BASIC IMMUNOLOGY

1. INTRODUCTION OF IMMUNOLOGY
2. DEFINITIONS AND CLASSIFICATION OF IMMUNITY
3. DEVOLOPMEMT OF IMMUNE SYSTEM
4. CELLS OF THE IMMUNE SYSTEM
5. ANTIGEN
6. ANTIGEN PRESENTING CELLS
7. IMMUNOGLOBULINS
8. REGULATORY CELL SURFACE MOLECULES OF IMMUNE
SYSTEM
#MAJOR HISTOCOMPATABILITY COMPLEX
#CLUSTER OF DIFFERENTIATION
#CELL SURFACE RECEPTORS
#ADHESINS
9. EFFECTOR MOLECULES OF IMMUNE SYSTEM
# IMMUNOGLOBINS
#COMPLEMENT
#CYTOKINES
10. SPECIFIC IMMUNE RESPONSE
11. HYPERSENSITIVITY
12. AUTOIMMUNITY
13. PERIODONTAL IMMUNOLOGY
a) Immunological aspect in gingivitis
b) Immunological aspect in periodontitis
14. CONCLUSION
15. REFERENCES

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INTRODUCTION:

IMMUNOLOGY may be defined as a study of the resistance of living

organisms to harmful agents, irrespective of the nature of the agent.

STUDY OF IMMUNOLOGY involves the process by which a body

defends and maintains the constancy of its internal milieu against invasion
by foreign organisms or mutation or development of unwanted cells or cell
products within itself.
Thus it deals with antigen, antibody and cell mediated functions especially
as they relate to immunity to disease, hypersensitive biological reactions,
allergies and rejection of foreign tissues.

The recent outburst of advances in immunology has been responsible for

notable progress in the field of various sciences.
In Periodontics, periodontal disease emphasizes a specific bacterial etiology
of periodontitis than a non-specific indictment of plaque. Now, it is
recognized that host response plays a role in most forms of periodontal
disease.
In gingivitis and periodontitis, the development of the disease
depends on the interaction between resistant micro biota and host response.
In desquamative gingivitis, the lesions frequently result from a host
response. Since most of the host responses triggered by bacterial infections
are immunologic, the study on immunology is relevant.

DEFINITIONS;
1. IMMUNITY is defined as a state of resistance or insusceptility to toxic
molecules, microorganisms and their products. It is a state of increased
reactivity and protection against a substance that comes in contact with a
host.

2. ANTIGEN is a substance which when introduced into a body can

generate an immune response

3. HAPTEN is a non-protein structure, which combines with a protein, and

the resulting complex behaves as an antigen

4.ANTIBODY OR IMMUNOGLOBULINS are serum molecules

produced by B-lymphocytes, found in plasma and destroy toxins liberated

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from bacteria or coat the bacteria so that they are subsequently
phagocytozed.

5. RECEPTORS are highly specialized structures present on target cells

designed to combine a highly specific chemical compound or even specific
cells.

6. MAJOR HISTOCOMPATABILITY COMPLEX [MHC]- The antigen

fragments are presented on the surface of the cell by a specialized group of
molecules which are encoded in a set of genes referred to as MHC

7. HUMAN LEUCOCYTE ANTIGEN is a class of antigens produced by

the MHC, which is glycoprotein in nature

CLASSIFICATION

1. INNATE IMUNITY
a) Non specific
b) Specific
2.ACQUIRED IMMUNITY
a) Active Natural
Artificial
b) Passive Natural
Artificial
INNATE IMMUNITY is the resistance to infections that an individual
possess by virtue of his genetic and constitutional make up. It acts as a first
line of defense against infectious agents.
It may be:
NON SPECIFIC when it indicates a degree of resistance to infections in
general.
SPECIFIC when resistance to a particular pathogen is concerned.
SPECIES IMMUNITY refers to the total or relative refractoriness to a
pathogen shown by all members of the species
Eg: Human beings are totally insusceptible to plant pathogens and to many
pathogens of animals

RACIAL IMMUNITY -Different races may show differences in

susceptibility to infections. This is known as racial immunity

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Eg: High resistance of Algerian sheep to Anthrax

INDIVIDUAL IMMUNITY Differences in innate immunity exhibited by

different individuals in a race is known as individual immunity.

INNATE IMMUNITY results from the following:

1.Resistance of the skin to invasion by organisms
2.Phagocytosis of bacteria and other invaders by WBC and cells of the tissue
macrophage system (derived from bone marrow)
3. Presence of certain chemical compounds in the blood and other secretions
that attach to foreign organisms or toxins to destroy them
Eg: Lysozyme, complement complex
4. Natural killer cells
5.Normal bacterial flora and protection from infection

DETERMINANTS OF INNATE IMMUNITY

1.Species
2.Individual differences and influence of age
3. Nutritional factors and hormonal influences
4. Temperature
5. Complement system
6. Oxygen concentration
7. Genetic differences

2. ADAPTIVE OR ACQUIRED IMMUNITY

The resistance that an individual acquires during life is known as acquired or
adaptive immunity. It is antigen specific and may be based on antibody (hum
oral immunity) or may be cellular (cell mediated immunity) associated with
activation of lymphocytes. It is sub divided as follows:
a) Active- 1) Natural
2) Artificial
b) Passive-1) Natural
2) Passive

Actively acquired immunity (Natural)

A degree of naturally acquired active immunity develops from any infection
from which a person recovers. During the illness, the individual receives an

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antigenic stimulus, which initiates antibody production against that specific
pathogen. These antibodies will assist in the body’s defense on a subsequent
exposure to that antigen.

Artificial acquired immunity- the immunity resulting from injection of

vaccines or toxoids is called artificially acquired active type.

Passively acquired immunity (Natural)

Naturally acquired passive immunity refers to the transplacental passage of
antibodies from the mother to her unborn child. This is caused by
immunoglobins.

Artificial acquired immunity (Passive)- refers to the resistance passively

transferred to a recipient by administration of antibodies. The agent used
includes hyper immune sera of animal or human origin and pooled human
gamma globulin.

DEVELOPMENT OF IMMUNE SYSTEM

Many of the cells involved in the immune response are derived from
undifferentiated haematopoitic stem cells (HSC) and are thought to
differentiate into various cell lineages under the influence of different
microenvironmental factors. The HSC are formed in the foetal liver, spleen
and bone marrow. They give rise to 4 major cell lineages
-Erythroid
-Megakaryocyte
-Myeloid
-Lymphoid.
The latter 2 are critical to the functioning of the immune system

DEVELOPMENT OF MYELOID CELLS

The first progenitor cell derived from the HSC is the colony-forming unit.
which can give rise to granulocyte, erythrocyte, monocyte and
megakaryocyte. Development of these into mature cells is regulated by
colony stimulating factors and IL-1, 3,4,5 and 6.

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a)Granulocyte development
Promyelocytes first differentiate into Myelocytes and are released into
circulation as mature neutrophils,basophils and eosinophils.The
differentiation of cells into mature granulocytes is the result of acquisition of
specific growth differentiation factor receptors at different stages of
development. Surface differentiation markers disappear or appear on the
cells as they develop into granulocytes.
Eg; The CFU-GM carries MHC class2 and CD 34 on its surface.

MONOCYTE DEVELOPMENT
Colony Forming Unit –Granulocyte first differentiate into proliferating
monoblast,then into promonoblast and finally into mature circulating
monocyte

DEVELOPMENT OF ANTIGEN PRESENTING CELLS [APC]

APCs include follicular dendritic cells, langerhan cells and inter digitatory
follicular cells present at birth.
One school of thought says that they are derived from the stem cells. The
other school believes that they are derived from different stem cells and
represent separate lineages of differentiation

DEVELOPMENT OF COMPLEMENT SYSTEM

Complement has at least 20 distinct plasma proteins, which during foetal
development are detectable before circulating Immunoglobin M. In neonates
they comprise 50-60% of adult serum levels.

DEVELOPMENT OF LYMPHOID CELL

Lymphocytes develop in the primary lymphoid organs
T cells-Thymus
B cell-Avian Bursa of Fabricus/ or for mammals in foetal liver and bone
marrow. These cells then migrate to secondary lymphoid tissues where they
can respond to antigen

T cell
The thymic rudiment develops from the 3rd pharyngeal pouch as an
outgrowth pushing the gut endoderm, which then becomes seeded with
blood borne lymphoid stem cells. Few of them give rise to mature T cells.
Migration of thymus is not a random process. The thymocytes become
organized into well-defined lobules forming a cortex and a medulla. Cortical

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cells represent 85-90%of the thymocytes and they are less mature than
medullary thymocyte. Here epithelial cells and bone derived dendritic cells
rich in MHC class 2 antigens are important in differentiation of T
Lymphocyte. Presently, two T cell receptors have been identified- the
gamma / delta (TCR1) and the alpha/beta (TCR2). Also, phenotypic studies
of surface membrane antigens suggest that there are 2 pathways of T cell
differentiation in the thymus. Most thrombocytes differentiate into TCR2
which account for majority of T lymphocytes found in secondary lymphoid
tissue in circulation

DEVELOPMENT OF B CELLS
These cells develop directly from lymphoid stem cells in the haematopoetic
tissue of foetal liver from 8-9 weeks of gestation. Later the site of B cell
production moves from liver to bone marrow in adult life. Each B cell
progenitor may produce up to 64 progeny. These migrate towards the centre
of each cavity of the spongy bone and reach the lumen of a venous sinusoid
In the bone marrow, the cells mature in close association with stromal
reticular cells. The stromal reticular cells are found both adjacent to the
endosteum and in close association with the central sinus, where they are
termed adventitial reticular cells. These cells may be important for the
release of mature B cells into the central sinus. The majority of B cell
maturing in the bone marrow do not reach the circulation but undergo a
process of programmed cell death (apoptosis) which are phagocytosed by
bone marrow macrophages.

DEVELOPMENT OF MEMORY B CELLS

Following antigen activation, B cells mature either into antibody forming
cells or then into plasma cells or develop into memory cells.
There are germinal tissues in lymphoid organ, which are sites for
development of memory B cells. At these sites, B cells undergo hyper
mutation of antibody variable region –leads to apoptosis of some cells, but
cells with receptors for foreign antigen are rescued from cell death by
antigen presented by APC.

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 B cell blast

Go to germinal center

Proliferate at the rate of 104 cells in 3-4 days

On the 4th day

Centro blasts (No surface I g)

Centrocytes

Undergo hyper mutation of antibody variable region

Cells with receptors for foreign antigen

Secondary blasts

Memory B cells

CELLS OF THE IMMUNE SYSTEM

All cells arise from pluripotent stem cells through 2 main lines of
differentiation.
1. The lymphoid lineage- producing lymphocytes
2. The myeloid lineage –producing phagocytes. They include
(Monocyte, macrophages and neutrophils) and other cells

Lymphoid cells
Lymphocytes are produced in the primary or central lymphoid organs
(thymus & adult bone marrow) at a high rate (109 cells/day). Some of these
cells migrate via the circulation into the secondary lymphoid tissue
(spleen,lymph nodes, tonsil & mucosa associated lymphoid
tissue).Lymphoid tissue as a whole represent 2% of total body weight.
Lymphoid cells represent about 20% of the total white blood cells present in

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adult circulation. Lymphocyte measure about (6-10μm) in
diameter.Functionally they can be divided into 2 major groups
T Lymphocytes
B Lymphocytes

T Lymphocyte-----70-80%
B Lymphocyte----10-15%
Natural killer ------5-10%

MARKERS ON LYMPHOCYTES
Lymphocytes express a large number of different molecules or markers on
their surfaces, which can be used to distinguish cell populations. The term
cluster of differentiation refers to groups or clusters of monoclonal
antibodies, each cluster binding specifically to a particular cell marker
Eg a) CD3 which is exclusive to T cell and is involved in cell triggering
b) T cell growth factor receptor (IL-2 receptor, CD 25) is an activation
marker of T cells; only being expressed when the cell is stimulated by
antigen

T CELLS
The definitive T cell lineage marker is the ‘T cell antigen receptor’

Two types
TCR 1 consists of γ and δ polypeptides
TCR 2 consists of 2 disulphide linked polypeptides [α, β]

Thus T cell is a cell that expresses either TCR1 or TCR2

(80-85% of blood T cells express TCR2 & 15% TCR1)

TCR 2 bearing cells can be divided into 2 distinct sub populations

a) Which carries CD4 marker and helps or induces immune response(TH)
b) Which carries CD8 marker which is Cytotoxic(TC)

CD4 T cells recognize specific antigens in association with MHC class 2

molecules
CD8 cells recognize antigens in association with class 1 molecules
B CELLS

B Lymphocyte represents 5-15% of circulating lymphoid pool.

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Defined by the presence of surface Immunoglobin. These immunoglobins
are inserted into the surface membrane of the B cell where they act as
specific antigen receptors. The majority of the B cells carry MHC class 2
antigens, which are important for interaction with T cells. These class 2
molecules consists of Human leukocyte antigen DP,DQ and DR in man.
B cells contain complement receptor C3b

NATURAL KILLER CELLS

Accounts for 15% of blood lymphocytes

Function: 1. They are cytotoxic for virus infected cells and to targets coated
with Immunoglobin.
2. Also able to kill certain tumor cells
Marker include CD16 / CD56
Also called ‘Null cells’
Require IL-2 for their action and are depressed by prostaglandins.

MYELOID CELLS
In the immune system, there are 2 different types of cells
1. Monocyte/ Macrophages, which are phagocyte
2. Antigen presenting cells
The progenitor of the myeloid cell gives rise to promonocyte in the bone
marrow.They differentiate into blood monocytes which represent a
circulating pool. Then, they migrate into various organs and tissue systems
to become macrophages

MONOCYTE
Large (10-18 μm diameter) and has a horse shoe shaped nucleus and contain
faint azurophilic granules. Ultrastructurally, they posses ruffled membranes,
well-developed Golgi complex, lysosomes. These lysosomes contain
peroxides and acid hydrolases, which are important in intracellular killing of
microorganisms.
Marker CD14, a receptor for LPS , also have receptor for cytokines IFN-γ,
IL-4

POLYMORPHONUCLEAR GRANULOCYTE
Produced in the bone marrow at the rate of 80 million /minute and are short
lived (2-3 days).Granulocytes makes up about 60-70% of the total normal

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blood leukocytes. They have a multilobed nucleus and many granules.
Classified into neutrophils, eosinophils and basophils on the basis of staining
reaction of their granules with histological dyes. Play an important role in
acute inflammation in protection against microorganism. Predominent role is
phagocytosis.

NEUTROPHILS
Constitute 90% of circulating polymorphs. 10-20μm in diameter
They posses 2 main types of granules.
Primary (Azurophilic granules) are lysosomes containing acid hydrolases,
myeloperoxidases and muramidase
Secondary granules contain lactoferrin in addition to lysozyme

Chemotactic agents for neutrophils include

*C5a
*Factors derived from fibrinolytic and kinin system
*Products of other leukocytes
*Platelets
*Products of certain bacteria

EOSINOPHILS
Comprise 2-5% of blood leukocytes. Granules are membrane bound
organelles with a crystalloid core. They have a bilobed nucleus with many
cytoplasmic granules.
Function: Capable of phagocytosing and killing ingested organisms. They
release histaminase and aryl sulphatase, which inactivate histamine and
SRS-A. The effect of these 2 factors is to dampen down inflammatory
response and decrease granulocyte migration into sites of invasion.

BASOPHILS
Comprise less than 0.2% of leucocytes. Characterized by deep violet blue
granules. It contains heparin, SRS-A and ECF-A and these substances are
released on degranulation.

PLATELETS
They are myeloid cells derived from megakaryocytes in the bone marrow
and contain granules. Play a role in blood clotting and also in immune
response, especially in inflammation. They express class1 MHC products
and also receptors for IgE and IgG

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ANTIGENS
An antigen has been defined as any substance which when introduced
parenterally into the body stimulates the production of antibody with which
it reacts specifically and in an observable manner. Some antigens may not
induce antibodies but may sensitize specific lymphocyte leading to cell
mediated immunity. The word ‘parenteral’ is used because orally
administered antigens are usually hydrolyzed by digestive enzymes and
antigenicity destroyed. There are some exceptions and some antigens can be
immunogenic when given orally
EG: Oral vaccines

An antigen introduced into the body reacts only with those particular (B and
T) Lymphocytes which carry the specific marker for that antigen and which
produce antibody complementary to that antigen only.
Antigen complete
Hapten complex (precipitate with specific antibody)
Simple (non precipitating)

Smallest unit of antigenicity is known as ‘antigenic determinant or epitope’

Epitope is a small area on the antigen possessing a specific chemical
structure ad spatial configuration capable of sensitizing an immunocyte and
of reacting with its complementary site on the specific antibody. The
combining area on the antibody molecule, corresponding to epitope is called
‘Paratope’.
Eg: Antigens such as bacteria or viruses carry many different types of
epitopes

DETERMINANTS OF ANTIGENICITY
1.Size- Very large molecules as hemocyanins (Mw 6. 75million) are highly
antigenic.
2. Chemical nature-A certain degree of structural complexity is required for
antigenicity. Thus proteins, which are composed of about 20 different amino
acid, are better antigens than polysaccarides, which have only 5
monosaccharide units.
3.Susceptibility to tissue enzymes- Only substances which are metabolized
and are susceptible to action of tissue enzymes behave as antigens
4. Foreignness-An individual does not normally mount an immune response
against his own normal constituent antigens. Tolerence of self-antigens is

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conditioned during the development of immune apparatus. Breakdown of the
homeostatic mechanism result in autoimmunization and autoimmune disease
5. Antigen specificity—is not absolute. Cross-reaction can occur between
antigens and may actually be due to sharing of identical antigenic
determinants by different antigens.

BIOLOGICAL CLASS OF ANTIGEN

Depending on the ability to induce antibody formation, antigen are classified
as
1.T cell dependent
2 T cell independent
1) Can directly stimulate antibody production
2) Require T cell participation to generate an immune response

1) Structurally more complex

Eg: erythrocyte, serum protein
Immune response is not dose dependent
Immune response is limited to IgG,M,A

2) Structurally simple
Eg: LPS, Pnuemococcal capsular polysaccharide
Immune response is dose dependent
Immune response is limited to IgM, and G
Metabolized very slowly and remain in the body for long periods

ANTIGEN PRESENTING CELLS

These are a heterogeneous population of leucocytes with immuno
stimulatory capacity. Some have a pivotal role in the induction of functional
activity of the T helper cells and some communicate with other leucocytes.
Cells other than leukocytes, such as endothelial or epithelial cells can also
acquire the ability to present antigens when stimulated by cytokines.
APC are found primarily in the skin, lymph nodes, spleen and thymus.
The main types are:
1.Langerhan cell- in the skin
2.Follicular dendritic cells—found in the lymph node, B cells and
macrophages

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1) Langerhan cells —are found in the epidermis characterized by Birbecks
granules (Tennis Rachet shaped). These are rich in class 2 MHC molecules,
which are important for presenting antigen to T helper cells. They migrate as
‘veiled cells’ via the afferent lymphatic into the lymph nodes. Here they
interdigitate with T cells and these cells present antigen to lymphocytes.
2) Follicular dendritic cells present antigens to B cells and lack class 2 MHC
molecules.
3) APCs are also present in the thymus. They are rich in self-antigens,
including class 2 MHC and molecule. The interdigitatory cells play a role in
deleting Tcells that reacts against self-antigens referred to as ‘Negative
selection’

IMMUNOGLOBULINS are a group of glycoproteins present in the serum

and tissue fluids of all mammals. Some are carried on the surface of B cells
where they act as receptors for specific antigens. Some are free in the blood
or lymph as antibodies. Contact between B cells and antigen is needed to
cause the B cells to develop into antibody forming cells also called plasma
cells- secrete antibody. Constitutes 20% of total plasma protein by weight.

Function—Antibodies defend against infection by inactivating viruses and

bacterial toxins and bacterial toxins by recruiting the complement system
and various types of WBC to kill extra cellular organisms and larger
parasites.
Immunoglobin molecules are divided into classes and sub- classes. There are
5 classes—IgA, IgM, IgG, IgD and IgE (Alpha, Gamma, Mu, Delta,
Epsilon)
IgG class is divided into 4subclass (IgG1, IgG2, IgG3, IgG4)
IgA class is divided into 2 subclass (IgA1, IgA2)

STRUCTURE - In 1962 given by Rodney Porter

They are Y shaped molecules with 2 identical antigen binding sites-one at
the tip of each arm of the Y.Because of their 2 antigen binding sites, they are
said to be bivalent. Antibody bound to antigen can be readily phagocytosed
and degraded by macrophages. The basic subunits of each Ig are comprised
of heavy and light polypeptide chain. Heavy chains usually contain 440
amino acid and light chain about 220 amino acid s. The 4 chains are held
together by a combination of non-covalent and covalent bonds.
The amino terminal ends of the light and heavy chains come together to
form antigen binding site. A light chain consists of one variable and one

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constant chain, while most heavy chains consists of a variable domain and
constant domains (CH1,CH2,CH3)

Fc receptors-Immunoglobins can bind to cells by their Fab fragments as

antibodies recognizing foreign antigens on these cells. They can also bind
via their Fc region and these react with complementary molecules on
lymphocytes, phagocytes and on the accessory cells called Fc receptors.

There are Fc receptors specific for IgG, IgA, IgM and IgE

3receptors for IgG—Fc-r-R1, Fc-r-R2, Fc-r-R3

2receptors for IgE----Fc-E-R1 and Fc-E-R2

Fc-r-R2 on neutrophils, macrophages and platelets

Fc-r-R1on macrophages and monocyte
Fc-r-R3 on natural killer cells, neutrophils, macrophages and eosinophils.

Thus, depending on Ig class and receptor various antibody-mediated

reactions can occur
Eg: If antibody activity is in IgE class, it will bind by Fc-E receptors to mast
cells and basophils and subsequent antigen stimulation will trigger those
sensitized mast cells to release their contents.Eg; Histamine.

The number of binding sites is called Valence of the molecule

IgG has valence of 2
IgA has valence of 4
IgM has valence of 10

Antibody molecule can be divided into 3 antigenic determinants or epitopes

-Isotopic
-Allotopic
-Idiotypic
The isotypic determinant is at the Fc constant region of the heavy and light
chains, it defines class and subclass of the antibody which is common to a
species. The idiotopic determinant is at the Fab or variable region of the
antibody molecules

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BIOLOGICAL PROPERTIES OF IMMUNOGLOBINS

IgG: Most abundant of serum Ig distributed equally in blood and extra

cellular fluids.They form 80%of total serum. Passes through placental
barrier and provides newborn with humoral immunity of the mother.
Neutralizes bacterial toxins.

IgM: First to be formed after challenge with most antigens. Most efficient
activator of complement system. Found in lower concentration than IgG.

IgE: also called as reaginic antibody. Present in human sera at about

1/125,000 th level of IgG.Antibody responsible for acute allergic reaction.
Found in exocrine secretions. Found in patients with asthma, hay fever, drug
and food allergies

IgD: Low levels in serum. Plays an important role in triggering Bcell

stimulation by antigen thus stimulating immune response.

IgA: Principle Ig in exocrine secretions.It forms 1/5th the concentration of

IgG in human sera. There are 2types-Serum IgA and SecretoryIgA. Serum
IgA is a monomer-more in GCF.Secretory IgA is a dimer. Activates
complement by alternate pathway.

REGULATORY CELL SURFACE MOLECULES OF THE IMMUNE

SYSTEM
Interaction of the immune cells is not only regulated by effectors molecules
such as Ig and cytokines but also by a complex set of molecules, which are
on the surface of the immune cells. They are
1.The MHC or Major histocompactibility complex
2.The CD or cluster of differentiation
3.Cell surface receptors
4.Adhesins

A) The Major Histocompatability Complex

When tissue from an individual is transplanted to another it is generally
rejected. This rejection is mediated by antigens of the donor, which differ
from those of the recipient. These antigens determine whether a tissue will

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be immunologically compatible with an individual and hence are termed
‘Histocompatibility antigens’
The MHC family of proteins are encoded in a set of cluster loci or genes
termed as MHC and hence the name MHC antigens. They cause tissue
destruction and another important physiologic function is to introduce
foreign antigen to the T lymphocyte. MHC in humans is called Human
leukocyte antigen complex or HLA.
In humans, gene complex and chromosomes 6 and 15 encode the HLA
complex
Three classes of HLA molecules have been identified (1,2and 3)
Class 1and 2 molecules represent distinct structural entities but have similar
overall structure

MHC molecules have two important properties

1) They are overwhelming in the preferred target antigen for T cell mediated
transplantation reaction
2) An unusually large fraction of T cell are able to recognize foreign MHC
molecules

PHYSIOLOGIC FUNCTION OF MHC MOLECULES

When an antigen-presenting cell presents antigen to T cell, the T cell
simultaneously binds the antigen and the MHC molecules on the antigen-
presenting cell. This allows differentiation between self and nonself. In other
words, the foreign antigen is recognized by the T helper cell in the context of
hosts own MHC molecule.

CLUSTER OF DIFFERENTIATION
They are a family of cell surface molecules found on lymphocytes (and other
leukocytes) and are used to distinguish (mark) cell population. CD cell refers
to groups of monoclonal antibodies, each cluster binding specifically to a
particular cell marker. Monoclonal antibodies with similar character are
grouped together and given a CD number
CD markers can be further defined according to the information they offer
about the cell.
Eg: 1) Lineage markers are exclusive to a particular line-CD 3 which is
found only on T-cells.
2) Maturation markers are transiently expressed during cell
differentiation -CD1 found on developing cells in the thymus and is not
present on peripheral T cells

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 3) Activation marker- CD 25, IL- 2 receptors which is only expressed
when the cell is stimulated by an antigen

CELL MARKERS CAN BE GROUPED INTO ‘FAMILIES’

A) The immunoglobulin super family contain contains molecules whose
structural characteristics are similar to those of Ig.This family includes CD2,
CD3, CD4 and CD8
B) The integrin family consists of alpha and beta chains. There are number
of integrin subfamilies – all members of a particular subfamilies share a
common beta chains, but each has a unique alpha chain.
C) Selectins (E, L and P) are expressed on leukocytes and activated
endothelial cell are also cell markers
D) Proteoglycans typically CD44 can bind to components of extra cellular
matrix. Thus cell marker CD4 is found on TH cells, CD8 on Ts, CD21
functions as complement receptor,receptor for Epstein- Barr virus

CELL SURFACE RECEPTOR

Another set of regulatory molecules on the surface of the immune cells are
specific receptors ie:They bind other molecules in a specific manner. As a
result of this binding, cells are caused to differentiate or to produce a
product.
Eg; T cell receptor
Two types of receptor
1) One comprises of alpha and beta heterodimer, which is expressed on 90%
of peripheral blood T helper and T cytotoxic lymphocytes
2) The other Tcell receptor comprise of gamma and delta chain heteromer

Eg; Immune cells have other receptors. They have receptor for complement
and complement sub fragments

ADHESINS
Many cell interaction depends on binding of cells to each other or to a
substrate. These interactions are controlled by receptors on the surface of
immune cells and ligands on other cells or on the substrate called Adhesins.
There are 4 main groups:
1) Intergrins
2) Adhesion of Immunoglobin super gene family
3) Lectin like adhesin molecule

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4) The CD 44 or Hermes group, which interacts with ligands, called
adhesions on vascular endothelium

1) INTEGRINS: Large family of molecules and each member is a

heterodimer composed of alpha and beta chains. Divided into families with
proteins in each family showing one type of beta chain
Eg; Fibronectin receptor family shares beta 1 chain
Complement receptor family shares beta 2chain
They have alpha chains, which are unique.

2) ADHESION MOLECULE OF Ig SUPERGENE FAMILY

ICAM-1 and ICAM-2 present on capillary epithelium
ICAM- 1 also expressed on T and B cells are involved in interaction
between lymphocytes and antigen presenting cells and also in
transendothelial migration of cells. They can be induced by IL-1,IFN
-gamma and also TNF –alpha

3) SELECTINS: Molecule termed ME- 14,GMP-140 and ELAM.

ELAM is induced on endothelium following TNF-α, IL-
1activation.Neutrophils bind to ELAM as a critical first step in nuetrophils
migration

4) The CD44 homing receptors found in lymphocytes mediate binding of

lymphocytes to endothelial venules of peripheral lymph nodes

THE COMPLEMENT SYSTEM

The term complement was applied by Ehrlich to describe the activity in
serum, which could complement the ability of specific antibody to cause
lysis of bacteria. Complement is a interlacing network of about 20
membrane associated cell receptors and soluble serum glycoproteins. It
consists of 5% serum proteins. Most of the complements are synthesized by
the liver, but many are also produced by the macrophages.
Function:
1) Control of inflammatory reactions
2) Elimination of antigens
3) Activation of cells
4) Preparation of microbes and foreign particles for phagocytosis
5) Play a role in the development of immune response

The activation of system occurs in a cascade fashion via 2 pathways

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A) Classical pathway
B) Alternate pathway
The classical pathway is triggered by antigen antibody complex
Alternate pathway is triggered by a variety of surfaces

CLASSICAL PATHWAY - is activated by immune complexes

containing IgG or IgM.The proteins of this pathway and membrane attack
system are each assigned a number and react in the order C1q,
C1r,C1s,C4,C3,C5,C6,C7,C8,C9
Thus C1qrs serves as a serine protease and also serves as a C4/2 convertase
and leads to the formation of a C3 convertase which activates
C5,C6,C4,C8and C9

ALTERNATE PATHWAY
Is activated in the presence of variety of molecules on the surface. The
proteins of this pathway are known as factors or ‘F’
Eg: Factor B.This pathway causes direct activation of third component of the
complement C3 without triggering the beginning of the cascade. Thus it
begins with the cleavage of C1and then it is identical to classic pathway
C5,C6,C7,C8,C9
Both the pathways activate C3which is the initial reactant of the complement
cascade. After C3 activation occurs there is activation of components from
C3 to CQ and formation of membrane attack complex, which inserts into
membranes of cells causing them to lysis.In the process of activation sub
fragments are produced termed C3a,C4a,C5a
They take part in the defence reactions in the tissue fluids and are referred to
as anaphylotoxins(induce smooth muscle contraction, permeability of blood
vessels and release of histamine from the mast cells).Thus direct killing of
organisms occurs when the complement system is activated and a membrane
attack complex forms on the surface and lysis the cell.

CYTOKINES: are glycoproteins of relatively low molecular weight (called

as lymphokinins).They regulate all important biological process
-Cell growth
-Cell activation
-Inflammation and immunity
-Tissue repair
-Heamotopsis

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Cytokines chemotactic for specific cell type is known as chemokines. Some
cytokines exhibit autocrine function i.e. binding to the cell that produced
them. Others are paracrine –binding to the near by cells. Cytokines may be
pleotrophic-eliciting different biologic activity from different cells.
Originally cytokines were named for their biologic activity
Eg; OAF,MAF
Now they are renamed as interleukins referring to their role in
communication between leukocytes. Others include TNF, TGF and IFN

INTERLEUKINS
1.IL-1(Alpha and beta)
It is a pleiotrotic cytokine earlier referred to as LAF or OAF. Its functions
include:
1) Affects the macrophages making them chemotactic,increase their
cytocidal activity and prostaglandin production
2) Is chemotactic for neutrophils and activates them
3) Stimulates B-lymphocytes to proliferate and produce antibody
4) Stimulates T lymphocytes to produce lymphokinins
5) Stimulates osteoclast formatiuon and bone and cartilage resorption
6) Stimulates epithelial cells to proliferate and produce collagen
7)Stimulates endothelial cell to proliferate and produce prostaglandin

2. IL2-Previously known as T cell growth factor. Produced by T cell and

activates the T cell. IL-2 is used in renal cancer therapy as it can activate
cells having anticancer effects

3.IL-3-Activates the precursors of all haemopoitic lineage (red cell,

granulocytes, macrophagesand lymphocytes) including mast cell growth and
histamine secretion. Activated TH cells and Natural killer cells secrete it

4. IL-4 - Known as B cell activating factor. It acts on B cells to induce

activation, proliferation and differentiation for the production of IgG, IgE

5. IL-5- In man, it is a growth and activation factor for eosinophils. Secreted

by TH cells

6. IL-6- Secreted by T cells, macrophages, B cells, fibroblasts and

endothelial cells. Induce B cells to differentiate into antibodies. Increases in
the sites of gingival inflammation and plays a role in bone resorption

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7. IL-7- Described as pre B cell growth factor. Acts on thymocytes and is a T
cell growth and activation factor and also macrophage activation factor
8.IL-8-Produced by macrophages and endothelial cells. Powerful
chemotactic for neutrophils and their adherence to endothelial cells

9.IL-9-Produced by TH cells. Induce proliferation of TH cell in the absence of

antigen or APCand promote the growth of mast cells

10.IL-10-Increases the B cell activation. Decreases the production of IFN

alpha 1 and also macrophage production of IL-1, 6and TNF-α

11.IL-11-Potentiates IL-3 induced growth of megakaryocytes. Promotes T

cell depended IgG secretion by B cells

12.IL-12-Acts opposite to IL-10

13.IL-13-Structural and functional similarities to IL-4and promotes B cell
division

INTERFERONS:(Alpha, Beta, Gamma)

These are glycoproteins, which are potent immunoregulators and growth
factors
IFN Alpha: Produced by leucocytes in response to viruses and nucleic acids.
IFN Beta: Produced by fibroblasts
IFN Gamma: Single protein produced by T and Natural Killer cells
TNF (Alpha and beta): Produced by macrophages and TH cells. Gram –ve
bacteria stimulation with LPS forms TNF.Aids leukocytes in their ability to
adhere to endothelial cells and in their phagocytosis and chemo taxis

SPECIFIC IMMUNE RESPONSES (T AND B CELL ACTIVATION)

Four phases can be involved in the specific immune responses
1) CLONAL ACTIVATION: The selection of lymphocytes that bear
receptors (BCR or TCR) recognizing the specific antibody
2) CLONAL EXPANSION: the proliferation of those lymphocytes
3) CLONAL CONTRACTION: The death of effector lymphocytes
4) MEMORY: The maintenance of clone of cells that bear specific receptors
recognizing the antigen

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T CELL RESPONSES- To obtain a specific immune response, the Tcell
must interact with the antigen presenting cells This is a complex process
requiring that the T cell recognize the antigen on the APC.Antigens are
presented to TCR by MHC class1or class 2 molecules on APC.
Eg:CD1 is a related AP molecule that presents specific antigens to Tcell. The
TCR recognizes and binds the MHC peptide complex. Antigens are
contacted by the TCR at the N terminus of the TCR alpha and beta subunits.
The low affinity of the TCR enables the T cell to bind APC in a reversible
manner. This time depended interaction of many TCR’s with few antigens is
called ‘scanning’. Scanning that lead to T cell activation is called serial
triggering. It takes 2-20 hrs to fully activate T cells.

MATURATION OF T CELLS
It is initiated by IL-1beta to different T cell phenotype like THO
IFN gamma, TNF alpha, IL-2, 4,10-TH1, TH2, TH3
TH1----controls altered cell and intracellular molecules
TH2----important in proinflammatory responses against extracellular
antigens
TH3----important in anti-inflammatory responses against extra cellular
antigens

B -CELL RESPONSES
When B cell exit the bone marrow, they possess receptors only for IgM and
produce soluble IgM. This facilitates antigen clearance. The abilility of B
cell to respond to antigen depends on BCR.If antigen is bound, they are
ingested and processed and parts of antigen are presented to T cell using
MHC class 2. After antigen presentation,T- cell cause activation of B cell by
signaling .Activators include GT39and GP34. GP39 enables B cell entry into
memory pathway whereas absence of GP39 leads to terminal differentiation
into plasma cells. B cell that differentiate into plasma cell no longer carry
surface Ig. Later T cell switch signals to promote inflammatory
Immunoglobins (IgE and IgG)

HYPERSENSITIVITY : Increased tissue reactivity to specific antigenic

stimuli which may be proteins, protein linked substances or certain
chemicals.
Coomb’s and Gel classification----Immediate hypersensitivity is divided
into
Type 1---------------Anaphylactic reaction
Type 2---------------Cytotoxic reaction

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Type3----------------Immune complex reaction
Type4----------------Delayed cell mediated sensitivity
ANAPHYLAXIS is a condition of acute shock usually terminating in death
following introduction of antigen into a previously sensitized host.
Anaphylactic reaction in humans is divided into
a) Systemic anaphylaxis ------following parenteral administration of drugs
Eg: Penicillin
Insect bite
b) Local anaphylaxis----------contact of antigen with respiratory mucosa
Eg: Bronchial asthma, Hay fever
c) Mixed anaphylaxis
Food allergy Eg: to prawns

Mechanism of anaphylaxis
T helper cells initiate anti allergen IgE responses, which in turn secrete IL-4,
5,6 and 10 and TNF alpha. Introduction of antigen (sensitizing dose),
following this antibodies are formed (IgG, IgE). During the waiting period
of 2 or 3 weeks, IgE gets fixed to mast cells and basophils which contain
high affinity receptors (Fc R1) for the Fc portion of IgE
Further introduction of antigen ---allergen interacts Fc receptor bound IgE
---antigen IgE complex formed---express Adenyl cyclase AMP system in
cell membrane---leads to the release of pharmacologically active
substances---anaphylactic reaction

Type 2 (Cytotoxic /Cytolytic reaction)

This reaction is mediated by antibodies, which reacts with antigen present on
the surface of a cell or other tissue components leading to cell damage
Mechanism-IgG or IgM combines with the antigen which may be a
microbial product or drugs or self molecules on the cell .The antigen binds
to the antibody via the Fab region and forms a bridge to complement via its
Fc region leading to cell lysis
Eg: Isoimmune reaction
a) Blood transfusion reaction
b) Erythroblastis foetalis

Type 3 (Immune complex)

Is an antibody mediated hypersensitivity reaction with the following
characteristics
a) Deposition of antigen antibody complex in the tissues

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b) Activation of complement
c) Massive infiltration of PMNL’s
d) Cell damage

Type4
A mixed cellular reaction specifically provoked, slowly evolving (24-48 hrs)
mainly involving sensitized T lymphocyte
Eg; Intracellular microbial infection, contact dermatitis—wristwatch allergy

AUTOIMMUNITY is a condition in which structural and functional

damage is produced by the action of immunologically competent component
of the body.Autoreactive T and B cell persist in normal subjects but in
disease, they are selected by auto antigen for the production of autoimmune
response. The body must develop self-tolerence mechanism to distinguish
between self and non-self determinants so as to avoid autoimmunity

2 types of autoimmune disease

a) Organ specific---------------Thyroid, Adrenals, Stomach, Pancreas
b) Non organ specific-----------skin, kidney, joints, muscle
Eg: Hashimotos Thyroiditis is an autoimmune disease where serum of
patients contain antibodies to thyroglobulins

ETIOLOGY:
1) It is antigen driven and T cell play an important role

a) Cross reactivity can stimulate auto reactive T and B cells

b) In some cases foreign antigen can directly stimulate auto reactive cells
c) Cytokine dysregulation, inappropriate MHC expression may induce
autoimmunity
d) Pre existing defect in target cells may increase susceptibility

When auto antibodies are found, there are 3 inferences

1) The autoimmunity is responsible for producing the lesion of the disease
2) There is a disease process which through the production of tissue damage
to the development of auto antibodies
3) There is a factor, which produces both the lesions and the auto immunity.
Thus the autoantibodies are pathogenic

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PERIODONTAL IMMUNOLOGY
Host responses play an important role in the pathogenesis of many types of
periodontal disease by contributing to the disease process or by modulating
the effects of bacteria. Immune response may be both beneficial and
determinal. Several component of immune response are active in periodontal
disease. The neutrophils, lymphocyte, plasma cell, macrophages vary in
number depending on the disease status of the tissues. Local and systemic
antibodies to oral bacteria and complement are also significant. This host
variable may influence
- Bacterial colonisation, invasion, tissue destruction, healing and
fibrosis

1. Bacterial colonization and survival in the periodontal region

Bacterial adherence
Host tissue invasion
Bacterial evasion of host defense mechanism
2.Microbial mechanism of host tissue damage

3.Bacterial adherence: Bacterial species that colonize must attach to

available surface to avoid displacement by the fluid flow. The surface
available include tooth or root, tissues and pre existing plaque mass.
Numerous interactions between bacteria and these surfaces have been
characterized

4.Host tissue invasion

Bacteria may enter the host tissue through the ulceration in the epithelium of
gingival sulcus or pocket. Localization of bacteria to the tissue provide an
ideal position from which organism can effectively deliver toxic molecules
and enzymes to host tissues

5.Bacterial evasion of host defence

To survive bacteria must evade or neutralize host mechanisms
Eg: It might function to facilitate phagocytosis of bacteria by opsonisation or
block adherence by binding to the bacterial cell surface and restricting
access to bacterial adherence by binding to the bacterial cell surface and
restricting access to bacterial adhesins. The production of Ig degrading
proteases may counteract these host defenses. Certain bacteria produce

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substances that suppress the activity of PMN’S and lymphocytes normally
involved in the host defense
Eg: Aa produce two toxins (Luekotoxin and Cytolethal distending toxin)

MICROBIAL MECHANISM OF HOST TISSUE DAMAGE

1. Bacterial properties causing direct degradation of host tissues
2. Release of biological mediators from host tissue cells leading to host
destruction.
3. Some bacterial products inhibit the growth or alter the metabolism of host
tissue cells
Eg; Ammonia, Volatile sulphur compounds,Fatty acids, peptide, indole
Enzymes capable of degrading host tissues-Collagenase, Trypsin like
enzyme, Keratinase, Aryl sulpatase, Neuraminidase, Phospolipase-A

IMMUNOLOGICAL ASPECT OF MICROBIAL INTERACTION

WITH THE HOST
In response to a bacterial infection like periodontitis, the following takes
place:
a) Innate factors such as complement, cytokines, resident leukocytes and
especially mast cells play an important role in signaling endothelium thus
initiating inflammation
b) Acute inflammatory cells, macrophages and lymphocytes protect the
entire host from within the subjacent connective tissue and prevent a local
inflammation from becoming systemic.

IMMUNOLOGY OF SPECIFIC PERIODONTAL DISEASES

1) GINGIVITIS: Continued exposure to bacterial antigens in the
gingival crevice and within the gingival tissue induces systemic and
local host responses.These have both protective and destructive
functions

Protective-GCF contain immunoglobulin and complement, which

constantly bathe and react with subgingival bacteria. This reaction may
modulate or alter the subgingival microflora. The bacterial mass could also
be reduced by antigen –antibody complex with complement activation
leading to bacterial cytolysis and phagocytosis. The important role of
neutrophils in control of periodontopathogenesis is evident in the occurrence
of more severe periodontal disease in cases of decreased neutrophils
function.

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Destructive-In gingivitis, early lymphocytic infiltrate is dominated by T
cells but later B cells become dominant.
Established lesion---Predominance of B cells that are transformed into
plasma cells. Neutrophils continue to dominate in junctional epithelium and
gingival crevice with increase in GCF flow.
Page & Schroeder demonstrated a predominance of plasma cells in
established lesion. Gingivitis associated with hormonal changes,
medications and with systemic diseases show an altered host response that
increase host susceptibility to gingivitis
Eg; In pregnancy, inflammatory response to plaque is increased. Also
alteration in subgingival micro biota are observed (Predominance of
Prevertella Intermedia)

PERIODONTITIS
1) CHRONIC PERIODONTITIS: is characterized primarily as involving
alternate pathway of complement activation with c3 cleavage in gingival
fluids observed
Kinane in 1999 showed increase in serum and crevicular fluid antibody
specific to certain pathogens like Porphyromonas gingivalis, Actinobacillus
actinomycetem comitans, Prevotella Intermedia etc
Collagenase activity is increased 6 times from gingivitis and some
microorganisms may modulate nuetrophils secretion of collagenase
Eg: F. Nucleatum& Treponema Denticola are associated with the release of
high level of elastase from neutrophils
Engebretson (1999) stated that variations in periodontal disease
susceptibility could be due to an association between a composite genotype
involving IL-1 genes and occurrence of periodontitis

2) AGGRESSIVE PERIODONTITIS
Approximately 75% of patient with localized aggressive periodontitis have
dysfunctional neutrophils involving a decreased expression of G protein
coupled receptors. The defect is evident as a decrease in chemotactic
response to chemotactic agent (C5a, Luekotrine B4). The defect is
associated with a 40%defeciency in a 100 Kiloprotein glycoprotein called
GP110 on the neutrophils surface(Global membrane receptor defect).This
defect is inherited as an intrinsic cellular defect. Thus neutrophils
chemotaxis is affected in aggressive periodontitis with high titer of Ig2. This

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antibody response may necessitate high levels of antibody for efficient
opsonisation and phagocytosis of organisms.

CONCLUSION
The patient response to periodontal infection is complex. The complexity of
the local tissue components including the bacteria or their products and
virtually all aspects of host response mechanism has complicated our ability
to elucidate the critical protective function in the tissue and has continually
provided evidence for the potential for host destructive factors as the
ultimate causative parameters in the disease
Rapid progress in immunology, more information about the role
of host in periodontal disease, coupled with recent advances in
biotechnology, should lead to a better understanding of the pathogenesis of
periodontal disease and provide useful diagnostic and prognostic aids.

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