3. History
• Began infecting the first human ancestors as long as
500,000 years ago
• In 1882 – claimed the lives of 1 in 7 people
• Ran rampant in crowded European and American cities
• March 24 – Robert Koch discovers Mycobacterium
tuberculosis
• Koch’s discovery allowed scientists to begin working on a
treatment and vaccine for TB.
• 1908 - Albert Calmette and Camille Guérin: BCG
vaccine
o First used in 1921 preventatively
4. History
• 1943 - microbiologist Selman Waksman
discovered streptomycin
• 1970s – Most people believe TB is
completely irradiated
• Until the mid 1980s, in the USA & Western
countries there was a decline in TB
infection
5. The incidence in Western population increased
in HIV-infected persons & in immigrants from
high prevalence areas
The lung is the most common important
clinical site of infection
6. • 1998 – genetic sequencing of
Mycobacterium tuberculosis
• 2006 – first case of extensively drug
resistant TB in South Africa
• 2008 – 49 countries reported cases of
extensively drug resistant TB
7. History
• In 2008 highest incidence was in Southeast
Asia
• 98% of TB related deaths occur in developing
countries
• In the US, there were 4.2 cases per 100,000
people in 2008
• Most of the US cases occurred in Florida,
Texas, California, and New York
11. • Has no known exotoxins, endotoxins
• Has waxy coat “high contents of complex
lipids” ( i.e.mycolic acids )that causes
them to retain the red dye when treated
with acid in acid-fast stain & resist
decolorization
• Intracellular organisms
12. Tuberculosis
• Tuberculosis(TB) is defined as a disease
caused by members of the M.tuberculosis
complex, which includes the tubercle
bacillus (M. tuberculosis), M. bovis, M.
africanum, M. microti, M.canetti, M.
caprae and M. pinnipedi ( Van Soolingen
et al. 1997 )
13. Tuberculosis - Pathogenesis
• TB is spread person to person through the air
via droplet nuclei
• M. tuberculosis may be expelled when an
infectious person:
– Coughs
– Sneezes
– Speaks
• Transmission occurs when another person
inhales droplet nuclei
14.
15. Tuberculosis - Pathogenesis
• A number of factors predispose to the
development of TB :
• Access of organism: close contact with open
cases of disease, e.g. increased in crowded &
unhygienic working and living conditions
• Susceptibility of individual: the old, very
young, black & Asian populations have and
increased susceptibility
16. • Nutrition: a disease of the undernourished & under
privileged “poor”
• Occupation: increased incidence of TB in some types of
pneumoconiosis (silicosis & in health workers)
• Other Diseases: such as;
• pre-existing chronic lung disease, chronic renal
• failure, Hodgkin diseases, diabetes mellitus,
• alcoholism, corticosteroid, immunosuppressive
cytotoxic drug therapy, immunodeficiencies; AIDS
17. • Macrophages are the primary cells infected
by M. tuberculosis.
• Early in infection, tuberculosis bacilli
replicate essentially unchecked, while later
in infection, the T-helper response
stimulates macrophages to contain the
proliferation of the bacteria
18. • M. tuberculosis enters macrophages by
endocytosis mediated by several macrophage
receptors:
• Macrophages mannose receptors
• Complement receptors
• Once inside the macrophage, M. tuberculosis
replicates within the phagosome by blocking
fusion of the phagosome & lysosome
19. • The earliest stage of primary tuberculosis (<3
weeks) in the nonsensitized individual is
characterized by unchecked proliferation of
bacteria in the pulmonary alveolar macrophages
& airspaces, with resulting bacteremia & seeding
of multiple sites
• Despite the bacteremia, most patients at this stage
are asymptomatic or have a mild flulike illness
20. o The genetic make-up of the host may
influence the course of the disease
o In some people with polymorphisms in the
NRAMP1 gene, the disease may progress
from this point without development of an
effective immune response “↓microbicidal
function”
21. NRAMP1 protein is a transmembrane
protein found in endosomes and
lysosomes & may have role in generation
of anti-microbial oxygen radicals
About 3 weeks after infection, a TH1
response against M. tuberculosis is
mounted that activates macrophages to
become bactericidal
22. • TH cells are stimulated by
mycobacterial antigens drained to the
lymph node, which are presented with
class II major histocompatibility
proteins by antigen presenting cells
“macrophages” .
23. Differentiation of TH1 cells depends on
the presence of IL-12, which is produced
by antigen presenting cells that have
encountered the mycobacteria
Mature TH1 cells, both in lymph nodes
and in the lung, produce IFN-γ
24. IFN-γ is the critical mediator which
activates macrophages to become
competent to contain the M. tuberculosis
infection
IFN-γ stimulates formation of the
phagolysosomes in infected
macrophages, exposing the bacteria to an
inhospitable acidic environment
25. IFN-γ also stimulates inducible nitric
oxide synthase (iNOS), which produces
nitric oxide (NO)
NO generates reactive nitrogen
intermediates and other free radicals
capable of oxidative destruction of
several mycobacterial constituents, from
cell wall to DNA
26. In addition to stimulating macrophages to kill
mycobacteria, the TH1 response orchestrates the
formation of granulomas & caseous necrosis
Activated macrophages, stimulated by IFN-γ,
produce TNF, which recruits monocytes
These monocytes differentiate into the
"epithelioid histiocytes" that characterize the
granulomatous response
27. CD4+ TH1 cells also facilitates
development of CD8+ T cells, which can
kill the TB-infected macrophages
Defects in any of steps of TH1 response
result in poorly formed granulomas,
absence of resistance, & disease
progression .
28. In many people, this response contains
the bacteria and doesn't cause significant
tissue destruction or illness
In other people, the infection progresses
and the ongoing immune response results
in tissue destruction due to caseation
&cavitation .
29.
30.
31.
32. Immune biomarker (s) of infection
• Biomarkers are biological features
or substances that can be used as
indicators of infection
ocytokine levels in broncho-alveolar
lavage (BAL) could be
good markers of infection
33. Immune biomarker (s) of infection
• TNF, IFN-γ and IL-2 levels
oMoreover, other candidate
biomarkers for TB infection such
as lactoferrin, CD64
34. Aim of study
oStudy the herd immunity of Iraqi
community to Tb , find out why
some idividuals from the same
family are infected other are not , in
any rate recent used vaccines usful
for preventing Tb
