INTRODUCTION TO IMMUNOLOGY

Immunity refers to protection against infections.

The immune system is the system responsible for

defending the body against pathogenic microbes in

the environment.

Deficiencies in immune defenses result in an

increased susceptibility to infections.

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The immune system is collection of organs, tissues,

cells, and soluble factors that allow individuals to

defend against harmful agents such as viruses,

bacteria, fungi, parasitic organisms, and tumor

cells.

The ultimate goal of this system is to prevent or

limit infections or damage by these agents.

The immune response involves recognizing any

foreign material and mounting a reaction to

eliminate it.

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INNATE AND ADAPTIVE IMMUNITY

The immune response is divided into two categories: the

innate and the adaptive branches.

Innate immunity (also called natural, or native,

immunity) is mediated by cells and proteins that are

always present to fight against microbes and are called

into action immediately in response to infection.

The major components of innate immunity are:

1- epithelial barriers of the skin, gastrointestinal tract, and

respiratory tract, which prevent microbe entry;

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2- phagocytic leukocytes (neutrophils and macrophages);

3- the natural killer (NK) cell;

4- several circulating plasma proteins, the most important

of which are the proteins of the complement system.

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MECHANICAL AND SECRETORY BARRIERS

TO INFECTION 12

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ADAPTIVE IMMUNITY

The innate immune response is able to prevent and

control many infections. However, many pathogenic

microbes are able to overcome innate immune

defenses.

Protection against these infections requires the more

powerful mechanisms of adaptive immunity (also

called acquired, or specific, immunity).

Adaptive immunity is normally silent and responds

(or "adapts") to the presence of infectious microbes by

becoming active, expanding, and generating potent

mechanisms for neutralizing and eliminating the

microbes.

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The components of the adaptive immune system are

lymphocytes and their products.

There are two types of adaptive immune responses:

humoral immunity, mediated by soluble antibody

proteins that are produced by B lymphocytes (also

called B cells), and cell mediated immunity, mediated

by T lymphocytes (also called T cells) .

Antibodies provide protection against extracellular

microbes in the blood, mucosal secretions, and tissues.

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T lymphocytes are important in defense against

intracellular microbes.

They work by either directly killing infected

cells (accomplished by cytotoxic T-lymphocytes)

or by activating phagocytes to kill ingested

microbes, via the production of soluble protein

mediators called cytokines (made by helper T

cells).

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When the immune system is inappropriately

triggered or not properly controlled, the same

mechanisms that are involved in host defense

cause tissue injury and disease.

The reaction of the cells of innate and adaptive

immunity may be manifested as inflammation.

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COMPARISON BETWEEN ADAPTIVE AND INNATE

IMMUNITY 12

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STRUCTURAL ORGANISATION OF THE

IMMUNE SYSTEM

The lymphoid system is composed of:

The primary lymphoid organs, in which lymphopoiesis

(Lymphopoiesis refers to the generation

of lymphocytes) occur

The secondary lymphoid organs, in which immune

responses occur.

The primary, or central, lymphoid organs are the

anatomical locations in which lymphocytes develop the

ability to specifically recognize foreign antigen and to

distinguish self from nonself.

These lymphoid organs are the bone marrow and thymus.

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SECONDARY LYMPHOID ORGANS

The secondary lymphoid organs are the sites for

presentation of foreign antigens to cells of the immune

system.

The major secondary, or peripheral, lymphoid organs and

tissues include:

The lymph nodes ( العقد الليمفاويه)

The spleen

The mucosa-associated lymphoid tissue (MALT) of the

gut the respiretory and genitourinary tracts.

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THE LYMPHOID ORGANSAND LYMPHATIC VESSELSARE WIDELYDISTRIBUTED IN THEBODY. THE LYMPHATIC VESSELSCOLLECT LYMPH FROMMOST PARTS OF THEBODY AND DELIVER ITTO THE BLOODCIRCULATION PRIMARILYTHROUGH THETHORACIC DUCT.

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CELLS OF THE IMMUNE SYSTEM

T LYMPHOCYTES,

B LYMPHOCYTES,

PLASMA CELLS (MODIFIED B CELLS)

MACROPHAGES, “HISTIOCYTES”

“DENDRITIC” CELLS ( Antigen Presenting Cells)

NK (NATURAL KILLER) CELLS

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All lymphoid cells originate in the bone marrow

Lymphoid precursors destined to become T-

lymphocytes mature in the thymus.

Development of B-lymphocytes occurs entirely

in the bone marrow.

Lymph nodes, spleen and mucosa-associated

lymphoid tissue are secondary lymphoid organs.

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L

Y

M

P

H

S

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Plasma cells are B-lymphocytes that are

specialized to produce antibodies or

immunoglobulins.

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MACROPHAGES are

MONOCYTES that have come

out of circulation and have

gone into tissue.

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A major function of macrophages is the phagocytosis of invading organisms and other antigens.

Macrophages have prominent lysosomalgranules containing acid hydrolases and other degradative enzymes with which it destroy phagocytosed material.

They are also important for the presentation of antigen to other cells of the immune system

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DENDRIDIC CELL

A Dendridic cell is a type of macrophage with many

spiny cytoplasmic processes, found in many places

especially skin (Langhans cells) and brain

(microglia), and

many other places

like liver. They are

APC’s.

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NATURAL KILLER CELLS

NK cells are types of lymphocytes which

specialize in direct killing of cells that come in

contact with.

Natural killer cells

(or NK cells) are a type

of cytotoxic lymphocyte

that play a major role in

the rejection of tumors

and cells infected by

viruses.

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NEUTROPHILS OR POLYMORPH NUCLEAR

LEUCOCYTES

Neutrophils play a major role in the body's

defence against acute infection. They can

migrate out of, blood vessels into tissues

They do this in response to chemotactic agents

produced at the site of inflammation.

Neutrophils are phagocytic cells able to kill

ingested microbes.

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Eosinophils have bilobed nucleus, with large

pink granules.

Eosinophiliais a hallmark of:

.Allergic reactions

.Worm infections

It can also be seen in collagen vascular diseases

and any skin disorder.

Basophils are secretory cells with bilobed

nucleus and large blue granules.

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CYTOKINES/CHEMOKINES

Cytokines are protiens produced by many cells, but usually LYMPHOCYTES and MACROPHAGES.

They have numerous roles in acute and chronic inflammation, and immunity.

They are soluble mediators which act as stimulatory or inhibitory signals between cells. Cytokines which act between cells of the immune system are called interleukins.

CHEMOKINES are small proteins which are attractants for neutrophils.

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MAJOR HISTOCOMPATIBILITY COMPLEX

A genetic “LOCUS” on Chromosome 6, which codes for cell surface compatibility.

MHC antigens also called HLA (Human Leukocyte Antigens) are cell surface glycoproteins of two basic types: class I and class II.

It’s major job is to make sure all self cell antigens are recognized and “tolerated”, because the general rule of the immune system is that all UN-recognized antigens will NOT be tolerated.

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Class I are present in all nucleated cells and platelets.

They are designated A, B and C.

Class II are present in APC and lymphocytes.

Their subclasses are DP, DQ and DR.

They play a fundamental role in the normal immune

response by presenting antigenic peptides to T-cells.

Helper T-cells(CD4+) recognise antigen in association

with MHC class II molecules, while cytotoxic T-

cells(CD8+) recognise antigen associated with MHC

class I.

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MHC LOCUS 12

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HUMAN MHC SUMMARY

MHC Class I MHC Class II

Names HLA-A, HLA-B, HLA-C HLA-DP, HLA-DQ, HLA-

DR

Tissue distribution All nucleated cells;

platelets .

B lymphocytes,

monocytes,

macrophages,

dendritic cells,

Langerhans cells,

activated T.

Recognized by Cytotoxic T cells

(CD8+)

Helper T cells (CD4+)

Function Elimination of

abnormal (infected)

host cells by cytotoxic

T cells.

Presentation of foreign

antigen to helper T

cells

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ANTIGEN ANTIBODY REACTION

Dr. Sulafa Eltayeb Ahmed

ANTIGEN

Antigens are substances able to provoke an

immune response and react with the products of

that response.

They react both with the T-cell receptor and with

antibody.

An antigenic molecule may have several antigenic

determinants (epitopes); each epitope can bind with

an individual antibody.

a single antigenic molecule can therefore provoke

many antibody molecules with different binding

sites.

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The tertiary structure, as well as the amino acid

sequence, is important in determining antigenicity.

Some low molecular weight molecules, called

haptens, are unable to provoke an immune

response themselves, but they can react with

existing antibodies.

Such substances need to be coupled to a carrier

molecule in order to have sufficient epitopes to be

antigenic.

For some chemicals, such as drugs, the carrier may

be a plasma protein.

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Complete antigen: A substance that induces an

immune response and that can specifically react

with the product of that response (the antibody).

Incomplete antigen (hapten): A low-molecular-

weight substance (a short peptide or drug) that only

acts as an antigen once it binds to macro-

molecules like plasma proteins.

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STRUCTURE OF THE IMMUNOGLOBULIN

1. Basic structure: Immunoglobulins act as

antigen-specific receptors on B cells and,

when secreted by plasma cells, mediate

humoral responses.

The basic structural unit of an

immunoglobulin molecule is a glycoprotein

monomer, consisting of four polypeptide

chains linked covalently by disulfide bonds.

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The molecule contains two identical light

chains and two identical heavy chains.

The structure has two identical antigen

binding sites consisting of both light and

heavy chains.

Heavy and light chains have variable

regions on their most N terminal ends.

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HEAVY AND LIGHT CHAINS:

These chains are subdivided into variable and

constant regions.

The light chains have two domains, one variable

and one constant. The heavy chains have four to

five domains, one variable and three or four

constant depending on the type of immunoglobulin.

The light chains may be of two different classes,

kappa (к) or lambda (λ),on the basis of structural

differences in the constant domain.

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MAJOR IMMUNOGLOBULIN CLASSES

There are five classes or isotypes of human

immunoglobulins. These are designated by the type

of heavy chain they have.

1. IgG: gamma( )H(heavy) chain

2. 1gA:alpha(α) H chain

3. IgM: mu (μ) H chain

4. 1gE:epsilon ( ) H chain

5. IgD: delta ( ) H chain

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Subclasses

1. IgG is further divided into four subclasses: IgGI,

IgG2, IgG3, and IgG4.

2. IgA: There are also two subclasses of IgA, called

IgAl and IgA2.

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CHARACTERISTICS OF THE FIVE CLASSES

IgG

It is the Ig present at the highest concentration in

plasma;

It is actively transported across the placenta;

It activates complement;

It opsonizes organisms to facilitate phagocytosis;

It is the Ig characteristically produced during the

secondary immune response.

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IgM

present in serum it is a pentameric molecule held

together with a J-chain as well as disulfide bonds;

It is the Ig characteristically produced during the

primary immune response;

It is the most efficient Ig at activating complement;

The monomeric form serves as the antigen

receptor on the B-cell surface.

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IgA

It is the main Ig in external secretions such as milk,

saliva, tears, and respiratory and intestinal mucusa

so it protects mucosal surfaces

It is the major protective factor in colostrum

It is present in secretions as a dimer with a J

(joining) chain and secretory piece

There are two subclasses: IgA1 and IgA2

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1gE

It is present in plasma as a monomer in very low

levels

It binds to mast cells and basophils that have FC

receptors for epsilon heavy chains.

The bridging of two 1gE molecules on cell

membranes causes release of granule contents

It is important in providing immunity against

parasitic infestation

It mediates Type I hypersensitivity (allergic)

reactions

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IgD

It is present in plasma at very low concentrations

It is present in the membrane of mature B cells at

very high levels

It functions as an antigen receptor (with IgM

monomers) on B cells.

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The functions of the constant region of

immunoglobulins are:

1- activation of the complement system,

2- binding to cell surface receptors on granulocytes

or macrophages to initiate phagocytosis

(opsinization).

The function of the variable region primarily

involves antibody-antigen interactions, including

precipitation, agglutination, and neutralization of

antigen.

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T-CELL RECEPTORS

The TCR has certain similarities to immunoglobulin

in that it is made up of two non identical polypeptide

chains that have constant and variable regions.

TCR has only one antigen binding site per

molecule but immunoglobulin has two.

The majority of TCR have α β chains but < 10%

are γ δ chains.

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ANTIBODY-ANTIGEN INTERACTIONS

The strength of binding of the Fab portion to the

epitope is known as affinity.

As antibodies are made in immune responses to

an infectious agent or its toxins, the quality of the

antibody tends to improve, with increasing affinity.

The total strength of antigen-antibody binding, not

just one interaction, is called avidity.

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The antigen antibody reaction leads to formation of

an antigen antibody complex or immune complex.

Its fate depends on its size and solubility.

The solubility of an immune complex is determined by

the nature of components involved and by their

relative quantities.

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Where the quantities of antigens and antibodies are

nearly in equilibrium, alarge immune complex will

form.

This will not remain in solution, but will precipitate

out.

Across-linked immune complex oragglutination will

form even in reactions with cell bound antibodies,

such as blood group antibodies.

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FATE OF AN IMMUNE COMPLEX AGGREGATION

Large, precipitating immune complexes are rapidly

attacked by macrophages.

Large, soluble immune complexes penetrate

vessel walls, successively leading to deposits on

the basement membrane and to tissue damage

from ongoing formation of immune complex.

Small soluble immune complexes are excreted by

the kidney.

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HUMORAL AND CELL MEDIATED

IMMUNITY

ROLE OF CELL-MEDIATED IMMUNITY IN HOST

DEFENSE

Host defenses against extracellular infectious

agents, such as extracellular bacteria, protozoa,

worms and fungi, are mediated by antibody,

complement, and phagocytes.

However, once an infectious agent invades a host

cell, these defenses are virtually useless.

Recovery from intracellular infection requires an

entirely different defense system ie: the cell-

mediated immunity (CMI)

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In CMI, the first goal of the immune system is to

destroy the intracellular infectious agent by killing

the host cell that harbors it.

In many cases, this will also kill the pathogen,

which may require the host cell for its own

reproduction.

Virus infection always requires the induction of cell-

mediated cytotoxicity, mediated by cytotoxic T cells,

natural killer (NK) cells, or activated macrophages.

The same cytotoxic mechanisms may be effective

against most tumor cells.

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In the special case where intracellular organism

infect a macrophage, activation of macrophage by

helper T cell (Thl ) may be sufficient for destruction

of the pathogen.

This results in the process called delayed-type

hypersensitivity (DTH).

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INDUCTION OF CELL-MEDIATED IMMUNITY

Like antibody production in humoral immunity, CMI

requires T-cell help.

Thl cells must first recognize antigen presented by

an MHC class II molecule on an antigen-presenting

cell.

The activated Thl cell secretes IL-2 and IFN- ,

which activate the cytotoxic effector cells.

Cytotoxic T-Iymphocyte recognition requires

recognition of both the antigenic peptide in the

infected cell and the MHC class I molecule.

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How do cytotoxic T cells kill their targets? They use:

a. Perforin: Fully activated CTLs contain granules

that are released when the CTL contacts a target

cell.

The granules contain perforin, a pore-forming

molecule that polymerizes in the membrane of the

target cell.

These pores damage the cell membrane, causing

lysis.

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b. Granzymes: The granules also contain enzymes

that damage the target cell, by passing through the

perforin pores into the target cell.

c. Fas and Fas ligand: Fas ligand interacts with the

Fas molecule on the target cell surface, inducing

apoptosis.

NK cells kill by releasing perforin, granzymes, and

cytokines (IFN- and TNF- ), in a manner similar

to T cells can kill target cells.

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GRANZYME PATHWAYS

ANTIBODY-DEPENDENT CELLULAR

CYTOTOXICITY ADCC

NK cells are the major cell type that carries

out antibody-dependent cellular cytotoxicity

(ADCC).

NK cells have Fc receptors that recognize

the Fc domains of IgG.

When IgG is bound to foreign antigen on the

surface of an infected cell, NK cells can

recognize it, bind, and deliver a lethal hit.

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HUMORAL IMMUNITY

When a helper T lymphocyte comes in contact with

the APC, the T cells will be activated to secrete

cytokines.

The cytokines include interleukin (IL)-4, which

activates B cells, and interferon- , which activates

macrophages.

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REGULATION OF THE IMMUNE RESPONSE

The naïve helper Tcell, is capable of producing all

T-cell cytokines.

It may differentiate into either aTh1or a Th2 cell.

The T h1 cell assists cell mediated immunity by

producing interferon-y and by activating

macrophages and cytotoxic CD8 cells.

The T h2 cell produces IL-4, IL-5, and IL-6,

provoking plasma cell differentiation from B cells.

There is also cross-regulation and inhibition

between T hl and T h2 cells mediated by IL-l0 and

IFN-y.

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HUMORAL IMMUNITY

Mature B cells bind and internalize antigen by using

their antigen receptors, the surface immunoglobulins

(lgM and IgD).

This binding is antigen specific, and B cells can

recognize, bind, and internalize unprocessed antigen.

The B cells process the antigenic peptides, and

present them on the B-cell surface bound to MHC class

II molecules.

When an activated helper T cell bind to the B cell this

will signals the helper T cell to release cytokines (include

IL-2, IL-4, and IL-5) that are essential for B-cell division

and differentiation to antibody-producing plasma cells.

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CLONAL SELECTION

One B cell, one antibody specificity; one T cell, one

T-cell antigen-receptor specificity.

All specificities that will ever be needed are made

all the time by random selection of variable region

structures.

Antigen selects the cells that have complementary

receptors by binding to them, and only those cells

undergo clonal expansion (cell division) and

differentiation.

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Secondary Immune Response:

A secondary immune response occurs on

subsequent exposure to an antigen that has

previously been encountered.

There are many differences between primary and

secondary immune responses.

In a secondary response:

1. More antibody is produced.

2. The lag phase is always shorter.

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3. Less antigen is required to trigger a response.

4. Antibody affinity changes in the immune response.

5. The antibody isotype (class) differs as follows:

In the primary response, IgM always appears first. In

the secondary response to an injected antigen, IgG

is the predominant antibody;

for an antigen administered via a mucosal route

(oral, inhaled), IgA is usually the predominant

antibody isotype.

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How humoral immune response combats

microbes:

Antibodies bind to microbes and prevent them from

infecting cells, thus "neutralizing" the microbes.

IgG antibodies coat ("opsonize") microbes and

target them for phagocytosis.

IgG and IgM activate the complement system by

the classical pathway, and complement products

promote phagocytosis and destruction of microbes.

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Decline of Immune Responses :

The majority of effector lymphocytes induced by an

infectious pathogen die by apoptosis after the

microbe is eliminated, thus returning the immune

system to its basal resting state.

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The initial activation of lymphocytes also generates

long-lived memory cells, which may survive for

years after the infection.

Memory cells respond faster and more effectively

against the antigen than do naive cells.

This is why the generation of memory cells is an

important goal of vaccination.

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