CHAPTER – 1 INTRODUCTION 1 .B and Typhoid are some of the serious diseases which are still public health threat globally. These are major causes of morbidity and mortality worldwide. Each year millions of new infections occur which cause more than million death incidences. These diseases are endemic in many countries of the World. Clinically, it is difficult to diagnose the disease as, many medical symptoms of both the diseases. For example, other febrile syndromes such as dengue fever, reckettsial infection and malaria exhibit many symptoms common to typhoid, besides that these infections frequently prevail in the same geographic regions. Mycobacterium tuberculosis complex and nontuberculous mycobacteria are different clinically. The tuburculi infection symptoms are almost indistinguishable from pleurisy, pneumonia, chronic bronchitis and other similar diseases. More than 10 million incidence of tuberculosis are estimated in 2000 by WHO. Among T.B. patients, 92% suffer from pulmonary tuberculosis and remaining 8% have other T.B. Many strategies are adopted to detect these diseases at early stage and with continuity. Among them serodiagnostic tests are developed with varying sensitivity and specificity. An essential component of the disease control program is rapid and accurate identification of new cases (of the disease). New diagnostic techniques are urgently needed to confirm the disease with the highest degree of sensitivity and specificity especially in low income countries where the diseases (T.B. and Typhoid) are endemic and the incidences are high. PCR and other amplification technique are too sophisticated and expensive for routine use in developing countries. We need to develop T
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CHAPTER – 1 INTRODUCTION
1
.B and Typhoid are some of the serious diseases which are still
public health threat globally. These are major causes of
morbidity and mortality worldwide. Each year millions of new infections
occur which cause more than million death incidences. These diseases are
endemic in many countries of the World. Clinically, it is difficult to
diagnose the disease as, many medical symptoms of both the diseases. For
example, other febrile syndromes such as dengue fever, reckettsial
infection and malaria exhibit many symptoms common to typhoid, besides
that these infections frequently prevail in the same geographic regions.
Mycobacterium tuberculosis complex and nontuberculous mycobacteria
are different clinically. The tuburculi infection symptoms are almost
indistinguishable from pleurisy, pneumonia, chronic bronchitis and other
similar diseases. More than 10 million incidence of tuberculosis are
estimated in 2000 by WHO. Among T.B. patients, 92% suffer from
pulmonary tuberculosis and remaining 8% have other T.B. Many
strategies are adopted to detect these diseases at early stage and with
continuity. Among them serodiagnostic tests are developed with varying
sensitivity and specificity.
An essential component of the disease control program is rapid and
accurate identification of new cases (of the disease). New diagnostic
techniques are urgently needed to confirm the disease with the highest
degree of sensitivity and specificity especially in low income countries
where the diseases (T.B. and Typhoid) are endemic and the incidences are
high. PCR and other amplification technique are too sophisticated and
expensive for routine use in developing countries. We need to develop
T
CHAPTER – 1 INTRODUCTION
2
simple affordable and highly sensitive diagnostic tool, suitable for use in
poor parts of the world.
Antibody response to infectious agent provides useful diagnostic
marker of the infection caused in the host. Specific IgG and IgM antibodies
appear against the specific pathogen. IgM antibodies appear quickly
within some time after the infection but their life / appearance in the blood
remains for short time. IgG antibodies appear later in the primary
response, but in subsequent encounters with the pathogens, these
antibodies are produced quickly and more abundantly which persist for
long time even for years. Serological tests exploit the distinction between
IgM and IgG antibodies.
1.1 THE IMMUNE SYSTEM – THE OVERVIEW
The Immune system is a remarkably adaptive defence system. It
has evolved in vertebrates to protect them from invading pathogenic
microorganisms. The immune system is capable of generating an
enormous variety of cells and molecules capable of specifically recognizing
and eliminating an apparently limitless variety of foreign invaders which
is evident from the majority of infection in normal individual, in them it
appears for a limited duration and leaves very little permanent dosage
(Roitt et al., 1985).
Functionally, an immune response can be divided into :-
1. Recognition
2. Response
Immune recognition is remarkable for its specificity. The immune
system is able to recognize subtle chemical difference that distinguish one
of the foreign pathogens from the other. At the same time, it is capable of
discrimination between “Foreign Molecule” and “Self Molecule” once the
CHAPTER – 1 INTRODUCTION
3
foreign molecule is recognized the immune system enlists the participant
to mount an appropriate response, known as effector response, to
eliminate or neutralize the organism. Thus, the immune system is able to
convert the initial recognition event into different effector responses.
These effector responses are uniquely suited to eliminate a particular
pathogen. Exposer to the same foreign organism at a later stage induces a
memory response.
The immune system can be divided in to two functional divisions.
1. Innate immune system 2. Adaptive immune system
Innate immune system acts as a first line of defence against
infectious agents and potential pathogens and is checked before they
establish an infection.
Adaptive immune system produces a specific reaction to each
infectious agent that normally eradicates that agent. In addition, the
adaptive immune response remembers that particular infectious agent
and prevents from disease or infection at a later stage. (Memory response)
1.1.1 Cells Involve in Immune Response
The cells involve in immune response of vertebrate are of different
type. Which are able to specifically recognize the 'non self‟ antigen on
microorganisms and thereby enhance there elimination. (Table 1.1)
All the cells of the immune system arise from pleouripotent stem
cells with two differentiation (Fig. 1.1)
1. The Lymphoid Lineage – Producing Lymphocytes
2. The Myloid Lineage – Producing phagocytic & other cells
Among different cells involve in immune system, the lymphocytes
and Antigen presenting cells (A.P.Cs) are important for present study,
discussed below.
CHAPTER – 1 INTRODUCTION
4
Table 1.1 : Summary of the cells of immune system
S.
No. Type of Cells
Site of Origin
/Maturation Function
1. Lymphocytes
B Lymphocytes
T Lymphocytes
Null cells
Bone Marrow
Thymus
Humoral Immunity
Cell mediated immunity
Majority of natural killer
cells.
2. Mononuclear
Phagocytic cells
– APC (in the
blood)
Skin, lymphnodes
spleen and thymus
present antigen to
antigen sensitive
lymphoid cell
– Macrophage (in
the tissue)
Alveolar
macrophage
(in lungs)
Phagocytosis
Histiocytes (in the
connective tissue)
Phagocytosis
Kupffer cells (in the
liver)
Phagocytosis
Mesengial cells (in
kidney)
Phagocytosis
Microglial cells (in
the brain)
Phagocytosis
3. Granulocytic cells
Neutrophils Bone marrow Active phagocytic cells.
Eosionophil Bone marrow Active phagocytic cells.
Basophils Bone marrow Non-phagocytic act by
releasing content of their
granules.
4. Mast cells Bone marrow Important role in
development of allergen.
5. Dendritic cells Bone marrow Process and present
antigen to Thymus cells.
Lymphocytes are one among the different type of WBCs produced in
the bone marrow during the process of hemotopoeisis. On leaving from
bone marrow, lymphocytes circulate in the blood and lymph system and
CHAPTER – 1 INTRODUCTION
5
reside in various lymphoid organs. The two major populations of
lympocytes which subserve various function are B-Lymphocytes (B-cells)
and T-Lymphocytes (T- cells).
1.1.2 Organs of Immune System
A number of morphologically and functionally diverse organs and
tissue have various functions in the development of immune response.
They can be divided on the basis of function into:
(a) Primary lymphoid organs
(b) Secondary lymphoid organs
The Thymus and bone marrow constitute the primary lymphoid
organs where maturation of lymphocytes occurs. The lymph node, Spleen
and various Mucosal Associated Lymphoidal Tissue (MALT) constitute the
secondary lymphocytes to interact with antigen. In addition to these,
Tertiary Lymphoid Tissues normally contain free lymphoid cells during
an inflammatory response. Most prominent of these are Cutaneous
Associated Lymphoid Tissue (CALT) and Nasal Associated Lymphoid
Tissue (NALT).
1.2 IMMUNITY
Immunity involves a specific defence response when a forigen
organism or other foreign substance infects host. The immune system
recognizes the foreign substance as not belonging to the body it develops
an immune response against them. Organisms or substances that provoke
such a response are called Antigens. This immune response involves the
production of proteins called Antibodies and specialized lymphocytes.
Immunity can be classified into naturally acquired and artificially
acquired immunity. Artificially acquired immunity accordingly, refers to
CHAPTER – 1 INTRODUCTION
6
the protection that person develops against a certain type of microbe or
foreign substance. Acquired immunity develops daily in individuals
lifetime. Immunity can be acquired either actively or passively. Immunity
is acquired actively when a person is exposed to microorganisms or foreign
substance and the immune system responds.
Immunity is acquired passively when antibody are transferred from
one person to another. Passive immunity lasts only as long as antibodies
are present say from few days to months. Both actively acquired and
passively acquired immunity can be obtained by natural or artificial means.
The various type of acquired immunity are summarized in (Table 1.2).
Table 1.2 : Types of Acquired Immunity
Naturally acquired Artificially acquired
Active Passive Active Passive
Antigen enters
the body
naturally, body
produces
antibodies and
specialized
lymphocytes.
Antibodies pass
through mother
to fetus via
placenta to
infant from her
milk.
Antigens
introduce via
vaccine; body
produces
antibody and
specialized
lymphocytes.
Preformed
antibody by
immune system
and introduced
by injection in
others body.
1.3 HUMORAL AND CELL MEDIATED IMMUNE RESPONSE
1. Humoral response
2. Cell mediated response
The name humoral response was delivered from Latin word
Meaning „body fluid‟ thus humoral immunity can be conferred on a non
CHAPTER – 1 INTRODUCTION
7
immune individual by administration of serum antibody from an immune
individual.
Humoral immunity involves interaction of B cell with antigen and
their subsequent proliferation and differentiation into antibody secreating
plasma cells. Antibody acts as the effector unit of humoral response by
binding to antigen and neutralizing it or facilitating its elimination.
Cell mediated immune response is one in which T cell are
involved. Unlike humoral immunity, cell mediated immunity can be
transferred only by administration of T cell from an immune individual.
Both activated T cell and CTLs serve as effector cells in cell mediated
immune reaction. These effector T cells generates in response to antigen,
are responsible for cell- mediated immunity.
1.4 ANTIGENS
Antigen and antibody play a key role in the response of immune
system. Substances capable of inducing a specific immune response are
commonly refered to as antigens more appropriately immunogen. Most
antigens are either protein or large polysaccharides, lipids and nucleic
acids are antigenic only when combined with proteins and
polysaccharides. Antigenic compounds are often component of invading
microbe such as the capsule, cell wall, flagella, fimbriae and toxins of
bacteria; the coats of virus; or the surfaces of other type of microbes. Most
antigens have a molecular weight of 10,000 or higher. A foreign substance
that has low molecular weight is often not antigenic unless it is attached
to a carrier molecules. These small compounds are called haptens.
Generally, antibodies recognize and interact with specific region in
antigen called antigenic determinant or epitopes.
CHAPTER – 1 INTRODUCTION
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Immunogenicity and antigenicity are related, but have distinct,
immunological properties that sometimes are confusing. Immunogenicity
is the ability to induce a humoral and or cell mediated immune response.
B cells + Antigen – effector B cells + memory B cells
(plasma cells)
T cells + Antigen – effector T cells + memory T cells
(CTLs)
Antigenicity is the capacity to stimulate the production of
antibodies or cell-mediated immune responces.
1.5 ADJUVANTS
Adjuvants are substance that when mixed with an antigen and are
injected with it, serve to enhance the immunogenicity of the antigen.
Adjuvants are often used to boost when an antigen has low antigenicity.
1.6 ANTIBODIES
Antibodies or protein that are generated in response to an antigen
and can recognize and combine to that antigen. Antibodies can therefore,
help to neutralize or destroy that antigen. Antibodies are highly specific in
recognizing the antigen that stimulate their formation. Antibodies are
members of a group of soluble proteins collectively known as
immunoglobulin (Igs).
1.6.1 Structure of Immunoglubulin
A bivalent antibody has the simplest molecular structure and is
called monomer. A typical immunoglobulin molecule as shown in Figure
has four protein chains; two identical light (L) chains and two identical
heavy (H) chains. The chains are joined by disulphide links and other
bonds to form a Y shaped molecule.
CHAPTER – 1 INTRODUCTION
9
The two sections located at the ends of Y arm are called variable
(V) regions and constant (C) regions. Each antibody has atleast two
identical sites that bind to antigenic determinants. The site are known as
antigen-binding sites. These antigen binding sites are present at the
variable region.
1.6.2 Immunoglobulin Classes
The five major classes of immunoglobulin (Ig) are designated as
IgG, IgM, IgA, IgD and IgE. Each class plays a difficult and distinct role
in immune response.
Structure of Immunoglobulin
1.6.1.1 Immunoglobulin G (IgG)
IgG, the most abundant class in serum, constitutes about of 80% of
the total serum Immunoglobulins. These antibodies are capable of crossing
the walls of blood vessels and enter tissue fluids. There are four IgG
subclasses in humans (IgG1 to IgG4). IgG antibodies offer protection
against circulating bacteria, toxins as well as trigger the complement
system and when bound to antigens, enhance the effectiveness of
phagocytic cells.
CHAPTER – 1 INTRODUCTION
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1.6.2.2 Immunoglobulin M (IgM)
IgM, account for 5-10% of the total serum immunoglobulin. IgM is
secreted by plasma cells as a pentamer. Its monomeric form is expressed
as membrane bound antibody on B cell. The large size of molecules
prevent IgM from moving about as freely as IgG does. IgM generally
remains in blood vessels and does not enter the surrounding tissue. IgM is
predominant type of antibody involves in response to the ABO blood group
antigens present on the surface of red blood cells. It is also effective in
aggregating antigens. It also can enhance the ingestion of target cell by
phagocytic cells. IgM antibodies are the first antibodies to appear in
response to initial exposer to an antigen and they are relatively short
lived.
1.6.2.3 Immunoglobulin A (IgA)
IgA accounts for only 10-15 % of the total immunoglobulin in serum.
It is the predominant immunoglobulin class in external secretions such as
saliva, tears, breast milk and mucous of the bronchial, gastrourinary and
digestive tracks. In serum, IgA exists primarily as monomer. The most
effective form of IgA is a dimmer called secretary IgA, consisting of two
monomer connected by a J chain. It is produced in this form by plasma
cells in the mucous membrane. Each dimmer then enters and passes
through a mucosal cell, where it acquires a polypeptide called secretary
component and protects it from enzymatic degradation.
1.6.2.4 Immunoglobulin D (IgD)
IgD antibodies constitute about 0.25 of the total serum
immunoglobulin. IgD together with IgM is the major membrane-bound
immunoglobulin expressed by mature B-cells and is thought to function
for the activation of B-cells by antigen.
CHAPTER – 1 INTRODUCTION
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1.6.2.5 Immunoglobulin E (IgE)
IgE constitutes to about 0.002 % of the total serum antibody. IgE
antibodies mediate the immediate hypersensitivity reactions that are
responsible for the symptoms of hay fever, asthma, hives and anaphylactic
shock. IgE binds to Fc – receptor on the membrane of blood basophils and
tissue mast cells.
1.7 INFECTIVE DISEASES
Infective diseases are caused by microbes that can be passed among
humans by several methods and kill more people worldwide than any
other single cause. Infectious diseases are caused by germs. Germs are
tiny living things that are found everywhere-in air, soil and water. One
can get infected by touching, eating, drinking or breathing, something that
contains a germ. (Specially in case of typhoid and TB)
TB is the third most dangerous infective disease responsible for
human death worldwide. The present study is based on diagnosis of
Typhoid and TB.
1.8 TYPHOID
Typhoid is one of the major infective diseases which is spread
widely in India specially in rural areas. The disease is caused due to a
bacterium which is commonly spread by dirty water and contaminated
food, S.typhi. Large number of cases are reported against S. typhi.
Typhoid fever : A gastrointestinal condition mainly in the developing
world is caused by a bacterial toxin.
Typhoid fever is a life-threatening illness caused by the bacterium
Salmonella typhi.
CHAPTER – 1 INTRODUCTION
12
Life Cycle of Salmonella typhi
CHAPTER – 1 INTRODUCTION
13
Transmission
S typhi has no non human vectors. The following are the modes of
transmission:
Oral transmission via food or beverages handled by an individual
who chronically sheds the bacteria through stool or, less commonly
urine.
Hand-to-mouth transmission after using a contaminated toilet and
neglecting hand hygiene.
Oral transmission via sewage-contaminated water or shellfish.
(especially in the developing world)
An inoculum as small as 100,000 organisms causes infection in
more than 50% of healthy volunteers.
1.8.1 Typhoid and Types
There are two types of Typhoid, paratyphi O and H which are
responsible for having typhoidal infection.
1.8.2 Structure of S. typhi
S. typhi is a gram negative pathogenic bacterium which in human
body creates disturbances and a disease the typhoid. Salmonella can enter
by dirty water or contaminated food.
Early diagnosis of the infection of bacteria is the best, otherwise it
creates a number of problems.
Hardly any receptors are found on Salmonella but on the second
and third layer of cell wall of all strains „O‟ antigen is present which varies
from strain to strain due to change in „O‟ antigenic structure and sugar
composition. The variation in the „O‟ antigen of strains and the antigenicity
of this particular bacteria generate variation in humoral immunity.
CHAPTER – 1 INTRODUCTION
14
Lipid „A‟ present in it is very toxic and is the major cause of fever.
The Vi antigen not only protects the bacteria from being phagocytosed but
enhances virulence of the germ.
1.8.4 Case History of Typhoid In India and other Countries
Typhoid fever is a systemic infection caused by Salmonella enterica
serotype Typhi (S. typhi). The disease remains an important public health
problem in developing countries. In 2000, it was estimated that over 2.16
million episodes of typhoid occurred worldwide, resulting in 2.16 lacs
deaths, and that more than 90% of this morbidity and mortality occurred
in Asia. Although improved water quality and sanitation constitute
ultimate solutions to this problem, vaccination in high-risk areas is a
potential control strategy recommended by WHO for the short-to-
intermediate term.
1.9 SIGNS AND SYMPTOMS
Typhoid fever is characterized by a slowly progressive fever as high
as 40°C (104°F), profuse sweating, gastroenteritis, and non bloody
diarrhea. Less commonly, a rash of flat, rose-colored spots may appear.
Classically, the course of untreated typhoid fever is divided into four
individual stages, each lasting approximately one week. In the first week,
there is a slowly rising temperature with relative bradycardia, malaise,
headache and cough. A bloody nose (epistaxis) is seen in a quarter of cases
and abdominal pain is also possible. There is leukopenia, a decrease in the
number of circulating white blood cells, with eosinopenia and relative
lymphocytosis, a positive diazo reaction and blood cultures are positive for
Salmonella typhi or paratyphi. The classic Widal test is negative in the