Immunology of tuberculosis

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Immunology of tuberculosis
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Introduction

• It is estimated ???? that almost 2 billion
  people
• worldwide are infected with M.tuberculosis
  .
• T.B. is an example of an infection in
  which
• protective immunity pathologic
  hypersensitivity
• coexist ??????? ??????? ???? ?? ???????
  ????????? ??? ???? ????? ????? , and the lesions
  ???????? are caused mainly by the
• host response
  ??????? ?????? ( ????? ????? ?????? )

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The incidence ???? ????? has recently been
increasing due to

• emergence ????? of antibiotic resistant
  strains ????? ?????? ????????
• Increased incidence of immunodeficiency
• caused by HIV infections
• immunosuppressive therapy

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• mode of transmission ????? ????????
• infection is acquired by inhalation of
• M. tuberculosis in aerosols ???? and dust
• ( airborne transmission ??????
  ?????? ??????? )

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infected people cough up large numbers
of mycobacteria into the environment

• the organisms have waxy outer coats
• therefore can withstand drying and survive
  for long periods in air and house dust .

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airborne
transmissionby inhalation of droplets from a
cough or sneeze .
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Primary infection ??????? ?????? ( ??? ??? )
( i.e. infections in individuals for the
first time ).

• organisms are inhaled from air or dust .
• engulfed by alveolar macrophages .
• ( non- resident ????? ????? ??????
  macrophages are also attracted )
• macrophages ingest the pathogens
• and carry them via the lymphatics to the
• local (hilar ??? ?? ??????????????
  ??????) lymph nodes

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Mycobacterium tuberculosis stimulate macrophages
by binding Toll-like receptors.

• - these receptors recognize
• mycobacterial lipoproteins
• and polysaccharides
• this stimulate
• phagocytosis.
• secretion of cytokines

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Mycobacteria persist ???? inside macrophages
- waxy coat block the effect of phagocyte
enzymes -they also secrete catalase which
prevent the effects of the respiratory burst
- macrophages seal off ?????? ??????? ??
?????? mycobacteria inside
phagososmes
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Mycobacterial peptides presented by
macrophages

• elicit ???? strong T helper (TH1) response
• activated T-cells secrete cytokines
• tumor necrosis factor interferon-gamma
• (TNF) (IFN)

???? ?? ???????? ??????? ??? ??? ??????
IFN-? A 21-25 kD glycoprotein lymphokine encoded
on chromosome 12q and produced by activated T and
NK cells IFN-? is antiviral, regulates class II
MHC antigen expression, Fc receptors and
immunoglobulin production and class switching,
activates monocyte cytotoxicity and enhances NK
cell activity
?? ???????A protein that is produced in the
presence of an endotoxin, especially by monocytes
and macrophages, is able to attack and destroy
tumor cells, and exacerbates chronic inflammatory
diseases.
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By 6-8 weeks after infection

• Macrophages localize in the draining
  ???? lymph nodes
• CD4 T-cells become activated
• and secrete IFN-gamma
• ( CD8 T-cells become activated later
  )
• ( IFN )
• activate (infected)
  macrophages
• (to enhance their ability to kill
  phagocytosed bacilli)
• because it is hard to kill them
  mycobacteria are sealed ???? ?????
• in
  phagososmes

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activated T-cells and activated
macrophages

• secrete tumor necrosis factor (TNF).
• TNF play a role in
• 1. local inflammation
• 2. further macrophage activation
• The resulting T-cell reaction (CMI) is
  
• adequate to control bacterial spread
• ( bacilli are contained within tubercles
  small granulomas )

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DTH reactions (delayed type
hypersensitivity reactions)

• DTH reactions may occur as
• 1. collateral ????? damage during a
  protective
• response to a microbe
• 2. DTH may be entirely pathologic as in
• certain autoimmune diseases

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DTH reactions in tuberculosis

• Chronic DTH reactions develop when the
  TH 1
• response to mycobacteria activates
  macrophages
• but fails to eradicate ???? ???? ???
  phagocytosed microbes
• this will lead to
• granulomatous inflammation which is a form
• of DTH reactions to the bacilli

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In chronic DTH reactions macrophages undergo
changes in response to cytokines

• they develop increased cytoplasm.
• and become epithelioid cells
• they fuse to form multinucleated giant cells
• these cells surround the ingested bacilli to
  
• form part of the granuloma

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Tuberculous granuloma .
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Granulomas may undergo central necrosis
(caseous necrosis)

• Necrosis result from macrophage products
  
• (lysosomal enzymes reactive oxygen
  radicals)
• necrosis serve to eliminate infected
  macrophages
• and provide an anoxic ????? ????????
  environment in which bacilli cannot divide
• (even the tissue injury may serve a protective
  function)

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outcome of primary infection

• depend on immune state of the individual.
• 1. complete healing
• 2. progressive infection
• 3. excessive response to primary
  infection
• 4. post primary (reactivation)

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outcome of primary infection

• In most patients ( 90), primary infection heal
  to
• to leave a small visible scar on
  radiograph
• (mycobacteria remain alive inside macrophages)
• this is called
• the Ghon (or primary) complex

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The Gohn complex consist of
The lung lesions (tubercles small granulomas)
plus the enlarged lymph nodes

tubercles may heal become
fibrotic or calcified and persist
???? as such for a lifetime show up on chest
x- ray as radio-opaque nodules
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In individuals with impaired immunity

• mild immunodeficiency severe
  immunodeficiency
• lead to reactivation, leads to
  more widespread
• usually in the apices
  infection beyond the
• of the lung
  lungs

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In patients with excessive TNF production ,
lesions can break down leading to
open T.B.

• In a small proportion of young patients,
• widespread primary T.B. occur.
• may present as
• 1- miliary T.B ?? ??????? Miliary
  tuberculosis. Tuberculosis TB that has
  disseminated throughout the body, especially the
  lungs the minute, millet seed-sized lesions ???
  ????? ????? ??? ?????
• 2- ( or) tuberculous
  meningitis ?????? ???????

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• Outcome of primary infection
• - 5 progressive infection
• - 90 remain asymptomatic
• - 5 reactivation

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Reactivation of dormant ???? mycobacteria is
usually a consequence of impaired immune
function resulting from

• 1. malnutrition . ??? ?????
• 2. infection (e.g. AIDS ).
• 3. chemotherapy for treatment of
  tumors.
• 4. corticosteroids ??? ????? for
  treatment of inflammatory disease .

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Test for immunity against T.B. (Delayed
hypersensitivity skin test.)

• The delayed hypersensitivity skin test asses
  immunologic memory to mycobacteria (T-cell recall
  response)
• The test is known as
• Tuberculin test, or (Mantoux)
• The test is carried out with
• Intradermal ??? ????? injection of PPD.
• (purified protein derivative
• ?????? ????????? ??????)

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The tuberculin test

• - Toll-like receptors on dermal macrophages
  recognize mycobacteria and secrete
• TNF Chemokines.
• Dendritic cells (loaded with mycobacterial
  antigen) migrate from site of injection to
  draining lymph nodes activate primed T-cells

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Activated T-cells subsequently migrate to
injection site and interact with activated
macrophages. The cytokines released produce
erythema ???? and induration at the site . -
positive test may be due to - BCG
vaccination ??? ???? ???? ?? - recent
exposure to T.B .- negative test may suggest
immunodeficiency (secondary to HIV)
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Tuberculin test after intradermal injection
of PPD measure diameter of induration after 48
hours
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???????? ?????? Blood test for T.B. exposure .

• The blood test measures interferon
  gamma
• secreted in response to mycobacterial
  antigen
• - mycobacterial peptides are added to the
  patients
• blood which is then incubated for 12
  hours
• - the amount of (IFN) produced is then
  measured
• by ELISA test

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Prevention

• 1. immunoprophylaxis ????? ??????
• ???? vaccination ?????
• 2. chemoprophylaxis
• anti- tuberculous drugs ?????
  ?????

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Immunoprophylaxis

• B.C.G. Vaccine ( Bacillus Calmette
  Guerin ).
• A live attenuated non-virulent strain
  of M. bovis
• - BCG has been used effectively in situations
  where
• tuberculosis is prevalent
• Immunization does not prevent infection but allow
  the
• body to react quickly to limit proliferation
  of the organism

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• In areas of low prevalence immunization has
  largely been replaced by chemoprophylaxis
• After BCG vaccination the skin test cannot be
  used
• as an effective monitor of exposure to M.
  tuberculosis .

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