Chapter 9 Immunology
an infectious agent
I. Primary function of the immune system is:
- To defend against and eliminate foreign material
- To minimize any damage as a result of the
presence of such material
Foreign means:
-Pathogenic microorganisms and cells
recognized as non-self
- Ex. Human bodys own virally infected or
transformed host cells (cancerous cells)
- Foreign material would also include
allogeneic (within species) or xenogeneic
(between species) transplant tissue,
- Proteins that arose from a different species
or of human origin but had undergone
inappropriate posttranslational modifications
II. Terms:
Pathogen an organism which has the ability to
cause disease
Virulence degree of pathogenicity of the
microorganism
Attenuation reduction in the virulence of a
pathogen
Avirulent complete lack of virulence
Antigen A component of the foreign material that
gives rise to the primary interaction with the bodys
immune system
Immunogen antigen that elicits an immune
response
Antigenic determinants or epitopes Represent the
antigen recognition sites for the adaptive immune
system
Monoclonal antibody Antibody nominally
recognizing only a single antigen and within which
only a single common epitope is recognized
Polyclonal antibody Antibody nominally
recognizing only a single antigen but within which a
number of different epitopes are recognized
III. Immune system
- Innate immune response non specific, no
time lag in responsiveness, and is not
intrinsically affected by prior contact with
- Adaptive immune response displays a time
lag in response, involves highly specific
recognition of antigen and affords
generation of immunological memory (ex.
Lymphocyte memory cell)
o Memory cells reside over a long term
in our lymphoid tissue and permit a
more rapid and pronounced
protective immunological response
on future exposure to the same
antigen
- Adaptive immune system: humoral
immunity and cell mediated immunity
- Humoral immunity effector cells are B-
lymphocytes and where antigen recognition
occurs through interactions with antibodies
- Cell-mediated immunity effector cells are
T-lymphocytes and where antigen
recognitions occur through interactions of
peptide antigen with T-cell receptors (TCR)
on the plasma membrane of the T-
lymphocytes
- In cell mediated immunity, the peptide
antigen must be presented to T-lymphocytes
by other cell types in association with a class
of plasma membrane molecules called major
histocompatibility complex (MHC) proteins
- Most cells arise from progenitor cells in the
bone marrow.
- Growth factors such as granulocyte colony
stimulating factors (G-CSF) and
macrophage colony stimulating factors (M-
CSF), released by monocytes and
macrophages cells as well as fibroblasts and
active endothelial cells control the
differentiation of these progenitor cells
- Growth factors promote the growth and
maturation of monocyte and macrophage
populations within the bone marrow before
their release
Principle cells of the innate immune system:
- Mononuclear phagocytic cells short lived
monocytes macrophages
- Granulocyte cells neutrophil, basophil and
eosinophil
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- Mast cell triggered by tissue damage or
infection to release numerous initiating
factors leading to an inflammatory response
o Ex. Histamine, leukotrienes B4, C4,
D4, proinflammatory cytokines
(TNF-) and IL-8
- Natural killer (NK) cell exploits non
specific recognition to elicit cytotoxic
actions against host cells infected with virus
and host cells that have acquired tumour cell
characteristics
- B-lymphocytes mature in the bone marrow
- T-lymphocytes undergo maturation in the
thymus
IV. Innate immune system
- Innate barriers at the epidermal and mucosal
surfaces involves non specific mechanisms
o Commensal microorganisms on the skin
and conjunctiva
o Barriers include: Flow of secretions from
tear ducts, the urogenital tract and the
skin
o Possess bactericidal and bacteristatic
activity due to low pH and presence of
hydrolytic enzymes (ex. Lysozyme)
o Mucus barrier covering mucosal surfaces,
with beating cilia
- Innate defense once epidermal or mucosal
barriers are compromised phagocytosis
and activation of alternate complement
pathway
o Phagocytosis mononuclear phagocytic
cells and granulocyte populations
(neutrophil- most important)
o Mononuclear phagocytic cells include
monocytes and macrophages
- Mononuclear phagocytic cells secrete a wide
range of molecules:
o Molecules which can break down or
permeabilize microbial membranes and
thereby mediate extracellular killing
enzymes (lysozyme and cathepsin G),
reactive oxygen species and cationic
proteins
o Cytokines provide innate protective
antiviral (INF-) and antitumour (TNF-)
activity against other host cells
o Chemokines group of cytokines that
attracts other leucocytes into an area of
ongoing inflammation. IL-8 attracts
neutrophil
o Cytokines with proinflammatory function
IL-1 and TNF- - which leads to
activation of endothelial and leucocyte
cells
o Bioactive lipids further promote the
inflammatory response leukotrienes,
thromboxanes and prostaglandins
- Receptors that interact with the environment:
o For chemotaxis toward microorganism
formylmethionyl peptide
o For complement proteins that serve as
leucocyte activators (C3a and C5a) and
opsonize microorganisms (C3b)
o For promoting adherence lectin
receptors interacting with carbohydrate
moiety or receptors for Fc domains or
integrin receptors for cell-cell adhesion
o For cytokines including those involved in
macrophage activation (IFN-) or limiting
macrophage mobility (macrophage
inhibiting factor MIF)
- Granulocyte cell populations
o Neutrophil is most abundant and most
important in terms of phagocytosis
o Neutrophil doesnt present antigen via
MHC class 2 proteins
o Eosinophils are poor phagocytic cells, role
in killing extracellular parasites
o Basophils are non-phagocytic cells
- Phagocytosis
o Macrophages and neutrophils
Steps:
o Chemotaxis of the phagocyte toward the
microorganism
o Adherence of the microorganism to the
surface of the phagocyte
o Membrane activation of the phagocyte
actin-myosin contractile network to extend
pseudopodia around the attached
microorganism
o Enclosure of phagocytosed material
initially within a phagosome where
membrane degradation begin. Followed by
fusion of the phagosome with lysosome to
form phagolysosome
- Alternate complement pathway
o Zymogens proenzymes requiring
hemolytic cleavage to be enzymatically
active
3 Main Functions:
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 o Opsonization of microbial membranes - B cell antigen is a substance or molecule
covalent bonding of complement proteins to specifically interacting with an antibody and
the surface of microbial membranes. Promotes which may lead to further production of
adherence of the opsonized microbial antibody and an immunological response
components to the cell membranes of - Polysaccharides are not good immunogens
phagocytic cells for B-lymphocytes. Gives T cell
o Activation of leucocytes raising the level of independent humoral response and does not
functioning of the leucocytes in immune elicit helper T-lymphocyte cooperation. This
defense means that no memory B-cells were formed
o Lysis of target cell membrane forming a and the plasma cell isnt able to synthesize a
Membrane Attack Complex (MAC) which full range of antibody subclasses. (only IgM
leads to formation of membrane pores and is available)
ultimately, microbial cell lysis - Proteins are more effective and are T-cell
dependent (theres production of memory
Process: cells and the full range of antibody
subclasses
1. C3C3a and C3b
- Antibody monomer (IgG, IgE and IgD) has
2. C3b attaches to the microbial membrane. Then
4 polypeptide subunit structure that are
Factor B binds to it, forming C3bB
linked by disulfide bonding
3. Complex is stabilized by Properdin
- IgM is a pentamer, IgA is a dimer
4. Factor D then cleaves the bound Factor B
- 2 identical heavy chains and 2 identical light
forming, C3bBb (C3 convertase of the alternate
chains with each containing a constant
pathway)
region (CH and CL) and a variable region
5. C3b + C3 convertase = C3bBb3b (C5
(VH and VL)
convertase)
- The light chain variable region and the
6. C5 convertase + C5C5a and C5b
heavy chain variable region are involved in
7. C5b + C6+C7+C8+C9 MAC
antigen recognition
- Extreme tips of the variable region are
- The pathway is only activated in the presence of
called hypervariable domains (serve specific
microbial membrane and not host cell
antigen recognition)
membrane
- Each antibody monomer binds 2 identical
- Differences between host cell and microbial
epitopes
membrane:
- Fab domain the antigen recognition
o LPS and peptidoglycan in microbial
domain of an antibody monomer
membrane promote C3b binding
- Fc domain CH defines the different
o High sialic acid content of host cell membrane
classes of antibody that are produced and the
promotes dissociation of C3 convertase
effector functions arising from antibody-
o Decay activating factor (DAF) and
antigen interaction
complement receptor type 1 (CR1) are host
- 5 antibody classes: IgG. IgA, IgM, IgE, IgD
cell membrane proteins that block binding of
Factor B to C3b
Clonal selection and expansion
o Membrane cofactor protein (MCP) and CR1
- Antigen will be specifically recognized by
also promote displacement of factor B from its
IgM molecule present on the surface of the
binding with C3b
nave B-lymphocyte
o CD59, a protein in host cell membrane,
- Some daughter cells will differentiate into
prevents unfolding of C9
plasma cells while others will become B-
V. Humoral adaptive immune system
lymphocyte memory cells
- Mediated through antibody-antigen
- Initial introduction of antigen gives rise to a
interactions
primary response (latent period before
- B-lymphocytes possess antibody molecules
increased serum antibody levels are
on their cell membrane
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 observed); IgM is the main antibody
produced
- Re-exposure to the same antigen
secondary response (a reduced latent period
between antigen challenge and increase in
serum antibody); IgG is produced
- In the absence of T helper lymphocytes, no
B-lymphocyte memory cells are produced
and antibody class switching is restricted.
Hence both primary and secondary response
are indistinguishable and IgM is the main
serum antibody
Humoral immune effector functions
- Cognitive function on B-lymphocyte cell
surface antibody on the surface of nave or
memory B-lymphocytes serves to recognize
and bind specific antigen
o IgM serves this main cognitive function
o IgD also contributes to cognition
- Neutralization of antigen by secreted
antibody IgA, IgG and IgM can bind
antigen and sterically hinder the interactions
of microorganisms with host cell surfaces
o IgM in circulatory and interstitial
fluids for primary response
o IgG in circulatory and interstitial fluids
for secondary response
o IgA mucosal immunity
- Opsonization of antigen secreted antibody
(in particular, IgG) opsonizes antigenic
material and promotes association of the
antigenic material with phagocyte
membranes
- Mucosal immunity involves interaction of
antibody with antigen at mucosal surfaces
o IgA major antibody for mucosal
immunity; limited role in systemic
immunity
- Antibody dependent cell cytotoxicity (ADCC)
antibody can direct the close association of
killing cells such as neutrophils, eosinophils,
NK cells and even cytotoxic T-lymphocytes
with the foreign membrane. This close
association depends on the antibodys Fc
domain binding to the respective Fc receptor
present on the surface of killing cell. Such close
proximity to the foreign cell enables the
efficient and targeted release of cytotoxic
molecules into the extracellular environment.
o IgG important mediator of ADCC
o IgE directs ADCC mediated eosinophils
against certain parasites
- Immediate hypersensitivity Mast cells possess
IgE monomers able to recognize different
antigenic epitopes
- Neonatal immunity maternal IgG is
transported across the placenta, maternal IgA
secreted into breast milk will provide mucosal
protection
- Activation of the classical complement
pathway activated by IgM and IgG
- Process:
1. Specific binding of IgG or IgM to antigen
2. C1 (composed of 1 C1q. 2 C1r, 2C1s) binds to
Fc domains and the catalytic activity of C1r
and C1s is activated.
3. C1s cleaves C4 C4a (leucocyte activator)
and C4b (opsonin)
4. C4b + C2 = C4b2
5. C1s cleaves the bound C2a C4b2b (C3
convertase)
6. C3 convertase + C3b C4b2b3b (C5
convertase)
7. *Same with alternate pathway
- Activation in classical pathway requires specific
antigen-antibody interactions
- C1 can only be catalytically active when it is
bound to at least 2 Fc domains (when
corresponding Fab domains bind antigen)
- When C1 is free, it is bound to a C1 Inhibitor
(C1-INH) which prevents any activation of C1
- The presence of 2 pathways provides for rapid
(alternative) and specific (classical) activation
of key defense mechanism.
VI. Cell-mediated adaptive immune system
- Mediated by T-lymphocytes
- Cognitive function is served by T-lymphocyte
receptor cells (TCR) present on the cells
plasma membrane
- In response to antigen, T-lymphocytes will
undergo clonal proliferation and form a
population clone of memory T cells specific for
a single epitope
- 2 types of T cells:
o Helper T-lymphocytes
o Cytotoxic T-lymphocytes
- Helper T-lymphocytes coordinator of adaptive
immune system, providing activation signals, in
the form of cytokines, to promote the
functioning of both cytotoxic T cells and that of
antibody producing B lymphocyte and plasma
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 cell populations. It also promotes the function of
innate immune system.
o Th1 (for cell mediated immunity) and Th2
(for humoral immunity)
o Possess CD4+ molecules
- Cytotoxic T-lymphocytes kills host cells that
have undergone a transformation such as viral
infection or cancer and they recognize specific
antigens on the surface of host cells that have
arisen
o Possess CD8+ molecules
- Epitopes for T-lymphocytes comprise of linear
peptide sequences. And T-lymphocytes respond
only to peptide antigens presented to T-
lymphocytes by surface proteins on plasma
membrane of host cells
- MHC has 2 classes:
o MHC class I expressed on the surface of all
host cell membranes and present peptide
antigen to cytotoxic T-lymphocytes
o MHC class II Expressed on a specialized
group of cells termed antigen-presenting cells
(APCs) and present peptide antigen to helper
T-lymphocytes
- All cells of the body possess MHC class 1
proteins
Processing of Proteins to allow peptide presentation
by MHC Molecules
MHC I
- MHC I is composed of 2 polypeptide chains, an
chain which has 1 2 3 domains and a
second polypeptide termed 2-microglobulin.
The 1 and 2 domains form a peptide binding
cleft which can accommodate up to 11 amino
acids in length.
- The synthesized protein is degraded by a
proteosome. The peptide fragments are
transported via TAP peptide transporter
lumen of ERbinding clefts of MHC I trans-
Golgi network (TGN) *via endosomes*
plasma membrane of CD8+ T-lymphocytes
MHC II
- Peptide proteins are derived from proteins
present in extracellular fluid
- MHC II is composed of 2 polypeptide chains, an
chain which has 1 and 2 domains, and a
chain which has 1 and 2 domains. The 1
and 1domains form a binding cleft that can
accommodate 20 amino acids in length.
- Protein is internalized from the extracellular
fluid by the APCs and restricted to an
endosomal compartment without access to the
APCs cytoplasm
- The endosome delivers the protein to a
lysosome compartment which degrades the
protein into peptide fragments and then theyre
returned to the endosome compartment
- In the lumen of the ER the MHC II molecule +
invariant chain (blocks access of peptides to
binding cleft of the MHC II) = MHCII-invariant
chain transferred to TGN endosomal
compartment
- Peptides+ MHC-invariant chain -invariant
chain= access of peptides to binding cleft in
MHC II
- MHC II-peptide plasma membrane of CD4+
T-lymphocytes
Effector T-helper cell subtypes
- Antigen-driven activation signals involve
initially TCR interactions with MHC-presented
peptide and subsequent CD3 activation then
interactions of costimulatory molecules on the
surface of the APC with surface receptors on the
helper T cell
- activation of helper T-cells differentiation
o Th1 IFN- and IL-12, TNF-
o Th2 IL-4, 5,6,10,13
T-regulatory cells
- Are a subset of T-lymphocytes that serve as an
immune suppressor function leading to
peripheral tolerance to self- or foreign antigen
- Characterized by either CD4+ or CD8+
phenotype
- Display the expression of Foxp3 transcription
factor
- TGF appears important for the expression of
Treg phenotype and IL-2 as the Tcell mitogen is
also important
- Tregs essentially serve to suppress immune
responses of effector T cells, effector B cells
and APCs leading to peripheral immune
tolerance
- Self-limits immune responses
VII. Transplantation rejection
- Process of transferring cells, tissues or organs
termed a graft from one location to another
- Autologous graft transplant between 2 sites
within the same individual
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- Allogeneic graft transplant between 2
genetically different individuals of the same
species
- Xenogenic graft transplant across different
species
- Hyperacute rejection occurs within minutes to
hours following revascularization of graft. Its
due to the presence of preformed circulating
antibody (IgG) that reacts with blood cell
antigens
- Acute rejection occurs within weeks to
months following transplantation and involves
humoral and cell mediated induced cytotoxicity
- Chronic rejection occurs many months or
years following transplantation
VIII. Hypersensitivity
- Defined as an exaggerated response of the
immune system leading to host tissue damage
- Type I immediate hypersensitivity
o Anaphylactic or acute hypersensitivity
o IgE antibody
o Degranulation of mast cells leading to
release of preformed factors which promote
an influx of immune cell to the site and
initiation of a rapid inflammatory response
- Type II antibody-mediated
o Caused by antibodies that are directed
against cell surface antigens (IgM and IgG)
- Type III complex mediated
o Formation of large antigen-antibody
complex that circulates in the blood and are
deposited in tissue capillary beds
- Type IV Cell-mediated
o Inappropriate accumulation of macrophages
at the localized site and may or may not
involve the presence of an antigen which
may lead to continuing damage to normal
cell

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