Complement System Definition

The complement system, also known as the

complement cascade, is a component of the immune
system that boosts the ability of antibodies and
phagocytic cells to eliminate germs and damaged cells
from an organism, stimulate inflammation, and assault
the cell membrane of a pathogen.
 The complement system is an incredibly potent
system composed of fast acting glycoproteins,
numerous proenzymes, and components, and it
exists in a state of inactivity in the plasma.
 Normal persons have complement components in
their blood at all times.
 The term complement refers to the capacity of a
system of nonspecific proteins in normal human
serum to enhance the effects of other immune
system components, such as antibodies.
 The complement system, a vital component of the
human innate host defence system, is comprised
of roughly 20 proteins found in normal human
serum.
 It is a component of the innate immune system,
which is not adaptive and does not change during
the course of an individual.
 However, the complement system can be recruited
and activated by antibodies produced by the
adaptive immune system.
  The complement system is comprised of several
tiny proteins generated by the liver and circulating
in the blood as inactive precursors.
 Proteases in the system cut certain proteins in
response to one of several stimuli, releasing
cytokines and initiating a cascade of subsequent
cleavages.
 This complement activation or fixation cascade
results in the activation of the cell-killing
membrane assault complex and the stimulation of
phagocytes to remove foreign and damaged
material.
 The complement system is composed of around 50
proteins and protein fragments, including serum
proteins and cell membrane receptors. About 10%
of the globulin fraction of blood serum is composed
of these proteins.
 The complement system is triggered by three
biochemical pathways: the classical complement
pathway, the alternative complement pathway,
and the lectin pathway.
 Considering that the alternative pathway is
responsible for the majority of terminal pathway
activation, therapeutic attempts in disease have
centred on its suppression.
Properties of Complement
Complement demonstrates the following attributes:
 It is found in the blood of all mammals, including
humans, as well as birds, amphibians, and fishes.
  These compounds are inactivated by heating
serum to 56°C for 30 minutes.
 These are glycoproteins that are largely generated
by liver cells and to a lesser extent by
macrophages and numerous other cell types. The
rate of complement glycoprotein production
increases when complement is activated and
eaten.
 The complement does not often bind to antigens or
antibodies, but rather to antigen–antibody
complexes.
 The significance of the complement rests in the
fact that it contributes to an individual’s acquired
and innate immunity.
Nomenclature of Complement
 Components of the complement are indicated by
the numerals C1–9. In the form of inactive
proenzymes, these components circulate in
plasma.
 Activation involves proteolytic cleavage into
peptide fragments.
 C3 is divided into two parts, C3a and C3b, for
example.
 Typically, the large component is called “b,”
whereas the small portion is designated “a.”
However, for historical reasons, the larger part of
C2 is called C2a and the smaller fragment is
designated C2b.
Effects of complement
Four principal impacts of complement:
 It causes cell lysis (such as bacteria, viruses,
allografts, and tumour cells).
 It creates mediators that contribute to the
activation of certain cellular activities,
inflammation, and immunoregulatory molecule
secretion.
 It enhances opsonization, the process by which
phagocytes more rapidly and effectively ingest
germs.
 It results in immunological clearance, in which
immune complexes are removed from the
circulation and delivered to the spleen and liver.
Activation of Complement
These components must be activated because they are
proenzymes that must be cleaved in order to become
active enzymes. Complement activation can be started
by antigen–antibody complexes or by a number of non-
immunologic substances, such
as endotoxin (lipopolysachharides).
Complements are typically denoted by the letter
C followed by a number, such as C1, C2, C3, etc.
Some have merely the letters, such as B and D. Some
are represented solely by their names, such as
homologous restriction factor. The subunits of C1 are
C1q, C1r, and C1s. a and b are the two
constituents of C2-C5. The larger subunits are
marked by the letter b, whereas the smaller ones
are denoted by the letter a. (except C2a, which is
larger than C2b). Activation of complement and
cell lysis.

Complement activation happens via the following

three pathways:
[Link] pathway
[Link] pathway
3. Lectin pathway (or mannose binding lectin
pathway)

Activation of Complement
The initial step of the complement system varies
between routes. C3 convertase, which cleaves C3
into C3a and C3b, and C5 convertase, which
cleaves C5 into C5a and C5b, produce enzyme
complexes. Thus, C3b binds C3 convertase to
produce C5 convertase. C5 convertase, which is
 produced via the alternative, classical, or lectin
pathway, promotes the activation of late
components of the complement system to create
the membrane attack complex (MAC), which finally
kills the pathogen. This occurs via three pathways:
the Classical pathway, which is activated by an
antigen-antibody response; the Alternative
pathway, which is activated on microbial cell
surfaces; and Mannose binding. Activation of the
lectin pathway by a plasma lectin that binds to
mannose residues on microorganisms.
Function of C3b
The C3b performs two essential functions:
 First, it joins with other complement components to
form C5 convertase, the enzyme that leads to the
formation of membrane attack complex.
 Second, it opsonizes bacteria due to the presence
of C3b receptors on the phagocytes’ surface.
Classical Pathway of Complement Activation
 To begin the classical pathway, antigen-antibody
complex formation is required (immune complex).
 The antibody (IgM/IgG) attaches to the antigen
when it enters the body. Changes in the Fc region
of the antibody are triggered by this process,
revealing a region that can bind to C1 protein.
 That’s why the antibody can’t trigger the
complement system unless it’s attached to an
antigen.
 C1 is a massive multimeric protein complex with
one C1q molecule and two C1r and C1s molecules.
 C1q combines with an antibody that has attached
to an antigen (Fc portion). Both C1r and C1s are
proteases that aid in the cleavage of C4 and C2.
 C4 is a protein called by the immune complex
linked to C1. C4 is cleaved into C4a and C4b.
 Activated C4b binds to the target surface in the
vicinity of C1q, whereas C4a dissociates. Next, C4b
pulls in C2, which is then split into C2a and C2b.
 When C2a binds C4b, the resulting C4b2a complex
displaces C4b. For C3, the active C4bC2a is the
trigger.
 Since the C4b2a complex is responsible for
converting inactive C3 into an active form by
cleaving C3a and C3b apart, it is also known by
that name.
 C4b2a can cleave several C3 molecules with just
one molecule. C3b can interact with the convertase
or the microbial surface.
 By binding to C3 convertase, C3b stimulates C5 to
be cleaved into C5a and C5b by the enzyme
C4bC2aC3b (C5 convertase). However, C5b is held
in place by binding C6, whereas C5a is free to
diffuse away.
 Later, C5bC6 links to C7. After binding C8, the
C5bC6C7 complex is introduced into the
phospholipid bilayer of the cell membrane.
 All of these (C5b678) work together with C9 to
generate the membrane assault complex (MAC).
 This creates a breach in the bacterial cell wall,
allowing for the escape of internal contents and the
entry of foreign chemicals. As a result, the cell
undergoes lysis due to an input of water and a loss
of electrolytes since it is unable to maintain its
osmotic stability.
 The outer membrane of Gram-negative bacteria is
conducive to MAC production, making this strategy
more effective than it would be against Gram-
positive bacteria, which have a thick, hard coating
of peptidoglycan in their place.
 Some C3b molecules do not interact with C4b2a,
but they do serve as opsonin’s by coating immune
complexes or microbial cell surfaces.
 Opsonization is the process by which opsonin
molecules connect to the receptor of phagocytic
cells (such as neutrophils and macrophages) and
facilitate the engulfment of foreign particles (such
as bacteria, tumour cells, and RBCs).
 Complement’s smaller subunits diffuse away from
the site and can trigger localised inflammatory
reactions by binding to certain receptors.
Proteins of Classical Pathway
Alternative Pathway
 The Ag-Ab complex is unnecessary for the
beginning of the complement pathway in the
alternative pathway.
 Foreign components of the cell surface set off the
process. This outer layer of molecules could consist
of lipopolysaccharides or something similar.
 When inflammation allows bacteria to enter the
host body, complements travel to the place where
C3 molecules come into contact with antigen and
activate.
 Serum C3, which contains an unstable thioester
link, undergoes delayed spontaneous hydrolysis to
produce C3a and C3b by this mechanism. C3b
attaches to the outside of a foreign cell and then
joins forces with a serum protein known as factor
B.
 Serum protein D, which has catalytic activity, now
has its substrate exposed thanks to factor B.
 Next, factor D splits B into Ba and Bb, which
assemble into C3 convertase (C3bBb). Similar to
the traditional process, C3 convertase gives rise to
C5 convertase, which in turn gives rise to a MAC.
Classical Pathway
Mannose binding Lectin (MBL) Pathway
 It is possible for some bacteria to trigger the
complement system in the absence of both
antibodies and endotoxins.
 This is because the binding of circulating lectin
(MBL) to mannose residues on glycoproteins or
carbohydrates on the surface of bacteria activates
the MBL pathway.
 Among the microorganisms that can activate the
MBL pathway include pathogenic bacteria
like Salmonella, Listeria, and Neisseria strains, as
well as fungi and viruses like HIV-1. It is known that
MBL, an acute phase protein, is present in higher
amounts when inflammation is present.
 It is the carbohydrate on the target cell that the
lectin identifies and attaches to, which triggers the
complement response.
 The MBL route produces activated complement
system proteins via the action of C4 and C2, much
like the classical pathway.
 Similar to C1q in structure, MBL has the same
functional effect. Two components, MASP-1 and
MASP-2, bind to MBL after it has bound to
carbohydrate residues on the surface of a cell or
pathogen.
 Serine proteases related with MBL. An enzyme pair,
analogous to C1r and C1s, forms a tetrameric
complex that cleaves C4 and C2 to generate C3
convertase.
 Following this step, the formation of C5 convertase
and the MAC proceeds along the traditional
pathway.
Activation of Complement
Regulation of Complement System
Due to the complex nature of the complement system
and the large number of biologically active compounds
it generates, the human body has developed a wide
variety of regulatory mechanisms to limit any
unnecessary harm to the host. Several mechanisms
control the complement activation cascade by
regulating the activity of the various complement
components activated at each stage. The complement
system is controlled by the following:
1. Level of antibody
 The conventional process begins with the
regulation of antibody levels.
 The complement-binding sites on the heavy chains
of IgG and IgM are inaccessible to the C1
component of the complement if antigen is not
linked to the antibodies.
 This indicates that even if IgM and IgG are always
present in the blood, complement is not activated.
 A conformational change occurs upon antigen
binding with particular antibodies, allowing the C1
component to bind and kick off the cascade
process.
2. C1 inhibitors
 Antibodies like these are essential for keeping
complement activation to a minimum. These
trigger C1s dissociation from C1qrs, preventing the
formation and function of C1qrs complex.
 C1 inhibitors have the potential to aid in the
clearance of the complete C1 complex from
antigen-antibody complexes.
3. Other inhibitory substances
 Several chemicals can block the classical route at
various points in its activation process.
  These are examples of defensive mechanisms
employed by the host cell.
 These defence mechanisms probably aid in
shielding host cells from any bystander damage
that may be caused by activated complement
fragments (C3b and C4b) forming on and near the
cell surface.
4. Decay-accelerating factor (DAF)
 It is another type of inhibitory chemical found in
the membranes of many different kinds of host
cells. This is because it has been shown to hasten
the dissociation of active C4b2a complexes, hence
inhibiting their capacity to activate native C3.
 As an added bonus, DAF sticks around after
membrane-bound C4b and C3b are done
interacting with C2a and factor B, respectively.
 Host cells are protected from complement-
mediated membrane damage because they do not
produce the two forms of C3 convertases (C4b2a
and C3bBb).
5. Regulation of alternative pathway
 The proteins and processes that control the
alternate pathway are distinct from those that
control the canonical one.
 Factor H binds to C3b and is cleaved off of the
complex by the plasma protease inhibitor factor I.
 Thus, less C5 convertase is accessible.
Biological Effects of Complement
For the most part, complement is used to boost the
body’s humoral immune response. The complement
through its various products participates in the
inflammatory response, opsonization of antigen, viral
neutralization, and clearance of immune complexes as
follows:
Chemotaxis
 Polymorphonuclear leukocytes and phagocytic cells
specifically identify the chemotactic ligand C5a.
When an antigen-antibody response is taking
place, this substance recruits leukocytes to the
area. A phagocytic cell may identify and consume
opsonized particles at that location.
 In addition to its chemotactic impact, C5a
stimulates neutrophils, leading to the reversible
aggregation of these cells and the release of their
stored enzymes, including proteases.
 Additionally, neutrophils’ ability to adhere to the
endothelium is improved by C5a.
Opsonization
 Opsonization of infectious bacteria and viruses is
facilitated by complement. Phagocytic cells have
an easy time engulfing bacteria and viruses when
the complement component C3b is present.
 As a result, many phagocytes have receptors for
the C3b component on their surface.
Hypersensitivity Reactions
  To some extent, complement is involved in both
type II (cytotoxic) and type III (immune-complex)
hypersensitivity reactions.
 Mast cells’ degranulation and subsequent release
of mediators like histamine is prompted by C3a,
C4a, and C5a components.
 Vasoactive amines (such as histamine) and heparin
are released from storage when the C3a fragments
bind to receptors on basophils and mast cells.
 An increase in capillary permeability and
smooth muscle contraction follows histamine’s
release into the tissues.
 The release of fluid into the tissue leads to edoema
and swelling. C3a and C5a may also improve
permeability of blood vessels by acting directly on
endothelial cells.
 What happens when IgE antibodies attached to the
membranes of mast cells and basophils react with
their respective antigens is remarkably similar to
the typical anaphylactic reaction. This is why C3a
and C5a get the name “anaphylatoxins” (allergy
toxins).
Cytolysis
 Cytolysis is mediated by complement. C5b-9 complex
(MAC) insertion into the cell membrane causes
erythrocyte, bacterial, and tumour cell death or lysis.
 The membrane is disrupted by the entrance of the
MAC complex, allowing water and electrolytes to
enter the cell.
Antibody Production Enhancement
 C3b’s attachment to activated B cell surface
receptors greatly boosts antibody production
compared to B cells triggered by antigen alone.
Therefore, there is a correlation between C3b
deficiency and decreased antibody production.
 As a result, severe pyogenic infections occur when
there is a shortage of both C3b and antibodies,
which compromises the host’s defence.
Deficiency of Complement
 A healthy complement system is crucial to human
health. Many diseases have been linked to
deficiencies in specific nutrients.
 Angioedema is brought on by a lack of C1 esterase
inhibitors, which can be inherited. Overproduction
of esterase is caused by a deficiency in C1
esterase inhibitors. Because of this, more
anaphylatoxins are released, leading to increased
capillary permeability and swelling.
 Increased complement-mediated hemolysis is a
side effect of developing a deficit in DAF.
Paroxysmal nocturnal hemoglobinuria is the clinical
hallmark of this disorder.
 Susceptibility to Neisseria bacteremia and other
infections is dramatically increased in people who
lack C5-8 components, whether by genetics or
through other means. Severe recurring pyogenic
sinusitis and respiratory infections result from a
lack of C3.
  Severe liver illness, like chronic hepatitis or
alcoholic cirrhosis, impairs the body’s ability to
produce enough complement to fight infections.
Therefore, pyogenic bacterial infections are more
dangerous for these people.

Deficiency of Complement
Biosynthesis of Complement
 The complement is created in several different
organs. The intestinal epithelium produces C1,
macrophages produce C2 and C4, the spleen
produces C5 and C8, the liver produces C3 and C6,
and the intestines produce C9 and C10.
  During the initial stages of inflammation, the levels
of complement components 3, 4, 5, and 6 rise.
 Plasma levels of complement and other proteins in
the acute phase reactants family rise with a severe
inflammatory response.
Hypersensitivity: Types, Mechanisms, and Causes
Explained
August 28, 2024 by Sagar Aryal, PhD
✔ Reviewed and Edited by Dr. Sagar Aryal, PhD
Hypersensitivity is increased reactivity or increased
sensitivity by the animal body to an antigen to which it
has been previously exposed.
The term is often used as a synonym for allergy, which
describes a state of altered reactivity to an antigen.
Hypersensitivity has been divided into categories based
upon whether it can be passively transferred by
antibodies or by specifically immune lymphoid cells.
The most widely adopted current classification is that of
Coombs and Gell which designates immunoglobulin-
mediated (immediate) hypersensitivity reactions as
types I, II, and III, and lymphoid cell-mediated (delayed-
type) hypersensitivity/cell-mediated immunity as a type
IV reaction.
“Hypersensitivity” generally represents the “dark side,”
signifying the undesirable aspects of an immune
reaction, whereas the term “immunity” implies a
desirable effect.
A hypersensitive response (HR) is an anti-pathogen
response in plants produced by avr-R system activation
that leads to alterations in Ca+ flux, MAPK activation,
and NO and ROI formation.
There is rapid necrosis of plant cells in contact with the
pathogen.
This process prevents spread of the pathogen and
releases hydrolytic enzymes that facilitate injury to the
pathogen’s structural integrity.
Table of Contents
 Causes of Hypersensitivity
 Mechanism of Hypersensitivity
 Types of Hypersensitivity Reactions
 Hypersensitivity Type I, II, III and IV- Summary in
table form
 Hypersensitivity Type I: Immediate Reaction
 Hypersensitivity Type II: Antibody-mediated
cytotoxic reaction
o A) Complement-mediated
o B) many cell types (macrophages, neutrophils,
NK cells) cause lysis of target cell coated by
IgG
o C) Antibody-mediated cellular dysfunction
 Hypersensitivity Type III: Immune complex-
mediated reaction
o A) SYSTEMIC DISEASE (serum sickness serum
sickness type, SLE)
o B) LOCAL DISEASE (Arthus reaction)
  Hypersensitivity Type IV: Delayed-type
hypersensitivity reaction
o A) Acute (within 2-3 days)
o B) Chronic (> 1 week)
 References
Causes of Hypersensitivity
Immune responses that are the cause of
hypersensitivity diseases may be specific for antigens
from different
sources:
 Autoimmunity: reactions against self antigens.
 Reactions against microbes.
 Reactions against non-microbial environmental
antigens.
Mechanism of Hypersensitivity
Hypersensitivity diseases are commonly classified
according to the type of immune response and the
effector
mechanism responsible for cell and tissue injury. These
mechanisms include some that are predominantly
dependent on antibodies and others predominantly
dependent on T cells, although a role for both humoral
and cell-mediated immunity is often found in many
hypersensitivity diseases.
Immediate (type I) hypersensitivity
It is caused by IgE antibodies specific for environmental
antigens and is the most prevalent type of
hypersensitivity disease. Immediate hypersensitivity
diseases, commonly grouped under allergy or atopy,
are often caused by activation of interleukin-4 (IL-4), IL-
5, and IL-13 producing Th2 cells and the production of
IgE antibodies, which activate mast cells and
eosinophils and induce inflammation.
Antibody-mediated (type II) hypersensitivity
IgG and IgM antibodies specific for cell surface or
extracellular matrix antigens can cause tissue injury by
activating the complement system, by recruiting
inflammatory cells, and by interfering with normal
cellular functions.
Immune complex-mediated (type III)
hypersensitivity
IgM and IgG antibodies specific for soluble antigens in
the blood form complexes with the antigens, and the
immune complexes may deposit in blood vessel walls in
various tissues, causing inflammation, thrombosis, and
tissue injury.
T cell-mediated (type IV) hypersensitivity
In these disorders, tissue injury may be due to T
lymphocytes that induce inflammation or directly kill
target cells. In most of these diseases, the major
mechanism involves the activation of CD4+ helper T
cells, which secrete cytokines that promote
inflammation and activate leukocytes, mainly
neutrophils and macrophages. CTLs contribute to tissue
injury in some diseases.
Types of Hypersensitivity Reactions
The Gell’s and Coombs’ classification of
hypersensitivity reactions considers four types of
reactions. Type I, II, and III reactions are basically
mediated by antibodies with or without participation of
the complement system; type IV reactions are cell-
mediated. While in many pathological processes
mechanisms classified in more than one of these types
of hypersensitivity reactions may be operative, the
subdivision of hypersensitivity states into four broad
types aids considerably in the understanding of their
pathogenesis.

Types of Hypersensitivity Reactions. Image

Source: Open Stax.
Hypersensitivity Type I, II, III and IV- Summary in
table form
Alternative Name

Type I Type II Type III Type IV

Allergic Cytotoxic Immune Cell-mediated

 hypersensitivit
complex y/ Delayed
hypersensitiv hypersensitiv
hypersensitiv type of
ity ity
ity hypersensitivit
y

Principle

Type I Type II Type III Type IV

Antibody-
Antigen-
mediated Antibody- T
antibody
degranulation of mediated lymphocytes
complex-
granulocytes destruction mediated the
mediated
leads to the of healthy destruction
destruction
destruction of cells. of cells.
of cells.
cells.

Primary Mediator

Typ Type Type

Type IV
eI II III

IgG/ IgG/ Specific subsets of CD4+ helper T cells

IgE
IgM IgM or CD8+ cytotoxic T cells.

Other components as mediators

Type I Type II Type III Type IV

Mast cells, Complemen Complement Dendritic

Basophils, t, , phagocytes cells,
histamine & Neutrophils and K cells macrophages
other , and
pharmacological
cytokines
agents

Reaction time

Type Type
Type I Type IV
II III

Immediate or After 24 hours only,

5-8 2-8
within a few mostly 48-72 hours after
hours hours
hours contact

Antigen

Type I Type II Type III Type IV

Free in Free in
Fixed Soluble or
circulation circulation
on cells cell-bound
(Soluble) ( Soluble)

Antigen origin

Type I Type II Type III Type IV

Exogeno Endogenous or Exogenous or Exogenous or

us exogenous endogenous endogenous

Antibody

Type I Type II Type III Type IV

Fixed on mast cells Free in Free in Not

and basophils circulation circulation applicable

Mechanism
Type I Type II Type III Type IV

Antigen-antibody
IgG or IgM
complexes are
Allergen-specific antibody binds to
deposited in
IgE antibodies a cellular antigen,
tissues.
bind to mast leading to Th2 cells
Complement
cells via their Fc complement secrete
activation
receptor. When activation and cytokines,
provides
the specific cell lysis. IgG can which
inflammatory
allergen binds to also mediate activate
mediators and
the IgE, cross- ADCC with macrophages
recruits
linking of IgE cytotoxic T cells, and cytotoxic
neutrophils.
induces natural killer T cells.
Enzymes
degranulation of cells,
released from
mast cells. macrophages,
neutrophils
and neutrophils.
damage tissue.

Complement activation

Type I Type II Type III Type IV

No Yes Yes No

Appearance

Type I Type II Type III Type IV

Weal & Lysis & Erythema & Erythema &

flare necrosis edema induration

Transfer with serum

Type I Type II Type III Type IV

Passive Cannot be transferred

transfer Passive Passive with serum; but
possible with transfer transfer possible with T cells
serum transfer

Desensitization

Type I Type II Type III Type IV

Easy but Easy but Easy but Difficult but

short-lived short-lived short-lived long-lived.

Examples

Type I Type II Type III Type IV

Asthma, Rhesus Glomerulonephritis The

Rhinitis, incompatibility , Systemic Lupus tuberculin
Atopic (Rh hemolytic Erythematosus, reaction,
eczema, disease), Farmer’s lung Granuloma
Bee Transfusion arthritis, Vasculitis formation,
sting Reactions, Cell Allergic
reaction Destruction due contact
to autoantigens, dermatitis,
 Drug-Induced
Type-1
Hemolytic
diabetes
Anemia

Hypersensitivity Type I: Immediate Reaction

Some antigens (allergens), such as insect venom,

foods, pollen, and dust mite, can induce the
formation of IgE antibodies in individuals with a
corresponding predisposition.
The IgE antibodies bind via Fc receptors to mast
cells (sensitization). If the individual is re-exposed to
the allergen, cross-linkage of the membrane-bound IgE
occurs. This results in the immediate release of
mediators (e.g., histamine, kininogen), which induce
vasodilation, smooth muscle contraction, mucus
secretion, edema, and/or skin blisters. Most allergens
are small proteins that can easily diffuse through the
skin or mucosa. They are frequently proteases and are
active at very low doses. IL-4 favors the differentiation
of TH2 cells. The exact mechanism that leads B cells to
produce IgE is not known.
The allergen stimulates the induction of CD4+T cells.
These T cells secrete cytokines that cause IgE
production by plasma cells.
The IgE molecule will bind to the Fc receptor on mast
cells and basophils which in turn causes vasodilation
increased vascular permeability and vascular spasm.
this type may occur as a systemic or local reaction:
 systemic reactions: skin erythema, followed by
respiratory difficulty due to bronchial constriction.
 local reactions: generally on the skin or mucosal
surface at the site of Ag exposure. Allergy to
penicillin, Aspergillus spores, rupture of
Echinococcus cyst.
Hypersensitivity Type II: Antibody-mediated
cytotoxic reaction
The immunization of individuals to erythrocyte antigens
during pregnancy is a typical example of a type II
reaction. Children who inherit the RhD erythrocyte
antigen from their father can induce immunization
against the RhD+ antigen in their RhD-mother.
Sensitization usually occurs at birth when fetal blood
cells come into contact with the maternal immune
system. In any subsequent pregnancies, maternal anti-
RhD antibodies of the IgG type can pass into the
placenta and cause severe hemolysis of fetal RhD+
erythrocytes.
Other examples: Drugs (e.g., penicillin) can passively
bind to erythrocytes. Antibodies directed against
penicillin then lead to lysis of the erythrocytes. The
formation of antibodies directed against the basement
membrane (BM) of the glomerulus can develop during
the course of kidney inflammation. Lung damage
accompanied by pulmonary hemorrhage and renal
inflammation (glomerulonephritis) may occur due to
cross-reaction of these antibodies with the basement
membrane of the lung (Good-pasture’s syndrome).
In this type Ab are formed against target Ag that are
cell membrane components. Not really hypersensitivity,
but cytotoxic reactions:
A) Complement-mediated
 Ab reacts with cell surface Ag leading to fixation of
the complement system and then cell lysis. eg. red
cells are the most common cells damaged by this
mechanism>>>HEMOLYTIC ANEMIA NO
MICROBES!
B) many cell types (macrophages, neutrophils, NK
cells) cause lysis of target cell coated by IgG
 Poststreptococcal rheumatic fever: molecular
mimicry: Antibodies produced against S.
 pyogenes cross-react with various tissue eg. heart,
joints – inflammation
 Oncocerca worm infection may lead to
blindness because of the cross-reaction of Ab
produced against pathogens and proteins of the
retina.
C) Antibody-mediated cellular dysfunction
 In some cases Ab is directed against cell surface
receptor impairing the function but not cause cell
injury>>>MYASTHENIA GRAVIS; Ab reacts with ACh
receptors on the motor endplate.
Hypersensitivity Type III: Immune complex-
mediated reaction
Antibody-antigen complexes (immune complexes) can
form during an immune response. Immune complexes
can settle in vessel walls, the basement membrane of
the lungs and/or kidneys, and in the joints (synovia).
They can induce inflammatory processes in these
structures by binding complement factors C3a and C5a
(anaphylatoxins). A particular type III reaction is the
Arthus reaction: when an antigen has penetrated the
skin of an individual who has preformed IgG antibodies,
the immune complexes can bind to Fc receptors of
most cells inducing degranulation inflammatory cells
are recruited and complement is activated, leading to
the release of C5a and local inflammation, platelet
accumulation, and eventually to blood vessel occlusion
with necrosis.
This type is mediated by ag-ab complexes which initiate
an inflammatory reaction in the tissue. there are 2
patterns of immune-complex mediated injury:
A) SYSTEMIC DISEASE (serum sickness serum sickness
type, SLE)
 This is because of a large excess of Ab and
immune complexes are deposited at the site of
injury especially within the vessel wall, the
subsequent events will result in necrotizing
vasculitides and accumulation of
neutrophils>>>SLE
B) LOCAL DISEASE (Arthus reaction)
 Arthus reaction: intraductal injection of antigens
to a personalized person may lead to local
 intradermal Ab – Ag complex formation and local
vasculitis, redness, swelling.
 Example: Repeated (booster) vaccination with
diphtheria or tetanus rarely leads to local
vasculitis.
 Poststreptococcal acute Poststreptococcal acute
glomerulonephritis glomerulonephritis
glomerulonephritis: Ab-ag complexes deposit in
glomeruli HBV infection: HBsAg-Ab complexes may
HBV also cause acute glomerulonephritis
Hypersensitivity Type IV: Delayed-type
hypersensitivity reaction

Haptens are molecules of very small molecular weight

(often < 1 kDa). They are too small to function as
antigens, but they can penetrate the epidermis and
bind to certain proteins in the skin (carrier proteins).
Hapten-carrier complexes are bound by antigen-
presenting cells of the skin (Langerhans cells), which
then migrate to regional lymph nodes. T-cell stimulation
then occurs at the lymph node. The so-called
sensitization phase lasts ca. 10-14 days. If the
individual is reexposed to the hapten, antigen-specific T
cells migrate to the skin, where they accumulate and
proliferate. They also cause edema formation and local
inflammation with the help of cytokines. Compounds
containing nickel or chrome and chemicals such as
those found in rubber are typical triggers of type IV
hypersensitivity reactions.
This is mediated by T-cells. There are 2 types that
involve CD4/8+T Cells.
A) Acute (within 2-3 days)
 Tuberculin test, contact dermatitis: mediated by
CD4+ T helper cells cd4+ cells recognize ag
(tuberculin), this leads to the formation of
sensitized cd4+ cells.
 Upon cutaneous injection into previously sensitized
individual sensitized cd4+cells become activated
and secrete cytokines.
 Tuberculin/Mantoux Tuberculin/Mantoux Mantoux
test test test: intradermal injection of tuberculin =
purified tuberculoprotein leads to swelling after 48-
72 h if the patient has been exposed to
Mycobacterium tuberculosis previously.
 Important: BCG vaccination? Yes/No!
B) Chronic (> 1 week)
 Granuloma formation, graft rejection: mediated by
cd8+ cytotoxic T cell.
 lymphocytes surrounding epitheloid cells lead to
the formation of granuloma.
Hypersensitivity and immunodeficiency
 Hypersensitivity diseases: Diseases or
ailments caused by impaired immune responses are
called hypersensitivity disorders. 35.1 Causes of
hypersensitivity diseases Autoimmunity Reactions
against microbes Reactions against environmental
antigens Autoimmunity It may be defined as the failure
of normal process of an individual to distinguish
between self and non-self i.e when the individual fails
to recognize its own parts as self and develops an
immune response against its own cells and tissues.
Diseases that occur because of autoimmunity are called
as autoimmune diseases. Reactions against microbes
Reactions against persistent microbial agent may occur
in the form of T-cell response. Tuberculosis,
inflammatory bowel disease and viral hepatitis are
some of the related conditions. Reactions against
environmental antigens It does not occur in majority of
the population but very less percentage of the
individuals may show reaction against some harmless
environmental products. As a result of allergy such
patients generate immunoglobulin E (IgE) antibodies
that cause allergic reactions or disease. 35.2
Mechanism and classification of hypersensitivity
reactions Based on immune response and some
miscellaneous factors, hypersensitivity reactions are
classified as follows Type I hypersensitivity or
immediate hypersensitivity It is characterized by the
stimulation of helper T cells that are associated with
production of IgE antibodies and inflammation. Type I is
the most common hypersensitive reaction. Atopy or
allergic reaction is the best example of type I reactions.
Immunoregulation
Immunoregulation is defined as the complex system of
mechanisms employed by the immune system to
maintain balance, responding appropriately to foreign
invaders while preventing excessive activation that
could harm tissues or trigger autoimmune reactions. It
involves the coordination of immune cells, signaling
molecules, and regulatory pathways to achieve immune
homeostasis, ensuring effective defense against
pathogens and tolerance to self-antigens.
Immune regulation is the regulation and control of the
immune response by the immune system in order to
maintain homeostasis of the organism. Once started,
the immune response is like an accelerating train that
must be braked to keep it running smoothly and
eventually come to a stop. In the whole process of
immune response, immune regulation plays the role of
braking, which is accomplished through immune
regulatory cells, so the main body of immune regulation
is immune regulatory cells. By regulating the direction
and intensity of the immune response, immune
regulatory cells orient the immune response towards
cellular immunity or humoral immunity and keep it in
the most appropriate state of physiological response,
thus maintaining the physiological balance and stability
of the body. However, if the immune regulation is out of
control, it can cause the body to have abnormally
excessive immune response, leading to immune
damage or even death by shock. Therefore, immune
regulation determines to some extent the physiological
state and immune tolerance of animals, especially in
the adaptive immune response where immune
regulation plays a key role.

The immune system is a complex network of organs,

cells and proteins that defends the body against
infection, whilst protecting the body's own cells. The
immune system keeps a record of every germ
(microbe) it has ever defeated so it can recognise and
destroy the microbe quickly if it enters the body again.
1st lineofdefense The first line of defense against
infection are the surface barriers that prevent the entry
of pathogens into the body Physical and chemical
barrier TheSkinBarrier One of the body’s most
important physical barriers is the skin barrier, which is
composed of three layers. The thin upper layer is called
the epidermis. A second, thicker layer, called the
dermis, contains hair follicles, sweat glands, nerves,
and blood vessels. Alayer of fatty tissue called the
hypodermis lies beneath the dermis and contains blood
and lymph vessels. the epidermis, consists of cells that
are packed with keratin. The keratin makes the skin’s
surface mechanically tough and resistant to
degradation by bacterial enzymes. Keratin also helps to
make the outer surface of the skin relatively
waterproof, this helps keep the surface of the skin dry,
which reduces microbial growth. In addition sebaceous
glands and sweat glands in the dermis secrete oily
substance called sebum and sweat respectively which
act as anticeptic as they contain lactic and fatty acids
and the low pH of sebum and sweat inhibits growth of
most pathogens. MucousMembranes The mucous
membranes lining the nose, mouth, lungs, and urinary
and digestive tracts provide nonspecific barrier against
potential pathogens. Mucous membranes consist of a
layer of epithelial cells bound by tight junctions. The
epithelial cells secrete a moist, sticky substance called
mucus, which traps debris and particulate matter,
including microbes. Mucus secretions also contain
antimicrobial peptides. Cilia The epidermal cells of the
respiratory passage are lined with the cilia. The
microorganism trapped in the mucous of the respiratory
passage are swept away by the constant movement of
these cilia. Hairs inside the nose may trap larger
pathogens and other particles in the air before they can
enter the airways of the respiratory system
SecreationofthedigestivetractThe high acidity of the
stomach has a microbial effect and this is due to the
presence of HCl in the gastric juice . Also, lysozyme
found in tears, sweat, and saliva acts as a vital
antimicrobial agent to destroy
pathogens. Mechanicalbarrier  Mechanical defenses
include the flushing action of urine and tears which
carry microbes away from the body. The flushing action
of urine is largely responsible for the normally sterile
environment of the urinary tract, which includes the
kidneys, ureters, and urinary bladder.  Theeyelashes
and eyelids prevent dust and airborne microorganisms
from reaching the surface of the eye.  Mechanical
action of Coughing and sneezing help in driving out the
foreign particlesthat enter the respiratory tracts. 2nd
lineofdefense  Thesecondline of defense are the non-
specific phagocytes and other internal mechanisms
that comprise innate immunity  Thesecondline of
defense includes the inflammatory response and
phagocytosis by nonspecific leukocytes 1. Inflammation
Inflammation is the 1st response of the body to protect
tissues from infection, injury or disease. The
inflammatory response begins with the production and
release of chemical agents by cells in the infected,
injured or diseased tissue. These agents cause redness,
swelling, pain, heat and loss of function. Inflamed
tissues generate additional signals that recruit
leukocytes to the site of inflammation. Leukocytes
destroy any infective or injurious agent, and remove
cellular debris from damaged tissue.2. Phagocytosis
Phagocytosis is an important feature of
innate immunity that is performed by cells classified as
phagocytes. In the process of phagocytosis, phagocytes
engulf and digest pathogens or other harmful particles.
Macrophages, cytotoxic T cell, dendritic cells are
example for phagocytes. 3. Neutrophils Neutrophils are
leukocytes that travel throughout the body in the blood.
They are the first immune cells to arrive at the site of
an infection. They are the types of phagocytes, and
they accounting for about 50-60% of the circulating
white blood cells. Their primary function is to prevent
infections in the body by engulfing and destroying
invading pathogens 4. Monocytes they accounting for
about 3-8% of the circulating white blood cells. They
are precursors of tissue macrophages and dendritic
cells. Before they enter the tissues monocytes circulate
in the blood for 1-3days. Monocytes migrate quickly
and are usually 2nd cell after neutrophiles arrive at the
site of infection5. Macrophages
Whenmonocytesenterthetissuesandbeco
memacrophagestheydonotreenterthecirculation. They
are the most efficient phagocytes, and they can
phagocytize substantial numbers of pathogens or other
cells. Macrophages are also versatile cells that produce
a wide array of chemicals — including enzymes,
complement proteins, and cytokines — in addition to
their phagocytic action. As phagocytes, macrophages
act as scavengers that rid tissues of worn-out cells and
other debris, as well as pathogens. In addition,
macrophages act as antigenpresenting cells that
activate the adaptive immune system. 6. DendriticCells
Like macrophages, dendriticcells develop from
monocytes. They reside in tissues that have contact
with the external environment, so they are located
mainly in the skin, nose, lungs, stomach, and intestines.
Besides engulfing and digesting pathogens, dendritic
cells also act as antigen-presenting cells that trigger
adaptive immune responses. 7. Eosinophils, Eosinophils
so named because of their intense colour when stained
with [Link] specialize in defending
against parasites. They are very effective in killing large
parasites (such as worms) by secreting a range of
highly-toxic substances when activated. Eosinophils
may become overactive and cause allergies or asthma.
8. Basophils Basophils are non-phagocytic leukocytes
that are related to neutrophils. They are the least
numerous of all white blood cells. Basophils secrete two
types of chemicals that aid in body
defenses: histamines and heparin. Histamines are
responsible for dilating blood vessels and increasing
their permeability in inflammation. Heparin inhibits
blood clotting, and also promotes the movement of
leukocytes into an area of infection. 9. Mastcells Mast
cells are non-phagocytic leukocytes that help
initiate inflammation by secreting histamines. In some
people, histamines trigger allergic reactions, as well as
inflammation. Mast cells may also secrete chemicals
that help defendagainst parasites. [Link]
 Natural killer or NK cells are a part of innate immunity
and they do not have antigen-specific receptors present
on the surface. They play a major role in eliminating
tumour cells and infected cells. They distinguish the
normal cells from the infected or cancerous cells by
MHC class I surface molecules, which is absent in most
of the abnormal cells.  NKcellsare also activated by
cytokines known as interferons. Activated natural killer
cells release cytotoxic granules, which kill infected
cells. Immunity  Immunityis the ability of the body to
defend itself against disease-causing organisms.
TypesofImmunity There are two major types of
immunity: 1. Innate Immunity or Natural or Non-specific
Immunity. 2. Acquired Immunity or Adaptive Immunity.
InnateI mmunity  Thistype of immunity is present in an
organism by birth.  Innate immunity is non-
specific because it does not depend on previous
exposure to foreign substances  Thisis activated
immediately when the pathogen attacks.  Innate
immunity includes certain barriers and defence
mechanisms that keep foreign particles out of the body.
Innate immunity can be categorized based on
individual, racial and species 1. Individual Immunity–
Sometimes, individuals belonging to the same race and
who have been exposed equally to the virus, pathogens
or worms can show a different level of immunity to a
disease or infection This can be due to health, age and
hereditary traits 2. Racial Immunity– When one race is
immune to a certain disease, and another race is
susceptible to it, it is referred to as racial immunity
factors such as genetic make-up, food habits, climate
conditions play an essential part in determining racial
immunity. 3. Species Immunity– When a disease attacks
a species only and another species is entirely immune
to it, it is known as species immunity. For
example, Birds are resistant to anthrax but Human are
susceptible. Cellsinvolvedininnatei mmunity
TheSkinBarrier One of the body’s most important
physical barriers is the skin barrier, which is composed
of three layers. The thin upper layer is called the
epidermis. A second, thicker layer, called the dermis,
contains hair follicles, sweat glands, nerves, and blood
vessels. Alayer of fatty tissue called the hypodermis lies
beneath the dermis and contains blood and lymph
vessels. the epidermis, consists of cells that are packed
with keratin. The keratin makes the skin’s surface
mechanically tough and resistant to degradation by
bacterial enzymes. Keratin also helps to make the outer
surface of the skin relatively waterproof, this helps keep
the surface of the skin dry, which reduces microbial
growth. In addition sebaceous glands and sweat glands
in the dermis secrete oily substance called sebum and
sweat respectively which act as anticeptic as they
contain lactic and fatty acids and the low pH of sebum
and sweat inhibits growth of most pathogens.
MucousMembranesThe mucous membranes lining the
nose, mouth, lungs, and urinary and digestive tracts
provide nonspecific barrier against potential pathogens.
Mucous membranes consist of a layer of epithelial cells
bound by tight junctions. The epithelial cells secrete a
moist, sticky substance called mucus, which traps
debris and particulate matter, including microbes.
Mucus secretions also contain antimicrobial peptides.
Cilia The epidermal cells of the respiratory passage are
lined with the cilia. The microorganism trapped in the
mucous of the respiratory passage are swept away by
the constant movement of these cilia. Hairs inside the
nose may trap larger pathogens and other particles in
the air before they can enter the airways of the
respiratory system Secreationofthedigestivetract The
high acidity of the stomach has a microbial effect and
this is due to the presence of HCl in the gastric juice .
Also, lysozyme found in tears, sweat, and saliva acts as
a vital antimicrobial agent to destroy
pathogens. Mechanicalbarrier  Mechanical defenses
include the flushing action of urine and tears which
carry microbes away from the body. The flushing action
of urine is largely responsible for the normally sterile
environment of the urinary tract, which includes the
kidneys, ureters, and urinary bladder.  Theeyelashes
and eyelids prevent dust and airborne microorganisms
from reaching the surface of the eye.  Mechanical
action of Coughing and sneezing help in driving out the
foreign particlesthat enter the respiratory tracts.
CellsInvolvedInInnateI mmunity  Phagocytes: These
circulate through the body and look for any foreign
substance. They engulf and destroy it defending the
body against that pathogen.  Macrophages: These
have the ability to move across the walls of the
circulatory system. They release certain signals as
cytokines to recruit other cells at the siteof infections. 
MastCells: These are important for healing wounds and
defence against infections.  Neutrophils: These contain
granules that are toxic in nature and kill any pathogen
that comes in contact.  Eosinophils: These contain
highly toxic proteins that kill any bacteria or parasite in
contact.  Basophils: These attack multicellular
parasites. Like the mast cells, these release histamine.
 Natural Killer Cells: These stop the spread of
infections by destroying the infected host cells. 
Dendritic Cells: These are located in the tissues that are
the points for initial infections. These cells sense the
infection and send the message to the rest of the
immune system by antigen presentation. Acquiredi
mmunity  Acquired immunity or adaptive immunity is
the immunity that our body acquires or gains over time.
Unlike the innate immunity, this is not present by birth.
 Anindividual acquires the immunity after the birth,
hence is called as the acquired immunity.  Itis specific
and mediated by antibodies or lymphocytes There two
types of acquired immunity are active and passive
immunity 1. ActiveaquiredI mmunity 
the immunity which results from the production
of antibodies by the immune systemin response to the
presence of an antigen  Active immunity can be
acquired through natural immunity or artificial
immunity.  Naturallyacquiredactivei mmunity involves
the development of an immune response when an
individual comes in contact with disease causing
pathogens. In this case, the individual's immune
system starts producing antibodies For example-
children who develop chickenpox and recover from the
illness, get better because they have made an effective
immune response against the chickenpox 
Artificialacquiredactivei
mmunityisthetypeofimmunitywhichisacquired artificia ly
by vaccination. Vaccines containdeadorlive
butattenuated(weakened)
pathogensThevaccine isintroducedintothebodytostimula
tetheformationof antibodies
[Link] example,poliovaccineavailable
whichhelps to provideprotectionfrompoliomyelitis. 2.
passivei mmunity  Whenready-madeantibodies are
directly injected into a person to protect the body
against foreign agents, it is called passive immunity. It
provides immediate relief. Passive immunity may be
natural or artificial. 1. Naturallyacquiredpassivei
mmunity Natural passive immunity is the resistance
passively transferred from the mother to the foetus
through placenta. IgG antibodies can cross placental
barrier to reach the foetus. After birth,
immunoglobulin’s are passed to the new-born through
the breast milk. 2. .Artificialacquiredpassivei mmunity
Artificially acquired passive immunity results when
antibodies or lymphocytes produced outside the host
are introduced into a infected host. example of artificial
passive immunity is an injection such as snake anti-
[Link] mmuneresponse 
AprimaryImmuneResponseoccurs when the body’s
immune response encounters an antigen for the first
time.  Duringthis immune response, the body learns to
recognize the antigen, produce antibodies against the
antigen, and induce a long-term memory response
against the antigen.  Thisresponse involved the
activation of naive B-cells and naive T-cells. 
Theresponselasts about 14 days to resolve. 
Therearefour phases of immune response that take
place when the body responds to an antigen for the
first time. 1. Thelag (latent) phase 2. Theexponential
phase 3. steady state phase (plateau phase 4. declining
phase 1. Thelag (latent) phase- is the period from the
initial exposure of immunogen to the time of detection
of antibodies (In humans the average time of lag phase
is about one week). During this lag phase specific T
cells and B cells are activated by their contact with
immunogen. 2. Theexponential phase- is the period
during which there is a rapid increase in antibody levels
due to secretion of antibodies by many plasma cells. 3.
steady state phase (plateau phase)- The antibody level
remains relatively at a constant level because the
secretion and degradation of antibodies occur almost at
equal rates. 4. declining phase- The antibody level
gradually declines because new plasma cells are no
longer produced and the existing plasma cells are
dying. This generally indicates that the immunogen has
been eliminated from the body and consequently there
is no stimulus for continued antibody
[Link] Secondary response
occur when a similar antigen enters the host for the
second and subsequent times, the immune responses
induced are called secondary immune responses.  This
response is mediated by the memory lymphocytes that
were produced during the primary response.
Immediately after the same antigen is encountered the
memory lymphocytes induce the production of
antibodies.  The lagphaseis usually very short (e.g. 3
or 4 days) due to the presence of memorycells. and The
antibody production levels increase rapidly within a
short period, normally within a few days This is because
of the antigen-specific memoryTandB-cells produced
during the primary response.  During this response the
antibodies remain in circulation for a longer period. 
Because of the rapidity of the secondary response, the
antigen gets eliminated as soon as it encounters the
memory cells and before it can cause disease.
Antigenpresentingcells(APC)  Antigen presenting cells
are a group of immune cells that are capable
ofprocessing and presenting antigens for recognition
by T cells to initiate the adaptive immune responses. 
Tcells cannot recognize antigens on its own. They can
only recognize and respond to antigen that has been
processed and presented by APC cells  B-lymphocytes,
macrophages, and dendritic cells are the three primary
antigenpresenting cells.  Theyconstitutively express
class II MHC comlex on their surface and they activate
helper T cells. Mechanism 
whenapathogensuchasabacteria, virus are enter to the
body the APC cells engulf the pathogen . Once inside
the APC Cells, the pathogen becomes enclosed within
an intracellular vesicle called a phagosome. The
phagosome then fuses with another vesicle called
a lysosome, forming a phagolysosome. in which it is
degraded into antigen fragments then this ultimately
associate with class II MHC molecules transported to
surface of the cell then this MHCII-peptide complex is
recognized by helpet T cells which induce adaptive
immune response
Blymphocytes  Blymphocytes or Bcell is a type of
lymphocytes  Inhumansandsomeothermammals,
themainsite of B lymphocytes development and
maturation is the bone marrow.  OnceBcellencounter
antigen it multiply rapidly and differentiates to become
either memory B cells or plasma cells.  Plasmacells:
Plasma cells produce antibodies in response to antigens
, hence they are known to trigger the humoral immune
response Once a B-cell becomes a mature plasma cell,
it can release up to 2,000 antibodies per second.
Plasma cells are also called plasmacytes or effector
cells. They have a shorter lifespan than memory cells.
Memorycells: MemoryBcells are formed after primary
infection and they remain in the blood for decades.
They circulate in the blood, identify and act against
previously infected antigens. Memory cells remember
particular antigens so, if they appear in the body in the
future they differentiated into plasma cells and produce
antibodies . For example, most vaccines work because
they expose immune system to antigens that the
memory cells remember. If an invader appears, body
can mount an attack quickly. TLymphocytes  Tcells
gettheir name from the site of maturation, i.e. thymus.
 Tcells also have surface receptors to recognize
antigens but they do not directly bind to the antigens
like surface receptors on B cells.  Itrecognize an
antigen when they bind with major histocompatibility
complex (MHC) molecules on the surface of the APC
cells. T lymphocytes differentiate into three main
subtypes: 1. 2. Thelper(TH)cells-  Theygenerally
contain CD4 membrane glycoprotein on their surface
and recognise antigens with class II MHC. 
Themajorfunction of Helper T-cells is stimulate the B-
cells to make antibodies  Thelpercells also trigger
different types of immune cells to act against the
antigens like macrophages, B lymphocytes and
cytotoxic T cells.  Theyalsosecrete different types of
cytokines, which mediate inflammation and regulate
other types of immune cells. Tcytotoxic(TC)cells
Theygenerally contain CD8 membrane glycoprotein on
their surface and recognise antigens with class I MHC. 
cytotoxic T lymphocytes eliminates virus-infected cells,
tumour or cancerous cells and also foreign grafts, etc.
3. regulatoryTcell itis atype of immune cell that blocks
the actions of some other types of lymphocytes, to
keep the immune system from becoming
overactive. thereby maintaining the homeostasis and
self-tolerance.  regulatory T cell are able to inhibit T
cell proliferation and cytokine production and play a
critical role in preventing autoimmunity. 4.
ThememoryTcells are antigen-specific T cells which
have a longer life span. They play a key role in rapid
immune response on the re-exposure of a pathogen.
They are responsible for the secondary response.
cellmediatedi mmunity  cell-mediated immunity does
not depend on antibodies for its adaptive immune
functions.  Cell-mediated immunity is primarily driven
by mature T cells, macrophages, and the release of
cytokines in response to an antigen. mechanism 
itbegins when an invading bacteria is engulfed by an
antigen presenting cells inside the APC Cells, the
pathogen becomes enclosed within an intracellular
vesicle called a phagosome a lysosome containg
digestive enzymes combines with the phagosome to
process the antigen  theprocessed antigens combine
with the MHCII molecules and are presented on the
surface of the APC  HelperTcells (CD4+) recognize the
displayed antigen on the APC with thehelp of CD4
receptor and bind to the MHC class II- antigenic peptide
complex  Theactivated helper T cell releases the
cytokine which stimulates the cytotoxic T cell which kill
the infected cells it also attract other immune cells to
the site of infection.  Thecytotoxic T cell releases
perforine molecule which makes hole in the cell
membrane pathogen resulting in the lysis of bacterial
cell.
humoralmediatedi mmunity  Humoral immunity is an
antibody-mediated response that occurs when
foreignmaterial– antigens- are detected in the body. 
Thismechanismis primarily driven by B cell lymphocytes
a type of immune cell that produces antibodies after
the detection of a specific antigen.  It’s also
called “antibody-mediated immunity” as antibody
production is one of the notable features of this
immunity mechanism  itbegins when an invading
bacteria is engulfed by an antigen presenting cells
inside the APC Cells, the pathogen becomes enclosed
within an intracellular vesicle called a phagosome a
lysosome containg digestive enzymes combines with
the phagosome to process the antigen  theprocessed
antigens combine with the MHCII molecules and are
presented on the surface of the APC  HelperTcells
(CD4+) recognize the displayed antigen on the APC
with the help of CD4 receptor and bind to the MHC
class II- antigenic peptide complex  Theactivated
helper T cell releases the cytokine which stimulates the
B cell to divide and differentiated into antibody
producing plasma cells and memory cells 
Theplasmacells produces antibodies. These antibodies
binds to the antigen in a lock and key fashion. This
makes easier for killer cells to attack and destroy the
bacteria by phagocytosis  Theactivated B cells and T
cells differentiated into memory cell this brings
secondary immune response when the same antigen
enters the body for the second time.
Hapten Ahapten is a substance that can combine with a
specific antibody but lacks antigenicity of its own. Many
small molecules of Mr < 1000 such as toxins, drugs and
hormones are not capable of invoking immune
response when injected directly into animals. They are
thus not immunogenic by themselves, and are called
haptens. they stimulates the production of antibody
only when conjugated to a larger molecule, called a
carrier molecule.
TOLERANCE AND AUTOIMMUNITY

TOLERANCE
Introduction
Tolerance refers to the specific immunological non-
reactivity to an antigen resulting from a previous
exposure to the same antigen. While the most
important form of tolerance is non-reactivity to self
antigens, it is possible to induce tolerance to non-self
antigens. When an antigen induces tolerance, it is
termed tolerogen.
Tolerance to self antigens
We normally do not mount a strong immune response
against our own (self) antigens, a phenomenon called
self-tolerance. When the immune system recognizes a
self antigen and mounts a strong response against it,
autoimmune disease develops. Nonetheless, the
immune system has to recognize self-MHC to mount a
response against a foreign antigen. Thus, the immune
system is constantly challenged to discriminate self vs
non-self and mediate the right response.
Induction of tolerance to non-self
Tolerance can also be induced to non-self (foreign)
antigens by modifying the antigen, by injecting the
antigen through specific routes such as oral,
administering the antigen when the immune system is
developing, etc. Certain bacteria and viruses have
devised clever ways to induce tolerance so that the
host does not kill these microbes. Ex: Patients with
lepromatous type of leprosy do not mount an immune
response against Mycobacterium leprae.
Tolerance to tissues and cells
Tolerance to tissue and cell antigens can be induced by
injection of hemopoietic (stem) cells in neonatal or
severely immunocompromised (by lethal irradiation or
drug treatment) animals. Also, grafting of allogeneic
bone marrow or thymus in early life results in tolerance
to the donor type cells and tissues. Such animals are
known as chimeras. These findings are of significant
practical application in bone marrow grafting.
Tolerance to soluble antigens
A state of tolerance to a variety of T-dependent and T-
independent antigens has been achieved in various
experimental models. Based on these observations it is
clear that a number of factors determine whether an
antigen will stimulate an immune response or tolerance
(Table 1).

Table 1
Factors that determine induction of
immune response or tolerance
following challenge with antigen

Factors
Favor
that affect Favor
immune
response tolerance
response
to Ag

Physical Large, Soluble,

form of aggregated, aggregate-
antigen complex free, relatively
molecules; smaller, less
complex
molecules, Ag
not processed
by APC or
processed by
cell without
class II MHC

Route of Ag Sub- Oral or

administrati cutaneous or sometimes
on intramuscular intravenous

Dose of Optimal dose Very large (or

antigen sometime
very small)
dose

Age of Older and Newborn

responding immunologica (mice),
animal lly mature immunological
 ly immature

Differentiati Fully Relatively

on state of differentiated undifferentiate
cells cells; memory d: B cells with
T and only IgM (no
memory B IgD), T cells
cells (e.g. cells in
thymic cortex)

Immunologic features of tolerance

Tolerance is different from non-specific
immunosuppression and immunodeficiency. It is an
active antigen-dependent process in response to the
antigen. Like immune response, tolerance is specific
and like immunological memory, it can exist in T-cells, B
cells or both and like immunological memory, tolerance
at the T cell level is longer lasting than tolerance at the
B cell level.
Induction of tolerance in T cells is easier and requires
relatively smaller amounts of tolerogen than tolerance
in B cells. Maintenance of immunological tolerance
requires persistence of antigen. Tolerance can be
broken naturally (as in autoimmune diseases) or
artificially (as shown in experimental animals, by x-
irradiation, certain drug treatments and by exposure to
cross reactive antigens).
Tolerance may be induced to all epitopes or only some
epitopes on an antigen and tolerance to a single
antigen may exist at the B cell level or T cell level or at
both levels.
Mechanism of tolerance induction
The exact mechanism of induction and maintenance of
tolerance is not fully understood. Experimental data,
however, point to several possibilities.
Clonal deletion
T and B lymphocytes during development come across
self antigens and such cells undergo clonal deletion
through a process known as apoptosis or programmed
cell death. For example, T cells that develop in the
thymus first express neither CD4 nor CD8. Such cells
next acquire both CD4 and CD8 called double-positive
cells and express low levels of αβ TCR. Such cells
undergo positive selection after interacting with class I
or class II MHC molecules expressed on cortical
epithelium. During this process, cells with low affinity
for MHC are positively selected. Unselected cells die by
apoptosis, a process called "death by neglect". Next,
the cells loose either CD4 or CD8. Such T cells then
encounter self-peptides presented by self MHC
molecules expressed on dendritic cells. Those T cells
with high affinity receptors for MHC + self-peptide
undergo clonal deletion also called negative selection
through induction of apoptosis. Any disturbance in this
process can lead to escape of auto-reactive T-cells that
can trigger autoimmune disease. Likewise,
differentiating early B cells when they encounter self-
antigen, cell associated or soluble, undergo deletion.
Thus, clonal deletion plays a key role in ensuring
tolerance to self antigen.
Peripheral tolerance: The clonal deletion is not a fool
proof system and often T and B cells fail to undergo
deletion and therefore such cells can potentially cause
autoimmune disease once they reach the peripheral
lymphoid organs. Thus, the immune system has
devised several additional check points so that
tolerance can be maintained.
Activation-induced cell death: T cells upon activation
not only produce cytokines or carryout their effector
functions but also die through programmed cell death
or apoptosis. In this process, the death receptor (Fas)
and its ligand (FasL) play a crucial role. Thus, normal T
cells express Fas but not FasL. Upon activation, T cells
express FasL which binds to Fas and triggers apoptosis
by activation of caspase-8. The importance of Fas and
FasL is clearly demonstrated by the observation that
mice with mutations in Fas (lpr mutation) or FasL (gld
mutation) develop severe lymphoproliferative and
autoimmune disease and die within 6 months while
normal mice live up to 2 years. Similar mutations in
these apoptotic genes in humans leads to a
lymphoproliferative disease called autoimmune
lymphoproliferative syndrome (ALPS).

Clonal anergy
Auto-reactive T cells when exposed to antigenic
peptides on antigen presenting cells (APC) that do not
possess the co-stimulatory molecules CD80 (B7-1) or
CD86 (B7-2) become anergic (nonresponsive) to the
antigen. Also, while activation of T cells through CD28
triggers IL-2 production, activation of CTLA4 leads to
inhibition of IL-2 production and anergy. Also, B cells
when exposed to large amounts of soluble antigen
down-regulate their surface IgM and become anergic.
These cells also up-regulate the Fas molecules on their
surface. An interaction of these B cells with Fas-ligand
bearing T cells results in their death via apoptosis.

Clonal ignorance
T cells reactive to self-antigen not represented in the
thymus will mature and migrate to the periphery, but
they may never encounter the appropriate antigen
because it is sequestered in inaccessible tissues. Such
cells may die out for lack of stimulus. Auto-reactive B
cells, that escape deletion, may not find the antigen or
the specific T-cell help and thus not be activated and
die out.

Anti-idiotype antibody
These are antibodies that are produced against the
specific idiotypes of other antibodies. Anti-idiotypic
antibodies are produced during the process of
tolerization and have been demonstrated in tolerant
animals. These antibodies may prevent the B cell
receptor from interacting with the antigen.

Regulatory T cells (Formerly called suppressor

cells)
Recently, a distinct population of T cells has been
discovered called regulatory T cells. Regulatory T cells
come in many flavors, but the most well characterized
include those that express CD4+ and CD25+. Because
activated normal CD4 T cells also express CD25, it was
difficult to distinguish regulatory T cells and activated T
cells. The latest research suggests that regulatory T
cells are defined by expression of the forkhead family
transcription factor Foxp3. Expression of Foxp3 is
required for regulatory T cell development and function.
The precise mechanism/s through which regulatory T
cells suppress other T cell function is not clear. One of
the mechanisms include the production of
immunosuppressive cytokines such as TGF-β and IL-10.
Genetic mutations in Foxp3 in humans leads to
development of a severe and rapidly fatal autoimmune
disorder known as Immune dysregulation,
Polyendocrinopathy, Enteropathy, X-linked (IPEX)
syndrome. This disease provides the most striking
evidence that regulatory T cells play a critical role in
preventing autoimmune disease.

Termination of tolerance
Experimentally induced tolerance can be terminated by
prolonged absence of exposure to the tolerogen, by
treatments which severely damage the immune system
(x-irradiation) or by immunization with cross reactive
antigens. These observations are of significance in the
conceptualization of autoimmune diseases.

AUTOIMMUNITY
Definition
Autoimmunity can be defined as breakdown of
mechanisms responsible for self tolerance and
induction of an immune response against components
of the self. Such an immune response may not always
be harmful (e.g., anti-idiotype antibodies). However, in
numerous autoimmune diseases it is well recognized
that products of the immune system cause damage to
the self.
Effector mechanisms in autoimmune diseases
Both antibodies and effector T cells can be involved in
the damage in autoimmune diseases.
General classification
Autoimmune diseases are generally classified on the
basis of the organ or tissue involved. These diseases
may fall in an organ-specific category in which the
immune response is directed against antigen(s)
associated with the target organ being damaged or a
non-organ-specific category in which the antibody is
directed against an antigen not associated with the
target organ (Table 2). The antigen involved in most
autoimmune diseases is evident from the name of the
disease (Table 2).
Genetic predisposition for autoimmunity
Studies in mice and observations in humans suggest a
genetic predisposition for autoimmune diseases.
Association between certain HLA types and
autoimmune diseases has been noted (HLA: B8, B27,
DR2, DR3, DR4, DR5 etc.).
Etiology of autoimmunity disease
The exact etiology of autoimmune diseases is not
known. However, various theories have been offered.
These include sequestered antigen, escape of auto-
reactive clones, loss of suppressor cells, cross reactive
antigens including exogenous antigens (pathogens) and
altered self antigens (chemical and viral infections).
Sequestered antigen

Lymphoid cells may not be exposed to some self

antigens during their differentiation, because they may
be late-developing antigens or may be confined to
specialized organs (e.g., testes, brain, eye, etc.). A
release of antigens from these organs resulting from
accidental traumatic injury or surgery can result in the
stimulation of an immune response and initiation of an
autoimmune disease.
Escape of auto-reactive clones

The negative selection in the thymus may not be fully

functional to eliminate self reactive cells. Not all self
antigens may be represented in the thymus or certain
antigens may not be properly processed and presented.
Lack of regulatory T cells

There are fewer regulatory T-cells in many autoimmune

diseases.

Table 2
Spectrum of autoimmune diseases, target
organs and diagnostic tests

Disease Orga Antibody Diagnostic

 n to Test

Org Hashimoto' Thyroi Thyroglob RIA, Passive,

an- s d ulin, CF,
Spe thyroiditis thyroid hemagglutin
cific peroxidas ation
e
(microso
mal)

Primary Thyroi Cytoplas Immunofluor

Myxedema d mic TSH escence (IF)
receptor

Graves' Thyroi Bioassay,

disease d Competition
for TSH
receptor

Pernicious Red Intrinsic B-12 binding

anemia cells factor to IF
(IF), immunofluor
Gastric escence
parietal
cell

Addison's Adren Adrenal Immunofluor

disease al cells escence
(Fig 1)

Premature Ovary Steroid Immunofluor

onset producing escence
menopaus cells
e
Male Sper Spermato Agglutinatio
infertility m zoa n,
Immunofluor
escence

Insulin Pancr Pancreati

dependent eas c islet
juvenile beta cells
diabetes

Insulin Syste Insulin Competition

resistant mic receptor for receptor
diabetic

Atopic Syste beta- Competition

allergy mic adrenergi for receptor
c receptor

Myastheni Muscl Muscle, Immunofluor

a graves e acetyl escence,
choline competition
receptor for receptor

Goodpastu Kidne Renal and Immunofluor

re's y, lung escence
syndrome lung basement (linear
membran staining)
e (Fig. 2)

Pemphigus Skin Desmoso Immunofluor

mes escence (Fig
3)

Pemphigoi Skin Skin Immunofluor

 d basement escence (Fig
membran 4)
e

Phacogenic Lens Lens

uveitis protein

AI Red Red cells Passive

hemolytic cells hemagglutin
anemia Platel ation
et Direct
Coomb's test

Idiopathic Platelet Immunofluor

thrombocy escence
topenia

Primary Liver Mitochon Immunofluor

biliary dria escence
cirrhosis
Non
- Idiopathic Neutr Neutrophi Immunofluor
org neutropeni ophils ls escence
an a
Spe
cific Ulcerative Colon Colon Immunofluor
colitis lipopolysa escence
ccharide

Sjogren's Secret Duct Immunofluor

syndrome ory mitochon escence
gland dria
s
 (Fig 5)

Vitiligo Skin Melanocyt Immunofluor

Joints es (fig 6) escence

Rheumatoi Skin, IgG IgG-latex

d arthritis kidne agglutinatio
y, n
joints
etc

Systemic joints, DNA, RNA-, DNA-

lupus eryth etc. RNA, latex
ematosus nucleopro agglutinatio
teins n, IF
(granular in
kidney)

Diseases are listed from the most organ-specific

(top) to the least specific (bottom)

Cross reactive antigens

Antigens on certain pathogens may have determinants
which cross react with self antigens and an immune
response against these determinants may lead to
effector cell or antibodies against tissue antigens. Post
streptococcal nephritis and carditis, anticardiolipin
antibodies during syphilis and association
between Klebsiella and ankylosing spondylitis are
examples of such cross reactivity.
Diagnosis
Diagnosis of autoimmune diseases is based on
symptoms and detection of antibodies (and/or very
early T cells) reactive against antigens of tissues and
cells involved. Antibodies against cell/tissue associated
antigens are detected by immunofluorescence.
Antibodies against soluble antigens are normally
detected ELISA or radioimmunoassay (see table above).
In some cases, a biological /biochemical assay may be
used (e.g., Graves diseases, pernicious anemia).
Treatment
The goals of treatment of autoimmune disorders are to
reduce symptoms and control the autoimmune
response while maintaining the body's ability to fight
infections. Treatments vary widely and depend on the
specific disease and symptoms: Anti-inflammatory
(corticosteroid) and immunosuppressive drug therapy
(such as cyclophosphamide, azathioprine,
cyclosporine ) is the present method of treating
autoimmune diseases. Extensive research is being
carried out to develop innovative treatments which
include: anti-TNF alpha therapy against arthritis,
feeding antigen orally to trigger tolerance, anti-idiotype
antibodies, antigen peptides, anti-IL2 receptor
antibodies, anti-CD4 antibodies, anti-TCR antibodies,
etc.
Models of autoimmune diseases
There are a number of experimental and natural animal
models for the study of autoimmune diseases. The
experimental models include experimental auto-allergic
encephalitis, experimental thyroiditis, adjuvant induced
arthritis, etc.
Naturally occurring models of autoimmune diseases
include hemolytic anemia in NZB mice, systemic lupus
erythematosus in NZB/NZW (BW), BXSB and MRL mice
and diabetes in obese mice.