MCB 503 (Immunology and Immunochemistry)

Hypersensitivity

This is an exaggerated immune response that results in tissue damage and is manifested in the
individual on second or subsequent contact with an antigen. Hypersensitivity can be classified as
either immediate or delayed. The main difference between them is in the nature of the immune
response to the antigen. Peter Gell and Robert Coombs developed a classification system for
reactions responsible for hypersensitivities in 1963.

The Gell-Coombs classification system divides hypersensitivity into four types;

 Type 1 hypersensitivity.
 Type II hypersensitivity.
 Type III hypersensitivity.
 Type IV hypersensitivity.
TYPE 1 HYPERSENSITIVITY

Allergic reaction occurs when an individual who has produced IgE antibody in response to an
innocuous antigen (allergy) subsequently encounters the same allergen. Type 1 hypersensitivity
reactions are characterized by an allergic reaction occurring immediately following an individual’s
second contact with the responsible antigen (allergen).

Mechanisms of Type 1 allergy

Upon initial exposure to soluble allergens, B cells are stimulated to differentiate plasma calls and
memory cells. These plasma cells, with the help of T cells produce immunoglobulin E (IgE), also
known as reagin, and the individual have a hereditary predisposition for its production. Once
synthesized, IgE will have the capacity to bind with great affinity to the Fc receptors of mast cells
(basophils and eosinophils can also be activated) and sensitize these cells, making the individual
allergic to the allergen. When a second exposure to the allergen occurs, the allergen attaches to the
surface-bound IgE on the sensitized mast cells, causing degranulation. Degranulation releases
physiological mediators such as histamine, leukotrienes, heparin, prostaglandins, PAF (platelet-
activation factor), ECF-A (eosinophil chemostactic factor of anaphylaxis), and proteolytic enzymes.
These mediators trigger smooth muscle contractions, vasodilation, increased vascular permeability
and mucous secretion. The inclusive term for these responses is anaphylaxis.

Anaphylaxis (Greek ana = up, back, again; and phylaxis= protection) allergy: This is divided
into systematic and localized reaction.

Systematic anaphylaxis is a generalized response that occurs when an individual sensitized to an

allergen receives a subsequent exposure to it. The reaction is immediate due to the large amount of
mast cell mediators released over a short period. Usually there is respiratory impairment caused by
smooth muscle constriction in the bronchioles. The arterioles dilate which greatly reduces arterial
blood pressure and increases capillary permeability with rapid loss of fluid into the tissue spaces.

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Because of these reactions, the individual can die within few minutes from reduced venous return,
asphyxiation, reduced blood pressure, and circulatory shock. Examples of allergens that can produce
systematic anaphylaxis include drugs (Penicillin), passively administered antisera, peanuts, and
insects’ venom from the stings or bites of wasps, hornets, or bee.

Localized anaphylaxis is called atopy (“atopic” meaning “out of place”) allergy: This is any
chronic local allergy such as

a) Hay fever involves the upper respiratory tract. Initial exposure involves airborne allergens- such
as plant pollen, fungal spores, animal dander and house dust mites-that sensitize mast cells located
within the mucous membrane. Reexposure to the allergen causes the typical localized anaphylactic
response: itchy and tearing eyes, congested nasal passages, coughing and sneezing. Antihistamine
drugs are used to help alleviate these symptoms.

b) Bronchial asthma (asthma means panting) :It involves the lower respiratory tract. Here, the air
sacs (alveoli) become overdistended and fill with fluid and mucus; the smooth muscle contracts and
narrows the walls of the bronchi. Bronchial constriction produces a wheezing or whistling sound
during exhalation. Symptomatic relief is obtained from bronchodilators that help relax the bronchial
muscles, and from expectorants and liquefacients that dissolve and expel mucous plugs that
accumulate.

Allergens that enter the body through the digestive system may cause food allergies. Hives (eruption
of the skin) are good diagnostic sign of a true food allergy. Once established, type 1 food allergies
are usually permanent but can be partially controlled with antihistamines or by avoidance of the
allergen.

Skin testing can be used to identify the allergen responsible for allergies. These tests involve
inoculating small amounts of suspect allergen into the skin. Sensitivity to the antigen is shown by a
rapid inflammatory reaction characterized by redness, swelling and itching at the site of inoculation.
The affected area in which the allergen-mast cell reaction takes place is called a wheal and flare
reaction site. Once the responsible allergen has been identified, the individual should avoid contact
with it. At times this is not possible, and desensitization is warranted. This procedure consists of a
series of allergen doses injected beneath the skin to stimulate the production of IgG antibodies rather
than IgE antibodies. The circulating IgG antibodies can then act as blocking antibodies to intercept
and neutralize allergens before they have time to react with mast cell-bound IgE. The suppressor T-
cell activity also may cause a decrease in IgE synthesis. Desensitization are about 65 to 75%
effective in individuals whose allergies are caused by inhaled allergens.

TYPE 11 HYPERSENSITIVITY

This is generally called cytolytic or cytotoxic reaction because it results in the destruction of host
cells, either by lysis or toxic mediators. There are mechanisms by which type 11 hypersensitivity
reactions can destroy or alter cells. All these mechanisms begin with antibody binding to tissue
associated antigens. 1) Complement-mediated lysis of cells. Antibody that is bound to the target cell
fixes complement, initiating the complement cascade and ultimately lysing the plasma membrane of
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the cell. Circulating erythrocytes (RBCs), for example are destroyed by this mechanisms in
individuals with autoimmune haemolytic anaemia or isoimmune reaction to transfused blood cells
from a donor. 2) Cell destruction is phagocytosis by macrophages of the mononuclear phagocyte
system. The Fc receptors on the macrophage recognize and bind the antibody on the opsonized cell.
Phagocytosis of the target cell follows. Antibodies against platelet specific antigen or aganis red
blood cell antigen of the Rh system will coat those cells at low density, resulting in their removal by
phagcytosis in the spleen, rather than by complement-mediated lysis. Example is that resulting when
a person receives a transfusion with blood from a donor with different blood group.

TYPE 111 HYPERSENSITIVITY

This involves the formation of immune complexes. These complexes are removed effectively by the
fixed monocytes and macrophages of the monocytes-macrophage system. In the presence of excess
amounts of some soluble antigens, the antigen-antibody complexes may not be efficiently removed.
Their accumulation can lead to a hypersensitivity reaction from complement that triggers a variety of
inflammatory processes. This inflammation causes damage, especially of blood vessels (vasculitis)
kidney glomerular basement membranes (glomerulonephritis), joints.

Diseases resulting from type 111 reactions can be placed into three groups:

1) A persistent viral, bacterial, or protozoan infection, together with a weak antibody response,
leads to chronic immune complex formation and eventual deposition of the complex in host
tissues.
2) The continued production of autoantibody of self-antigen during an autoimmune disease can
lead to prolonged immune complex formation. This overloads the monocyte-macrophage
system, and tissue deposition of the complexes occurs (eg., in the disease systemic lupus
erythematosus).
3) Immune complexes can form at body surface (such as the lungs), following repeated
inhalation of allergens from mold, plants, or animals. For example, in Farmer’s lungs disease,
an individual has circulating antibodies to fungi after being exposed repeatedly to moldy hay.
These antibodies are primarily IgG. When the allergens (fungal spores) enter the alveoli of
lungs, local immune complexes form, leading to inflammation.

TYPE IV HYPERSENSITIVITY

This involves delayed T-cell-mediated immune reactions. A major factor in the type iv reaction is
the time required for a special subset of TH1 cells (often called delayed –type hypersensitivity [TDTH]
cells) to migrate to and accumulate near the antigens. This usually takes a day or more.

Mechanism of action

Type iv reactions occurs when antigens, especially those binding to tissue cells, and phagocytosed
by macrophages and then presented to receptors on the T H1 surface in the context of class 1 MHC.
Contact between the antigen and T H1 cell causes the cell to proliferate and release cytokines.
Cytokines attract lymphocytes, macrophages, and basophils to the affected tissue. Extensive tissue

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damage may result. Examples of type IV hypersensitivities include tuberculin hypersensitivity (the
TB skin test), allergic contact dermatitis, some autoimmune disease, transplantation rejection, and
killing of cancer cells.

Tuberculin hypersensitivity

In tuberculin hypersensitivity a partially purified protein called tuberculin, which is obtained from
the bacillus that causes tuberculosis (Mycobacterium tuberculosis), is injected into the skin of the
forearm. The response in a tuberculin-positive individual begins in about 8 hours, and a reddened
area surrounding the injection sites becomes indurated (firm and hard) within 12 to 24 hours. The
TH1 cells that migrated into the injection site are responsible for the induration. The reaction reaches
its peak in 48 hours and then subsides. The size of the induration is directly related to the amount of
antigen that was introduced and to the degree of hypersensitivity of the tested individual. Other
microbial products used in type IV skin testing are histoplasmin for histoplasmosis, lepromin for
leprosy and brucellergen for brucellosis.

Allergic contact dermatitis

This is caused by haptens that combine with proteins in the skin to form the allergen that elicits the
immune response. The haptens are the antigenic determinants, and the skin proteins are the carrier
molecules for the haptens. Examples of these haptens include cosmetics, plant materials (catechol
molecules from poison ivy and poison oak), tropical chemotherapeutic agents, metals and jewelry
(especially jewelry containing nickel).

Several important chronic diseases involve cell and tissue destruction by type IV hypersensitivity
reactions. These diseases are caused by viruses, mycobacteria, protozoa and fungi that produce
chronic infections in which the macrophages and T cell are continually stimulated. Examples are
leprosy, tuberculosis, leishmaniasis, candidiasis and herpes simplex lesions.

IMMUNOPATHOLOGY AND IMMUNODEFICIENCY DISEASES

Immunopathology

Immunopathology is a branch of medicine that deals with immune responses associated with disease.
It includes the study of the pathology of an organism, organ system, or disease with respect to the
immune system, immunity, and immune responses. In biology, it refers to damage caused to an
organism by its own immune response, as a result of an infection. It could be due to mismatch
between pathogen and host species, and often occurs when an animal pathogen infects a human (e.g.
avian flu leads to a cytokine storm which contributes to the increased mortality rate).

Immunopathology could refer to how the foreign antigens cause the immune system to have a
response or problems that can arise from an organism's own immune response on itself. There are
certain problems or faults in the immune system that can lead to more serious illness or disease.
These diseases can come from one of the following problems.

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  Hypersensitivity reactions, where there would be a stronger immune response than normal.
There are four different types (type one, two, three and four), all with varying types and
degrees of an immune response. The problems that arise from each type vary from small
allergic reactions to more serious illnesses such as tuberculosis or arthritis.
 Autoimmunity, where the immune system would attack itself rather than the antigen.
Inflammation is a prime example of autoimmunity, as the immune cells used are self-
reactive. A few examples of autoimmune diseases are Type 1 diabetes, Addison's disease and
Celiac disease.
 Immunodeficiency, where the immune system lacks the ability to fight off a certain disease.
The immune system's ability to combat it is either hindered or completely absent. The two
types are primary immunodeficiency, where the immune system is either missing a key
component or does not function properly, and secondary immunodeficiency, where disease is
obtained from an outside source, like radiation or heat, and therefore cannot function
properly. Diseases that can cause immunodeficiency include HIV, AIDS and leukemia.
In all vertebrates, there are two different kinds of immune responses: Innate and Adaptive immunity.
Innate immunity is used to fight off non-changing antigens and is therefore considered nonspecific.
It is usually a more immediate response than the adaptive immune system, usually responding within
minutes to hours. It is composed of physical blockades such as the skin, but also contains
nonspecific immune cells such as dendritic cells, macrophages, and basophils.
Adaptive immunity. This form of immunity requires recognition of the foreign antigen before a
response is produced. Once the antigen is recognized, a specific response is produced in order to
destroy the specific antigen. Because of this idea, adaptive immunity is considered to be specific
immunity. A key part of adaptive immunity that separates it from innate is the use of memory to
combat the antigen in the future. When the antigen is originally introduced, the organism does not
have any receptors for the antigen so it must generate them from the first time the antigen is present.
The immune system then builds a memory of that antigen, which enables it to recognize the antigen
quicker in the future and be able to combat it quicker and more efficiently. The more the system is
exposed to the antigen, the quicker it will build up its responsiveness.
Immunodeficiency
Immunodeficiency disorders result in a full or partial impairment of the immune system.
Immunodeficiency is a defect in one or more components of the immune system that can result in
it’s failing to recognize and respond properly to antigen. Immunodeficiency can make a person more
prone to infection than those people capable of a complete and active immune response.
Immunodeficiency disorders prevent your body from fighting infections and diseases.
There are two types of immunodeficiency disorder:
1. Primary immunodeficiency (PID) – inherited immune disorders resulting from genetic
mutations, usually present at birth and diagnosed in childhood.
2. Secondary immunodeficiency (SID) – acquired immunodeficiency as a result of disease or
environmental factors, such as HIV, malnutrition, or medical treatment (e.g. chemotherapy).
Primary immunodeficiency (PID)

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PID disorders are inherited conditions sometimes caused by single-gene mutations, or more often by
an unknown genetic susceptibility combined with environmental factors. Although some PIDs are
diagnosed during infancy or childhood, many are diagnosed later in life. PIDs are categorised based
on the part of the immune system that is disrupted.
Examples of primary immunodeficiency disorders
B cell immunodeficiencies (adaptive) – B cells are one of two key cell types of the adaptive
immune system. Their main role is to produce antibodies, which are proteins that attach to microbes,
making it easier for other immune cells to detect and kill them. Mutations in the genes that control B
cells can result in the loss of antibody production. These patients are at risk of severe recurrent
bacterial infections.
T cell immunodeficiencies (adaptive) – T cells are the second of two key cell types of the adaptive
immune system. One role of the T cell is to activate the B cell and pass on details of the microbe’s
identity, so that the B cell can produce the correct antibodies. Some T cells are also directly involved
in microbe killing. T cells also provide signals that activate other cells of the immune system.
Mutations in the genes that control T cells can result in fewer T cells or ones that do not function
properly. This can lead to their killing ability being disrupted, and can often cause problems with B
cell function too. Therefore, T cell immunodeficiencies can often lead to combined
immunodeficiencies (CIDs), where both T and B cell function is defective. Some forms of CIDs are
more severe than others.
Severe combined immune deficiencies (SCID) (adaptive) – SCID disorders are very rare but
extremely serious. In SCID patients there is often a complete lack of T cells and variable numbers of
B cells, resulting in little-to-no immune function, so even a minor infection can be deadly. SCID
patients are usually diagnosed in the first year of life with symptoms such as recurrent infections and
failure to thrive.
Phagocyte disorders (innate) - phagocytes include many white blood cells of the innate immune
system, and these cells patrol the body eating any pathogens they come across. Mutations typically
affect the ability of certain phagocytes to eat and destroy pathogens effectively. These patients have
largely functional immune systems but certain bacterial and fungal infections can cause very serious
harm or death.
Complement defects (innate) – complement defects are some of the rarest of all the PIDs, and
account for less than 1% of diagnosed cases. Complement is the name given to specific proteins in
the blood that help immune cells clear infection. Some deficiencies in the complement system can
result in the development of autoimmune conditions such as systemic lupus erythematosus and
rheumatoid arthritis (please see our autoimmune briefing for more information). Patients who lack
certain complement proteins are highly susceptible to meningitis.
Treatments and outcomes
The prognosis of patients with PIDs is extremely variable and depends on the condition. Most SCID
patients will die before the age of 1 without prompt treatment, although 95% of those that receive a
bone marrow transplant (BMT) before 3 months of age will survive. BMT is the preferred long-term
treatment option for CIDs/SCIDs and some phagocyte disorders, although some SCIDs are now
routinely treated with gene therapy. Supportive therapy for all PID conditions involves routine
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preventative use of antibiotics and antifungals. B cell disorders can also be managed with
immunoglobulin (antibody) replacement therapy, where immunoglobulin G is purified from the
blood plasma of healthy donors and infused into the patient.
Key vaccines are recommended for patients with innate deficiencies, but live vaccines (such as
MMR) must be avoided for CID/SCID patients. It is therefore crucial that there is enough vaccine
coverage in their local communities to generate “herd immunity”, where vaccine rates are at 95% or
above ensuring resistance to disease transmission exists across the whole community, even for the
few patients who cannot be vaccinated.
Secondary immunodeficiency (SID)
SIDs are more common than PIDs and are the result of a primary illness, such as HIV, or other
external factor such as malnutrition or some drug regimens. Most SIDs can be resolved by treating
the primary condition.
Examples of secondary immunodeficiency disorders
Malnutrition – Protein-calorie malnutrition is the biggest global cause of SIDs. T cell numbers and
function decrease in proportion to levels of protein deficiency, which leaves the patient particularly
susceptible to diarrhoea and respiratory tract infections. This form of immunodeficiency will usually
resolve if the malnutrition is treated.
Drug regimens – There are several types of medication that can result in secondary
immunodeficiencies, but these drugs also perform critical roles in certain areas of healthcare.
Immunosuppression is a common side-effect of most chemotherapies used in cancer treatment. The
immune system usually recovers once the chemotherapy treatment has finished. Another common
use for immunosuppressive drugs is the prevention of transplant rejection, where medication is
required to suppress the transplant recipient’s immune system and prevent it from targeting the
transplanted tissue. These drugs can have significant side-effects and often suppress more areas of
the immune system than are required, leading to susceptibility to opportunistic infections. Use of a
new generation of medicines called biologics is becoming more widespread in treating transplant
rejection. These drugs are derived from biological sources like cells, rather than chemical structures.
Monoclonal antibodies are one such class of biologics and these drugs are made by farming
antibodies from B cells that will act against a specific part of the disease process. These agents are
more specific in their action than traditional drugs and have fewer side effects on non-target immune
cells.
Chronic infections – There are a number of chronic infections which can lead to SID disorders, the
most common of which is acquired immune deficiency syndrome (AIDS), resulting from HIV
infection. The virus attacks CD4+ T cells, a type of white blood cell that plays a critical role in
preventing infection, and gradually depletes their numbers. Once the T cell count is less than 200
cells per ml of blood, symptoms of AIDS begin to manifest and the patient is at high risk of recurrent
infections that will eventually lead to death. Anti-viral therapies, such as the HAART regimen
(Highly Active Antiretroviral Therapy), allow the T cell population a chance to recover and resume
normal function. These drugs have had a huge impact on increasing the life expectancy for
HIV/AIDS patients and improving their quality of life. Prior to the introduction of HAART, patients
with HIV diagnosed at age 20 had an average of 10 years before developing AIDS. Nowadays on
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average, patients diagnosed at age 20 can expect to live well into their 60s. However, these drugs
must be taken every day for life as they are not curative, and are only available to patients and
healthcare systems that can afford them.
Treatments and outcomes
For many SID disorders treatment of the primary condition will lead to resolution of the
immunodeficiency. This is of limited use in chronic conditions such as organ transplantation or HIV
where the emphasis is on managing the condition to minimise immunodeficiency. With advances in
medical science the prognosis for these patients is now much improved. There is evidence to suggest
that more patients with HIV now die from toxicity associated with the anti-retroviral therapy.
How can immunodeficiency disorders be prevented?
Primary immunodeficiency disorders can be controlled and treated, but they can’t be prevented.
Secondary disorders can be prevented in a number of ways. For example, it’s possible to prevent
yourself from getting AIDS by not having unprotected sex with someone who carries HIV.
Sleep is very important for a healthy immune system. According to the Mayo Clinic, adults need
about eight hours of sleep per night. It’s also important that you stay away from people who are sick
if your immune system isn’t working properly.
If you have a contagious immunodeficiency disorder like AIDS, you can keep others healthy by
practicing safe sex and not sharing bodily fluids with people who are not infected.
THE FUNCTION OF IMMUNE RESPONSE IN CANCER
The immune system has several functions such as defense against foreign organisms, homeostasis,
and the destruction of damaged cells and surveillance.
There are two types of immune responses: innate or non-specific immunity and adaptive or specific
immunity. Cytokines are naturally occurring proteins produced by cells of the immune system (such
as lymphocytes and macrophages) that coordinate and initiate effector defense functions.
Cytokines
Cytokines include the interleukins, interferons, colony stimulating factors and tumour necrosis
factor. Cytokines can be defined by the following properties:
 they mediate and regulate the immune defense functions by acting as messengers between
the various immune cells
 they usually function over short distances and their half-life is brief
 they are produced by a variety of cells types, and can act on diverse cell targets within the
immune system and on organs such as the liver
 their actions are both overlapping and contradictory in that they can both stimulate and
inhibit growth. They can act directly or indirectly on a cell causing a cytokine cascade.
Immune system response
An important function in the defense against cancer is surveillance and identification of foreign or
'non-self' substances. Foreign antigens may be exogenous microbes or endogenous altered or virally
transformed cells.
The immune system, which recognises foreign micro-organisms as 'non-self' and mounts a response
to destroy these disease-causing agents, plays a similar role in protecting the body from malignancy.
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The damaged DNA in cancer cells frequently directs the mutated cell to produce abnormal proteins
known as tumour antigens. These abnormal tumour proteins mark cancer cells as 'non-self'. The
immune system likely encounters and eliminates cancer cells on a daily basis. However, it is
apparent that cancer cells possess mechanisms that allow them to escape the immune responses that
ordinarily prevent the development of malignant tumours.
When the immune system loses its function of surveillance, tumour cells have the ability to form a
tumour. Tumour cells that evade detection can be explained by the following proposed mechanisms:
 down regulation of major histocompatibility class (MHC) I expression - allowing antigen to
go unrecognised
 lack of co-stimulatory signals needed for antigen presentation - loss or alteration of the MHC
molecule
 tumour secretion of immunosuppressive products inhibiting the body's immune response
 tumour being immunogenic by expression of one or more antigens
 antigen modulation - where the antigen either enters the cell or leaves it completely, limiting
the ability of the immune system to recognise the tumour cell as 'non-self'
 tumours do not give off inflammatory warning signals.
The Role of the Innate Immune System in Tumour Immunity
Innate immune responses may also play an important role in resistance against the development and
progressive growth of tumours. Macrophages and mast cells can activate vascular and fibroblast
responses in order to orchestrate the elimination of the malignant cell and to initiate local tissue
repair. DCs (Dendritic cell), on the other hand, take up tumour antigens and migrate to lymphoid
organs, where they present processed peptides to T cells for the induction of specific antibody and
CMI (Cell-mediated immunity) responses. NK cells (Natural killer cell)also participate in cellular
cross-talk between innate and adaptive immune cells through their ability to interact bidirectionally
with DCs. That is, certain NK cell subsets eliminate immature DCs, whereas others promote DC
maturation, which can also reciprocally regulate activation of NK cells.
Induction of efficient primary adaptive immune responses requires direct interactions with mature
antigen-presenting cells and a strong pro-inflammatory milieu.

The Role of the Adaptive Immune System in Tumour Immunity: Recognition of TAAs on
Tumour Cells by T Cells and Other Cells
TAAs (Tumour Associated Antigen) comprise short amino acid peptide segments, which might be
derived from any intracellular protein. T cells recognise these TAAs through their TCRs
(Temperature Coefficient of Resistance) in the context of MHC-I (major histocompatibility
complex) or MHC-II on the surface of tumour cells or APCs, respectively. Two distinct pathways
have been identified for the processing of TAAs, the exogenous and endogenous pathways.
In the endogenous pathway, tumour cells continually degrade unfolded intracellular proteins within
the proteosome into short peptide fragments. Following transport through several pathways in the
endoplasmic reticulum, these fragments are then loaded onto the MHC-I. The final MHC-I/peptide
complexes are then transported to the tumour cell surface through the Golgi apparatus for
presentation to CD8+ T cells.

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In the exogenous pathway, APCs (Antigen-Presenting Cell), through a variety of endocytic
pathways, take up intracellular proteins that have been released from damaged or injured tumour
cells. These intracellular proteins can then be degraded in lysosomal pathways to peptides that, when
complexed with MHC-II on the cell surfaces, are presented to CD4+ T cells.
Alternatively, APCs may also process the tumour proteins through the endogenous pathway. In this
way, APCs are able to prime both MHC-I and MHC-II responses and give rise to specific antibody
and cell-mediated immune responses important in tumour immunity. The MHC-II/peptide
complexes expressed on the surface of APCs and presented to naïve T cell CD4+ helper cells are
followed by further maturation into T helper 1 (Th1), Th2, Th17, and Treg populations that function
to promote delayed hypersensitivity, antibody production (through B cell interaction), inflammation,
or immunosuppression, respectively.
Recent studies have shown the active participation of Th17 in tumour immune responses
The CD8+ cytotoxic T cells that recognise the MHC-I/peptide complex expressed on tumour cells,
on the other hand, result in tumour cell lysis and apoptotic cell death. The recognition of peptide-
MHC complexes by T cells through their TCRs allows the immune system to discriminate those
tumour antigens that are distinct from self antigens, as the latter have either induced deletion of self
recognised T cells or developed tolerance. This development of tolerance is now considered a prime
mechanism underlying immune evasion by cancer cells and therefore a prime target for immune
intervention.
AUTOIMMUNITY
Autoimmunity is the system of immune responses of an organism against its own healthy cells,
tissues and other body normal constituents or Autoimmunity is a breakdown of tolerance in which
the body’s immune system begins to recognize self-antigens as foreign. Normally the mechanisms of
self tolerance protect an individual from potentially self-reactive lymphocytes. As a result of the
breakdown of tolerance, an individual develops hypersensitivity to himself after an abnormal attack
against self-antigens by autoantibodies and in some cases T cells, the mechanisms of breakdown are
many and vary among autoimmune diseases although in most of such diseases the mechanism is
unknown. Auto-pathology is the pathology that describes the autoimmune system.
Autoimmune disease results from the activation of self-reactive T and B cells that, following
stimulation by genetic or environmental triggers, cause actual tissue damage. Autoimmune diseases
are very often treated with steroids.
Autoimmunity means presence of antibodies or T cells that react with self-protein and is present in
all individuals, even in normal health state. It causes autoimmune diseases if self-reactivity can lead
to tissue damage.

Causes of autoimmunity

The adaptive immune responses are responsible for autoimmunity, and its actions are similar to the
way it acts against foreign antigens. However, in the case of self antigens, it is almost impossible for
the immune response mechanism to eliminate the antigen completely, thereby prolonging the
response, which could be detrimental to the affected tissues in most cases. There is no specific
explanation to why the adaptive immune response attacks its own self; rather susceptibility to

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autoimmune diseases seems to be caused by a combination of factors; genetics, sex and the
environment.

Genetic factors
Certain individuals that have a family or personal history of autoimmune diseases are likely to be
susceptible to autoimmunity. This susceptibility is discovered to be associated with a combination or
group of genes. Based on twin and family studies carried out for several autoimmune diseases e.g.
insulin-dependent diabetes mellitus, genes related to immunoglobulins, T-cell receptors, and the
major histocompatibility complexes (MHC) have been suspected to be mainly responsible for
autoimmunity. However, the most consistent association for susceptibility to autoimmunity has been
linked to the MHC genotype. This correlation of MHC genotype with autoimmune diseases is not
surprising, because autoimmune responses is linked to the adaptive immune response mechanism
which involves T cells, and the ability of T cells to respond to a particular antigen depends on MHC
genotype. Various studies also carried out on affected patients suggested that siblings affected with
the same autoimmune disease are far more likely than expected to share the same MHC type.
However the MHC genotype alone does not determine susceptibility, in fact monozygotic twins are
far more susceptible to autoimmunity than MHC- identical siblings, which is a confirmation to the
fact that genetic factors besides MHC affect susceptibility. Genes linked to immunoglobulins and T-
cell receptors, involved in antigen recognition, are inherently variable and susceptible to
recombination. This attribute enables the immune system to respond to a wide variety of harmful
pathogens, and as a result may give rise to lymphocytes capable of self- immunity.

Sex

It has been observed that the frequency of autoimmune diseases is higher in females than males,
although studies also show that the autoimmune diseases present in males tend to be severe.
However, the reasons for this anomaly are unclear, but there are few explanations to this wide range
in frequency between the two sexes. Compared to males, females are shown to exhibit larger
inflammatory responses, when their immune system is triggered, hence increasing the risk of
autoimmunity. Hormonal levels also tend to play a role in autoimmunity, based on indications that
autoimmune diseases fluctuate with hormonal changes during menstrual cycle or pregnancy. Some
studies carried on autoimmune thyroiditis, suggests that the high frequency of the females to
autoimmunity is as a result of the imbalanced X chromosome inactivation.

Environmental Factors
Various studies have shown that the expression of a disease could be influenced by environmental
factors. Since the presence of an autoantibody requires an autoantigen to cause autoimmunity,
certain factors have been observed to inhibit or affect the binding of the autoantibody to the
autoantigen, thereby modulating the expression of these diseases among different individuals. For
example, in the Goodpasture’s disease, it was observed that cigarette smokers exclusively exhibited
pulmonary haemorrhage while non cigarette smokers showed no sign of pulmonary haemorrhage.
This is because cigarette smoke stimulates an inflammatory response in the lungs, which damages
alveolar capillaries, as a result exposing autoantigen to autoantibody. Some studies also show the
existence of an inverse relationship between infectious diseases and autoimmune diseases. It was
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observed that autoimmunity seems to prevail in areas where there are no infectious diseases, while
autoimmune diseases are very rare in areas where infectious diseases are endemic. Various
hypotheses have tried to explain this correlation, but the details of the mechanism are not fully
known. Certain chemicals and drugs have also been implicated in the expression of autoimmunity
e.g. in the drug- induced lupus erythematosus, withdrawal of the drug removes the symptoms
automatically. Exposure to heavy metals such as mercury and lead, have been shown to induce
autoantibodies, hence causing autoimmunity.

Classification of autoimmune disease

Autoimmune diseases can be classified according to several criteria. One of them is the location of
the autoimmune attack. Based on this criterion, autoimmune diseases are distinguished into systemic
or organ-specific

Organ-Specific Autoimmune Diseases

Some autoimmune diseases are considered organ specific, meaning that the immune system targets
specific organs or tissues. Examples of organ-specific autoimmune diseases include celiac disease,
Graves disease, Hashimoto thyroiditis, type I diabetes mellitus, and Addison disease.
Systemic Autoimmune Diseases
Whereas organ-specific autoimmune diseases target specific organs or tissues, systemic
autoimmune diseases are more generalized, targeting multiple organs or tissues throughout the
body. Examples of systemic autoimmune diseases include multiple sclerosis, myasthenia gravis,
psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.
The table below summarizes the causes, signs, and symptoms of select autoimmune diseases.
Select Autoimmune Diseases

Disease Cause Signs and Symptoms

Addison disease Destruction of adrenal gland cells by Weakness, nausea, hypotension, fatigue;
cytotoxic T cells adrenal crisis with severe pain in
abdomen, lower back, and legs;
circulatory system collapse, kidney
failure

Celiac disease Antibodies to gluten become Severe diarrhea, abdominal pain, anemia,
autoantibodies that target cells of the malnutrition
small intestine

Diabetes mellitus Cytotoxic T-cell destruction of the Hyperglycemia, extreme increase in

(type I) insulin-producing β cells of the pancreas thirst and urination, weight loss, extreme
fatigue

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Select Autoimmune Diseases

Disease Cause Signs and Symptoms

Graves disease Autoantibodies target thyroid- Hyperthyroidism with rapid and irregular
stimulating hormone receptors, resulting heartbeat, heat intolerance, weight loss,
in overstimulation of the thyroid goiter, exophthalmia

Hashimoto Thyroid gland is attacked by cytotoxic Thyroiditis with goiter, cold intolerance,
thyroiditis T cells, lymphocytes, macrophages, and muscle weakness, painful and stiff joints,
autoantibodies depression, memory loss

Multiple sclerosis Cytotoxic T-cell destruction of the Visual disturbances, muscle weakness,
(MS) myelin sheath surrounding nerve axons impaired coordination and balance,
in the central nervous system numbness, prickling or “pins and
needles” sensations, impaired cognitive
function and memory

Myasthenia Autoantibodies directed against Extreme muscle weakness eventually

gravis acetylcholine receptors within the leading to fatal respiratory arrest
neuromuscular junction

Psoriasis Cytokine activation of keratinocytes Itchy or sore patches of thick, red skin
causes rapid and excessive epidermal with silvery scales; commonly affects
cell turnover elbows, knees, scalp, back, face, palms,
feet

Rheumatoid Autoantibodies, immune complexes, Joint inflammation, pain and

Arthritis complement activation, phagocytes, and disfigurement, chronic systemic
T cells damage membranes and bone in inflammation
joints

Systemic lupus Autoantibodies directed against nuclear Fatigue, fever, joint pain and swelling,
erythematosus and cytoplasmic molecules form hair loss, anemia, clotting, a sunlight-
(SLE) immune complexes that deposit in sensitive “butterfly” rash, skin lesions,
tissues. Phagocytic cells and photosensitivity, decreased kidney
complement activation cause tissue function, memory loss, confusion,
damage and inflammation depression

Superantigen
Superantigens (SAgs) are bacterial proteins. Superantigens are a class of antigens that result in
excessive activation of the immune system. These superantigens nonspecifically stimulate T-cells to
proliferate by interacting with both classs 11 major histocompatibility complex products on antigen-
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presenting cells and the T-cell receptor. Good examples of superantigens are staphylococcal
enetrotoxins that cause food poisoning and the toxin that cause toxic shock syndrome. Superantigens
cause symptoms by stimulating the release of massive quantities of cytokines from T cells and
should be considered possible chronic associates in such diseases as rheumatic fever, arthritis,
kawasski syndrome, atopic dermatitis and one type of psoriasis, diabetes mellitus, eczema, nasal
polyps, scarlet fever, toxic shock syndrome.
Direct effects
The T-cells are stimulated and produce excess amounts of cytokine resulting in cytokine-mediated
suppression of T-cells and deletion of the activated cells as the body returns to homeostasis. The
toxic effects of the microbe and SAg also damage tissue and organ systems, a condition known as
toxic shock syndrome.
If the initial inflammation is survived, the host cells become anergic or are deleted, resulting in a
severely compromised immune system.
Superantigenicity independent (indirect) effects
Apart from their mitogenic activity, SAgs are able to cause symptoms that are characteristic of
infection.
One such effect is vomiting. This effect is felt in cases of food poisoning, when SAg-producing
bacteria release the toxin, which is highly resistant to heat. There is a distinct region of the molecule
that is active in inducing gastrointestinal toxicity. This activity is also highly potent, and quantities
as small as 20-35 μg of SAg are able to induce vomiting.
SAgs are able to stimulate recruitment of neutrophils to the site of infection in a way that is
independent of T-cell stimulation. This effect is due to the ability of SAgs to activate monocytic
cells, stimulating the release of the cytokine TNF-α, leading to increased expression of adhesion
molecules that recruit leukocytes to infected regions. This causes inflammation in the lungs,
intestinal tissue, and any place that the bacteria have colonized. While small amounts of
inflammation are natural and helpful, excessive inflammation can lead to tissue destruction.
One of the more dangerous indirect effects of SAg infection concerns the ability of SAgs to augment
the effects of endotoxins in the body. This is accomplished by reducing the threshold for
endotoxicity. Schlievert demonstrated that, when administered conjunctively, the effects of SAg and
endotoxin are magnified as much as 50,000 times. This could be due to the reduced immune system
efficiency induced by SAg infection. Aside from the synergistic relationship between endotoxin and
SAg, the “double hit” effect of the activity of the endotoxin and the SAg result in effects more
deleterious that those seen in a typical bacterial infection. This also implicates SAgs in the
progression of sepsis in patients with bacterial infections.

Treatment for autoimmune disorders

Treatments for autoimmune disease have traditionally been immunosuppressive, anti-inflammatory,
or palliative. Managing inflammation is critical in autoimmune diseases. Non-immunological
therapies, such as hormone replacement in Hashimoto's thyroiditis or Type 1 diabetes mellitus treat
outcomes of the autoaggressive response, thus these are palliative treatments. Dietary manipulation
limits the severity of celiac disease. Steroidal or NSAID treatment limits inflammatory symptoms of
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many diseases. IVIG is used for CIDP and GBS. Specific immunomodulatory therapies, such as the
TNFα antagonists (e.g. etanercept), the B cell depleting agent rituximab, the anti-IL-6 receptor
tocilizumab and the costimulation blocker abatacept have been shown to be useful in treating RA.
Some of these immunotherapies may be associated with increased risk of adverse effects, such as
susceptibility to infection.
Helminthic therapy is an experimental approach that involves inoculation of the patient with specific
parasitic intestinal nematodes (helminths). There are currently two closely related treatments
available, inoculation with either Necator americanus, commonly known as hookworms, or Trichuris
Suis Ova, commonly known as Pig Whipworm Eggs.
T-cell vaccination is also being explored as a possible future therapy for autoimmune disorders.
 anti-inflammatory drugs – to reduce inflammation and pain
 Corticosteroids – to reduce inflammation. They are sometimes used to treat an acute flare of
symptoms
 pain-killing medication – such as paracetamol and codeine
 immunosuppressant drugs – to inhibit the activity of the immune system
 physical therapy – to encourage mobility
 treatment for the deficiency – for example, insulin injections in the case of diabetes
 surgery – for example, to treat bowel blockage in the case of Crohn's disease
 High dose immunosuppression – the use of immune system suppressing drugs (in the doses
needed to treat cancer or to prevent the rejection of transplanted organs) have been tried
recently, with promising results. Particularly when intervention is early, the chance of a cure
with some of these conditions seems possible.
TISSUE AND TRANSPLANTAION IMMUNOLOGY
Transplantation: This is the introduction of biological materials-organs, tissue, cells into an
organism.
Tissue Transplant rejection is when the immune system can act detrimentally. However, the major
obstacle to the use of tissue transplantation as a routine medical treatment is the adaptive immune
response. Blood transfusion, which is the earliest and commonest form of tissue transplantation
involves only four major ABO blood types and two Rhesus blood types, hence matching between
individuals to avoid destruction by antibodies is relatively easy. When tissues containing nucleated
cells are transferred from one individual to another, the responses of T cells to the Major
Histocompatibility Complex molecules, triggers an elaborate response against the grafted organ,
causing destruction. For a successful tissue transplant to take place there must be a perfect match of
the MHC molecules of the donor with that of the recipient, which is only possible amongst related
individuals. In spite of that, genetic differences at other loci can still trigger tissue rejection.
Immune Responses to Tissue Grafts
The extent to which the immune system responds to a tissue graft will depend on the level of genetic
differences between the graft and the host. A number of terms have been used to classify a graft,
according to its origin and possible outcome in the host.
Autograft: Transplantation of tissues or organs from the same individual e.g. skin. Transplantation
is always 100% successful, since they do not elicit rejection.

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Syngeneic graft: Transplantation of tissues or organs between genetically identical animals or
individuals. Similar to Autograft, Syngeneic graft undergoes no rejection.

Xenograft: Transplantation of tissues or organs from one species to another. This elicits the
maximum immune response.
Allograft: Transplantation of tissues or organs between genetically unrelated individuals. This is the
most common form of transplantation, and the graft is initially accepted but it is then rejected after
some days. The degree of rejection is dependent on the level of disparity in the MHC molecules
between the donor and the recipient. MHC molecules present endogenous and exogenous peptides to
T lymphocytes, which decide whether the peptide-MHC complex is a potentially threatening
antigen, thereby triggering an immune response. In humans, the MHC is known as the human
leukocyte antigen (HLA), located on the short arm of chromosome 6, near the complement genes.
HLA matching has been shown to improve the success rate of tissue or organ transplant, but in itself
does not prevent the risk of rejection. This is due to the imprecise nature of HLA matching, as
unrelated individuals who possess identical HLA type with antibodies against MHC proteins rarely
have similar MHC genotype. However, this is not the case with HLA identical siblings because the
siblings inherit their MHC gene as a haplotype; that is one sibling in four is expected to be HLA
identical. In spite of this, graft rejection is still possible although less rapid. The minor H antigens
also known as minor histocompatibility antigens are responsible for the rejection of HLA identical
grafts between donor and recipient.
Two mechanisms are involved in the recognition of alloantigens in grafted organs:
 The direct recognition; whereby T cells bind directly to donor MHC-peptide complex,
causing graft rejection.
 Indirect Recognition; is similar to the process whereby T cells become activated in response
to a pathogen.
In contrast to direct recognition pathway, T cells bind to allogeneic peptides presented by the
recipient antigen presenting cells and not MHC molecules expressed on the donor graft itself.
Rejection of transplant is divided into stages:
1) Hyperacute rejection; this is the most aggressive form of graft rejection, as it occurs within
minutes or hours. This stage of rejection is mediated by antibodies that are thought to be
induced by prior blood transfusion, prior transplants, xenografts or even multiple
pregnancies. Damage to the transplant is as a result of these antibodies binding to the target
antigens in the graft, activating the complement and blood clotting cascades and blocking the
vessels of the graft, which leads to the immediate death of the transplant. Kidney are
observed to be more susceptible to hyperacute rejection, because preservation time is longer
when compared to the heart and liver, due to pretransplant cross match test often required in
kidney transplant.
2) Acute rejection; direct recognition is thought to be responsible for acute rejection. This is as
a result of the immune system recognizing new foreign antigens, and is mediated either by
antibodies or T lymphocytes. Acute rejection usually occurs within the first few weeks after
transplantation and may be triggered at a much later date mostly by infection.
3) Chronic rejection; this is the major form of graft rejection, and it takes place months to
years after transplant. This is because tissue typing methods and immunosuppressive drugs
have assisted in the survival of allografts within the first year of transplant. However, chronic
rejection is yet to benefit from these recent technological advancements. Chronic rejection is
mostly likely caused by antigraft immune response, as supported by the fact that previous
episodes of acute rejection determine the degree of chronic rejection. It is also associated
with the level of HLA mismatch between donor and recipient, and is characterized by

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 gradual decline in transplant functions. Antibodies are observed to play a major role in
chronic rejection, although studies have also implicated T lymphocytes.
The response of the immune system to transplants also varies with the type or source of grafts. Some
parts of the body are deemed to be immunologically privileged sites, since they rarely evoke any
immune response e.g. eyes, the brain and the testis. Similarly, the developing foetus, which
expresses both maternal MHC antigen and the foreign paternal MHC antigen, is protected from the
mother’s immune system. Transplants at this site relatively require no tissue matching and they are
useful sites for the study of experimental transplantations and immunological tolerance mechanisms.

Transplant Tolerance
Several mechanisms have been postulated to explain transplant tolerance; clonal deletion,
suppression and anergy.
Clonal deletion involves the removal of all T cells that can aggressively respond to self MHC
molecules. In suppression, T regulatory cells which are known to maintain the state of
immunological unresponsiveness in individuals have been observed to prevent allograft rejection
when infused into transplanted mice. Allograft tolerance can also be achieved by altering the balance
of local and circulating cytokines in favour of those that maintain tolerance, through gene therapy
and antibody treatment.
Anergy also known as unresponsiveness, results in transplant tolerance when T cells are not
completely activated, hence causing the generation of T regulatory cells. Despite the reduction in
drug treatment for maintenance therapy after transplant, due to the use of modern
immunosuppressive induction techniques, immunological or transplant tolerance is still a field that
requires intense research as most patients are yet to benefit from these techniques.

Immunosuppressive Therapy
Immunosuppression in organ transplant cases also can be to graft-verse-host disease. This occurs
when the transplanted tissue contains immunocompetent cells that recognize host antigens and attack
the host. The immunosupressed recipient cannot control the response of the grafted tissue. Graft-
verse-host disease is a common problem in allogenic bone marrow transplant. The transplanted bone
marrow contains many mature post-thymic T cells. These cells recognize the host MHC antigens and
attack the immunosupressed recipient’s normal tissue cells. One way to prevent graft-verse-host
disease is to deplete the bone marrow of mature T cells by using immunosuppressive techniques.
Examples include drugs that attack T cells (azathioprine and cyclophosphamide),
immunosuppressive drug (cyclosporine), anti-inflammatory drug (corticosteroids), irradiation of the
lymphoid tissue, and antibodies directed against T-cell antigents.
IMMUNOPROPHYLAXIS AND SEROTHERAPY
Immunoprophylaxis is a branch of immunology that deals with the prevention of infectious diseases,
through the administration of immunological preparations, such as vaccines, gamma globulins and
hyperimmunesera, so as to create immunity. Immunoprophylaxis has helped in the eradication of
many diseases such as smallpox, tetanus and poliomyelitis in some parts of the world, and its study
is considered to be important in the prevention and further eradication of infectious and parasitic
diseases.

Types of Immunization
Immunization is simply the process of rendering an individual immune against infectious diseases.
Immunization can be passive or active, depending on the source of immune response.
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 Passive Immunization
This involves the administration of sensitized lymphoid cells or serum from immune individuals to
non-immune individuals, to create immunity. In passive immunity, recipients do not produce
antibodies to the infectious disease; rather the immune response is acquired. Passive immunity can
also be natural e.g. the transfer of antibodies of a mother to the foetus, and recently the cure of HIV
through bone marrow transplant from immune donors. In most cases, especially in the artificial form
of passive immunity, the conferred immunity is short-lived, usually 4-6 weeks. Examples of artificial
passive immunizations are the injection of serum for the treatment of tetanus or diphtheria, and the
administration of gamma globulin to hypogammaglobulin children.

Active Immunization
This is the treatment that provides immunity to an individual, through the administration of a
specific antigen, hence stimulating the recipient’s immune system to produce antibodies against the
organism. Immunity from this treatment develops slowly, but it’s long lasting, sometimes over the
course of the entire life of the recipient. Active immunization can also be natural, through previous
exposure to live pathogen. Active immunization is also referred to as inoculation or vaccination,
since the artificial form of active immunization is through the administration of vaccines.

Vaccine
Vaccine is an immunological preparation that provides immunity to a specific disease. Vaccines are
made to resemble a pathogen or disease causing microorganism, hence stimulating the immune
system to initiate a response against it. As a result, the immune system remembers ‘it’ and provides
an attack towards ‘it’ or any similar pathogen the immune system encounters in future. In as much as
the immune system generates a response against the vaccine, the response does not result in
symptoms associated with the disease. Vaccines are mostly made from weakened or killed form of
microbe or its toxins, and they can be therapeutic or prophylactic. Vaccines help to prevent diseases
such as cholera, diphtheria, rabies, poliomyelitis, tetanus and measles.

There are different types of vaccines, based on the strategy to try to reduce risks while retaining
the ability to generate a beneficial immune response.

Dead/Killed
These are vaccines that are made from the destruction of previously virulent microbes. The
microorganisms are destroyed either through heat (60°C), radiation, chemicals (formalin or phenol)
or antibiotics. Killed vaccines most times do not provide long lasting immunity, they do not
stimulate cytotoxic T cell response, they are safe and can be given to pregnant women, and they are
stable to heat. Examples are influenza vaccine, polio vaccine, cholera vaccine and rabies vaccine.

Live/Attenuated
These are vaccines made from living microorganisms that have lost their virulent properties, but are
still able to generate an immune response when administered to a recipient. Many of the
microorganisms used are viruses, while some are bacteria and they are known to provoke a durable
immune response, hence making them more preferable for healthy adults to other forms of vaccines.
Live vaccines are not stable to heat and are not safe for pregnant women. Examples are vaccines
developed against the viral diseases; measles, rubella and yellow fever, and the bacterial disease;
typhoid fever.

Toxoid

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These vaccines are made from the detoxification of bacteria toxins, rather than the bacteria
themselves. The toxins from bacteria are treated with formalin to destroy toxicity and retain
antigenic properties. Vaccines made from toxins are known to be efficient, but not all Toxoid
vaccines are made from microorganisms. Examples are vaccines for tetanus and diphtheria.

Subunit
These are vaccines made from part or fragment of a microorganism. Examples are the vaccine
against Hepatitis B virus, which is composed only of cell surface proteins of the virus, the vaccine
against Human papillomavirus, composed mainly of the major capsid proteins of the virus.

Conjugate
These are vaccines created by linking the polysaccharide outer coat of bacteria with a protein or
toxin, so as to enable recognition of the bacteria by the immune response team. Since the outer
polysaccharide coat on its own generates little or no immune response. An example is
Haemophilusinfluenzae type B virus vaccine.

Experimental
These are vaccines created from innovations, such as DNA recombination technology. They are also
known as synthetic vaccines, and they are very easy to produce and store. Experimental or synthetic
vaccines are composed mainly of carbohydrates, antigens or synthetic proteins.

Valence
Sometimes vaccines are designed to provide immunity to more than one microorganism or more
than one strain of a microorganism, and such are termed polyvalent vaccines. While those that
provide immunity to just one microorganism is termed monovalent vaccine.
The immune response triggered by the administration of vaccines, can be affected by various
factors such as:
The use of steroid by the recipient.
Age of the recipient.
Inability of the recipient immune system to trigger production of antibodies to the specific antigen.

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