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Nikhil Ladwa
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Immunology
1. Host defence overview
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Define and contrast innate and adaptive/acquired immunity, humoural
and cellular immunity. Name the important components of each.
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Innate immunity: Non antigen specific. This is the rapid, non-specific arm
of the immune system, which does not increase in effectiveness on
repeated exposure to a repeated pathogen. Elements of innate/ natural
immunity to fight disease/ infection include: enzymes, complement,
interferons, mucus, acids, phagocytes, natural killer (NK) cells, fever
Acquired/ adaptive immunity: The response of antigen-specific
lymphocytes to an antigen. It takes several days to develop and results in
the proliferation of lymphocytes with the ability to deal with the specific
offending antigen, but not any other antigens and with the development of
memory cells specific for the antigen in question. Elements include: T
lymphocytes, B lymphocytes, Antibody.
Humoral immunity: The part of the adaptive immune response mediated
by antibodies (antibodies, complement, cytokines)
Cellular/ cell-mediated immunity: The part of the adaptive immune
response mediated by the production of cytotoxic and helper T cells
Define active and passive immunity, antigen and immunogen, primary
and secondary immune response.
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Active immunity is when the body acquires immunity after immunisation
with an antigen.
Passive immunity is a short-lived immunity acquired by transfer of
preformed antibodies, as from mother to foetus across placenta or in
vaccination.
ANTIGEN: Any molecular feature that an immune system regards as
foreign. Antigens stimulate an immune response and this response often
includes the production of an antibody specific for the antigen.
IMMUNOGEN: This is any substance that generates an immune
response.
PRIMARY IMMUNE RESPONSE: The part of the adaptive immune
response which occurs on initial exposure to an antigen.
SECONDARY IMMUNE RESPONSE: This occurs when an individual is
exposed to an antigen for a second time. The response is greater and
more rapid than the primary immune response and the immunoglobulins
produced have higher affinity for antigen.
Nikhil Ladwa
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Summarise and give examples of the roles taken in host defence
mechanisms by: physical or chemical boundaries, mechnical removal,
colonisation resistance, non-specific immune response.
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PHYSICAL AND CHEMICAL BOUNDARIES:
 Skin acts as a watertight barrier against infections
 It releases fatty acids and lysozymes in sweat to combat bacteria/
pathogens
 Pepsin produced by gut kills pathogens
 The low pH of the stomach is unstable environment for pathogens
 Antibacterial peptides are present (paneth cells in intestine)
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MECHANICAL REMOVAL:
 Epithelial tight junctions
 Longitudinal flow of air or fluid (e.g. fluid-flushing? Action of urine in
urethra)
 Movement of mucus by cilia
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COLONISATION RESISTANCE:
 Normal flora compete for nutrients/ attachment sites with pathogens.
The normal flora are usually resident first so have a survival advantage
 Production of antibacterial substances by normal flora helps in the fight
against pathogens
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Other non-specific immune responses include avoiding pathogens due to
taste, smell, surface environment etc.
Outline the principals of adaptive immune response.
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Macrophage antimicrobial defence mechanisms:
 Toxic oxygen i.e. O2-, H2O2
 Toxic nitrogen oxides i.e. NO
 Enzymes i.e. lysozyme
 Antimicrobial peptides i.e. defensins
 All the above to kill pathogens
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Chemokines are released.
These are- chemoattractive proteins, made by many cell types, cause cell
recruitment to inflamed tissues, selective actions on inflammatory subsets,
influence the pattern of immunity/ pathology.
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Adaptive immunity includes phagocytosis, opsonins (membrane around
pathogens to encourage engulfment by phagocytes), lymphocytes (T and
B), NK killer cells. (make intruders and infected cells die by apoptosis)
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NK cells can cause: direct binding to microbes, lysis of infected cells, and
cytokine secretion.
Antibodies released by lymphocytes
B cells possess the machinery for immunoglobulin synthesis- antibody
secretion.
List defence mechanisms operative against major pathogens.
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Innate defences against bacteria:
 Surface defences (mechanical and chemical)
 Antibody opsonisation
 Activation of complement (alternative pathway) causing lysis/
opsonisation
 Phagocytosis
 Trigger release of soluble inflammatory mediators and acute phase
proteins by host cells (especially phagocytes) causing fever,
opsonisation.
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Innate defences against viruses:
 Surface defences (mechanical and chemical)
 NK cells
 Interferons
 Antibody opsonisation (partially effective)
 Trigger release of soluble inflammatory mediators and acute pahse
proteins by host cells (especially phagocytes) causing fever,
opsonisation, etc.
2. Immune cells and organs
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Name the primary and secondary lymphoid organs and briefly
differentiate between their functions.
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THE PRIMARY LYMPHOID ORGANS: Are the major sites of
lyphopoiesis. Here lymphoid stem cells differentiate into mature functional
lymphocytes.
 THE THYMUS: Is bilobed in mammals and located in the thorax. Each
lobe is organised into lobules with cortex and medulla regions. The
cortex contains the immature thymocytes some of which are selected
to become mature thymocytes in the medulla.
 THE BONE MARROW: Bone marrow produces stem cells and Blymphocytes. Those stem cells destined to be T lymphocytes migrate
to the thymus throughout life. For B cells, differentiation is centripital
with the stem cells under the bone and the most mature phases of the
B cell pathway found nearer the centre of the marrow.
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THE SECONDARY LYMPHOID ORGANS: Provide an environment in
which lymphocytes can interact with antigen and with other lymphocytes.
They have special vascular adaptations to recruit lymphocytes from the
blood. Secondary lymphoid tissue includes the spleen, lymph nodes, and
mucosa associated lymphoid tissue.
 THE SPLEEN: Contains two main types of tissues, the red pulp and
the white pulp. The red pulp acts as a general filter and the white pulp
is the lymphoid tissues and constitutes the major initiator of responses
to blood borne antigens. Around the central arteriole are concentric
cuffs of lymphoid tissues = the peri arterial lymphatic sheath. The
region nearest the arteriole is a T cell zone. Periodically, there are B
cell follicles, either primary or secondary and around this is the
marginal zone which seems to be the primary site of entry of B and T
cells into the white pulp.
 HUMAN LYMPH NODES: Are 1- 15 mm across, are round or kidney
shaped, lymph arrives at the lymph node through several afferent
vessels and leaves through one efferent vessel at the hilus. During
passage of lymph through the node there is removal of particulate
antigens by the phagocytic cells and then this is transported to the
lymphoid regions of the node. The cortex is a B cell area and the
paracortex a T cell area.
 MUCOSAL ASSOCIATED LYMPHOID TISSUE: are aggregates of
lymphoid tissue which do not have a tough outer capsule. They are
found in the lamina propria, and sub-mucosal areas of the
gastrointestinal respiratory and genito-urinary tracts. Typical examples
of MALT are tonsils and appendix or Peyer’s patches ( these are
organised regions of lymphoid tissue found in the wall of the gut)
Draw simple diagrams to illustrate the structure of the thymus, lymph
node, spleen, Peyers patch and indicated the changes that occur after
stimulation by antigen.
The thymus
Dividing lymphocyte
Lymphoblast
Cortex
Dense aggregates
of cortical small
lymphocytes
Macrophage
Small lymphocytes
Medulla
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B cell area
The Spleen
Capsule
Trabecular
vein
Trabecular
artery
T cell area
Marginal
zone
Lymph node
Afferent vessels
Paracortex
Cortex
Efferent Vessel
Peyers Patch
Lumen
Gut Wall
T Cell
B Cell
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Outline the re-circulation of lymphocytes.
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Small B and T lymphocytes which have matured in the bone marrow or
thymus and which have not yet encountered antigen are called NAÏVE
lymphocytes. These cells circulate constantly from the blood into the
secondary lymphoid tissue (the spleen, lymph nodes, mucosal associated
lymphoid tissue) and leave the vasculature through a specialised section
of the post capillary venule known as the high endothelial venule (HEV)
(i.e. they move from the capillary networks into the lymphatic system).
They move from the lymph node to the lymphoid vessels and eventually
return to the blood via the thoracic duct. In the presence of an infection
these cells which recognise the infectious agent are held in the lymphoid
tissue where they proliferate and differentiate.
Explain the use of CD (cluster of differentiation) markers for
distinguishing different immune cell types.
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Clusters of differentiation, are cell surface molecules on white blood cells
which are denoted by CD no.s. Some of these cell surface molecules
characterise certain subsets of white blood cells i.e. they are ‘phenotypic
markers’. E.g. CD8 is expressed on cytotoxic T lymphocytes. However,
not all CD antigens are ‘lineage specific’ in this way.
Compare and contrast the phenotypic characteristics of T and B
lymphocytes and T lymphocyte subsets.
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T cells: Recognise antigen presented at the cell surface by MHC
molecules. Antigen receptor is either  or (?) TCR (T cell receptor
molecule). All T cells express CD3,  T cells express CD4 or CD8. They
are produced by the thymus.
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B cells: Recognise free antigen in the body fluids. Antigen receptor is
surface Ig (immunoglobulin) like molecule. They express CD19 and CD20
at surface. They are produced by bone marrow.
Give examples of professional antigen presenting cells (APC’s) and
state their locations.
Cell
Langerhans cells
(dendritic cells)
Follicular dendritic cells
B cells
Activated macrophages
Location
Widely spread e.g. skin
and mucosal tissue
Follicles
Lymphoid tissue
Lymphoid tissue
Presents to
T cells
B cells
T cells
T cells
Nikhil Ladwa
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3. Innate immunity
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Briefly describe the functions of the important phagocytic cells;
neutrophils, monocytes/ macrophages.
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Macrophages: Are less abundant, dispersed throughout the tissues; signal
infection by release of soluble mediators (they develop from monocytes)
such as cytokines. The macrophage expresses receptors for many
bacterial constituents. Bacteria binding to macrophage receptors initiate a
response release of cytokine. Macrophages engulf and digest bacteria to
which they bind.
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Phagocytes can be mobile or fixed in a particular location. Phagocytosis
involves chemotaxis, adherence, ingestion, digestion, killing.
They are also involved with antigen presentation to lyphocytes, where the
cells that they phagocytose’s suface antigens are presented on their
surface as part of their MHC (major histocompatability complex).
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Neutrophils: (polymorphonuclear leucocytes), Short lived cells, circulate in
blood then migrate into tissues. They are first cells to arrive at a site of
tissue damage/ infection.
Killing mechanisms of neutrophils: Oxygen independent:: enzymes,
lysozyme, hydrolytic enzymes, antimicrobial peptides (defensins). Oxygen
dependent: Respiratory burst: toxic metabolites such as superoxide anion,
hydrogen peroxide, hydroxyl radical, nitric oxide.
Define cytokines and describe their general properties.
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Cytokines are proteins made by certain cells that affect the behaviour of
other cells. Cytokines interact with surface receptors on the surface of
target cells.
They are the messengers of the immune system.
Generally act locally
Has biological effects at very low concentrations.
Types of cytokine:
 INTERLEUKINS (IL-x): Communication between leukocytes
 INTERFERONS (IFN): Antiviral effects
 CHEMOKINES: Chemotaxis, movement
 GROWTH FACTORS
 CYTOTOXIC: Tumor necrosis factor (TNF)
Cytokines
Inducing
Stimulus
Biological Effects
Cytokine producing cell
Target Cell
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A given cytokine that has different biological effects on different cells is
PLEIOTROPIC
Cytokines that mediate similar functions are redundant
Cytokine synergism occurs when the combined effect is more than
additive
Antagonism occurs when one cytokine inhibits the effects of another.
IL-12 for example directs adaptive immunity and activates NK cells. It
is secreted by macrophages.
Define complement, list its major functions, and draw a simple diagram
of the complement pathways.
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The complement system is a defensive system consisting of plasma
proteins that attack and destroy microbes. The system can be activated in
one of two pathways (classical or alternative) both of which are an ordered
sequence or cascade of reaction.
Both pathways lead to the same events: Inflammation, enhancement of
phagocytosis (opsonisation) and bursting of microbes by the MEMBRANE
ATTACK COMPLEX.
Lectin
Pathway
Alternative Pathway
Classical Pathway
MB2
CRP
C1
B
C4b
D
P
C2a
C3b
C4a, C3a, C5a
Pro-inflammatory
molecules
C3b is the principal opsonin
C5
Cb
C7
C8
C9
Membrane Attack Complex
cell lysis results
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The classical pathway- initiated by antigen-antibody complexes
The alternate pathway- continuous tick-over production, with full
activation upon fixation to pathogen surfaces
Nikhil Ladwa
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The Lectin pathway- antibody-independent activation of classical
pathway
Classical and alternative pathways converge at C3- meeting point for
the adaptive and innate immune systems
C3 leads to the final common pathway
Ends with the formation of the MEMBRANE ATTACK COMPLEX
Major functions of complement:
 Opsonisation of micro-organisms, to enhance phagocytosis
(complement fragments C3b binds to the surface of a microbe and
interacts with receptors on phagocytes to promote phagocytosis).
 Direct lysing of micro-organisms; several complement proteins
come together to form a membrane attack complex that inserts into
the plasma membrane of the microbe forming large holes which
allows fluids to enter causing plasmolysis and then lysis.
 Promotion of inflammation. Some complement proteins promote
this by dilating arteries and causing the release of histamines form
mast cells and basophils.
 Promotes chemotaxis of neutrophils and leukocytes
 Process Immune Complexes
 Augments induction of a specific antibody
Describe a typical inflammatory response to a localised infection
involving recruitment of neutrophils, and phagocytosis and killing of
bacteria.
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Cytokines released which encourages chemotaxis (produced by T-cells
and macrophages) of neutrophils, lymphocytes, monocytes.
Histamine secreted by mast cell
*(see diagram in notes)
Phagocytosis by activated macrophages
Opsonisation of bacteria by complement (complement released)
Briefly outline the events involved in a systemic acute phase response.
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Local inflammatory response may be accompanied by a systemic
response, ‘acute phase’ after 1- 2 days
Fever, increased production of white blood cells (leukocytosis) and the
production of ‘acute-phase’ proteins occur in the liver.
This is induced by cytokines
The acute phase proteins are:
 C-reactive protein (CRP): activates complement, level may increase
1000 fold
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Mannan binding protein (MBP): opsonin for monocytes, activates
complement.
Serum Amyloid A
Complement
Fibrinogen
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Outline the phenotype and functions of natural killer (NK) cells.
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Natural killer cells are lymphocytes that lack the membrane molecules that
identify T and B cells yet have the ability to kill a wide variety of infectious
molecules plus certain spontaneous arising tumour cells
They are large granulated lymphocytes
10% of the leukocytes in the blood are NK cells
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NK cells attack cells that display abnormal MHC antigens
NK cells achieve cell destruction in at least two ways: by releasing
perforins- chemicals which make the plasma membrane of a microbe so
leaky that cytolysis occurs by osmosis. Or by binding to the target cell and
inflicting damage by direct contact.
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Cytotoxicity of NK cells activated by the type 1 interferon.
NK cells secrete interferon-
Are recruited to sites of infection by chemokines
4. Antibodies
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Describe with the aid of a simple diagram the immunoglobulin molecule,
identify the antigen-binding site (Fab) and Fc portions of the molecule.
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An antibody is a protein that is produced in response to a foreign molecule
(antigen) and has the property of binding specifically to the antigen that
induced its formation.
Antibodies constitute the class of proteins known as immunoglobulins.
N
Light chain
Fab
S
S
N
Heavy chain
C
S
S
C
Fc
S
S
N
Constant
Fab
N
Variable
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Briefly describe the properties of the antigen-binding site.
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Variable; highly specific
Antibodies are said to be bivalent which means flexibility at the hinge (can
adopt a T or Y shape) which allows antibodies to simultaneously bind to
two different antigens.
Distinguish between antibody affinity and antibody avidity.
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ANTIBODY AFFINITY: Is a measure of the strength of binding between a
single binding site of an antibody and its antigen.
ANTIBODY AVIDITY: Is the overall strength of binding between antibody
and antigen, taking into account the number of binding sites on the
antibody and the number of sites on the antigen (antigenic determinats or
epitopes) that can be bound.
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List the immunoglobulin classes and sub-classes in man. Describe
their functions and relate these to their individual structure.
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The classes are G, A, M, E, D.
 IgG: - Most abundant Ig in blood and tissue spaces and is most
important in defence.
- IgG neutralises toxins and viruses
- It performs a number of functions that are dependent on the
nature of its Fc
- It binds to bacterium causing opsonisation. Macrophages or
neutrophils recognise the Fc (they possess Fc receptors)
- It triggers the complement system.
- IgG can cross the placenta and protect a newborn child for up
to 3 months.
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IgA: - Makes up 10- 15% of antibodies in blood
- Occurs in monomer and dimer form
- Important role in seromucous secretions where it binds
together with a J chain and secretory component which protect
it form degradative enzymes
- Secretory IgA can neutralise toxins
- By binding to infectious agents it can block their infectivity often
by preventing adherence of the agents to the epithelial cell.
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IgM: - Makes up 5-10% of all antibodies in blood
- Is first Ig to be made following contact with an antigen
- Its 5 Fab pairs allow it to bind strongly to the surface of
bacteria causing agglutination
- Like IgG it is adept at activating complement
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IgM antibodies also make up the anti-A and anti-B antibodies
of the ABO blood typing
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IgE:- Makes up 0.1% of antibodies in the blood
- Mast cells and basophils have a high affinity receptor for the Fc
of IgE
- When IgE that is bound in this way is cross linked by antigen,
degranulation of the cells occurs with release of inflamatory
mediators such as histamine.
- This process is important in protection against certain parasitic
infections but it can be a nuisance giving rise to allergic
reactions.
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IgD: - Makes up some 0.2% of blood antibodies
- Found in blood, lymph and on the surface of B cells as antigen
receptors
- They are involved in the activation of B cells
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One of the constant heavy domains on the antibodies is a complement
binding site which initiates the classical pathway of the complement
system.