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 specificity4. 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

Epitopes2, 103, 821

No specialized receptor

Epitopes2, 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 SchoolImmunology 02

Cells, Tissues & Organs of the Immune System

Dr. Saber Hussein

Objectives1. B and T lymphocytes and NK cells2. T cells Subpopulations: Helper, cytotoxic and suppressor3. Antigen presenting cells4. Phagocytes: Monocytes (macrophages) & granulocytes

(eosinophil, neutrophil, basophil & mast cells)5. granulocyte and platelet role in inflammatory response6. 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 response

Cells involved in the immune response

Polymorphonuclear neutrophil

• Subject to chemotactic stimulation by:– Complement fragments (C5a)– Products of platelets & leukocytes– Bacterial products– Other protein products of

fibrinolysis

• Lysosomes containi. Primary granules (Azurophilic) contain

• Hydrolases • Peroxidases• Lysozyme

ii. Secondary, specific, granules contain:

• Lactoferrin • Lysozyme

Primarygranules

Secondarygranules

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 & Mast cells

• Basophils are in circulation– Have S-shaped nucleus– 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 mast cells

• Basophils and mast cells are the least prevalent of the leukocytes

• They possess high affinity Fc receptors for IgE

• They release the chemical mediators of immediate hypersensitivity, including: – Histamine– Prostaglandins– Thromboxanes– Leukotrienes– Heparin

• They also produce eosinophil chemotactic factor (ECF) – which causes eosinophils to

enter the area of worm infestation or allergen localization

MC

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

• Monocytes enter circulation from bone marrow then migrate into 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

M in the process of surrounding

tumor cell

Differential White Blood Cell Count

CELL TYPE % OF WBC'S CELLS/cmm

Neutrophil

Eosinophil

Basophil

Lymphocyte

T cell

B cell

NK cell

Monocyte

50 – 60

1 – 4

0.5 – 2

20 – 40

80 - 85*

5 - 15*

5 - 15*

2 - 9

3000 - 7000

50 – 400

25 – 100

1000 – 4000

100 - 600

*% of lymphocytes in peripheral blood

ReticuloendothelialSystem

(mononuclear phagocyte System)

Platelets • Anucleate• 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

– increase vascular permeability,

– activate complement and – attract leukocytes

Platelets aggregating at the site of a wound

in a blood vessel

NK

Functions of Lymphocytes

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 – T-helper cells (TH)

– T-cytotoxic cells (Tc)

• TCR is an immunoglobulin

• Carry Gall body (Gb) in the cytoplasm– Gb: A cluster of lysosomes

+ Lipid droplet

MHC-I

CD4CD8

TH Cell TC Cell

Subpopulations of T cells

T

TH

CD4

T

TH2

TcCD

TH1

T0

B cells have:– MHC I (like all nucleated

cells) &– MHC II proteins on their

surfaces• MHC proteins are members of

the Ig superfamily that have Ag 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

• B cells have two different receptors for complement:– CR1 (CD35) and – CR2 (CD21)

that probably have regulatory functions

• CR2 is the target for Epstein-Barr virus (EBV) binding

MHC-I

•Resting B cells have:

•No Gall bodies

•No LGL morphology

•Monoribosomes scattered in

the cytoplasm

•Activated B cells have rough ER

MHC-II

MHC-I

EBV

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 bone marrow

How can you distinguish NK from T & B?

1. No specific receptor

2. NK can lyse certain tumor cell lines

in vitro without prior sensitization

• 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

Antigen presenting cells

What cells can serve as APC?

1. Langerhans’ cells (LC)

2. Dendritic cells1. 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 organs• Bone marrow in which B cells develop

• 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