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            Vertebrates develop a highly
specialized system of defense mechanism due to continuous stimulation by
foreign materials from the environment1.Towards the close of
nineteenth century, the humoral basis of immunity was established by the demonstration
of the introduction of an antigen into an animal. Certain substances called
antibodies appeared in the serum and tissue fluids, and reacted with antigen
specifically in some observable manner. Depending on the observable reaction
produced on mixing with antigens, the antibodies were designated as
agglutinins, precipitin and so on. Sera having high antibody levels following
infection or immunization were called ‘immune sera’.

            Fractionation of immune sera by
half saturation with ammonium sulfate separated serum proteins into soluble
albumins and insoluble globulins. Globulins could be separated into water
soluble pseudoglobulins and insoluble euglobulins. Most antibodies were found
to be euglobulins.  Tiselius (1937) separated serum proteins
into albumin, alpha, beta and gamma globulins based on their electrophoretic
mobilities. He showed that antibody activity was associated with the
gammaglobulin fraction.

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           WHO in
1964 gave the generic term
‘Immunoglobulin’ and defined as “Immunoglobulins are proteins of animal origin
endowed with known antibody activity and certain proteins related to them by
chemical structure and hence antigenic specificity”. Immunoglobulins provide
structural and chemical concept while the term “antibody” is a biological and
functional concept. All antibodies are immunoglobulins but all immunoglobulins
may not be antibodies2.

            Immunoglobulins are synthesized by
plasma cells and to some extent by lymphocytes. 
Antibodies play key role in the recognition and protection of the body
against foreign substances,when present freely in body fluids or attached to
cell surfaces. Apart from the plasma, immunoglobulins may be found in other
body fluids or tissues such as urine, spinal fluid, milk, saliva, tears, lymph
nodes and spleen. They are produced by plasma cells and lymphocytes at various
stages of differentiation.

            Immunoglobulins represent a
heterogeneous population in respect to their physico-chemical and biological
properties. Immunoglobulins are divided into five classes on the basis of the
structure of H chains and designated as follows: IgG, IgA, IgM, IgD and IgE (WHO 1964, Bennich et al 1968, Rowe and Fabey 1965).

            Immunoglobulins are multichain
glycoproteins composed of two types of polypeptide chains (Edelman 1959, Edelman and Poulik 1961). Due to differences in
molecular weight it was possible to isolate two types of chains heavy (H) and
light (L).Two H and L chains connected covalently by disulfide bonds form a
basic unit of the immunoglobulin molecule.

            Human studies have shown that
periodontal patients can have circulating antibodies specific for oral bacteria
and can be shown to be hypersensitive to antigens and plaque bacteria. Brandtzaeg and Kraus (1965) found that
in healthy gingiva many of cells contained immunoglobulin G, very few contained
immunoglobulin A and only rarely as immunoglobulin M. They also found that in
many clinically inflamed specimens the number of immunoglobulin A containing
cells were greatly increased, compared to the number of immunoglobulin G
containing cells3.

        

               
WHO  in 1964 defined
“Immunoglobulins are proteins of animal origin endowed with known antibody
activity and certain proteins related to them by chemical structure and hence
antigenic specificity”.  

              
Immunoglobulins constitute 20-25 percent of the total serum proteins. Based on
physicochemical and
antigenic differences, five classes of immunoglobulins have been recognised—IgG, IgA, IgM, IgD and IgE. (Both Ig and ? are accepted
abbreviations for immunoglobulins.

 

Structure
of Immunoglobulin:

 

              Edelman(1967), Nisonoff (1961)and Porter (1959) conducted studies involving the cleavage of
the immunoglobulin molecule and
gave detailed picture of its structure.

The
following enzymes have been examined to determine their effect upon immunoglobulin

molecules:
papain, pepsin, trypsin, chymotrypsin, and thermolysin . Rabbit IgG antibody to
egg albumin, digested by papain in the presence
of cysteine, was split into two fractions—an insoluble fraction Fc ( c for crystallisable), and
a soluble fraction Fab (ab for
antigen binding). Each molecule of immunoglobulin is split by papain into three parts, one Fc and two Fab pieces,
having a sedimentation coefficient of
3.5 S.  

 

                Immunoglobulins are
glycoproteins, each molecule
consisting of two pairs of polypeptide chains of
different sizes. The smaller chains are called
‘light’ (L) chains and the larger ones ‘heavy’ (H) chains. The L chain has a molecular weight of approximately 25,000 and the H chain of
50,000. The L chain is attached to the
H chain by a disulphide bond. The two
H chains are joined together by 1-5
S-S bonds, depending on the class of
immunoglobulins. The H chains are
structurally and antigenically distinct
for each class and are designated by the Greek letter corresponding to the immunoglobulin class as shown as:

 

 

IMMUNOGLOBULIN CLASS

H CHAIN

IgG

? (gamma)

IgA

? (alpha)

IgM

µ (mu)

IgM

? (delta)

IgE

? (epsilon)

                    

              
The L chains are similar in all classes of immunoglobulins. They occur in two varieties,
kappa (?) and lambda (?). Kappa and
lambda are named after Korngold and Lapari who originally described
them.The kappa and lambda chains occur in a ratio of about 2:1 in human sera. A
molecule of immunoglobulin may have either
kappa or lambda chains, but never both together.

                The antigen combining site of
the molecule is at its
aminoterminus. It is composed of both L and H chains. L and H
chains consist of two portions
aminoterminus. L chain is made up of the 214
aminoacid residues about 107 that constitute the carboxyterminal half which occur only in a constant sequence. This
part of the chain is called  ‘constant region’. Only two sequence patterns are seen in the constant region — those
determining the kappa and lambda
specificities. Aminoacid
sequence in the aminoterminal half of
the chain is highly variable, the variability determine the immunological specificity of the antibody molecule. It is therefore called the
‘variable region’. The H chain also has ‘constant’ and ‘Variable’ regions. While in the L chain the two regions are
of equal length, in the H chains the
variable region constitutes
approximately only a fifth of the chain and is located at its aminoterminus. The infinite range of the antibody specificity of immunoglobulins
depends on the variability of the aminoacid sequences at the ‘variable regions of the H and L chains which
form the antigen combining sites.

                The aminoacid sequences of the
variable regions of the
L and H chains are not uniformly variable along their length, but consist of relatively invariable and some highly variable zones. The highly
variable zones numbering
three in the L and four in the H chains are known as hypervariable regions (or hot spots) and are involved with the formation
of the antigen binding sites. The sites on the
hypervariable regions that make
actual contact with the epitope are called ‘complementarity determining regions’ or CDRs. The Fc fragment
is composed of the carboxyterminal portion
of the H chains. It does not possess
antigen combining activity but determines
the biological properties of the immunoglobulin molecule such as complement fixation, placental transfer, skin
fixation and catabolic rate.
The portion of the H chain present in the Fab
 fragment is called the Fd piece. The H chain carries a carbohydrate moiety which
is distinct for each class of
immunoglobulins.

                Each immunoglobulin peptide
chain has internal
disulphide links in addition to interchain disulphide bonds which bridge the H and L chains. These interchain disulphide bonds form
loops in the peptide
chain, and each of the loops is compactly folded to form a globular domain, each domain having a
separate function. The variable region domains VL and VH are responsible for the formation of a specific antigen binding
site. The CH2
region in IgG binds Clq in the classical complement sequence, and the CH3 domain mediates adherence to the monocyte surface.
The areas of the H chain in the C region
between the first and second
C region domains  (CH1 and CH2)
is the hinge region. It is more flexible
and is more exposed to
enzymes and chemicals. 

IMMUNOGLOBULIN CLASSES

                       Five classes of immunoglobulins have been recognized. They
are IgG, IgA, IgM, IgD and IgE in the descending order of concentration.

                  IgG: This is the major serum  immunoglobulin, constituting about 80 per cent of the total. It has a molecular weight of 150,000 (7S). The normal serum concentration of IgG is
about 8-16 mg per ml. IgG may occasionally exist in a polymerised form.  It has a half -life of approximately 23 days. It is distributed approximately equally between the intravascular and extravascular
compartments. The catabolism of IgG
is unique in that it varies with its
serum concentration. IgG is the only
maternal immunoglobulin that is normally transported across the
placenta and provides natural
passive immunity in the newborn. It is not synthesised by the fetus in any significant amount. IgG binds to microorganisms and
enhances their phagocytosis. IgG participates in most immunological reactions such as complement fixation, precipitation, and neutralisation of toxins and viruses. It may be considered a general
purpose antibody, protective against those infectious agents which are active in
the blood and tissues. Four
subclasses of IgG have been recognised (IgG 1, IgG2, IgG3, IgG4), each possessing a distinct
type of gamma chain, identifiable with specific antisera. The four IgG subclasses are distributed in human serum in the approximate
proportions of 65 per cent, 23 per
cent, 8 per cent and 4 per cent, respectively.

                  IgA: IgA is the second most abundant class, constituting about 10-13 per cent of serum immunoglobulins. The normal serum level is 0.6­-4.2 mg per ml. It has a half life of 6-8
days. It is the major immunoglobulin
in the colostrum, saliva and tears.IgA occurs in two forms. Serum IgA and secretory IgA.
Serum IgA is principally a
monomeric 7S molecule (MW 160,000).
IgA is found on mucosal surfaces and in secretions is a dimer formed by two monomer units joined together at their carboxyterminals by a glycopeptide termed the J chain (J for
joining )This is called the secretory IgA (SIgA). Dimeric
SIgA is synthesised by plasma cells situated
near the mucosal or glandular epithelium. SIgA contains another glycine rich
polypeptide called the secretory component or secretory piece. The secretory piece is believed to protect IgA from denaturation by bacterial proteases. in sites such as the intestinal
mucosa which have a rich and varied bacterial flora.
SIgA is a much larger molecular weight of 
SIgA is about 400,000.IgA antibodies 
function by inhibiting the adherence of microorganisms 
to the surface of mucosal cells by covering the organisms and thereby preventing their entry into body tissues. IgA does not
fix complement but can activate the alternative complement pathway. It promotes
phagocytosis and intracellular
killing of microorganisms.Two
subclasses IgA are IgA1 and
IgA2. IgA2 lacks interchain disulphide bonds between the heavy and light chains. Though IgA2 is a minor component of serum IgA, it is the dominant form in the secretions.

               IgM: IgM constitutes 5-8 per cent of serum immunoglobulins, with a normal level of
0.5-2 mg per ml. It has a
half-life of about five days. It is a heavy molecule (19S; moL wt 900,000 to 1,000,000, hence called ‘the millionaire molecule’).
IgM molecules are polymers of five
four-peptide subunits, each bearing an extra CH
domain. Polymerisation of the subunits
depends upon the presence of the J
chain. Most of IgM (80 %) is
intravascular in distribution. IgM is
the oldest immunoglobulin class. It
is also the earliest immunoglobulin to be synthesised by the fetus, beginning by about 20 weeks of age. IgM is
not transported across the placenta,
the presence of IgM in the fetus or
newborn indicates intrauterine infection
and its detection is useful in the diagnosis of congenital infections such as syphilis, rubella, HIV infection and
toxoplasmosis. IgM antibodies are
relatively short lived, their
demonstration in serum indicates recent
infection. The isohemagglutinins
(anti-A, anti-B) and many other
natural antibodies to microorganisms are
usually IgM. The unique structural features of IgM is providing
protection against microorganisms and other
large antigens that have repeating antigenic determinants on their surface. A single molecule of IgM can bring about immune hemolysis, whereas 1000 IgG molecules are required for the same effect.
IgM
is also 500-1000 times more effective than IgG in opsonisation, 100 times more
effective in bactericidal action and about 20 times in bacterial agglutination.  However,
in the neutralisation of toxins and viruses, it is less active than IgG.
 IgM
is believed to be responsible for protection
against blood invasion by microorganisms.
IgM deficiency is often associated with septicemias. Monomeric IgM is
the major antibody receptor on the surface of
B lymphocytes for antigen recognition.

              IgD: IgD resembles IgG structurally. It is
present in a concentration of about 3 mg per 100 ml
of serum and is mostly intravascular. It has
a half-life of about three
days and molecular
weight of about 180,000-200,000.
 IgD 
occurs on the surface of unstimulated B lymphocytes and serve as recognition receptors for antigens. Combination of cell membrane bound IgD or IgM with the
corresponding antigen leads to specific
stimulation of the B cell
either activation and cloning
to produce antibody, or suppression.

               IgE.: This immunoglobulin was discovered in
1966 by Ishizaka
during the investigation of atopic reagin antibodies.
It is an 8S molecule (MW about 190,000)with a half
life of about two days. It resembles IgG
structurally. It exhibits unique properties such as heat
lability (inactivated at 56 °C in
one hour) and affinity for the surface of tissue cells (particularly mast
cells) of the same species (homocytotropism).
It mediates the Prausnitz ­Kustner reaction. It does not pass the placental barrier or fix complement. It is mostly extravascular in distribution. Normal serum contains only traces  but
greatly elevated levels are seen in atopic  conditions such as asthma, hay fever and
eczema. IgE is chiefly produced in the linings of
the respiratory and intestinal tracts. IgE is responsible for the anaphylactic type of hypersensitivity. The physiological role of
IgE, appears to be protection against pathogens
by mast cell degranulation and release of
inflammatory mediators. It is also believed to have a special role in defense against helminthic infections.

In general IgG protects the body fluids,
IgA the body surfaces and IgM the bloodstream,
while IgE mediates
reagenic hypersensitivity. IgD is a recognition molecule on the surface of B lymphocytes2.

 

                The immune system has evolved
to protect us from pathogens. A highly discriminatory immune system is
fundamental to survival. The primary function of the immune system is to
eliminate infectious agents & minimize the damage they cause. Some
pathogens evoke ‘humoral immunity’, lmmunoglobulins are an essential component
of humoral immunity. They are present in serum, tissue fluid or on cell
membranes. Amongst the five classes of Immunoglobulin namely IgG, IgA, IgM,
IgD, IgE, the immunoglobulin IgG is the predominant immunoglobulin in normal
human serum & IgA is predominant immunoglobulin in seromucous secretions.
There are several methods to measure these antibodies of which immunoassays,
immunoelectrophoresis, radioimmunoassay, ELISA are common. Antibody clearly
plays a crucial role in dealing with the pathogens & this important
function is performed mainly by IgG & IgA. Because IgG is the
immunoglobulin class found in highest concentration in blood, it plays the
major role in antibody-mediated defense mechanisms.

                                                                                                                                                               
                                                   Periodontal
disease is one of the most prevalent afflictions worldwide. The most serious
consequence is the loss of the periodontal supporting structures which includes
gingiva, cementum, periodontal ligament and alveolar bone. The level of
infection can range from gingivitis, which is the inflammation of the gingiva
all the way to  periodontitis that can
result in tooth loss. Although Periodontitis is initiated by the subgingival
microbes, it is generally accepted that mediators of connective tissue breakdown
are generated to a large extent by the host response to a pathogenic infection,
in a susceptible host, microbial virulence factors trigger the release of host
derived enzymes & pre-inflammatory cytokines that can lead to colonial
tissue destruction. The implication of periodontal microbes associated by
products such as endotoxin on induction of the innate immune response, cells
like receptors signaling generation of pathogen associated molecular patterns
(PAM’s) & their role in periodontal disease pathogenesis are crucial to the
extent of disease severity. The majority of plasma cells and IgG-bearing
lymphocytes in periodontitis have cell-associated immunoglobulins IgG1, IgG3,
or IgG4 subclasses. Immunoglobulins which form immune complexes are known to
provoke complement fixation or stimulate the release of other mediators. The
predominance of IgG in gingival organ culture supernatants and the
statistically significant findings showed that the overall mean levels of IgG
between mild gingivitis and periodontitis and between severe periodontitis
suggested a possible indicator of periodontal disease.

 

 

 

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