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Chapter (1)IMMUNITY

Immunity is the ability of human body to resist almost all types of

organisms or toxins that tend to damage the tissues and organs(Guyton

and Hall, 2006).

The immune system is a complex network of cells, proteins,

tissues, and organs that work together to protect the body against

infectiousdiseases or other insults. The immune system is composed of a

number of cell types that function in different ways, and other blood-

borne factors to provide a large variety of defense

mechanisms(Moazzamet al,2013).

Structure of immune system :

The organs of the immune system are positioned throughout the

body. They are called lymphoid organs because they are home to

lymphocytes, a type of white bloodcells (WBCs) that are the key players

in the immune system.

There are two groups of immune system organs:

A) Primary (central) organs:where immature lymphocytes develop,

these organs are:

1-Bone marrow:It is the soft tissue in the hollow center of bones which is

the ultimate source of all blood cells, including lymphocytes.

2-The thymus:It is a lymphoid organ that lies behind the sternum.

Lymphocytes known as T lymphocytes or T cells (“T” stands for

“thymus”) mature in the thymus and then migrate to other tissues. B

lymphocytes, also known as B cells (“B” stands for “bone marrow”),

become activated and mature in the liver during the fetal life and in the

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bone marrow after birth into plasma cells, which make and release

antibodies(Janeway et al,2005).

B) Secondary (peripheral) tissues:Where antigen (an agent or substance

that can trigger an immune response) is localized so that it can be

effectively exposed to mature lymphocytes, these tissue are :

1-Lymph nodes: They are Small bean-shaped structures ,which are

located in many parts of the body along the lymphatic vessels, with

clusters in the neck, axilla, abdomen, and groin. They are lymphoid

tissues that contain numerous specialized structures.

Each lymph node contains specialized compartments where the

immune cells congregate , and where they can encounter antigens. As

regard structure of lymph node, it is divided into 3 compartments; the

outer cortex, the inner medulla and the paracortex inbetween. The cortex

consists mainly of the B cells arranged as follicles, which may develop a

germinal center when challenged with an antigen, while T cells from the

thymus concentrate in the paracortex and plasma cells located in the

medulla (Tomoya et al, 2004).

Immune cells, microbes, and foreign antigens enter the lymph

nodes via incoming lymphatic vessels or the lymph nodes’ tiny blood

vessels. All lymphocytes exit lymph nodes through outgoing lymphatic

vessels. Once enter in the bloodstream, lymphocytes are transported to

tissues throughout the body. They circulate everywhere for foreign

antigens, then gradually drift back into the lymphatic system to begin the

cycle all over again.

Cells and fluids are exchanged between blood and lymphatic

vessels, enabling the lymphatic system to monitor the body for invading

microbes(Tomoya et al,2004).

2-The spleen: It is a flattened organ at the upper left of the abdomen.

Like the lymph nodes, the spleen contains specialized compartments

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where immune cells gather and work. The spleen serves as a meeting

ground where immune defenses confront antigens (Mebius and Kraal,

2005).

3- Mucosal-Associated Lymphoid Tissue (MALT): They are clumps of

lymphoid tissue which are found in many parts of the body, especially in

the linings of the digestive tract, airways, and lungs that serve as

gateways to the body. These tissues include:

GALT (Gut-Associated Lymphoid Tissue): Include the tonsils,

adenoids, appendix, and peyer's patches.

BALT (Bronchial/Tracheal-Associated Lymphoid Tissue).

LALT (larynx-associated lymphoid tissue).

NALT (Nose-Associated Lymphoid Tissue).

VALT (Vulvovaginal-Associated Lymphoid Tissue).

CALT (conjunctival-associated lymphoid tissue).

LDALT (lacrimal duct-associated lymphoid tissue).

SALT (skin-associated lymphoid tissue)(Cesta,2006).

Types of cells of immune system:The cells associated with the immune system are generally termed

leukocytes, or WBCs. Leukocytes are divided into two main categories:

phagocytes (granulocytes, monocytes, and macrophages) and

lymphocytes (T-lymphocytes, B-lymphocytes, and natural killer cells)

which are the major players in the immune response.

A)Phagocytes:

1) Macrophages: Its function is mediated through phagocytosis; it is

initiated by Chemotaxis; the process by which phagocytes are attracted

and adhere to microorganisms. Macrophages have cell-surface receptors

that recognize certain molecules on the surface of various pathogens.

Then the pseudopods of phagocytes engulf the microorganism and

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enclose it in a phagocytic vesicle (phagosome) to complete ingestion by

lysosomal enzymes and oxidizing agents(Aderem and Underhill, 1999).

Also, macrophages can Processes and presents antigens to T

cellswhich named antigen-presenting cells (APCs).They cansecret

cytokines, interleukin-1 (IL-1) to induceproliferation of B cells and also,

secret interferon that stimulates T cell growth(Joke MM den Haan et al,

2014).

2)Monocytes:can develop into two types of cell:

a) Dendritic cells (DCs):which are APCs able to mark out foreign

bodies to be destroyed by lymphocytes.

b) Macrophages:they are phagocyte cells able to act as

APCs(Ziegler-Heitbrock et al, 2010).

3)Granulocytes: (Microphages) :

a) Neutrophils:They may be subdivided into segmented neutrophils

and banded neutrophils. They form part of the polymorphonuclear

cell family (PMNs) together with basophils and eosinophils. They

are phagocytes, capable of ingesting bacteria and other

microorganisms or particles(Nathan, 2006).

b) Eosinophils: They are involved in allergic reactions and attack

multicellular parasites such as worms(Rothenberg & Hogan,

2006).

c) Basophils: They are involved in allergic reactions. They can

release histamine, which helps to trigger inflammation and release

heparin, which prevents blood from clotting(Nakanishi, 2010).

B)Lymphocytes:

1)T-Lymphocytes:They are classified into :

a) Cytotoxic T (killer T) (CD8)cells:They carry the CD8 protein

surface cell marker. They can kill foreign cells through chemical

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lysis. Also They release cytokines, interferon-gamma (IFN-γ) that

attractmacrophages and increases their phagocytic activity. They

also prevent macrophage migration from site of action.

b) Helper T (CD4) cells:Theycarry the CD4 protein surface cell

marker. They Cooperate with B cells to amplify antibody

production by plasma cells. They Secrete interleukin-2 (IL-2) to

help to stimulate proliferation of T and B cells and also secrete

IFN-γ and tumor necrosis factor (TNF), which stimulate the

inflammatory response.

c) Suppressor T (regulatory T)(Tregs)cells:They regulate the actions

of T cells and B cells and help to prevent the immune system from

overreacting. They may directly destroy activated lymphocytes.

d) Memory T cells:They remainin lymphoid tissue and recognize

original invading antigens, even years after exposure(Janeway et

al,2001).

2) B lymphocytes:They differentiated into :

a) Plasma cells:They produce antibodiesor immunoglobulins, which

are Y shaped proteins that bind to infected microbes or cells of our

body that have become infected. Antibodies can either neutralize

the target microbe or can mark it out for attack by T lymphocytes.

b) Memory B cells: They can respond more rapidly and forcefully if

the same antigen enter the body in the future(Janeway et al,2001).

3) Natural killer (NK) cells: They are non-T, non-B lymphocytes.They

can destroy cells with malignant transformation or infected with

viruses(Janeway et al,2001).

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Immunoglobulins (Antibodies)Immunoglobulins (Igs) or antibodies (Abs) are glycoprotein

molecules produced inresponse to antigens (Ags) which are foreign

substances entering the living body. Theybinding to them and forming

antigen-antibody complexes resulting in Ag elimination andprotection of

the body of the host. Igs are produced by B-lymphocytes(plasma cells)

and are found in fraction of blood called gamma globulin.Igs are

synthesized with a molecular arrangement that fits the shape of molecules

on the antigens, in order to allow effective binding of the Igs. Igs binding

to Ags basically help toinactivate, weaken or enhance phagocytosis of

Ags(Schroeder and Cavacini, 2010).

Basic structure of immunoglobulins:All Igs have the same basic structural units of 2 identical light

chains and 2 identical heavy chains, theheavy and light chains are joined

together by interchain disulphide bonds and non-covalent

interactions.The number of interchain disulphide bonds varies among

different Igs. Amino acid sequence ofboth heavy and light chains of an Ig

characterizes two distinct regions known as variable (V) and constant (C)

regions (Janeway et al,2001).

Light and heavy chainsare composed of both a variable and

constant region designated as VL and CL (light chains) and VH and

CH(heavy chains).The amino acid sequence of the variable region

determine antigenic specificity of the Igs. Constant regions are the same

for each specific class of Igand carry the effector sites(Schroeder and

Cavacini, 2010).

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Fig.(I):Basic structure of Immunoglobulin(Janeway et al, 2001).

There are two types of light chains,kappa (κ) and lambda (λ).No

functional difference has been found between Igs having λ or κ light

chains. The ratio of the two types of light chain varies from species to

species. In mice, the average κ to λ ratio is 20:1, whereas in humans it is

2:1. The reason for this variation is unknown. Differences in the type of

light chains also form a basis for grouping of Igs into various

types(Redegeld and Nijkamp, 2003).

There are 5 types of heavy chains whichdefines the class of Igs,

namely, Alpha (α), Gamma (γ), Miu (μ), Delta (δ) and Epsilon (ε). The

hinge region is the area of the Ig where the arms of the Abs form a ‘Y’,it

is a flexible region(Janeway et al,2001).

Fragmentation of Ig using reducing & denaturing agents produce

subunits of Ig, two heavy (H) chain and two light (L) chain which are

found in equimolar amounts with 2 H and 2 L chains. While proteolytic

digestion by proteasesproduce fragments. Papain enzyme cleaves the

immunoglobulin molecule into three pieces, two Fab fragmentsand one

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Fc fragment. So, molar ratio of Fab/Fc is 2:1. While pepsin enzyme

cleaves immunoglobulin to yield one F(ab')2 fragment and many small

pieces of the Fc fragment, the largest of which is called the pFc' fragment.

These fragments are:

1-Fab (fragment for antigen binding):It is the region of Ig that bind

to Ag. It is gotten upon digestion of Ig with papain and its cleavage at the

hinge region. It is composed of one constant and one variable

domainfrom each heavy and light chains of the Ig (the antigen binding

site) which is particular to the kind of antigenic determinant the Ig will

bind(Janeway et al,2001).

2-Fc(fragment crystallizable):It is the region of Ig which mediate

effector functions of an Ig to Ag.It is called fragment crystallizable

because it is readily crystallized. It is gotten upon digestion of Ig with

papain and its cleavage at the hinge region. It is composed of two heavy

chains that contribute two or three constant domains depending on the

class of the antibody.Variations in the Fc determines the different classes

of Igs.The hinge region is between the Fab and the Fc portion and

controls interactions between these portions(Janeway et al,2001).

3- F(ab')2 : Treatment of Igs with pepsin results in cleavage of the

heavy chain, resulting in a fragment that contains both antigen binding

sites held together by disulfide bonds, it is called F(ab')2 because it is

divalent. Fc portion is digested into small peptides by pepsin, the largest

of which is called the pFc′ fragment. The F(ab')2 binds to Ag but does not

mediate effector functions. F(ab')2 is written with a prime because it

contains a few more amino acids than Fab, including the cysteines that

form the disulfide bonds(Janeway et al,2001).

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Fig.(II):The Y-shaped immunoglobulin molecule can be dissected by partial

digestion with proteases(Janeway et al,2001).

General functions of immunoglobulins:

1) Antigens binding: Igs bind to specific Antigenic determinants (ADs)

on the antigen surface. They bind to at least 2 or in a few cases more

ADs. The number of ADs to which an Ig can bind is referred to as its

valency. Ag binding result in formation of antigen-antibody complexes,

resulting in Ag elimination and protection of the body of the host.

Different Igs molecules can have different Ag binding properties

because of different variable region of heavy chain (VH) and variable

region of light chain (VL)(Janeway et al,2001).

2) Most Igs mediate several effector functions which include:

a-Activation (fixation) of complement:It is an important means

of clearance of opsonized pathogens that results into lysis of cells and

release of biologically active molecules.

b-Binding to various cells: It is donethrough Fc receptors on these

cells to facilitate specific functions by bound cells e.g. phagocytic cells,

lymphocytes, platelets etc.

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Most effector functions of Igs are carried out after the Ig binds to

Ags (Janeway et al,2001).

** Fc receptor(FcR):It is a protein found on the surface of most of

immune system cells including B lymphocytes, follicular dendritic cells,

natural killer cells, macrophages, neutrophils, eosinophils, basophils,

human platelets, and mast cells that contribute to the protective functions

of the immune system. Its name is derived from its binding specificity to

Fc (Fragment, crystallizable) region of the antibody. Fc receptors bind to

antibodies that are attached to infected cells or invading pathogens. Their

activity stimulates phagocytic or cytotoxic cells to destroy microbes, or

infected cells by antibody-mediated phagocytosis or antibody-dependent

cell-mediated cytotoxicity, so they are considered a key immune

regulatory receptors connecting the antibody mediated (humoral) immune

response to cellular effector functions(Owen etal, 2009).

Immunoglobulins types and classes : Based on differences in the amino acid sequences in the constant

region of the heavy chains. There are five classes of Igs:

1-IgG -Gamma (γ) heavy chains.

2-IgM -Mu (μ) heavy chains.

3-IgA -Alpha (α) heavy chains.

4-IgD -Delta (δ) heavy chains.

5-IgE -Epsilon (ε) heavy chains.

In each class of Ig small differences in the constant regions of the

heavy chain still occur, leading to subclasses of the Igs e.g. : IgG and IgA

Subclasses(Janeway et al,2001).

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1- IgG :

It is the predominant isotype found in the body so, It is the major Ig

in serum (systemic immunity) and It is also the major Ig found in

extravascular spaces. It has the longest serum half-life of all Igs.

All IgGs are monomers, subtypes and subclasses differ in number

of disulphide bonds and lengths of hinge region. Based on structural,

antigenic and functional differences in the constant region of the heavy

chain, IgG classified into 4 subclasses (IgG1, IgG2, IgG3 and IgG4), they

are IgG1 -Gamma 1 (γ1) heavy chains, IgG2 -Gamma 2 (γ2) heavy

chains, IgG3 -Gamma 3 (γ3) heavy chains and IgG4 -Gamma 4 (γ4)

heavy chains (Scharf et al,2001).

It is the most versatile Ig and can carry out all functions of Ig

molecules. IgG subclasses exhibit different functional activities.As regard

activation of the complement cascade, IgG4 is the only subclass that fails

to fix complement. All IgG subclasses have similarity in transplacental

transport and participation in the secondary immune response. It is

considered the only Ig that crosses the placenta.

IgG antibodies also contribute directly to an immune response

including neutralization of toxins and viruses which then destroyed by

phagocytosis(Cavacini et al,2003).

2- IgM :

It is the 3rd most abundant Ig in serum and the first Ig made by

fetus in most species.It normally exists as a pentamer in serum but also

occur as a monomer. It has an extra domain on the mui chain (CH4) and

another protein covalently bound via disulfide bond called J-chain. This

chain helps it to polymerize to the pentamer form.

Its function include that it is a good complement fixing Ig and a

good agglutinating Ig.IgM can bind to some cells via Fc receptors. One of

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the important functions ofIgM is to diagnose acute exposure to pathogen

as it is associated with a primary immune response (Boes, 2000).

3- IgA:

It is the second most abundant Ig in serum after IgG, but has higher

levels at mucosal surfaces and in secretions so, it is the major class of Ig

in secretions (tears, saliva, colostrums, mucus, gastric and pulmonary

secretions) and is important in mucosal (local) immunity.

Serum IgA is monomeric, but IgA found in secretions (secretory

IgA) is a dimer. Secretory IgA also contains a protein called secretory

piece or tail piece (T- piece) which help the IgA to move across mucosa

without degradation in secretions.

There are two subclasses of IgA, IgA1 and IgA2, whose structures

differ mainly in their hinge regions. They are IgA1 -Alpha 1 (α1) heavy

chains and IgA2 -Alpha 2 (α2) heavy chains.

IgA has a critical role in protection of mucosal surfaces from

toxins, virus and bacteria by direct neutralization or by prevention of

binding to the mucosal surface. Intracellular IgA may also be important in

preventing bacterial or viral infection and/or pathogenesis. It can bind to

Fc receptors on some cells as PMN cells and lymphocytes. It does not

normally fix complement (unless aggregated)(Woof andMestecky, 2005).

4- IgD:

It is found in low levels in serum (4th highest serum Ig) with a

short plasma half-life due to sensitivity of the molecule. It exists as

monomers and have a tail piece.IgD is expressed on the membranes of B

cells when they leave the bone marrow and populate secondary lymphoid

organs (Geisberger et al,2006).

Its function is unclear, as it is not known to participate in themajor

antibody effector mechanisms.However membrane-bound form of IgD is

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found primarily on B cells surface and serves as a receptor for Ag and

also regulates B cell fate. As regard complement fixation, it does not fix

complement(Riesbeck and Nordstrom,2006).

5- IgE :

It is the lowest serum Ig with the shortest half-life, however IgE is

a very potent Ig. It occurs as a monomer and has an extra domain (CH4)

in the constant region.

It binds very tightly to Fc receptors on basophils and mast cells

even before interacting with Ags cells (Does not require Ag binding) , so,

it is involved in allergic reactions. Also it plays a role in parasitic

diseases. Eosinophils have Fc receptors for IgEs and when eosinophoils

bind to IgEs coated helminthes death of the parasite results. As regard

complement fixation, it does not fix complement. The development of

anti-IgE antibodies has been used as therapy for allergy andasthma

(Chang et al,2007).

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Types of immunity The immunity can be divided into two major components:

I- Non-specific (innate) (natural) immunity :

It is the immunity that present at birth and comprises defense

mechanisms that provide a general response against invasion by a wide

range of antigens(Medzhitov, 2007).

It includes the following:

A) Mechanical and chemical barriers:

1) Theepithelium that covers the skin and the mucous membrane that

lines the gastrointestinal, genitourinary and respiratory tracts.

2) Destruction of swallowed organisms by the acid secretions of the

stomach and the digestive enzymes.

3) Other physiological properties of the body, such as temperature,

pH (acid/base), and oxygen levels, also act to destroy or keep out

potential antigens(Janeway et al, 2005)

B) Non-specific cellular defense mechanisms:

1. Phagocytosis of bacteria and other invaders by WBCs and cells of

the tissue macrophage system.

2. Natural killer (NK) cells, which are non-T, non-B lymphocytes

and can recognize and destroy foreign cells, tumor cells, and even

some infected cells(Janeway et al, 2005).

C) Non-specific humoral defense mechanisms:

Due to the presence of certain chemical compounds in the blood

that attach to foreign organisms or toxins and destroy them, as:

1) lysozyme, a mucolytic polysaccharide that attacks bacteria.

2) basic polypeptides, which react with and inactivate certain types

of gram-positive bacteria.

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3) thecomplement complex, a system of about 20 proteins that can be

activated in various ways to destroy bacteria and promote

clearance of dead cells and antibody complexes(Rus et al, 2005).

II- Specific (acquired) immunity:

It is the ability of the body to develop an extremely powerful

immunity against individual invading agents such as lethal bacteria,

viruses and toxins(Guyton and Hall, 2006).

Acquired immunity does not develop until after invasion by a

foreign organism or toxin and the body must have some mechanism for

recognizing this invasion. Each toxin or each type of organism almost

always contains one or more specific chemical compounds in its

membrane. In general, these are proteins or large polysaccharides, and

initiate the acquired immunity. These substances are called antigens

(antibody generations). For a substance to be antigenic, it usually must

have a high molecular weight, 8000 or greater. Furthermore, the process

of antigenicity usually depends on regularly recurring molecular groups,

called epitopes, on the surface of the large molecule. This also explains

why proteins and large polysaccharides are almost always antigenic,

because both of these have this stereochemical characteristicand so, Both

types of acquired immunity are initiated by antigens(Guyton and Hall,

2006).

This part of the immune system develops based on the exposure to

antigens and involves:

A)Humoral immunity or B-cell immunity:

It is mediated by production of specific

antibodies(immunoglobulins) (Igs) by B-lymphocytes into the body’s

fluids. Antibodies recognize antigens circulating in the bloodstream. They

are powerless, however, to penetrate cells. Each B cell is programmed to

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make one specific antibody. When a B cell encounters its triggering

antigen, it gives rise to many large cells known as plasma cells. Every

plasma cell is essentially a factory for producing an antibody(Guyton and

Hall, 2006).

Whenever antigen and antibody interlock, they form an antigen-

antibody (immune) complex. Antibodies themselves do not destroy

antigen; they inactivate and mark it for destruction by the following

mechanisms:

1- Neutralization:in which neutralizing antibodies bind to and block

specific sites on surface of antigens (viruses and bacteria), thus

preventing these antigens from binding to receptors on tissue cells and

render its attack ineffective,later destroyed by phagocytes.

2-Agglutination:in which antibodies bind the same determinant on more

than one antigen and make antigen-antibody complexes that are clumped

into large clumps (agglutination)that are attractive targets for

phagocytosis.IgMs are good at this with mismatched blood.

3-Precipitation:in which antibodies glue together withserum-soluble

antigens and form soluble molecules which are clumped into large

insoluble complexes, forcing them to precipitate out of solution in clumps

that are attractive targets for phagocytosis.

4-Complement activation (fixation):in which antibodies bound to cells

change their shape and exposecomplement binding sites.This triggers

complement fixation on the antigenic cell surfaceand thus activate the

classical complement pathway (known as complement dependent

cytotoxicity or CDC) resulting in cell lysis(Rus et al, 2005).

5-phagocytosis:it is initiated by Chemotaxis; the process by which

phagocytes are attracted and adhere to microorganisms. Macrophages

have cell-surface receptors that recognize certain molecules on the

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surface of various pathogens. Then the pseudopods of phagocytes engulf

the microorganism and enclose it in a phagocytic vesicle (phagosome) to

complete ingestion by lysosomal enzymes and oxidizing agents

(Aderem and Underhill, 1999) .

Activation of effector cells: Critically antibodies also act as a link

between the antibody-mediated and cell-mediated immune responses

through interaction with Fc receptors on effector cells to engage antibody

dependent cellular cytotoxicity (Powelland Hogarth, 2008).

In order to combat pathogens that replicate outside cells, antibodies

bind to pathogens to link them together, causing them to agglutinate.

Since an antibody has at least two paratopes, it can bind more than one

antigen by binding identical epitopes carried on the surfaces of these

antigens. By coating the pathogen, antibodies stimulate effector functions

against the pathogen in cells that recognize their Fc region(Pier et al,

2004).

Those cells that recognize coated pathogens have Fc receptors,

which, as the name suggests, interact with the Fc region of IgA, IgG, and

IgE antibodies. The engagement of a particular antibody with the Fc

receptor on a particular cell triggers an effector function of that cell;

phagocytes will phagocytose, mast cells and neutrophils will degranulate,

natural killer cells will release cytokines and cytotoxic molecules; that

will ultimately result in destruction of the invading microbe. The

activation of natural killer cells by antibodies initiates a cytotoxic

mechanism known as antibody-dependent cell-mediated cytotoxicity

(ADCC) – this process may explain the efficacy of monoclonal antibodies

used in biological therapies against cancer(Janeway et al,2001).

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Formation of memory B cells:After exposure to an antigen, some of

activated B-lymphocytes do not differentiate into plasma cells but forms

memory B cells that can respond more readily on second exposure to the

same antigen (the secondary response) (Janeway et al,2001).

B) Cell-mediated immunity or T-cell immunity:

It is mediated by activation of specific cells(activated T-

lymphocytes) against a particular pathogen or other foreign substance. T

cells recognize antigen infected cells through proteins, termed major

histocompatibility complex(MHC), displayed on the surface of an infected

cell. These cells include:

1) Cytotoxic (killer) T cells: They can recognize and destroy the

infected cells by secretion of hole forming proteins called

perforinsand then extracellular pathogens stimulate a response from

helper T cells(Guyton and Hall, 2006).

2) Helper T cells: They coordinate immune responses by

communicating with other cells of the immune system that can

destroy the infected cell by exchanging chemical messengers called

cytokines. Some cytokines function as chemical “switches” that turn

certain immune cell types on and off. Examples of cytokines include

interleukins (IL), tumor necrosis factor α (TNF-α), and interferon γ

(IFN-γ)(Janeway et al,2001).

3) Suppressor (regulatory) T cells (Tregs): Theymodulate the immune

system, maintain tolerance to self-antigens, and abolish autoimmune

disease. These cells generally suppress or downregulate induction and

proliferation of effector T cells and thus cause shutting down immune

responses after they have successfully eliminated invading organisms.

This is an important "self-check" built into the immune system to

prevent excessive reactions(Shevach,2000).

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The immune system must be able to discriminate between self and

non-self. When self/non-self discrimination fails, the immune system

destroys cells and tissues of the body and as a result causes autoimmune

diseases. Regulatory T cells actively suppress activation of the immune

system and prevent pathological self-reactivity, i.e. autoimmune disease

(Shevach,2000).

4) Memory T cells: After exposure to an antigen, some immune cells

become memory T cells and can respond more readily when the

immune system encounters that antigen again(Janeway et al,2001).

5) Antigen-Presenting Cells (APCs): These are another type of cells of

acquired immunity. They do not respond to specific antigens and Play

essential roles in immunity. They engulf foreign particles and present

fragments of antigens on their own surfaces to be recognized by T

cells.The major APCs are dendritic cells (DCs), macrophages, and

activated B cells. They are the major initiators of acquired immunity,

as they migrate to the lymph nodes and secondary lymphoid organs,

and present antigens to T and B cells(Janeway et al,2001).

Acquired immunity can be classified into:

1-Passive immunity:

It is the transfer of active immunity, in the form of readymade

antibodies, from one individual to another. Passive immunity can occur

naturally, when maternal antibodies are transferred to the fetus through

the placenta, and can also be induced artificially, when high levels of

human (or horse) antibodies specific for a pathogen or toxin are

transferred to non-immune individuals.Passive immunity provides

immediate protection, but the body does not develop memory, therefore

the patient is at risk of being infected by the same pathogen

later(Janeway et al,2001).

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2-Active immunity:

When Band T cells are activated by a pathogen, memory cells

develop, and the primary immune response results. Throughout the

lifetime of an animal these memory cells will "remember" each specific

pathogen encountered, and are able to mount a strong secondary

response, if the pathogen is detected again(Janeway et al, 2001).

Active immunity can occur naturally, when a person is exposed to

a live pathogen, and develops a primary immune response, which leads to

immunological memory. This type of immunity is "natural" because it is

not induced by intentional exposure. Also it can be induced artificially by

a vaccine, a substance that contains antigen. A vaccine stimulates a

primary response against the antigen without causing symptoms of the

disease. There are four types of traditional vaccines: Inactivated (killed)

vaccines, Liveattenuated vaccines,Toxoids (inactivated toxins) and

Subunit (conjugate)vaccines(Plotkin et al,2013).

Factors that can affect immune system:Our immune system is only as strong and healthy as we help itto

be. So, we can influence the health of our immune system.There are

many factors that can contribute to the general weakening of theimmune

system and also there are many factors within your control that can affect

the strengthof your immune system and help you live a healthier life

(Coico etal,2003).These factors include:

1) Stress : The successful management of stress is very important to the

health of your immune system. Studies have shown that high levels of

stress cause a decrease in the activity of the white blood cells,

depressing your entire immune system. Although people who

experience chronic stress or on-going stress have the poorest immune

function, even acute or temporary stress causes marked changes in the

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optimal functioning of the immune system. This relation will

discussed later in details(Salleh, 2008).

2) Environmental pollution and Radiation : They lead to weakening of

the immune system. Heavy metals as mercury, lead, cadmium,

arsenic, nickel, and aluminum are poisonous which can result from

environmental contamination due to industrial pollution. Mercury

causes a neurological side effect which decrease production of WBCs,

including T cells. While Cadmium creates retarded immune responses

due to effect on the kidneys, liver, and T cell production (Janeway

and Travers, 2004).

3) Nutrition :Eating a healthy well-balanced diet helps to receive the

protective effects of vitamins and minerals. Many vitamins

andminerals are being studied for their beneficial effect on the

immune system. Studies have shown that Vitamins A, C, and

E(antioxidants) may protect cell damage from free radicals - the

electrons that can damage healthy cells and lead to tumors.Vitamins

B6 and B12 may help boost the immune system, and zinc and

selenium are being studied for their ability toimprove white blood cell

activity. So, malnutrition (unbalanced diet/poor eating habits that

cause a lack of vitamins and minerals) lead to weakening of

theimmune system(Roitt and Delves, 2001).

4) Exercise : Studies have shown that regular exercise improves blood

circulation in the body and boosts immune systemresponse time. So,

lack of exercise as well as excessive exercise resulting in

physiological stress that lead to weakening of theimmune system

(Roitt and Delves, 2001).

5) Sleep : Good quality sleep aids your immune system while sleep

deprivation leads to impairedimmune cell function.A lot of studies

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have showedthat sleep deprivation cause decreased T-cells and

increased inflammatory cytokines(Born etal, 1997).

6) Age: Ability of the immune system to respond is decreased at early

and old age.The gradual deterioration of the immune system occurred

with natural age advancement is called immunosenescence. It involves

both the host’s capacity to respond to infections and the development

of long-term immune memory, especially by vaccination. It is

considered a major contributory factor to the increased frequency of

morbidity and mortality among the elderly (Muszkat etal, 2003).

Immunosenescence is a multifactorial condition leading to many

pathologically significant health problems in the aged population. Some

of the age-dependent biological changes that contribute to the onset of

immunosenescence are:

a. Reduction in the self-renewal capacity of hematopoietic stem

cells (HSC), which provide the regulated lifelong supply

of leukocyte progenitors that are in turn able to differentiate into a

diversity of specialised immune cells

(including lymphocytes, antigen-presenting dendritic

cells and phagocytes). This is due to the accumulation

of oxidative damage to DNA by aging and cellular metabolic

activity and the shortening of telomeric terminals of chromosomes

(Ito etal, 2004).

b. Decline in the total number of phagocytes in aged hosts with an

intrinsic reduction of their bactericidal activity(Strout and Suttles,

2005). 

c. Reduction in the cytotoxicity of NK-cells and the antigen-

presenting function of dendritic cells with old age(Mocchegiani

and Malavolta, 2004).

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Review of literature

d. Decline in humoral immunity caused by a reduction in the number

of antibody producing B-cells along with a

smaller immunoglobulin diversity and affinity(Gibsonetal, 2009).

7) Alcohol, drugs and tobacco :Alcohol and drugs such as heroin and

cocaine have shown a markedsuppression of immune system

functions. Smoking is one of the major causes of lung cancer and heart

disease and amajor contributor ofcell-damaging free radicals. Studies

have shown that cigarette smoke might contain radioactive particles

and when tobacco is inhaled, two dangerous alpha-emitting

radioisotopes enter the body and affect the lymph nodes(Coico

etal,2003).

8) Medications : Anti-cancer drugs, corticosteroids, immune suppressant

drugs, and antibiotics lead to weakening of the immune system.

9) Diseases : either infectious diseases or others causing more depression

on the immune system like:Cancer, and hematological malignancy

(such as leukemia, lymphoma and myeloma), Diabetes Mellitus,

Cystic fibrosis, Lupus Erythematosus, Nephrotic syndrome, Viral

infections, HIV, Ulcerative colitis, Sickle-cell disease, Liver

disease/cirrhosis, and Cushing's syndrome(Roitt and Delves, 2001).

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