II. Acquired (specific or adaptive)

immunity

•The adaptive immune system is

composed of highly specialized,

systemic cells & processes that

eliminate or prevent pathogenic

challenges.

• The adaptive immune response has

the ability to recognize and

remember specific pathogens (to

generate immunity), and to mount

stronger attacks each time the

pathogen is encountered.

•It is adaptive immunity because the

body's immune system prepares

itself for future challenges.

Antigen or Immunogens

•Antigen is a foreign substance of

high molecular weight that

induces a specific immunological

response in the form of antibody

mediated immunity (AMI), or

cell-mediated immunity (CMI) or

both.

Ag: antibody generator.

Molecules differ in their

effectiveness in stimulating Ab

production as proteins &

polysaccharides are generally

good antigens, whereas lipids &

DNA are rarely antigenic.

Epitope: is a part of antigen

recognized by the immune system

(antibody).

Any given antigen may have several

epitopes.

Each epitope is recognized by a

different antibody.

Ags are large molecules ( high M.W).

Hapten: partial antigen, specific non

protein substance which does not itself

elicit antibody formation but elicit the

immune response when coupled with

carrier protein.

As Penicillin: has low M. W. & by itself

is not an antigen, in body changed by

enzyme result in molecule that can

combine with large protein carrier to

form antigenic hapten carrier complex.

Origin of Antigens

1. Exogenous Antigens: Ags that

have entered the body from the

outside by inhalation, ingestion,

or injection.

2. Endogenous Antigens:

Ags generated within the cell, as a

result of normal cell metabolism,

or because of viral or intracellular

bacterial infection.

3. AutoAntigens:

Is usually a normal protein that is

recognized by the immune system

of patients suffering from a

specific autoimmune disease.

These antigens under normal

conditions, not be the target of the

immune system.

Types of antigen

A.Heterologous antigen:

is an Ag derived from one species

and is capable of stimulating an

immune response in another

species.

B. Homologous Antigen:

is an Ag in an individual of one

species which is capable of

eliciting an immune response in

genetically different individual of

the same species e.g. RBCs &

tissue Antigens.

C. Heterophile Antigens(common

to more than one species):

Antigens share the antigenic

determinants & the Antibody

formed to any of them could react

with the other (cross reaction).

Cross reactivity: reaction between

antibody & antigen that differ

from the immunogen.

a. Human heart valve tissue &

certain Antigen found in

Steptococcus pyogenes.

b. Forssman Antigen: glycopeptide

heterophile protein found in

certain animals as dog, horse, cat,

sheep (RBCs), pneumococci

which valuable in determining

infection with mononucleosis;

antibody formed in human react

with Forssman antigen on sheep

RBCs & make hemolysis of the

blood.

Antibody structure

Antibody structure

Monomer: A flexible Y-shaped

molecule with four protein chains:

2 identical light chains (L)

polypeptide chain of about 200

amino acids.

2 identical heavy chains (H)

polypeptide chain of about 450

amino acids.

These two chains are held

together by disulfide bonds.

Ab molecules combined with

large Ag molecules form different

angles around this flexible area,

& the arms of the Y rotate to

bring the variable regions of the

molecule into contact with the

Ag.

Constant Regions: Stem of

monomer & lower parts of Y arms.

The constant regions for all

molecules of the same antibody

class have the same amino acid

sequence & determines the

mechanism used to destroy antigen.

Fc region: Stem of monomer only

important because they can bind to

complement or cells.

Variable Regions: Two sections at

the end of Y’s arms. Contain the

antigen binding sites (Fab).

Identical on the same antibody,

but vary from one antibody to

another.

Ab Binding Sites

Typically, an Ab molecule has two

identical binding sites, one at the end

of each arm of the Y.

Ag-Ab relationships like lock & Key.

•In order for an Ag-Ab reaction to

be triggered, there must be a close

physical & chemical complementary

fit between the two.

1.Van der Waal's forces:

attract all molecules through their

electron clouds.

2.Hydrogen bonding:

electromagnetic interaction between

polar molecules in which hydrogen

is bound to a highly electronegative

atom as (N) or (O), strong than van

der waal’s

3. Electrostatic: attraction between

Ab & Ag molecules due to

electrically charged particles.

4. Hydrophobic regions: attracted in

an aqueous environment; this is

probably the strongest force

between them.

Affinity: the measure of binding

strength of antigen antibody

interaction.

Immunoglobulin isotype Heavy chain

IgG g

IgA a

IgD d

IgE e

Immunoglobulin Classes

IgM m

I. IgM

Structure: Pentamer

Percentage serum antibodies: 5-10%

Location: Blood, lymph, B cell surface.

Half-life in serum: 5 days

Complement Fixation: Yes

Placental Transfer: No

Known Functions: First antibodies

produced during an infection.

II. IgA (2 subclasses, IgA1-2)

Structure: Dimer

Percentage serum antibodies: 10-15%

Location: Secretions (tears, saliva, intestine,

milk), blood & lymph.

Vibrio cholerae, Streptococcus mutans, and

Neisseria gonorrhoeae will not bind to cell

surfaces in the presence of secretory IgA.

Some pathogenic bacteria produce an

enzyme splits the secretory IgA (IgA

protease).

Half-life in serum: 6 days

Complement Fixation: No

Placental Transfer: No

Known Functions: Localized protection of

mucosal surfaces.

III. IgG (4 subclasses, IgG1-4)

Structure: Monomer, has 2 epitope-

binding sites.

Percentage serum antibodies: 80%

Location: Blood, lymph, intestine

Half-life in serum: 23 days

Complement Fixation: Yes

Placental Transfer: Yes

Known Functions: Enhances

phagocytosis, neutralizes toxins &

viruses, protects fetus & newborn.

IV. IgE

Structure: Monomer

Percentage serum antibodies: 0.002%

Location: Bound to mast cells and

basophils

Half-life in serum: 2 days

Complement Fixation: No

Placental Transfer: No

Known Functions: Allergic reactions.

Possibly lysis of worms.

V. IgD

Structure: Monomer

Percentage serum antibodies: 0.2%

Location: B-cell surface, blood, and lymph

Half-life in serum: 3 days

Complement Fixation: No

Placental Transfer: No

Known Functions: initiate immune

response.

Consequences of Antigen-

Antibody Binding

1. Agglutination: Antibodies cause antigens (microbes) to clump together.

2. Opsonization: Antigen (microbe) is covered with antibodies that enhances

its ingestion & lysis by phagocytic cells.

3. Neutralization: IgG inactivates pathogen

by binding to their surface & neutralize

toxins by blocking their active sites.

4.Antibody-dependent cell-mediated

cytotoxicity: Used to destroy large

organisms (e.g.: worms). Target

organism is coated with antibodies &

bombarded with chemicals from

nonspecific immune cells.

5. Complement Activation: Both IgG & IgM

trigger complement system which results in cell

lysis.

Pattern of Antibody Levels During

Infection

Primary Response:

–After initial exposure to antigen, no

antibodies are found in serum for

several days.

–A gradual increase in antibody, first

IgM is observed.

–Gradual decline of antibodies follows.

Secondary Response:

Subsequent exposure to the same

antigen displays a faster & more

intense antibody response.

A secondary response usually involves

a change in Ab class, often from IgM to

IgG.

This is known as class switching and is

mediated by IL-4 produced by the Th

cell that activates the memory B-cell.

Antibody Response After Exposure to Antigen

IgM

IgG

Class switch

Three important feature of the

immunological response

1. Specificity. An Ab or reactive T-cell will

react specifically with Ag that induced its

formation; it will not react with other

Ags.

2. Memory. Once the immunological response

has reacted to produce a specific type of

Ab or reactive T-cell, it is capable of

producing more of the Ab or activated T-

cells rapidly & in larger amounts.

3. Tolerance. An animal generally does not

undergo an immunological response to its

own (potentially-antigenic) components.

The animal is said to be tolerant to self-

Ags.

This ensures that under normal conditions,

an immune response to "self" Ags (called

an autoimmune response) does not occur.

Autoimmune responses are potentially

harmful to the host.

Types of T-cell

1. Helper T (Th) Cells:

Helper T cells are named for their

ability to help other cells in the

immune system achieve

maximum efficiency.

2. Cytotoxic T (Tc) Cells:

•Cytotoxic T cells kill cells that

have been infected with viruses,

and some tumor cells.

•The cytotoxic T cell secretes a

protein called perforin, which

makes a hole in the cell

membrane, causing the cell to lyse

and die.

3. Regulatory T (Treg) Cells or

suppressor T-cell:

Shutting down the immune response

after they have successfully eliminated

invading organisms.

Maintain the tolerance to the self

antigen.

Modulation of Treg can treat

autoimmune disease, cancer &

facilitate organ transplantation.

Possible mechanisms of this action

1. Inhibit conversion of B-cells to plasma

cells & suppress the activity of some

of the T cells.

2. Absorption of essential cytokines thus

preventing the division of other

lymphocytes.

3.Release of non- specific

immunosuppressive molecules.

4. Delayed Hypersensitivity T (TD)

Cells:

Participate in cell-mediated

reactions but do not interact with

B-cells.

TD cells are responsible for

recruiting & activating

phagocytes.

TS and TC cells recognize Ag

fragments associated with MHC

class I molecules.

TH and TD cells recognize Ag

associated with MHC class II

molecules.

Cytokines

1. IL-1 & IL-2:

Macrophages secrete a potent

cytokine known as IL-1, which

acts on several different cell types.

IL1 binding by IL-1 receptors

(IL-1R) on the Th cell acts as an

activation signal & causes Th cell

to divide, producing clonal copies.

IL-1 is a key component of the immune

response because Th cells are one of its

main targets.

During this activation stage, the

stimulated Th cells begin to make IL-2,

which in turn stimulates other Th & Tc

precursors to form active Tc cells.

IL-2 secreted by Th cells acts with

other cytokines such as IL-4 to

stimulate Ag-activated B-cells to

proliferate & produce antibody

forming plasma cells.

The end result is stimulation of several

cells through the actions of IL-1 & IL-

2, resulting in both humoral & cell-

mediated immune responses.

2. interferon (IFN-α and IFN-ɤ)

Named interferon because it interfere with

viral replication.

Produced by leukocytes & inhibits viral

replication in virtually any cell in the body.

3.Tumor necrosis factors (TNF-α & TNF-β)

Capable of destroying a variety of tumors

provided that TNF-producing cells have

access to the tumor.

The complement system

It is a biochemical cascade which

helps clear pathogens from an

organism.

It is part of the larger immune

system that is not adaptable and

does not change over the course of

an individual's lifetime; as such it

belongs to the innate immune

system.

Over 25 proteins & protein fragments make

up the complement system.

These proteins are synthesized mainly in

the liver, and they account for about 5% of

the globulin fraction of blood serum.

Circulate in the blood as inactive

components.

•When stimulated by one of several

triggers, proteases in the system cleave

specific proteins to release cytokines &

initiate an amplifying cascade of further

cleavages.

The end result of this activation

cascade is massive amplification of the

response & activation of the cell-killing

membrane attack complex.

Membrane attack complex: typically

formed on the surface of pathogenic

bacterial cell as a result of complement

system & forms transmembrane

channels which disrupt the

phospholipid bilayer of the target cell

lead to cell lysis.

Membrane attack complex or Lytic complex

Three biochemical pathways activate

the complement system:

1. The classical complement

pathway.

2. The alternative complement

pathway.

3. Mannose-binding lectin pathway.

1- Classical pathway (adaptive immunity)

Activation of the C1-complex (C1q, C1r,

and C1s), which occurs when C1q binds to

IgM or IgG complexed with Ags.

C1 bind & split C4 & then C2 produce C2a

& C4b.

C2a & C4b bind to C3 convertase which

promote clevage of C3 into C3a & C3b.

C3a & C3b bind to C2a & C4b to make C5

which enhance phagocytosis.

2- Alternative pathway (innate

immunity)

The alternative pathway is triggered

by C3 hydrolysis directly on the

surface of a pathogen.

It does not rely on a pathogen-binding

protein like the other pathways.

C5a and C3a are known to trigger

mast cell degranulation.

3- Lectin pathway (Mannose-binding

lectin or MBL) (innate immunity)

The lectin pathway is homologous to

the classical pathway, but with the

opsonin, mannose-binding lectin

(MBL) & ficolins, instead of C1q.

This pathway is activated by binding

mannose-binding lectin to mannose

residues on the pathogen surface,

which activates the MBL-associated

serine proteases.

MASP-1 & MASP-2 very similar to C1r &

C1s respectively), which can split C4 & then

C2 produce C2a & C4b.

C2a & C4b bind to C3 convertase which

promote cleavage of C3 into C3a & C3b.

C3a & C3b bind to C2a & C4b to make C5

which enhance phagocytosis.

Ficolins (homologous to MBL): group of

oligomeric lectin with subunits of

fibrinogen like, collagen like molecules &

lectin.

Complement System

The Biological Effects of Complement

1.Opsonization: The C3b molecules are

opsonins which are any molecules

enhance phagocytosis such as antibody

or complement spilit .

2. Inflammation: The C5a and C3a

fragments are important inflammatory

activators inducing vascular

permeability & activation of

phagocytes.

3. Lysis: C5b binds & recruits C6 & C7

to the target surface

4.Immune complex clearance:

Complement has a very important role

in solubilizing & causing removal from

the circulation of immune complexes.

Immunization

Immunization: is the process by

which an individual's immune system

becomes fortified against an agent

(known as the immunogen).

Immunization can be done through

vaccination. Vaccines against M.O.s

that cause diseases can prepare the

body's immune system, thus helping

to fight or prevent an infection.

Types of Immunization

1. Naturally Acquired Immunity: Obtainedin the course of daily life.

A. Naturally Acquired Active Immunity:

– Antigens or pathogens enter bodynaturally.

– Body generates an immune response toantigens.

– Immunity may be lifelong.

B. Naturally Acquired PassiveImmunity:

– Antibodies pass from mother to fetusvia placenta or breast feeding.

– No immune response to antigens.

– Immunity is usually short-lived (weeksto months).

– Protection until child’s immune systemdevelops.

2. Artificially Acquired Immunity(vaccination):

Obtained by receiving a vaccine or immuneserum.

A. Artificially Acquired Active Immunity:

– Antigens are introduced in vaccines(immunization).

– Body generates an immune response toantigens.

– Immunity can be lifelong (oral poliovaccine).

B. Artificially Acquired PassiveImmunity:

– Preformed antibodies are introducedinto body by injection.

– Immunity is short lived (half life threeweeks).

– Host immune system does not respondto antigens.

Who should not be vaccinated?

Women who are pregnant (or plan a

pregnancy in the near future).

People with weakened immune systems

should not get live virus vaccines.

People who have had a major allergic

reaction to a specific vaccine or one of its

components should avoid revaccination

with that vaccine.

How are vaccines made?

•Vaccines are made in several

different ways.

1. Inactivate (killed vaccine, 3 doses):

grown in culture then killed using

method such as formaldehyde.

Viral: polio.

Bacterial: diphtheria, pertusis,

tetanus vaccines (DPT).

2. Attenuated (weakened live vaccine,

one dose):

Bacterial: BCG against T.B.

Viral: measles vaccine.

Immunity from a live virus vaccine is

generally lifelong. However, these

“live virus” vaccines should not be

given to people who are

immunocompromised, such as some

people with cancer or AIDS.

Immune tolerance

Specific non reactivity of the immune

system to a particular antigen.

1.Innate tolerance

Innate tolerance is the body's tolerance

for its own Ags & proteins. When

natural tolerance fails, or when the

body does not properly recognize itself,

an autoimmune disorder results.

2. Acquired tolerance

Acquired or induced tolerance is the

immune system's tolerance for

external Ags.

Such as medication used to avoid

transplant rejection.

Immunodeficiency

In medicine, immunodeficiency (or

immune deficiency) is a state in which

the immune system's ability to fight

infectious disease is compromised or

entirely absent.

A person who has an

immunodeficiency of any kind is said

to be immunocompromised.

Primary immune deficiency diseases:

The World Health Organization

(WHO) recognizes over 100

primary immune deficiency

diseases. The most common types of

primary immune deficiency

diseases:

1. X-Linked Agammaglobulinemia

(XLA)

Congenital.

Low or absent IgG due to failure of B-

lymphocyte precursors to mature into

B-lymphocytes & plasma cells. Since

they lack the cells responsible for

producing antibodies.

The gene responsible for maturation

found in X-chromosome, so the disease

mainly found in boys.

2. Common Variable Immunodeficiency

(CVID)

Normal B cell but with low levels of

antibody production.

It is a relatively common form of

immunodeficiency, hence, the word

“common.” The degree and type of

deficiency of serum immunoglobulins, and

the clinical course, varies from patient to

patient, hence, the word “variable.”

3. The X-Linked Hyper IgM Syndrome

Patients with the disease have an

inability to switch their Ab production

from IgM to IgG, IgA, and IgE.

As a result, patients have decreased

levels of IgG & IgA & normal or

elevated levels of IgM.

The most common form is inherited as

an X-chromosome & affects only boys.

4. Selective IgA Deficiency

Individuals with Selective IgA

Deficiency lack IgA, but usually have

normal amounts of the other types of

immunoglobulins.

Most affected people have no illness as

a result.

Others may develop a variety of

significant clinical problems & increase

risk of respiratory, GIT & urogential

disorders.

5. IgG Subclass Deficiency

The IgG class of immunoglobulins is itself

composed of four different subtypes of

IgG molecules called the IgG subclasses.

Patients who lack, or have very low

levels of, one or two IgG subclasses, but

whose other Ig levels are normal, are said

to have a selective IgG subclass

deficiency.

Defects occur in heavy chain genes in the

regulation of isotypes.

6. Severe Combined Immunodeficiency

(SCID)

Severe Combined Immunodeficiency is an

uncommon primary immunodeficiency in

which there is combined absence of T-

lymphocyte and B-lymphocyte function.

This condition is most serious of the

primary immunodeficiencies.

bone marrow transplantation, exist that

can cure the disorder and the future holds

the promise of gene

7. The Wiskott Aldrich Syndrome

Primary immunodeficiency disease

involving both T- and B-lymphocytes.

Platelets are also affected lead to

thrombocytopenia.

8. The DiGeorge Syndrome

Developmental defect in the thymus

gland & T-lymphocyte production

may be impaired, resulting in

recurrent infections.

9. Ataxia-Telangiectasia (neurologic

abnormalities)

Variable immunodeficiency involving

both cellular (T-lymphocyte) &

humoral (B-lymphocytes) immune

responses.

Destroy parts of the motor control area

of the brain leading to an unbalance

(ataxia), dilated blood vessels

(telangiectasia) of the eyes & skin.

10. Chediak-Higashi Syndrome

Hereditary fatal disease results from

the slow fusion of the lysozymes to

the phagosomes & hence ingested

bacteria are not destroyed.

Acquired immunodeficiency

Immune deficiency as a result of

particular external processes or

diseases"secondary“

immunodeficiency.

Common causes:

anti-rheumatic

Immunosuppressive drugs

Many specific diseases:

1. cancer with bone marrow &

blood cells.

2. acquired immunodeficiency

syndrome (AIDS), caused by the

human immunodeficiency virus

(HIV).

Hypersensitivity

Nearly 40 years ago Gell and

Coombs proposed a classification

scheme which defined 4 types of

hypersensitivity reactions.

The first 3 are mediated by Ab, the

fourth by T cells.

I.Type I Hypersensitivity (anaphylactic

reaction)

Immediate hyper sensitivity reaction to

exogenous antigen mediated by IgE.

Such as:

Hay fever (allergic rhinitis; allergic

condition affect mucous membrane of the

upper repiratory tract & eyes,

characterized by nasal discharge,

sneezing, itching, watery eyes caused by

abnormal sensitivity to airborne pollen.),

Eczema: pruritic dermatitis characterized

by erythema, edema, serous exudate in

the epidermis.

Asthma: chronic inflammatory disease of

the airways, inflammation cause the air

way to spasm & swell so the airway

narrow.

Urticaria: a vascular reaction of the the

skin marked by apprance of elevated red

batches with severe itching.

The high affinity IgE receptors are found

on mast cells & basophils. Each cell has a

high density of these receptors (40-

250,000 per cell) so that a wide spectrum

of Ag specificities is represented.

Such cross-linking leads to rapid

degranulation (60-300 secs) of the mast

cells & the release of primary

inflammatory mediators stored in the

granules.

These mediators cause all the normal

consequences of an acute inflammatory

reaction, increased vascular permeability,

granulocyte chemotaxis.

Mast cell activation via IgE also leads to

the production of two other types of

mediators. These secondary mediators,

unlike the stored granule contents, must

be synthesized de novo & comprise

arachadonic acid metabolites (essential

fatty acid) (prostaglandins &

leukotrienes).

Allergens

Ags that trigger allergic reactions &

provoke IgE-mediated responses.

Typical allergen sources include

pollens, food, insect venoms, fungal

spores and the feces of the HDM

(Human dust mite).

There are two types of allergic

reaction according to mode of entry

of the allergen:

1. Local (atopic) allergy

Occurs after inhalation or ingestion

of the allergen & causes a localized

reaction such as asthma, hay fever.

2. Systemic anaphylaxis

The consequences of a generalized

reaction are potentially fatal.

Ingestion of nuts or seafood, insect

bites (venom), & drug injection may all

cause life-threatening reactions in

highly sensitized individuals.

Death in such cases is due to systemic

release of vasoactive mediators

leading to general vasodilation &

smooth muscle contraction resulting

in sudden loss of blood pressure,

massive edema & severe bronchiole

constriction (systemic anaphylaxis).

Diagnostic tests for immediate

hypersensitivity

Include skin (prick & intradermal) tests

measurement of total IgE & specific IgE

antibodies against the suspected

allergens.

Total IgE & specific IgE measured by a

(ELISA).

Drop of allergy-producing substance on

the skin & making breaks by lightly

pricking the surface.

Symptomatic treatment

Antihistamines: block histamine

receptors.

Chromoglycate (mast cell stabilizer):

prevent the release of histamine.

Corticosteroids: used mainly for local

anaphylxis.

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