12-07 tb immunopathogenesis
DESCRIPTION
gggTRANSCRIPT
Darmawan Budi Setyanto, MD
Born: 11 April 1961
Education: Medical Doctor, Faculty of Medicine, University of Indonesia, 1986 Pediatrician, Faculty of Medicine, University of Indonesia, 1997 Respirology Consultant, 2005
Current position : Head of Respirology Division, Dept of Child Health, Faculty of
Medicine, University of Indonesia
Organization: Chairman of Respirology Coordination Working Unit, Indonesian
Pediatric Society
Darmawan B Setyanto Respirology Division, Department of Child HealthFaculty of Medicine, University of Indonesia
Tuberculosis immunopathoge
nesis
TB, how old?
Why TB is so strong?
04/11/2023 4
TB, strong & robust Nature of the bacilli Very complex & special pathogenesis Very effective & efficient transmission Difficult diagnosis, especially in children Multiple drug Only clinical cure but not bacteriological cure, Drug side effect, no better new drug yet Long term therapy No effective prevention - immunization Sub-standard management MDR, XDR, HIV, … etc Not medical problem only …
symptomatology
pathophysiology
pathology
insults
adaptiveresponse
Medical problem process
Dia
gnosis &
Treatm
ent
pathogenesis
TuberculosisThe reaction of the immune
system of the human host to the presence and multiplication of Mycobacterium tuberculosis or Mycobacterium bovis
symptomatology
pathophysiology
granuloma
M tb
CMI
Tuberculosis process Dia
gnosis &
Treatm
ent
pathogenesis
source
symptomatology
pathophysiology
granuloma
M tb
CMI
Tuberculosis process Dia
gnosis &
Treatm
ent
pathogenesis
source
Etiology Mycobacterium tuberculosis Mycobacterium bovisCharacteristics : live in weeks in dry condition no endotoxins, no exotoxins hematogenic spread grows slowly (24-32 hr) non specific clinical manifestation aerob, organ predilection - lung 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 & lower lobes
Location of primary focus in 2,114 cases, 1909-1928
Location %Lung 95.93Intestine 1.14Skin 0.14Nose 0.09Tonsil 0.09Middle ear (Eustachian tube) 0.09Parotid 0.05Conjunctiva 0.05Undetermined 2.41
lymphadenitis
lymphangitis
primary focus
TB pathogenesis
TB pathogenesis
Figure. Pathogenesis of primary tuberculosis
droplet nuclei inhalation
alveoli ingestion by PAM’S
intracellular replication destruction
of bacillidestruction
of PAM’S
hematogenic spread
multiple organs remote foci
disseminated primary TB
acute hematogenic spread
occult hematogenic spread
primary focus lymphangitis lymphadenitis
primary complex
TSTCMI
Lymphogenic spreadTubercle formation Hilar lymph nodes
M tb bacilli
Phagocytosisby alveolar
macrophage
Multiplicationof organisms
Cytokineproduction:
MIP-1IL-8
TNF-IL-1, IL-1raIL-10, IL-12,
IL-15
Lysis/deathof alveolar
macrophage
Release ofbacilli
Dendritic cell
Monocytes/macrophages
Antigen specific response
Migration to reg lymph nodesIntracellular killing
Migration &chemotaxis ofadd monocytes
Smith S, Jacobs RF, Wilson CB. J Pediatr; 131: 16-26
M. tuberculosis inhalation
phagocytosis by PAM
live bacilli
multipliesprimary focus formation
lymphogenic spreadhematogenic spread1)
Primary complex2)
Cell Mediated Immunity (+)TST (+)
incubation period(2-12 weeks)
Pri
mary
TB
3)primary complex complication
hematogenic spread complicationlymphogenic complication
TB disease
Dead
TB infection
Cured TB disease4)
immunity reactivation/reinfection
bacilli deadTB pathogenesi
s
Optimal immunity
Incubation period first implantation primary focus 4-6 weeks (2-12 weeks) incubation
period first weeks: logaritmic growth, : 103-
104 elicit cellular response end of incubation period:
o primary complex formationo cell mediated immunity o tuberculin sensitivity PrimaryTB infection has established
Hematogenic spread
during incubation period, before TB infection establishment: o lymphogenic spread o hematogenic spread
hematogenic spread (HS):o occult HSo acute generalized HSo 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
Acute HS less common large number immediate clinical
manifestation: disseminated TB
miliary 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
04/11/2023 22
TB infection & TB diseaseTB infection: CMI can control
infectionoprimary complex (+)o cell mediated immunity (+), strongo tuberculin sensitivity - DTH (+)o limited amount of TB bacilli,
controlledoNO clinical or radiological
manifestation TB disease: CMI can’t control TB
infectionoTB infection with weak CMI (or
strong bacilli)oWITH clinical & radiological
manifestation
04/11/2023 23
TB infection
TB CMI
TB CMI
04/11/2023 24
TB disease
TB
CMI
TB CMI
TB classification
TB class
Exposure
(contact+)
Infection
(Mantoux+)
Disease (sympto
m+)Explanatio
n
0 - - - Not TB
1 + - - Exposed, Not
infected
2 + + - Infected, No disease
3 + + + TB disease AJRCCM 2000, ATS Diagn standr & classf - modified
symptomatology
pathophysiology
pathology
insults
adaptiveresponse
Tuberculosis class 1 Dia
gnosis &
Treatm
ent
pathogenesis
source
TST -
+
TB classification
TB class
Exposure
(contact+)
Infection
(Mantoux+)
Disease (sympto
m+)Explanatio
n
0 - - - Not TB
1 + - - Exposed, Not
infected
2 + + - Infected, No disease
3 + + + TB disease AJRCCM 2000, ATS Diagn standr & classf - modified
symptomatology
pathophysiology
pathology
insults
adaptiveresponse
Tuberculosis class 2 Dia
gnosis &
Treatm
ent
pathogenesis
source +
TST +
-
-
+
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 hypersensitivity2. tuberculin type hypersensitivity3. 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. tuberculi
n
Ag-spec Tcells IFN
macrophages
TNF & IL-1
ICAM-1 & VCAM-1
Leucocytes-receptors
recruit cells monocytes
80-90%
Endothelial cells
induces, activates produces
Mantoux TSTMantoux : intracutan injection 0.1
ml PPDlocation : volar lower armreading time : 48-72 h post injectionmeasurement : palpation, marked,
measurereport : in millimeter, even ‘0 mm’Induration diameter :
0 - 5 mm : negative 5 - 9 mm : positive, weak > 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??
TST resultReading Induratio
n Interpretation
Negative
0 – 4mm
• NO TB infection• Incubation period• Anergy
Positive, weak
5 – 9mm
• Atypical M infection• BCG• Natural TB infection• Technical error
Positive 10- 14mm
• Natural TB infection• BCG• Atypical M infection
>15mm
• Natural TB infection, most likely
AnergyPatient 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, ...
BCG vaccination
BCG vaccination
Figure. Pathogenesis of primary tuberculosis
BCG i.c.injection
deltoid ingestion by macroph
intracellular replication destruction
of bacillidestruction
of PAM’S
hematogenic spread
multiple organs remote foci
disseminated primary TB
acute hematogenic spread
occult hematogenic spread
primary focus lymphangitis lymphadenitis
primary complex
TSTCMI
Lymphogenic spreadTubercle formation Axilla lymph nodes
Thank you
Presented as:
Lecture material FMUI, regular & international
class Respiratory module 4th semester, Medical Sciences Wed, 04 Jul 12, 08-09
M tb bacilli
Phagocytosisby alveolar
macrophage
Multiplicationof organisms
Cytokineproduction:
MIP-1IL-8
TNF-IL-1, IL-1raIL-10, IL-12,
IL-15
Lysis/deathof alveolar
macrophage
Release ofbacilli
Dendritic cell
Monocytes/macrophages
Antigen specific response
Migration to reg lymph nodesIntracellular killing
Migration &chemotaxis ofadd monocytes
Smith S, Jacobs RF, Wilson CB. J Pediatr; 131: 16-26