IMMUNOLOGY

Immunology
Study of immunity / immune system
Study of cellular and molecular events that occur after the encounter
of foreign substances
Study of body mechanisms that discriminate self from non-self
followed by elimination of non-self components
Study of medically-related consequences that arise when the immune
system fails to eliminate non-self and when the immune system
reacts in exaggerated manner
Experimental sciences

Primary function of the immune system:

Defend from and eliminate foreign material,
minimize any damage caused by the foreign material
Definitions and outline structure of
the immune system
Pathogen - organism which has the ability to cause disease
Virulence refers to the degree of pathogenicity of a given strain of
microorganism
Attenuation - Reduction in the virulence of a pathogen
Antigen foreign material; gives rise to the primary interaction with
the bodys immune system
Immunogen an antigen that elicits an immune response
antigenic determinants or epitopes - the antigen recognition
sites for our adaptive immune system
Definitions and outline structure of
the immune system
monoclonal antibody antibody recognizing only a single
antigen; only a single common epitope is recognized
polyclonal antibody - antibody recognizing only a single
antigen; but a number of different epitopes are recognized
Immunity protection from disease (infectious disease)
Immune system cells and molecules responsible for immunity
Immune response collective and coordinated processed
taken by the immune system upon the introduction of
foreign substances
Opsonin agent that identifies the invading organism to the
phagocyte; makes phagocytosis possible
Cells of the immune system
Mononuclear phagocytic cells monocytes differentiate to macrophages
Monocyte short-lived (8-hrs)
Macrophage long-lived

Granulocyte cell
neutrophil, basophil and eosinophil

Mast cell
Tissue-resident cell triggered by tissue damage / infection
release numerous initiating factors leading to an inflammatory response:
histamine, cytokines

Natural killer (NK)

elicit cytotoxic actions against host cells infected with virus and those host cells that have
acquired tumor cell characteristics

Lymphocytes
B lymphocytes - mature or differentiate in the bone marrow
T lymphocytes - undergo maturation in the thymus
Definitions and outline structure of
the immune system
Two Types of Immunity

Innate / Natural
First line of defense
Present at birth
Inherited from parents
non specific; not intrinsically affected by prior contact with infectious agent
Neutrophils

Adaptive / Acquired / Specific

Not present at birth
Not inherited from parents
Characterized by specificity, and memory (immunologic memory)
Lymphocytes
Innate & Adaptive Immunity
Innate Immune System
Natural resistance of species, individual
Innate barriers (physical barriers)
Skin 1st main line of defense
Fluid secretions (tear ducts)
Mucus barrier (with cilia)
Cellular components
Mononuclear phagocytic cells
Granulocyte: Neutrophil
Phagocytosis 2nd main line of defense
neutrophils
Monocytes
macrophages

Inflammation as indicator of immune response

Symptoms: pain, swelling, redness, heat
Increase of cellular and humoral defenses to infection
Secretions of the Epithelial Surfaces
Mononuclear
phagocytic cells
Include monocytes and macrophages

The mononuclear phagocytic cells secrete a wide range of molecules:

Enzymes: lysozyme
Cytokines
provide innate protective antiviral (e.g. interferon (IFN) - or - ) and
antitumor (e.g. TNF - ) activity against other host cells
Bioactive lipids
promote the inflammatory response: vasodilation, permeability
Receptors
Chemotaxis toward microorganism
Leukocyte activators - ex. C protein opsonize microorganism
Granulocyte cell populations

Include the neutrophils, basophils and eosinophils

Neutrophil - the most abundant granulocyte and is the most important

in terms of phagocytosis

Eosinophils - have a specialized role in the extracellular killing of

parasites
Phagocytosis
Macrophage, neutrophil
It is an active, energy-dependent process of engulfing
particles

Stages:
Chemotaxis
Adherence
Membrane activation of phagocyte
Enclosure of phagocytosed material
Phagocytosis
Chemotaxis of
phagocyte toward
microorganism
- Signals from the microorganism,
C protein, other WBCs
Adherence of
microorganism to the
phagocyte
- Lectin , C3b, Fc (receptors)

Membrane activation
of phagocyte actin-
myosin-contractile network
Enclosure of
phagocytosed material
Complement System
Consists of several plasma protein that are activated by
microbes and promote destruction of the microbes and
inflammation

Ways to initiate Complement Pathway:

1. Classical pathway (adaptive immunity)
1st to be discovered,
- uses plasma protein C1 to detect IgM, IgG antibodies
2. Alternative pathway (innate immunity)
discovered later than classical pathway, older.
- Triggered by direct recognition of microbes
- component of innate immunity
- C3
3. Lectin pathway triggered by plasma protein mannose-
binding lectin (MBL)
Alternative Complement Pathway
(Innate Immunity)
Three main functions:
Opsonization of microbial membrane
Promotes adherence of the opsonized microbial component to
the cell membranes of phagocytic cells
Complement protein C3b is a potent opsonin
Activation of leucocytes
Involves complement protein acting on leukocytes
C3a potent leucocyte chemoattractant
Lysis of the target cell membrane
Involves collection of complement proteins to form
membrane attack complex MAC
MAC leads to membrane pores then microbial cell lysis
Alternative Complement Pathway
(Innate immunity)
>C3 is cleaved
- C3b- attached to the microbial
surface and serves as an opsonin to
promote phagocytosis
C3b + factor B = C3bB (properdin)
factor D cleaves factor B = C3bBb
C3bBb cleaves C3 = C3bBb3b
- C3a released and serves as
chemoattractant for neutrophil
>C5
C5a stimulates the influx of
neutrophils to the site of infection,
inflammation
C5b initiates the formation of a
complex of the complement protein C6, C7,
C8, C9
> Assembly of a membrane pore
Membrane attack complex
MAC
- causes lysis of the cells
Adaptive Immune System

Humoral immunity
mediated by B- lymphocytes (production of antibodies)
Transferable to nave individuals through serum or plasma

Cell - mediated immunity

Mediated by T lymphocytes (antigen recognition through peptide antigen with
T-cell receptor TCR)
Transferable to nave individuals through T-lymphocytes but not through serum or
plasma
Peptide antigen presented to T-lymphocyte through MHC (major histocompatibility
complex)
Adaptive Immune System
B-cells (produced in the BM)
Mature in the BM
Released in the circulation
They are carried to the secondary lymphoid organs
(spleen, lymph nodes, tonsils, adenoids)
Lymphoid organs the trapping sites of pathologic organisms
(interaction of B-cells with pathologic organisms)

Plasma cells (Antigen Presenting Cells)

Produce Abs
Humoral immunity
Adaptive Immune System
T-cells (produced in the BM, matures in the thymus)
Cortex nursing area of T-cells
Medulla waiting area for the newly matured T-cells
Released in the circulation when mature
Secondary lymphoid organs
sensitized T-cells / immunocompetent T-cells
Produce lymphokines
Responsible for Cell Mediated Immunity
Adaptive Immune Response
Active Immunity
Stimulated when individual is exposed to antigen (infection)
Ex. Chickenpox-an against chickenpox
Passive Immunity
Immunity without antigen encounter
Produced by adoptive transfer (transfer of cells or serum from
immunized individual)
Ex. Transplacental leakage of abs
Adaptive Immune Response
Naturally acquired
Infectious diseases (active)
Transplacental leakage (passive)

Artificially acquired
Vaccination (active)
The Humoral Adaptive Immune System
Antibody-antigen interaction
B - lymphocyte (bound antigen)
Differentiates to plasma cell
Produce antibody

B-lymphocyte antigen
Basic structure of antibody
Clonal selection and expansion
Humoral immune effector functions
B - lymphocyte antigens
A substance or molecule specifically interacting with an antibody, and
which may lead to the further production of antibody and an
immunological response
Proteins

Molecules Characteristic Immunogenicity

Protein High MW, Complex Excellent ++++
structure
Polysaccharides Large, lack complexity Must be linked to a ++
(blood grp Ags) protein or lipid

Lipid Simple structure and low Must be linked to a +

stability protein or
polysaccharide
Nucleic acid Simple, flexible, degrades poor +
rapidly
GENERAL CHARACTERISTICS OF
ANTIBODIES
Antibodies
Immunoglobulins
Product of antigenic stimulation
Can be: monomeric 1 unit; basic unit
dimeric 2 monomers joined by J-chain
polymeric 3 or more monomers; J-cjain
Monomeric structure disulfide bond
2 heavy chains
2 light chains
GENERAL CHARACTERISTICS OF
ANTIBODIES
Where are antibodies located?
Surface of B-lymphocytes
ER and golgi apparatus of plasma cells
Blood plasma / serum (antiserum)
Surface of immune effector cells (phagocytes, NK cells,
mast cells)
Body fluids (tears, saliva)
Secretory fluids (mucus, milk-colostrum)
Antibody Structure
Chains
- heavy chains (H) - 2 identical
- light chains (L) 2 identical
Fragments
- antibody binding fragments (Fab)
- crystallizable fragments (Fc)
Regions
- variable region (V)
- constant region (C)
Domains (Ig domains)
- VL
- CL
-VH
- CH 1
- CH 2
- CH 3
Antibody Structure
Antibody Structure
Classes of Antibody:
1. IgM -
2. IgA -
3. IgD -
4. IgG -
5. IgE -
Clonal selection and expression
Review

Adaptive / Acquired / Specific Immunity

Not present at birth
Not inherited from parents
Characterized by specificity, and memory
(immunologic memory)
Lymphocytes
Effector cells of adaptive immunity
B-cells
Memory cells
T-cells
Th-Thelper cells inform Bcells-plasma cells-Abs
Ts-Tsuppressor cell suppresses action of Tcells and Bcells not to
produce Ab
Th > Ts normal 2:1
Reverse Ts > Th decreased resistance in the body- in HIV
Tc-Tcytotoxic cells cytotoxic molecules to kills organisms
TNK- natural killer cells kill cancer cells, viral organisms
 Skin 1st defense natural immunity

Phagocytes 2nd defense APC-natural immunity

Antibodies 3rd defense acquired immunity

Clonal Selection and Expression
Antigen
B-cells (short-lived)
Plasma cells
Antibody (IgM)

Other B-cells (long-lived)

In circulation
B-memory cells
2nd response on
subsequent exposure to
same antigen (IgG)
Clonal selection and expansion
10 response IgM
Increased latent period
on Ab production
20 response IgG
Reduced latent period
on Ab production
Anamnestic response
Humoral immune effector functions
1. Cognitive function on B-lymphocyte cell surface
Recognize specific antigen; IgM, IgD
2. Neutralization of antigen by secreted antibody
Hinder interaction of toxins, bacteria, viruses with host cell surface
IgM, IgG, IgA
3. Opsonization of antigen
Promotes association of antigen with phagocytes; IgG
4. Mucosal immunity
IgA neutralizes antigen, acts as opsonin
Humoral immune effector functions
5. Antibody-dependent cell cytotoxicity Eos, NK, Tc
IgG, IgE, IgA release of killing cells directed to the foreign
membrane
6. Immediate hypersensitivity
IgE - mast cell degranulation release of inflammatory mediators
7. Neonatal immunity
IgG (placenta), IgA (milk) mucosal protection to neonates
8. Activation of the classical complement pathway
Activation of
Classical Cpathway
ag-ab interaction-IgM,IgG
C1 binding Fc domain
C1q,C1r,C1s-activated
C1s cleaves C4 C4b, C4a
C4b binds C2
C1s cleaves C2 - C2a, C2b
C2b binds w/C4b
C4b2b (C3 convertase)
C3 convertase cleaves C3
C3b, C3a
C4b2bC3b C5 convertase
C5 convertase cleaves C5
Classical Complement Pathway
(humoral adaptive immune system)

Four main functions:

1. Opsonization of microbial membrane
2. Activation of leucocytes
3. Lysis of the target cell membrane
4. Promote clearance of potentially harmful complexes
(Ag-Ab immune complexes) kupffer cells of the liver
Cell - mediated adaptive
immune system
Mediated by T-lymphocytes
Produced by bone marrow; matures in thymus

B-lymphocyte T-lymphocyte
Cognitive function Membrane-bound TCR
antibodies
Response to Ag Memory cells Memory cells
Ab production B-cells T-cells
plasma cells
Cell mediated adaptive immune system
2 General Classes of T-lymphocytes

1. Helper T-lymphocyte
- coordinates with adaptive immunity antibody production
- promote the function of innate immune system
- phagocytic activity of macrophage
> TH1 regulate cell mediated immunity
> TH2 regulate humoral immunity

2. Cytotoxic T-lymphocyte
- Functions to kill host cells that had undergone transformation:
viral infection, cancer
- release perforin; lysis of affected cells
T-lymphocyte antigen recognition and
MHC proteins

MHC class I Ag presentation to cytotoxic T-cell CD8+

molecule
MHC class II Ag presentation to helper T-cell
CD4+
molecule
review
ADAPTIVE IMMUNE SYSTEM
Humoral immunity
Cell - mediated immunity
Peptide antigen presented to T-
lymphocyte through MHC (major
histocompatibility complex)
MHC II
(microorganism)
1. Binding of Ag to APC & internalization
of the Ag
(phagosome, phagolysosome)

2. Internalized protein (endosome)

degraded enzymatically to generate
peptide Ag that are able to bind to
peptide-binding cleff of class II MHC

3. ER-synthesis of MHC II and

transported to endosome via invariant
chain (Ii) (clip)

4. Ii dissociates from MHC II by

proteolytic enzyme, HLA-DM. Peptide
Ag able to bind w/ MHC II

5. MHC II stable and delivered to surface

of APC for CD4+ recognition
(T-cell or T-lymphocyte Th)
MHC I
(virus, tumor cells, microbes)

1. Cytosolic protein Ag -
Nucleated cell
2. Proteolytic
degradation of
protein = Peptide
(proteasome)
3. Peptide transported
by TAP to ER
4. Assembly of the MHC
I & peptide in the ER
5. Surface expression of
MHC I complex for
CD8+ recognition
(T-cell CTL)
Transplantation rejection
Transplantation is the process of transferring cells, tissues or organs
from one location to another (graft)

An autologous graft is a transplant between two sites within the

same individual, e.g. skin graft from the thigh to the hand

An allogeneic graft is a transplant between two genetically

different individuals of the same species
ex. Kidney transplant

A xenogenic graft is a transplant across different species

ex. pig to human
Transplantation rejection

Hyperacute rejection occurs within minutes to hours

Due to presence of preformed circulating antibody that reacts with blood cell antigen
(ABO sys); requires crossmatching

Acute rejection occurs within weeks to months following

transplantation
involves humoral (antibody) and cell - mediated induced cytotoxicity.
Damage may be reversed with early diagnosis and more aggressive
immunosuppressive therapy

Chronic rejection occurs many months or even years following

transplantation.
Characterized by fibrosis
Requires differential diagnosis: chronic rejection or recurrent of original disease
Hypersensitivity
Defined as an exaggerated response of the immune system leading to
host tissue damage

Type I immediate hypersensitivity

Anaphylactic or acute hypersensitivity.
involves IgE antibody
mediated via degranulation of mast cells, release preformed factors, promote influx of
immune cells, for rapid inflammatory reaction
Ex. Allergy; hay fever

Type II hypersensitivity antibody-mediated cytotoxicity

This is caused by antibodies that are directed against cell surface antigens
IgG and IgM are the key antibodies
Activation of classical complement pathway
Formation of MAC
Attraction and activation of killing cells
Ex. Mismatch of ABO blood type, autoimmune disorder
Hypersensitivity

Type III hypersensitivity complex - mediated

involves the formation of large antigen antibody complexes that circulate in the
blood
Kidney deposition site of antigen-antibody complex: glomerulonephritis

Type IV hypersensitivity cell - mediated

This results from inappropriate accumulation of macrophages at a localized site
Granuloma recruitment of macrophages into the site
A fibrotic core of tissue composed of tissue cells and macrophages surrounded by
layers of calcified collagenous materials
The End