Tuberculosis

immunopathogenesis
Respirology Division, Department of
Child Health
Faculty of Medicine, University of Indonesia
 Tuberculosis
The reaction of the tissues of the
human host to the presence and
multiplication of Mycobacterium
tuberculosis or Mycobacterium
bovis
 Etiology
Mycobacterium tuberculosis
Mycobacterium bovis
Characteristics :
1. live in weeks in dry condition
2. no endotoxins, no exotoxins
3. hematogenic spread
4. grows slowly (24-32 hr)
5. non specific clinical manifestation
6. aerob, organ predilection - lung
7. wide spectrum of replication: dormant
Transmission
adult patient, active lung TB
cough, sneeze, speak, sing
droplet nuclei: 1-5
airborne for long periodes
inhalation, reach alveoli
middle and lower lobes
 Location of primary focus
in 2,114 cases, 1909-1928

Location %
Lung 95.93
Intestine 1.14
Skin 0.14
Nose 0.09
Tonsil 0.09
Middle ear (Eustachian tube) 0.09
Parotid 0.05
Conjunctiva 0.05
Undetermined 2.41
TB pathogenesis
lymphadenitis

lymphangitis

primary focus
TB can occur in every organ
How can TB occur in every organ ?
TB pathogenesis alveoli ingestion by PAM’S

droplet nuclei intracellular replication

inhalation of bacilli
destruction
destruction of PAM’S of bacilli

Tubercle formation Lymphogenic spread Hilar lymph nodes

primary focus lymphangitis lymphadenitis

hematogenic spread
primary
acute hematogenic occult hematogenic
complex
spread spread

disseminated primary TB
multiple organs
remote foci
CMI TST

Figure. Pathogenesis of primary tuberculosis

 M. tuberculosis inhalation

phagocytosis by PAM bacilli dead

TB pathogenesis live bacilli

multiplies
incubation period
(2-12 weeks)
P
r
primary focus formation i
lymphogenic spread m
hematogenic spread1)
a
Primary complex2)
r
TST (+) Cell mediated immunity (+) y

T
TB disease TB infection
B
primary complex complication Optimal immunity
hematogenic spread complication
3)
lymphogenic complication

Dead

immunity 
reactivation/reinfection

Cured TB disease4)
 Alveolar Cytokine
Macrophage
Production
MIP-1
IL-8
Phagocytosis TNF-a
by Alveolar Multiplication IL-1
Macrophage IL-10
of Organisms
IL-1ra
Lysis/death IL-12
of Alveolar IL-15
Macrophage
Migration and Release of
Chemotaxis of Bacilli
Additional
Monocytes
Dendritic cell

Monocytes/
Macrophages Migration to Regional
Lymph nodes
Intracellular Killing
Antigen Specific Response

Smith S, Jacobs RF, Wilson CB. J Pediatr; 131: 16-26

 Incubation period
first implantation  primary focus
4-6 weeks (2-12 weeks)  incubation period
3 4
first weeks: logaritmic growth, : 10 -10 
elicit cellular response
end of incubation period:
primary complex formation
cell mediated immunity
tuberculin sensitivity
 PrimaryTB infection has established
Hematogenous spread
during incubation period, before TB
infection establishment:
lymphogenic spread
hematogenic spread
hematogenic spread (HS):
occult HS
acute generalized HS
protracted HS
Occult HS
most common
sporadic, small number
no immediate clinical manifestation
remote foci in almost every organ
rich vascularization: brain, liver, bones
& joints, kidney
including: lung – apex region
CMI (+): silent foci - dormant,
potential for reactivation
Acute HS
less common
large number
immediate clinical manifestation:
disseminated TB
milliary TB, meningitis TB
tubercle in same size, special
appearance in CXR
 Primary complex
end of incubation period
TB infection establishment
cell mediated immunity (CMI)
tuberculin sensitivity (DTH)
end of hematogenic spread
end of TB bacilli proliferation
small amount, live dormant in granuloma
new exogenous TB bacilli: destroyed / localized
 TB infection & TB disease
TB infection: CMI can control infection
primary complex
cell mediated immunity (CMI)
tuberculin hypersensitivity (DTH)
no clinical or radiological manifestation
TB disease: CMI failed to control TB infection
TB infection + clinical and/or radiological
manifestation
Tuberculin skin test
 Hypersensitivity type IV
delayed type hypersensitivity (DTH)
cannot transferred by serum, can be by T-cells
 cellular mediated
reflects the presence of Ag-specific CD4 T-cells
associated with protective immunity, but not a
complete correlation
three variants of DTH:
1. contact hypersensitivity
2. tuberculin type hypersensitivity
3. granulomas
 Tuberculin hypersensitivity
originally described by Koch  Koch
phenomenon
TB patients  tuberculin filtrate  fever &
generalized sickness
at the injection site, developed area of
swelling & hardening
TST is an example of the recall response to
soluble antigen previously encountered
during infection
 Tuberculin skin test (TST)
i.c. tuberculin Ag-spec Tcells IFN

macrophages

Leucocytes-receptors
TNF & IL-1

recruit cells endothelial cells

monocytes 80-90%

ICAM-1 & VCAM-1

induces, activates produces

 Mantoux TST
Mantoux : intracutan injection 0.1 ml PPD
location : volar lower arm
reading time : 48-72 h post injection
measurement : palpation, marked, measure
report : in millimeter, even ‘0 mm’
Induration diameter :
 0 - 5 mm : negative
 5 - 9 mm : doubt
 > 10 mm : positive
 Mantoux
tuberculin
skin test
 Tuberculin positive
1. TB infection :
 infection without disease / latent TB infection
 infection AND disease
 disease, post therapy
2. BCG immunization
3. Infection of Mycobacterium atypic
 Tuberculin negative

1. No TB infection
2. Anergy
3. Incubation period
 Anergy
Patient with primary complex do not give reaction
to TST due to supression of CMI :
Severe TB: miliary TB, TB meningitis
Severe malnutrition
Steroid, long term use
Certain viral infection: morbili, varicella
Severe bacterial infection: typhus abdominalis,
diphteria, pertussis
Viral vaccination: morbili, polio
Malignancy: Hodgkin, leukemia, ...
 TB classification (ATS/CDC modified)
Manage
Class Exposure Infection Disease
ment

0 - - - -

1 + - - proph I

2 + + - proph II?

3 + + + therapy
BCG vaccination
BCG vaccination deltoid ingestion by Mcrp

BCG intracellular replication

injection of bacilli
destruction
destruction of PAM’S of bacilli

tubercle formation lymphogenic spread axilla lymph nodes

primary focus lymphangitis lymphadenitis

hematogenic spread
primary
acute hematogenic occult hematogenic
complex
spread spread
CMI TST
multiple organs
disseminated primary TB remote foci

Figure. Pathogenesis of primary tuberculosis

Thank you
Lecture material
FMUI International class
Respiratory module
4th semester, Medical Sciences
 Primary & post primary TB
Primary TB :
first infection
usually in children
hematogenic spread
primary complex
tuberculin sensitivity (DTH) & CMI
infection only (class 2) or disease (class 3)
Post primary TB:
Primary & post primary TB
Primary TB :
Post primary TB:
usually in adults
no hematogenic spread
primary complex & CMI already exist
two models:
1. reinfection (new, secondary, exogenous)
2. reactivation of remote foci
(endogenous), as results of occult HS
 MHC II TCR
Naïve CD4+
Primary T Cell Expansion of Antigen Specific
IL-2
Response: T Cell Population
B7 CD28
Regional
Dendritic Cell Mycobacterial
Lymph Node Isoprenyl PO4
Macrophage/Monocyte

Memory CD4+
T Cell CD1
Secondary
ICAM-1 B7 CD28 2d2 T Cell
Mycolic Acid,
Response:
B7-1 CD40 CD40L TCR LAM
Limphoid Tissue B7-2
CD4-, CD8- T Cell
Metastatic Foci Dendritic Cell IFN
Lung Parechyma

Cytolysis
Th1, Memory CD4+ TCR MHC II
MHC I CD8+
T Cell
T Cell
CD40L CD40 Infected Cell
Activated
Macrophage
IL-2 TNF-  Mycobacterial Killing
Cytolysis IL-12
IFN
 Mycobacterial Killing
 IFN Production

Figure. The Antigen-specific, cell-mediated immune response to mycobacteria.