Clonal Selection Theory

1. T and B cells exist with almost unlimited specificities

before any contact with foreign Ags
2. Ag-specific receptors that recognize foreign Ags:
1. Abs are the B cell receptors on the surface of B cell &
2. T-cell receptor (TCR) on T cell
3. Each lymphocyte has a single specificity
4. The antigenic determinant (epitope) on the Ag binds
with lymphocyte (B or T) and triggers their
differentiation and proliferation
5. Negative selection by self Ags  shut off cells that
recognize them during maturation
Clonal Selection

No specialized
receptor

Epitopes
2, 103, 821
 Harmful Effects of the Immune System
• Hypersensitivity or allergic reactions:
– Type I, immediate hypersensitivity
– Type II, cytotoxic Ab-mediated reactions
– Type III,immune complex Ab-mediated
– Type IV, delayed-type cell-mediated
• Autoimmune diseases
– The immune system attacks body’s own Ags causing diseases
like rheumatoid arthritis, diabetes mellitus and systemic lupus
erythematosus
• Immunodeficiencies
– Occur when one or more components of the immune system fail
to function properly
– This can be result of genetic defect (SCID) or acquired (AIDS)
• Graft rejection
– Occurs because of immune response against transplant’s Ags
 Genetic Recombination & Immune
Response Diversity
• 106-107 of antigenic specificities might exist
• If 1 gene = 1 response, are 107 genes needed?
– No
• Genetic recombination “within “ a gene that
encodes the Ig proteins is the answer
• So, the basic Ab is composed of 2 types of
polypeptides: H-chain, L-chain and each chain
has a variable domain
• This mechanism generates Ab & T cell receptor
(TCR) specificity
 Regulation of the immune system
• Why regulation?
• Immune response  proliferation and increased
synthesis of specific molecules that will not be
useful after their job is finished (infection 
response  cure)
• Homeostasis or equilibrium must be established
by shutting down the system
• Deregulation of the immune system has severe
consequences
• Immune response to self Ags  Autoimmunity
LECOM-Pharmacy School
Immunology 02
Cells, Tissues & Organs of the Immune
System
Dr. Saber Hussein
 Objectives
1. B and T lymphocytes and NK cells
2. T cells Subpopulations: Helper, cytotoxic and suppressor
3. Antigen presenting cells
4. Phagocytes: Monocytes (macrophages) & granulocytes
(eosinophil, neutrophil, basophil & mast cells)
5. granulocyte and platelet role in inflammatory response
6. Primary tissues of the Immune System:
1. Bone marrow &
2. Thymus
7. Secondary tissues:
1. Lymph nodes,
2. spleen,
3. Payer’s patches
 Cells of the Immune System
• Lymphoid Lineage
– T helper cells (TH)
– Cytotoxic T cells (Tc or CTL)
– B cells
– Natural Killer [NK cells. A type of white blood cell that contains
granules with enzymes that can kill tumor cells or microbial cells.
Also called large granular lymphocytes (LGL)]
• Myeloid Lineage
– Polymorphonuclear granulocytes
• Neutrophil
• Basophil & Mast cells
• Eosinophil
– Mononuclear phagocytes
• Dendritic cells & Macrophages
• Megakaryocytic Lineage
– Platelets
 Hematopoiesis
• Hematopoiesis is the process of blood cell maturation
from the stem cell to the active, functional blood cell
(red or white)
• Red blood cells and white blood cells are formed in the
bone marrow
• Stem cells are totipotent or pluripotent
– Totipotency - The ability of a cell, such as an egg, to give
rise to unlike cells [differentiate] and thus to develop into or
generate a new organism or part.
– Pluripotency - The potential of a cell to develop into more
than one type of mature cell, depending on environment
• Myeloid cells and lymphoid cells are pluripotent cells
with a common ancestor, a totipotent cell
 Hematopoiesis
• Myeloid cell Erythrocyte;
Neutrophil,
Monocyte  Macrophage;
Eosinophil;
Basophil & Mast cell;
Megakaryocyte  Platelet
• Lymphoid cell Lymphocytes:
T cell
B cell  Plasma cell
NK cell
Cells involved in the immune
Cells involved in the immune response
response
 • Subject to chemotactic
Polymorphonuclear stimulation by:
neutrophil – Complement fragments (C5a)
– Products of platelets & leukocytes
– Bacterial products
– Other protein products of
fibrinolysis
• Lysosomes contain
i. Primary granules
Primary (Azurophilic) contain
granules • Hydrolases
• Peroxidases
• Lysozyme
ii. Secondary, specific,
Secondary granules contain:
granules • Lactoferrin
• Lysozyme
 Neutrophils
• Have multilobed nuclei
• Their primary function is
– Phagocytosis
• enhanced by opsonization with complement and Abs
• Important secondary function
– promote inflammation
• Neutrophils produce
– reactive oxygen metabolites
– hydrolytic enzymes
– nitric oxide and
– antibiotic proteins such as
• defensins
• seprocidins
• cathelicidins
• bacterial permeability inducing protein
 Polymorphonuclear Granulocytes
• PMNs include
– Mainly neutrophils
– Eosinophils
– Basophil & mast cells
• From bone marrow at 7 million/minute
• Short lived (2-3 days)
• About 60-70% of WBCs
• Diapedesis:
– PMNs leave the circulation by adhering to the endothelium
& squeezing out
– It is promoted by chemokines
• IL-1
• IL-8 (RANTES [Regulated on activation, normal T expressed and
secreted])
 Functions of PMNs
• Important part in acute inflammation
• No specificity for Ags
• Cooperate with Abs & complement
• Phagocytosis
• Polymorph extravasation deficient
individuals and those with low numbers
of PMNs  increased susiptibility to
infections
 • Basophils are in circulation
Basophils & – Have S-shaped nucleus
Mast cells – Are round
• Mast cells are stationary:
1. Mucosal mast cells (MMC)
2. Connective tissue mast cells
(CTMC)
• Granules’ contents are
called mediators such as:
– Heparin,
– Histamine
– SRS-A (slow-reacting
substance of anaphylaxis)
– ECF-A (eosinophil
chemotactic factor A)
Basophils and • Basophils and mast cells are
the least prevalent of the
mast cells leukocytes
• They possess high affinity Fc
receptors for IgE
• They release the chemical
mediators of immediate
hypersensitivity, including:
– Histamine
– Prostaglandins
– Thromboxanes
– Leukotrienes
– Heparin
MC • They also produce eosinophil
chemotactic factor (ECF)
– which causes eosinophils to
enter the area of worm
infestation or allergen
localization
 Eosinophils
• Bilobed nucleus
• Granules stain with acid
dyes- eosin
• Capable of
phagocytosing & killing
microorganisms
• Degranulation: release
of contents in
surrounding area
• Can kill parasites with
basic proteins and
cationic proteins
– Schistosoma mansoni
 Monocytes/Macrophages
M in the process
• Monocytes enter circulation from of surrounding
bone marrow then migrate into tumor cell
various organs and tissues
• There they mature into:
– macrophages
– Kupffer cells (liver)
– histiocytes (M found in connective
tissue)
– dendritic cells (lymph nodes, spleen)
– glial cells (brain)
– Langerhans' cells (skin)
• Collectively, these cells form a
network known as the
reticuloendothelial system (RES)
or the mononuclear phagocyte
system
 Differential White Blood Cell Count
CELL TYPE % OF WBC'S CELLS/cmm

Neutrophil 50 – 60 3000 - 7000

Eosinophil 1–4 50 – 400
Basophil 0.5 – 2 25 – 100
Lymphocyte 20 – 40 1000 – 4000
T cell 80 - 85*
B cell 5 - 15*
NK cell 5 - 15*
Monocyte 2-9 100 - 600

*% of lymphocytes in peripheral blood

 Reticuloendothelial
System
(mononuclear phagocyte
System)
 • Anucleate
Platelets
• Derived from
megakaryocytes
• Contain granules at the
ultrastructural level
• Their major functions are
– blood clotting
– inflammation
• Following injury to
endothelial cells, platelets
adhere to the surface of the
damaged tissue, where they
release substances that
Platelets aggregating – increase vascular
permeability,
at the site of a wound – activate complement and
in a blood vessel – attract leukocytes
Functions of Lymphocytes

NK
 B and T lymphocytes

• T cells develop in the thymus

• B cells differentiate
– in fetal liver &
– in postnatal bone marrow
• Ag recognition via specific receptors
• NK (natural killer) cells do not express Ag receptor
• Lymphocytes have
– high N:C (nucleus : cytoplasm) ratio
• LGL (NK; Large granular lymphocytes) have
– lower N:C ratio
 T Cells
• Majority of T cells
express -TCR TC Cell
TH Cell
– T-helper cells (TH) CD8
CD4
– T-cytotoxic cells (Tc)
• TCR is an
immunoglobulin
• Carry Gall body (Gb) in
the cytoplasm
– Gb: A cluster of lysosomes
+ Lipid droplet

MHC-I
 Subpopulations of T cells
Tc
CD

T
TH 1
TH
T0 CD4
TH 2
 T
 B cells have: •Resting B cells have:
– MHC I (like all nucleated •No Gall bodies
cells) & •No LGL morphology
– MHC II proteins on their
surfaces •Monoribosomes scattered in
• MHC proteins are members of the cytoplasm
the Ig superfamily that have Ag •Activated B cells have rough ER
binding capabilities but are not
nearly as specific as Ag binding
by Ig or T cell antigen receptors
• B cells function as APCs for
induction of immune response MHC-II
• B cells have two different
EBV
receptors for complement:
– CR1 (CD35) and MHC-I
– CR2 (CD21)
that probably have regulatory
functions MHC-I
• CR2 is the target for Epstein-
Barr virus (EBV) binding
 NK Cell
• Have LGL morphology
• Contain larger number of
azurophilic granules than
granular T cells
• Have no specific receptor
for Ag recognition
• Derived from lymphoid
cell progenitors in the How can you distinguish NK from T & B?
bone marrow 1. No specific receptor
2. NK can lyse certain tumor cell lines
in vitro without prior sensitization
 Antigen presenting cells
• APCs are heterogenous leucocytes
• They present Ags to TH or Tc cells
• Ability to digest protein Ags is important
• Present primarily in:
Skin
Spleen
Lymph nodes
 What cells can serve as APC?
1. Langerhans’ cells (LC)
2. Dendritic cells
1. Interdigitating dendritic cells (IDC)
2. Follicular dendritic cells (FDC)
3. Germinal center dendritic cells (GCDC)
3. B cells
4. Macrophages
 Lymphoid organs
• The lymphoid organs are those organs in which maturation,
differentiation and proliferation of lymphocytes take place
• The primary, or central, lymphoid organs are those in which T and
B lymphocytes begin expressing their antigen receptors
• The secondary lymphoid organs are those in which lymphocytes are
induced to proliferate and differentiate by contact with antigen
 Primary lymphoid
• Bone marrow in which B cells develop organs
• Thymus, where T cells develop. Progenitor cells from the bone marrow migrate to the thymus gland to
develop into T cells
– The thymus is a bilobed structure, whose size reaches its maximum at birth, then atrophies with age.
– The cortex contains mostly immature thymocytes, some of which
• mature & migrate to the medulla, where they learn to discriminate between self and nonself during fetal
development and for a short time after birth.
– T cells leave the medulla to enter the peripheral blood circulation, through which they are transported
to the secondary
lymphoid organs
• DiGeorge syndrome:
congenital absence of thymus
results in an immediate and
drastic reduction in T cells
that produces a potentially
lethal wasting disease
 Secondary lymphoid organs
• The secondary lymphoid organs have two major
functions:
– they trap and concentrate foreign substances, and
– they are the main sites of production of antibodies and
antigen-specific T cells
• The major secondary lymphoid organs include the
– Spleen, which is responsive to blood-borne antigens
– Lymph nodes, which protect the body from antigens that
come from skin or internal surfaces via the lymphatic
system
– Mucosa-associated lymphoid tissue (MALT) scattered
along mucosal linings, which protects the body from
antigens entering the body directly through mucosal
surfaces
 Spleen
• Schematic representation of the spleen and a cross-section
of the periarteriolar lymphoid sheath (PALS)
 Lymph nodes

• Clusters of lymph nodes (ovoid structures usually less than 1 cm in

diameter) are strategically placed in the neck, axillae, groin,
mediastinum and abdominal cavity, where they act to filter
antigens from the interstitial tissue fluid and the lymph during its
passage from the periphery to the thoracic duct
• Somatic nodes: Lymph nodes that protect the skin
• Visceral nodes: Deep lymph nodes protecting the respiratory,
digestive and genitourinary tracts
 Mucosa-associated lymphoid tissue (MALT)
• The bulk of the body's lymphoid tissue (>50%) is found associated
with the mucosal system.
• MALT is composed of
– gut-associated lymphoid tissues (GALT) lining the intestinal tract,
– bronchus-associated lymphoid tissue (BALT) lining the respiratory tract,
– lymphoid tissue lining the genitourinary tract.
• The major effector mechanism at these sites is secretory IgA (sIgA)
secreted directly onto the mucosal epithelial surfaces. Examples of
MALT include
– the Peyer's patches lining the small intestine,
– the tonsils and
– the appendix.
• "M" cells (because they have numerous microfolds on their luminal surface)
– absorb,
– transport,
– process and
– present antigens to subepithelial lymphoid cells