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T-cells activation
Immune response-regulation
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Cell mediated immune responses
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Antigen-specific cell –mediated responses are carried out by Tlymphocyte .T cells can lyse cells expressing specific
antigens(Cytotoxicity) or release cytokines which trigger inflammation
(delayed hypersensitivity). These two types of T-cell response are
mediated by distinct populations , Cytotoxicity is the role of cytotoxic T (Tc)
cells and delayed hypersensitivity that of helper T cells.
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These two types of T cells are responsible for combating intracellular
pathogens (all viruses, certain bacteria and parasites) which are
inaccessible to antibodies and drug. Cytotoxic T cells lyse cells infected with
virus. Such Cytotoxicity is virus specific and only cells expressing the
relevant viral proteins on their surface are killed .

Since infected cells express surface viral proteins prior to
the assembly of new virus particles and viral budding,
Cytotoxic T cells are important in the recovery phase of
an infection, destroying the infected cells before new
virus particles are generated. In contrast to helper T
cells ,Cytotoxic T cells recognize viral antigens together
with MHC class 1 molecules .They show exquisite
specificity for self MHC antigens in that they can only
lyse cells expressing the same MHC class 1
molecules.
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Delayed-type hypersensitivity(DTH) reactions are mediated by
specific T-cells which produce TH1 type cytokines on exposure to
antigen.
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The tuberculin test (Mantous test) is agood example of a DTH
response. Individuals who have previously been infected with
Mycobacterium tuberculosis mount a T cell response which evolves
over 24-72 h following intradermal injection of tuberculin .

This is clinically manifest as local swelling and induration, biopsy of
tissue granulomas in tuberculosis and sarcoidosis are further
examples of DTH .
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Like the induction of T cell help, the induction of delayed
hypersensitivity may also be subject to MHC polymorphism
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T- LYMPHOCYTES activation:
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T lymphocytes also arise in the bone marrow. Unlike B cells, which mature within the bone
marrow, T cells migrate to the thymus gland to mature. During its maturation within the
thymus, the T cell comes to express a unique antigen-binding molecule, called the T-cell
receptor, on its membrane. Unlike membrane-bound antibodies on B cells, which can
recognize antigen alone, T-cell receptors can recognize only antigen that is bound to cellmembrane proteins called major histocompatibility complex (MHC) molecules. MHC
molecules that function in this recognition event, which is termed “antigen presentation,” are
polymorphic (genetically diverse) glycoproteins found on cell membranes.

There are two major types of MHC molecules: Class I MHC molecules, which are expressed by
nearly all nucleated cells of vertebrate species, consist of a heavy chain linked to a small invariant
protein called _2-microglobulin. Class II MHC molecules, which consist of an alpha and a beta
glycoprotein chain, are expressed only by antigen-presenting cells. When a
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Naive T cell encounters antigen combined with a MHC molecule on a cell, the T cell proliferates and
differentiates into memory T cells and various effector T cells.
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There are two well-defined subpopulations of T cells:
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T helper (TH) and T cytotoxic (TC) cells. Although a third type of T
cell, called a T suppressor (TS) cell, has been postulated, recent
evidence suggests that it may not be distinct from TH and TC
subpopulations. T helper and T cytotoxic cells can be distinguished
from one another by the presence of either CD4 or CD8 membrane
glycoproteins on their surfaces. T cells displaying CD4 generally
function as TH cells, whereas those displaying CD8 generally
function as TC cells. After a TH cell recognizes and interacts with an
antigen–MHC class II molecule complex, the cell is activated—it
becomes an effector cell that secretes various growth factors known
collectively as cytokines.
 The
secreted cytokines play an important
role in activating B cells , cells, macrophages,
and various other cells that participate in the
immune response. Differences in the pattern of cytokines
produced by activated TH cells result in different types of immune
response. Under the influence of TH-derived cytokines, a TC cell
that recognizes an antigen–MHC class I molecule
complex proliferates and differentiates into an effector cell
called a cytotoxic T lymphocyte (CTL).

In contrast to the TC cell, the CTL generally
does not secrete many cytokines and instead
exhibits cell-killing or cytotoxic activity. The
CTL has a vital function in monitoring the
cells of the body and eliminating any that
display antigen, such as virus-infected cells,
tumor cells, intracellular bacteria, and cells
of a foreign tissue graft. Cells that display
foreign antigen complexed with a class I MHC
molecule are called altered self-cells; these are
targets of CTLs.
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ANTIGEN-PRESENTING CELLS
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Activation of both the humoral and cell-mediated
branches of the immune system requires cytokines
produced by TH cells. It is essential that activation
of TH cells themselves be carefully regulated,
because an inappropriate T-cell response to selfcomponents
can
have
fatal
autoimmune
consequences. To ensure carefully regulated
activation of TH cells, they can recognize only
antigen that is displayed together with class MHC
II molecules on the surface of antigen-presenting
cells (APCs).
These specialized cells, which include macrophages, B lymphocytes, and dendritic cells,
are distinguished by two properties:
(1) They express class II MHC molecules on their membranes.
(2) They are
able to deliver a co-stimulatory signal that is necessary for TH-cell
activation.
Antigen-presenting cells first internalize antigen, either by phagocytosis or by
endocytosis and pinocytosis , and then display a part of that antigen on their membrane
bound to a class II MHC molecule. The TH cell recognizes and interacts with the
distinctive membrane molecules on lymphocytes.
(a) B cells have about 100 000 molecules of membrane-bound antibody per cell. All the
antibody molecules on a given B cell have the same antigenic Specificity and can interact
directly with antigen.
(b) T cells bearing CD4 (CD4+ cells) recognize only antigen bound to class II
MHC molecules.
(c) T cells bearing CD8 (CD8+ cells) recognize only antigen associated with class I MHC
molecules. In general, CD4+cells act as helper cells and CD8+ cells act as cytotoxic cells.
Both types of T cells express about 100 000 identical molecules of the antigen binding Tcell receptor (TCR) per cell, all with the same antigenic specificity.
Pulmonary TB

Pulmonary TB may manifest itself in several
forms
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endobronchial TB with focal lymphadenopathy
progressive pulmonary disease
pleural involvement
reactivated pulmonary disease
 Symptoms
of primary pulmonary disease in the
pediatric population often are meager
 Fever, night sweats, anorexia, nonproductive cough,
failure to thrive, and difficulty gaining weight may
occur
Extrapulmonary TB
 Extrapulmonary TB includes
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peripheral lymphadenopathy,
tubercular meningitis,
miliary TB,
skeletal TB,
and other organ involvement.
Congenital TB


Congenital TB is a rare entity.
Symptoms typically develop during the second
or third week of life
 poor
feeding
 poor weight gain
 cough
 lethargy
 irritability
 Other possible symptoms include fever, ear
discharge, and skin lesions
Congenital TB

the infant should have proven TB lesions
and at least one of the following:
 Lesions
in the first week of life
 Documentation of TB infection of the placenta
or the maternal genital tract
 Presence of a primary complex in the liver
 Exclusion of the possibility of postnatal
transmission
TB Disease
Defects in cell-mediated immunity
 HIV
 Steroid therapy, cancer chemotherapy,
and hematologic malignancies increase
the risk of TB
 Malnutrition
 Non-TB infections, such as measles,
varicella, and pertussis,
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Lab Studies

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the diagnosis of TB in children is extremely
challenging because of difficulty in isolating M
tuberculosis
initial step is to obtain appropriate specimens for
bacteriologic examination
Gastric aspirates are used in lieu of sputum in
very young children (<6 y)
 An
early morning sample should be obtained, before
the child has had a chance to eat or ambulate, as
these activities dilute the bronchial secretions
accumulated during the night
 Regulation

of the immune response
The specific immune involving activation and clonal
expansion of B cells brings into play a variety of nonspecific effector mechanisms involving complement,
cytokines, granulocytes, macrophages, mast cells etc.
These have the potential to damage normal host tissues
,so it is crucial that the specific immune response be
swiftly curtailed once the initiating foreign invader has
been effectively neutralized.
•
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Anti-idiotypic antibody
Variable regions, or idiotypes (ids),of antibodies ,BCRs and TCRs represent novel
molecules not previously experienced by the immune system. Tolerance will not have
been induced against them and ,if present in sufficient quantity, as occurs during a clonally
expanded immune response, they will be immunogenic and induce anti-idiotypic
antibodies(ant-ids). Secreted antibody may be recognized by B cells bearing BCRs with
anti-id reactivity. This usually takes place on the surface of follicular dendritic cells and
transmits activation signal 1 to the anti-id B cell. The fully activated anti-idiotypic B cell
undergoes clonal expansion and secretes anti-id .This will form immune complex with
circulation id which will be removed by phagocytes. Anti-id will also bind to id (BCR) on
the surface of B cells. This will lead to cross –linking of FcRs,which generates an
inactivation signal. The TCR on clonally expanded activated T cells can also lead to the
generation of anti-id, which could induce tolerogenic signals when it binds to cell-bound
TCR, perhaps by inducing activation signal 1 in the absence of signal 2.
•
T suppressor cells
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Activation of immune effector mechanisms involving B cells ,cytotoxic T
cells,Macrophages or NK cells all require participation of T helper cells and their
secreted lymphokines . Termination of a successful immune response could the
driving T helper cells.

The phenomenon of T helper inactivation by T suppressor cells has
been difficult to prove, and although most immunologists now accept the
existence of this specialized T-cell subset ,its mode of action is still unclear . As T
helper cells recycle their TCRs and process TCR id peptides on to MHC-1,CD8 T
cells with appropriate ant-id TCRs might bind to and inactivate the T
helper cell by cytotoxic mechanism or by transmitting ،off signals ، through
membrane interactions.
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3-Cytokines
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An important mechanism of immune suppression is
induction of a different cytokine profile from the one
driving the ongoing reaction,e.g.suppression of cellmediated immunity by type 2 cytokines or suppression
of humoral immunity by type 1 cytokines (immune
deviation). A population of T regulatory cells that secrete
mainly TGFB and or IL-10 also suppresses cytokinedepende immune reactions.
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Antigen
Nature: polysaccharide antigens tend to elicit a predominant IgM+IgG2 response
in contrast to protein antigens which elicite both cellular and humoral response.
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Dose: in experimental animals large doses of antigen induce tolerance.

Route of administration: polio vaccine administered orally elicited a stronger
antibody response than intramuscular injection.
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Antibody
passive administration of antibody can be used to modulate immune response,
e.g. maternal administration of antibodies to the red cell Rh antigen is used to
prevent hemolytic disease of the newborn by removing fetal red cells from the
maternal circulation.
TST
 Induration
of 10 mm or more is considered
positive:

Children who are at a higher risk of dissemination
of tuberculous disease
younger than 5 years
 immunosuppressed
 diabetes mellitus
 malnutrition

those who were born in or whose parents were
born in high-prevalence areas of the world
 those with travel histories to high-prevalence
areas of the world
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TST

Induration of 15 mm or more is considered
a positive TST result in children aged 5
years or older without any risk factors for
the disease
TST

False-positive reactions often are
attributed to asymptomatic infection by
environmental nontuberculous
mycobacteria (due to cross-reactivity)
TST

False-negative results may be due to
 vaccination
with live-attenuated virus,
 immunosuppression,
 immune deficiency,
 malnutrition.
 subcutaneous injection
 injection of too little antigen improper storage

PPD has been recognized to have an
initial false-negative rate of 29%
Treatment
The ultimate goal of treatment is to
achieve sterilization of the TB lesion in the
shortest possible time
 the regimens for the treatment of TB
always should consist of multiple drugs.
 directly observed therapy (DOT) is
recommended for treatment of TB
 MDR
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Outpatient Care
Public health authorities should be notified of all
cases of TB
 DOT is mandatory for the treatment of patients
with coexistent HIV disease, those with MDRTB, and those who may be noncompliant.
 A regular follow-up appointment every 4-8
weeks should be scheduled to ensure
compliance and to monitor the adverse effects of
and response to the medications administered
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Outpatient Care
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Monitoring of liver function test

miliary TB,
 tubercular meningitis,
 coexistence of other hepatic disorders
 with concomitant hepatotoxic drug therapy
Outpatient Care

Follow-up CXR may be obtained after 2-3
months of therapy to observe the
response to treatment in patients with
pulmonary TB. However, hilar
lymphadenopathy may take several years
to resolve. Thus, a normal CXR is not
required for termination of therapy
Prevention
o
The risk of acquisition of TB is particularly
high in very young children (<5 y) and in the
adolescent population. Thus, patients in these
age groups with a positive TST result and no
other manifestations should receive INH
therapy. Active TB should be excluded
carefully prior to the initiation of preventive
therapy.
Prevention

For recent contacts of patients with
contagious TB (ie, in the past 3 mo), INH
therapy is indicated even if the TST result
is negative. This is especially true for
contacts who are infected with HIV or for
household contacts younger than 5 years.
Prevention
The recommendations of the AAP are to
administer 9 months of preventive therapy.
The drug of choice is INH.
 A period of treatment of 12 months is
recommended for patients with HIV
infection.
 For the management of contacts of INHresistant cases, rifampin is recommended
for 6 months in children

Vaccination
BCG is a live vaccine prepared from
attenuated strains of M bovis
 Although BCG vaccine has been in use
since 1921 and approximately 3 billion
doses have been administered, its efficacy
continues to be debated

Vaccination
Vaccine is efficacious against miliary and
meningeal TB. Controversy exists about
the efficacy of BCG against pulmonary TB
 The major role of BCG is the prevention
of serious and life-threatening disease
such as disseminated TB and tubercular
meningitis in children. BCG vaccine does
not prevent infection with M tuberculosis
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Vaccination
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From birth to age 2 months, administration
of BCG does not require a prior TST.
Thereafter, a TST is mandatory prior to
vaccination
Vaccination
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Adverse reactions due to the vaccine
include subcutaneous abscess formation
and the development of lymphadenopathy.
Rare complications, such as osteitis of the
epiphyses of the long bones and
disseminated TB, may necessitate
administration of antitubercular therapy,
except for pyrazinamide
Vaccination
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Contraindications

immunosuppressed conditions
 Steroid
 HIV infection.

However, in areas of the world where the
risk of TB is high, the WHO recommends
using the BCG vaccine in children who
have asymptomatic HIV infection
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