotrienes and prostaglandins are secondary mediators
...
Their effects are longer lived and more pronounced than those
of primary mediators
...

Systemic anaphylaxis is the most severe type of allergic response
...
It is usually
initiated by an allergen introduced directly into the bloodstream or absorbed into the
circulation from the gut or skin
...
This can lead to
asphyxiation and death
...
A wide range of allergens has been shown to trigger this reaction in
susceptible humans, including the venom from bee, wasp, hornet, and anti stings; drugs
such as penicillin, insulin, and antitoxins; foods such as seafood, and nuts; and latex
...
Epinephrine
counteracts the effects of mediators such as histamine and leukotrienes, relaxing the smooth
muscles of airways and reducing vascular permeability
...

In localized hypersensitivity reactions, the effects are limited to a specific target site in a
tissue or organ, often occurring at the epithelial surfaces first exposed ott allergens
...


Food allergens are a common type of atopy
...
Among
adults, nuts, fish, and shellfish are the predominant culprits
...
Some food allergens are capable of acting directly as
adjuvants and promoting a Th2 response and IgE production in susceptible individuals
...
Some individuals also have oral
hypersensitivity, leading to tingling and angioedema of the lips, palate, and thoat
...
Basophils play a role in acute food allergy symptoms
...
Allergic asthma is triggered by
activation and degranulation of mast cells, with subsequent release of inflammatory
mediators, contraction of the bronchial smooth muscles, mucus secretion, and swelling of
the tissues surrounding the airway all contribute to bronchoconstriction and airway
obstruction
...
Intrinsic asthma is induced by exercise or cold,
independently of allergen stimulation
...
Allergen cross-linking of the receptor bound to IgE
induces the release of histamine and other mediators from tissue mast cells, which then
cause vasodilation, increased capillary permeability, and production of secretions in the
eyes, nasal passages, and respiratory tract
...
Allergic rhinitis affects 15-50% of the global population
...
Allergic rhinitis is
associated with asthma
...

Atopic dermatitis (allergic eczema) is an allergic inflammatory disease of skin
...
It is observed most frequently in
young children, often developed during infancy
...
The
affected individual develops rash, erythematous skin eruptions that can fill with pus if there is
an accompanying bacterial infection, the skin lesions contain Th2 cells and an increased
number of eosinophils
...
There is some evidence that while the
immune system of newborns may be biased in the Th2 direction by the uterine environment,
that bias diminishes during the first few months of life in nonallergic individuals, but becomes
stronger in allergic children
...
In westernized
countries, where microbial infections are reduced as a result of sanitation, vaccinations,
antibiotics and less exposure to farm animals, a child's immune system may be less likely to
undergo the exposure to infections that would otherwise reorient it away from Th2
responses
...
Early exposure to a variety of
infections educates the immune system
...
Among genes that have
variants associated with predisposition to allergies and asthma are genes that affect the
integrity of the epithelial barrier, cytokines and chemokines, proteins controlling regulatory T
cells, transcription factors, and receptors and signaling proteins
...
Small amounts of potential allergens are introduced at specific skin sites,
either by intradermal injection or by dropping onto a site of a superficial scratch
...
Redness and swelling (the result of local mast cell
degranulation) indicate an allergic response
...

Treatment for allergies always begins with measures to avoid exposure to allergens
...
An
anti-IgE-antibody also can be effective, though expensive and difficult to administer
...
These drugs inhibit histamine
activity by binding and blocking histamine receptors on target cells
...
Immunotherapy by injection or sublingual administration of airborne
allergens has been successful in preventing allergic rhinitis
...

Type II hypersensitivity

Transfusion reactions are an example of type II hypersensitivity
...
individuals with different blood types express different
carbohydrate antigens
...
All individuals express antigen H, so no
antibodies are generated to this carbohydrate
...

Haemolytic disease of the newborn is caused by type II reactions
...
As red blood cells from a fetus enter the
maternal circulation during pregnancy and birth, the mother will develop Rh antibodies that
can cause haemolytic disease in subsequent pregnancies
...
Similar
immunization of mother against A and B blood group antigens of the fetus may also occur,
blood group antigen antibodies cause less severe hemolytic disease of the newborn
...

Certain antibiotics, eg
...
Income patients, such drug protein complexes
induce the formation of antibodies, these antibodies then bind to the adsorbed drug on the
red blood cells, inducing complement mediated lysis, and thus preogressive anemia
...

Type III hypersensitivity
The reaction of antibodies with antigen generates immune complexes
...
In some cases, however, the presence of large numbers and networks of
immune complexes can lead to tissue damaging type III hypersensitivity reactions
...
Failure to clear immune complexes may also result
from peculiarities of the antigen itself, or disorders in phagocytic machinery
...
Uncleared immune complexes can induce granulation of mast cells and inflammation,
and can be deposited in tissues and capillary beds where they induce mpoe innate immune
activity, blood vessel inflammation (vasculitis), and tissue damage, such as
glomerulonephritis in the kidneys, or arthritis in the joints
...
injection with antibodies from a different species, can cause
serum, typically mild and characterised by skin rashes, joint stiffness and fever
...
Arthus reactions are examples of immune

complex hypersensitivity reactions and can be induced by insect bites, as well as by
inhalation of fungal or animal protein in individuals with antibodies to those antigens
...

Type IV hypersensitivity
Type IV hypersensitivity, commonly referred to as delayed type hypersensitivity, is the only
hypersensitivity category that is purely cell mediated rather than antibody mediated
...

The presence of a type III reaction can be measured experimentally by injecting antigen
intradermally into an animal and observing whether a characteristic skin lesion develops
days later at the injection site
...
For example, to determine
whether an individual has been exposed to M
...
Development of a red, slightly
swollen, firm lesion at the site between 48 and 72 hours later indicates previous exposure
...
Contact dermatitis occurs when a
reactive chemical compound contacts the skin and binds chemically to skin proteins
...
The reactive chemical may be a pharmaceutical, a component of
a cosmetic or a hair dye, an industrial chemical such as formaldehyde or turpentine, an
artificial hapten such as fluorodinitrobenzene, a metal ion such as nickel, or the active
compound from poison ivy, poison oak, and related plants
...
The toxins, a family of related alkyl catechols, are known collectively as
urushiol
...
After
oxidation in the body, urushiol binds covalently to skin proteins, which can be taken up by
skin dendritic cells and carried to the draining lymph nodes, where they can be degraded
into peptides, presented bound to MHC class II proteins,, and induce the formation of Th1
cells
...
Urushiol can also enter cells where it can bind to
cytoplasmic proteins that may be degraded into peptides that enter the endoplasmic
reticulum and bind to MHC class I
...

Th17 cells generate DTH responses to urushiol
...
These T cells secrete
proinflammatory cytokines IL-17 and IL-22, which recruit and activate neutrophils and
macrophages which release inflammatory and tissue damaging mediators
...
The T cells are primarily of the Th1 subtypes, but can also be Th17, Th2 and CD8+
cells
...

Transplantation
Transplantation os the transfer (engraftment) of human cells, tissues or organs from a donor
to a recipient with the aim of restoring function(s) in the body
...
Transfusion is the transfer of blood resulting in antibody
mediated reactions, whereas transplantation is the transfer of tissues or organs and results
in T cell mediated reactions
...
Tissues that share sufficient antigenic
similarity, allow transfer without immunologic rejection, and are referred to as
histocomapatible
...
Tissues that display significant antigenic
differences are histoincompatible and typically induce an immune response leading to tissue
rejection
...
The
loci responsible for the most vigorous allograft rejection reactions are located within the
MHC
...
Xenografts exhibit the greatest genetic
and antigenic disparity, engendering a rapid and vigorous graft rejection response
...
When mice from two different inbred strains are mated, the
F1 progeny each inherit one maternal and one paternal haplotype
...
However, neither of
the parental strains from the F1 offspring because each parent lacks one of the F1
haplotypes and will therefore reject these MHC antigens
...
in matings between members
of an outbred population, there is only a 25% chance that two offspring will inherit identical
MHC haplotypes unless the parents share a haplotype
...

Acceptance of an autograft is completed within 12-14 days; with extraversion occurring
between days 3-7, and healing occurring between days 7-10, and finally resolution occurring
between days 12-14
...
Second set rejection (based on a secondary response) of an allograft begins
within 3-4 days, with full rejection by 5-6 days; cellular infiltration of leukocytes, phagocytes,
and other inflammatory cells occurs between days 3-4, and thrombosis and necrosis occurs
between days 5-6
...

MHC matching
The function of MHC molecules is to bind to peptide fragments derived from pathogens and
display them on the cell surface for recognition by the appropriate T cells
...
The MHC is polyallelic: contains multiple alleles at its genetic loci
...
MHC molecules are codominantly expressed
...
MHC polymorphism imparts an evolutionary survival advantage against mortality
from infectious disease
...
Given
immunosuppressive drug regimens and immune tolerance induction protocols, solid organ
transplantations between individuals with significant or even total mismatch can be
successful, and this is still the course of action with tissues like the heart or lungs that do not
survive for more than a few hours outside the body, as this window of time is too short to
transport MHC-matched organs any significant distance
...
Either serologic or molecular tests can be used to
determine the HLA compatibility - tissue typing
...
Molecular assays provide greater
specificity and higher resolution than assays that characterize MHC molecules serologically,
using antigen-antibody interactions alone
...

The transplant is rejected so quickly, the grafted tissue never becomes vascularised
...
Hyperacute rejection is an example of a type II
hypersensitivity reaction
...
The most common targets
are ABO blood group antigens or MHC alloantigens
...
This results in
endothelial damage that obstructs capillaries, preventing vascularisation of the graft
...
Several mechanisms can account for the presence of antibodies specific for
MHC alloantigens, including; past blood transfusions that induced antibodies to MHC
antigens expressed on allogeneic white blood cells in the blood; past pregnancies, in which
women develop antibodies against paternal alloantigens of the fetus; exposure to infectious
agents, which can elicit MHC cross-reactive antibodies; or a previous transplant, which
results in high levels if antibodies to the allogeneic MHC antigens present in that graft
...
Hyperacute rejection is irreversible and untreatable,
requiring removal of the transplanted organ
...
Acute rejection occurs in
the absence of pre-existing immunity
...
During the sensitisation phase, CD4+ and CD8+ T cells
recognize alloantigens expressed on cells of the foregin graft and proliferate in response
...
The response to minor
histocompatibility antigens is weak, although the combined response to several minor
differences can be rigorous
...
Activation of naive T cells requires presentation by an antigen presenting cell
that expresses the appropriate antigenic ligand/MHC molecule and provides the requisite
costimulatory signal
...
Antigen presenting cells of host origin can also migrate
into a graft and endocytose the forgein alloantigens (both major and minor histocompatibility
molecules), where they become activated and present these antigens indirectly as
processed peptides bound to self MHC molecules
...
The
cross-presentation ability of dendritic cells also allows them to present endocytic antigens in
the context of MHC class I molecules to CD8+ T cells, which can then participate in allograft
rejection
...
T cells that respond to antigen via the T cell receptor in the absence of
costimulation or danger signals can become tolerant
...
This suggests that exposure to
donor cells in this non-inflammatory context encourages tolerance to donor alloantigens
...
Hallmark of the effector phase is a large influx of leukocytes, especially CD4+ T
cells and macrophages
...

Th1 cells secrete IL-2 and IFN-gamma mediate graft rejection by promoting T cells
proliferation, delayed type hypersensitivity reactions, and the synthesis of IgG by B cells,
with resulting complement activation
...
Acute rejection is cellular mediated rejection
...

Alloreactive T cells
Alloreactivity refers to the ability of T cells to recognize peptide-allogeneic-MHC complexes
that were not encountered during thymic development, and manifests itself clinically as
transplant rejection and graft-versus-host-disease
...
High determinant density: all graft’s MHCmolecules can
act as ligands for the alloreactive T cell receptor, thus there are thousands more available
ligands to the T cell receptor
...
Numerous different T cell clones are activated by the allogeneic MHC/peptide
complexes
...
The mechanisms include
both humoral and cell-mediated responses
...
Chronic rejection is an example of a type III
hypersensitivity reaction
...
The recruitment of inflammatory cells
causes; damage to graft vascular endothelium, smooth muscle proliferation, and migration of
effector T cells, in the tissue causing increasing damage and leading to vascular occlusion
...
Chronic rejection is the
result of a chronic inflammatory state which results in diffuse scar tissue and stenosis of
vasculature of the transplanted organ
...

Chronic rejection is resistant to reversal by standard immunosuppression, necessitating
another transplant
...

The major clinical applications of bone marrow transplant include; providing a functional
immune system to individuals with a genetically determined immune deficiency such as
severe combined immunodeficiency, replacing a defective hematopoietic system with a
functional one to cure patients with life threatening non-malignant genetic disorders in
haematopoiesis such as thalassaemia, and restoring the hematopoietic system of cancer
patients after treatment with doses of chemotherapeutic agents and radiation so high they
destroy the system
...
Bone marrow HSCs are needle aspirated from a living donor and implanted into the
recipient by intravenous injection
...
Patients are severely
immunocompromised until bone marrow reconstitution, and thus are at high risk of infection
...

GVHD occurs; when the graft contains immunologically competent cells, the recipient
expressess tissue antigens that are not present in the transplant donor, and the recipient is
incapable of mounting an effective response to eliminate the transplanted cells
...
GVHD occurs when donor T cells respond to genetically defined proteins on host
cells, the most important proteins are human leukocytes antigens
...
Genetic
differences in minor histocompatibility antigens between host and recipient can also result in
GVHD
...
Clinical
features of chronic GVHD include; dyspigmentation, new onset alopecia, poikiloderma,
lichen planus-like eruptions of scleorotic features, nail dystrophy or loss, xerostomia, mouth
ulcers lichen type features, restrictions of mouth opening from sclerosis, dry eyes, sicca
syndrome, cleartical conjunctivitis, fasciitis, myositis, joint stiffness from contractures, vaginal
sclerosis, vaginal ulceration, anorexia, weight loss, esophageal web of strictures, jaundice,
transaminitis, bronchiolitis obliterans, pleural effusions, nephrotic syndrome, pericarditis,
thrombocytopenia, anemia, and neutropenia
...
The
development of acute GVHD occurs in three phases; activation of antigen presenting cells;
donor T cell activation, proliferation, differentiation, and migration; and target tissue
destruction
...
Damaged host tissues respond by
producing danger signals, including proinflammatory cytokines, chemokines, and increased
expression of adhesion molecules MHC antigens and costimulatory molecules of host
antigen presenting cells
...
The danger signals generated in phase I augment this
activation by increasing the expression of costimulatory molecules, CD4+ cells induced
acute GVHD to MHC class II differences, and CD8+ cells induce GVHD to MHC class I
differences, natural killer T cell subsets of both host and donor modulate acute GVHD
...
Th1 secrete
the cytokines IFN-gamma, IL-4 and TNF-alpha in large amounts in acute GVHD
...
It also increases the sensitivity to monocytes and
macrophages to stimuli such as LPS and accelerates intracellular cascades in response to
these stimuli
...
In contrast, IFN-gamma may suppress GVHD by hastening apoptosis of
activated donor T cells
...
These soluble and cellular mediators
synergize to amplify local tissue injury and further promote inflammation and target tissue
destruction
...
GVHD can also be
prevented through the use of umbilical cord blood as the source of HSCs, as the umbilical
cord is rich in stem cells and lacks alloreactive mature T cells, due to the lower risk of GVHD
with umbilical cord transplanted stem cells, a greater disparity of HLA can be tolerated
...
The treatment of acute GVHD involves the use of
steroids, due to their potent anti lymphocytes and antiinflammatory activity
...
During ECP, the
patient's white blood cells are collected by apheresis, incubated with the DNA intercalating
agent, exposed to ultraviolet light, and returned to the patient
...

Another strategy to treat GVHD is the blockade of inflammatory cytokine TNF-alpha
...
The pathophysiology of chronic GVHD remains poorly understood, and is
treated with a variety of immunosuppressive agents
...
Cross-matching is the

most important level of compatibility testing that occurs prior to solid organ transfer
...
A positive cross-match means that the recipient has antibodies against
HLA proteins expressed by the donor and that these are likely to lead to rapid hyperacute
rejection
...

Lymphocytes are obtained from peripheral blood and separated by centrifugation with a
ficoll-hypaque gradient
...
If the lymphocytes
carry molecules recognized by the antibody, the antibody will bind to the cell and the cell will
be lysed
...
Reactions are graded based on the percentage of lysis
...

Mixed lymphocyte culture
The mixed lymphocyte reaction (MLR) is an in vitro assay in which leukocytes, from two
genetically distinct individuals of the same species, are cultures resulting in cell blast
transformation, DNA synthesis, and proliferation
...
MLRs can identify
discrepancies in the HLA class II loci which microcytotoxicity may not detect
...
The donor's
lymphocytes are treated so that they will not proliferate in the presence of the recipient's
lymphocytes
...
If the recipient
lymphocytes react to the donor lymphocytes they will uptake the DNA and their radioactivity
can be measured and is a measure of the responsiveness of the recipient's lymphocytes to
the donor cells
...

DNA techniques for compatibility testing
Restriction fragment length polymorphism (RFLP) is a difference in homologous DNA
sequences that can be detected by the presence of fragments of different lengths after
digestion of the DNA samples with specific restriction endonucleases
...
Then the reaction fragments produced during DNA fragmentation
are analyzed using gel electrophoresis, the fragments are negatively charged and can be
easily separated by electrophoresis, which separates molecules based on their size and
charge
...
An
RFLP probe is a labelled DNA sequence, frequently a cDNA clone
...
RFLP can be used for HLA typing
...
The initial step is the
HLA-locus-specific amplification of DNA by polymerase chain reaction
...


Fluorochromes are linked with the probes to allow their detection by chemiluminescence
...
The higher the number of probes the better the resolution level
...
Most of the vast polymorphism of the HLA system results from conversion
events whereby small nucleotide sections of one allele are transferred to another allele
...

Therefore probes are used which are sequence specific
...

The advantages of molecular typing techniques over serological typing techniques include;
increased accuracy, increased resolution, high throughput, high reproducibility, and
simplified technique
...
Typically, an organism is tolerant to self antigens
...

Antigen sequestration
One effective means to avoid self reactivity is sequestration of antines away from immune
cells in immune privileged sites
...
However, one possible consequence of
sequestration is that the antigen is not involved in life long peripheral tolerance pathways
...
Active suppression of anti-slf responses
is ubiquitous, immune privileged sites may have only partial barriers to the influx of immune
cells or partitions that can be opened and closed as needed
...

Central tolerance
Central tolerance occurs in primary lymphoid organs, where many self-reactive lymphocytes
are eliminated before they can mature, and others are selected (at least in the thymus) to
later engage in immune inhibitory responses targeting self antigens at tissue sites, protecting
against autoimmunity
...
Due to the transcription factor AIRE, many
tissue-specific self antigens found only in particular organs are also expressed in medullary
epithelial cells of the thymus
...
Some lymphocytes with high affinity for self

antigens are selected for survival during development, such as regulatory T cells which
suppress or regulate autoimmune responses to self antigens in the periphery
...
Whereas, more sustained, high- affinity TCR engagement
in the thymus favors deletion of the self-reactive lymphocytes
...

Factors contributing to this phenomenon include; not all self antigens are expressed in the
central lymphoid organs where negative selection occurs, and there is a threshold
requirement for affinity to self antigens before clonal deletion is triggered allowing some
weakly self-reactive clones to survive
...
Peripheral tolerance processes occur after lymphocyte
development, when immune cells are induced to act as inhibitors of self reactivity for
antigen that is presented in a nonimmunogenic context
...
The same chemical compound can be both an
immunogen and a tolergen, depending on context
...
Naive T cells that enter the regulatory
pathway in the periphery can be induced to express FoxP3 and become pTreg cells, acting
as antigen-specific inhibitors of activation
...
Allergens are antigen specific
...
Factors that promote tolerance rather than stimulation of the immune system by a
given antigen include; fetal exposure, high doses of antigen, long term persistence of
antigen in the host, intravenous or oral introduction, absence of adjuvants (compounds that
enhance the immune response to antigen), low levels of costimulation, and presentation of
antigen by immature or unactivated antigen-presenting cells
...

Immune cells in the periphery that inhibit anti-self responses
Both CD4+ and CD8+ lymphocyte subsets of regulatory T cells down regulate immune
processes
...
The interaction between CD28 on the T cell and CD80/86 (B7) on the antigen
presenting cell (APC) provides the costimulatory signal required for T cell activation
...
The inhibitory molecule CTLA-4 plays an essential role in
maintaining peripheral tolerance
...

Interaction of CTLA-4 on Treg cells with CD80/86 on an APC inhibits APC functions,
including; reduced expression of costimulatory molecules (eg
...
IL-6 and TNF-alpha)
...
As
Treg cells express high levels of CD25, the high affinity IL-2 receptor, they absorb local IL-2
...
CD4+ Treg cells express
the FoxP3 transcription factor, CTLA-4, and IL-2R alpha chain (CD25)
...
Regulatory
CD8+ T cells express FoxP3, CTLA-4, CD8+ alpha alpha, both the high -and low- affinity
receptors for IL-2 (CD25 and CD122, respectively), and dendritic cell markers
...
HLA-E molecules play key
roles in presenting lipid antigens
...
Treg cells
can kill APCs or effector T cells directly, by granzyme and performing mediated killing, as
well as modulating the function of their cells responding to antigen via surface receptor
engagement
...
Treg cells inhibit APCs presenting their cognate antigen or effector T cells
that share their same antigen specificity, and not T cells with a different specificity
...
The result is inhibition of the APC, via both contact dependent and independent
pathways, as well as inhibition of the bystander T cell through soluble inhibitory factors and
decommissioning of the APC
...
This phenomenon, termed linked suppression, may represent another way in
which Treg cells support local self tolerance in tissues lacking any pathogen-induced danger
signals
...
Regulatory B cells
produce high levels of the inhibitory cytokine IL-10
...

Myeloid-derived suppressor cells (MDSCs) are a heterogenous group of immature myeloid
cells that can accumulate at sites of infection or immune activity, suppressing local antigenspecific T-cell responses
...

Autoimmunity
Autoimmune diseases result from the destruction of self proteins, cells, and organs by
auto-antibodies or self-reactive T cells
...
Autoimmune diseases can also be categorized based upon the
immune component that does the bulk of the damage: T cells or antibodies
...
Hashimoto’s thyroiditis is prevalent in middle aged women
...
The resulting delayed-type
hypersensitivity response is characterized by an intense infiltration of the thyroid gland by
lymphocytes, macrophages, and plasma cells, which form lymphocyte follicles and germinal
centres
...
The ensuing inflammatory response causes a goiter, or
visible enlargement of the thyroid gland, a physiological response to local inflammation
caused by antibodies against thyroid specific proteins
...
Hashitmoto’s thyroiditis is treated with replacement therapy
involving daily administration of thyroxine
...
The disease begins with
cytotoxic T lymphocyte infiltration and activation of macrophages, referred to as insulitis,
which leads to a cell-mediated delayed type hypersensitivity response, with resulting
cytokine release and production of autoantibodies
...
Antibodies specific or beta cells
contribute to cell destruction by facilitating either antibody-mediated complement lysis or
antibody-dependent cell-mediated cytotoxicity
...
The late stages of
the disease can be charcterized by atheroscleortic vascular lesions (which cause gangrene
of extremities due to impeded vascular flow), renal failure, and blindness
...
T1D is treated by daily administration of insulin
...
One of the best studied animal models of
this disease is the nonobsese diabetic (NOD) mouse, which spontaneously develops a form
of diabetes that resembles human T1D
...
NOD mice housed in
germ-free environments show a higher incidence of diabetes compared with those in regular
housing, suggesting that a diverse flora may help block development of autoimmune
disease
...
In addition, the anti-AChR auto-antibody activates
complement mediated lysis of the cells which damages the motor end plate of the muscle
...
Ultimately, the antibodies
cause the destruction of cells bearing ACh receptors
...
Without treatment,
progressive weakening of the muscles can lead to severe impairment in eating as well as
problems with movement
...
using
cholinesterase inhibitors), decreasing antibody production (using corticosteroids or other
immunosuppressants), and/or removing antibodies (via plasmapheresis: the removal and
exchange of blood plasma)
...
The rabbits develop antibodies against the AChR that cross reacted
with their own AChRs
...

Systemic lupus erythematosus
Systemic lupus erythematosus (SLE) has a higher incidence in women than men, and a
higher incidence in African American and Hispanic women than white women, SLE
symptoms appear between 20-40 years of age
...

SLE presents clinically with fever, weakness, arthritis, kidney dysfunction, and a
characteristic butterfly rash across the nose and cheeks
...
When immune complexes of auto-antibodies
with various nuclear antigens are deposited along walls of small blood vessels, a type III
hypersensitivity reaction develops
...
In
severe cases, excessive complement activation produces elevated serum levels of certain
complement fragments, leading to neutrophil aggregation and attachment to the vascular
endothelium
...
Laboratory diagnosis of SLE involves detection of antinuclear antibodies
directed against DNA, nucleoprotein, histones, or nucleolar RNA
...
The New Zealand mouse is an animal model for SLE
...
NZB/W F1 mice develop
autoimmune haemolytic anaemia between 2-4 months of age, at which point auto-antibodies
can be detected
...
Individuals with MS produce autoreactive CD4+ T cells
...
Since myelin functions to insulate the nerve fibres, a
breakdown in the myelin sheath leads to numerous progressive neurologic dysfunctions,
ranging from numbness in the limbs to paralysis or loss of vision
...
MS has both genetic and environmental associations
...
The environmental
factors that may impact MS susceptibility include; diet, smoking, obesity or BMI, and vitamin
D levels
...
Studies in patients with MS have noted
disruption in the gut flora associated with flare-ups
...
MS is induced in small animals by
immunization with myelin basic protein or proteolipid protein, both components of the myelin
sheaths surrounding neurons in the CNS
...
Germ-free mice are less
susceptible to induction of MS, and addition of particular gut commensals has been shown to
either exacerbate or attenuate disease, highlighting the role of diet and the microflora in
disease susceptibility
...
RA has a strong genetic susceptibility
component, the HLA-DRB1 locus is implicated
...
Individuals with RA produce antibodies that react with citrullinated protein antigens
(where an arginine residue is converted to the nonstandard amino acid citrulline)
...
The
classic RF is an IgM antibody
...
These can activate the complement cascade, resulting
in a type III hypersensitivity reaction and chronic inflammation
...
RA is associated with gum disease and bacteria that cause gingivitis, as well as with
smoking
...
Triggering or exacerbating the production of anti self antibodies in individuals who
are already susceptible to RA
...
Enteropathy, X-linked syndrome
Autoimmune polyendocrine syndrome type-1 (APS1), and immune dysregulation,
polyendocrinopathy
...
APS-1 and IPEX; are monogenic disorders, impact multiple organs, and display
a range of immune pathologies (endocrine dysfunction, autoimmunity and primary immune
deficiency)
...
The AIRE transcription factor ensures tha tissue specific antigens are expressed in
the thymus during T cell development
...

IPEX is caused by mutations in the FoxP3 gene, the master transcriptional regulator

associated with regulatory T cells, which are generated both during central and peripheral
tolerance
...
However, two individuals can have exactly the same
set of MHC alleles (monozygotic twins) and still be discordant for the development of
autoimmune disease
...
The strongest
association between HLA allele and autoimmunity is seen in ankylosing spondylitis (AS)
...
Other non-MHC immune genes are also associated with autoimmune
disease
...

Genes may have cumulative effects on susceptibility to autoimmune diseases
...
genes for; cytokines and their
receptors, antigen processing and presentation, C-type lectin receptors, signaling pathways,
adhesion molecules, and co stimulatory or inhibitory receptors, have all been linked to
specific autoimmune disease
...
This suggests a link between environmental and/or lifestyle factors, and the
development of autoimmune diseases
...
Certain gut
microbes or their secreted products make contact with immune cells in the intestinal mucosa
and elsewhere on body surfaces, and regulate peripheral tolerance and suppress induction
of autoimmunity
...

Th17 cells may be an important driver of multiple autoimmune diseases
...
The microbiome
has a role in systemic immunity
...

Exposure to carcinogens or infectious agents that favor DNA damage or polyclonal
activation can interfere with regulation of self-reactive T and B cells and/or lead to the
expansion and survival of rare T or B cell clones with autoimmune portnetial
...
The molecular mimicry hypothesis posits that some pathogens express protein
epitopes resembling self compounds, either in conformation or primary sequence, and when
these enter the body they inadvertently activate self-reactive cells in a proinflammatory
microenvironment, bypassing immune regulation
...

Broad-spectrum therapies for autoimmune disease
Broad-spectrum immunosuppressants do not cure autoimmune diseases but do reduce
symptoms and improve patients quality of life
...
They suppress
lymphocytes indiscriminately, by inhibiting their survival and proliferation, or by killing rapidly
dividing leukocytes, thus inhibiting overall inflammation throughout the body
...
hair follicles, intestinal lining,
blood cells), an increased risk of uncontrolled infection, and even the development of cancer
...
Plasmapheresis may also provide significant if short-term
benefit for diseases involving antigen-antibody complexes (eg
...

Strategies that target specific cell types
When antibodies and/or immune complexes are heavily involved in autoimmune pathology,
strategies aimed at killing or blocking B cell specific antigen CD20 (rituximab) depletes a
subset of B cells and provides short term benefit for patients with RA
...
anti-CD4 monoclonal antibodies, such as zanolimumab, partially
deplete CD4+ T cells, and are used in the treatment of arthritis
...
Current research into strategies that target
specific cell types is directed toward mimicking Treg-like mechanisms of suppression, eg
...
by using IL-17 or IL-23 blocking antibodies
...
These would be more
targeted than broad-spectrum anti-inflammatories and might therefore spare some arms of
the immune response to still work to protect us from foreign invaders
...
IL-1 receptor antagonists, antibodies
directed against the IL-6 receptor and IL-15 are used in the treatment of RA
...
All these treatments have some
side effects that overlap with broad spectrum antiinflammatory drugs, plus they are all much
more expensive
...
CRP is an indicator
of inflammation
...
Stains may be used in the treatment of RA and
MS
...
Compounds that block
the chemokine or adhesion molecule signals controlling lymphocyte movement into sites of
inflammation can also inhibit autoimmune processes
...
This compound is an analog of sphingosine and induces internalisation of
sphingosine 1-phosphate (S1P) receptors in the body, which are involved in the migration of
lymphocytes into blood and lymph nodes
...
Fingolimod also inhibits Th1 and
Th17 cells, and enhances Treg cell activity
...

Natalizumab is a monoclonal antibody specific for the adhesion molecule alpha 4 integrin
and is used in the treatment of MS
...
However, a significant number of patients developed a life-threatening CNS infection
in response to Natalizumab
...

Therapies that interfere with costimulation
T cells require both antigenic stimulation via the T cell receptor (signal 1) and costimulation
(signal 2) to become fully activated
...
CTLA-4 is a potent inhibitor of T cell
activity, binding to CD80/86 with a high affinity
...
This therapeutic fusion protein drug, Abatacept, was approved
for the treatment of RA and is designed to block CD8-/86 on antigen presenting cells from
engaging with CD28 on T cells, inhibiting costimulation
...
Qatiramer acetate, a polymer of four basic amino acids
found commonly in myelin basic protein, has been approved for treating MS
...
Quintana, et al
...
In vitro, treatment of murine dendritic cells with these
nanoparticles induced a tolerogenic phenotype, suppressed proinflammatory cytokine
production, and led to differentiation of T cells into a regulatory phenotype
...




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