Transcript GRANULOMATOUS INFLAMMATION

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OBJECTIVES
DEFINITION
CAUSES
TYPES
PATHOGENESIS
GRANULOMATOUS
DISEASES:TB,LEPROSY,LEISHMANIA,SCHIS
TOSOMIASIS,SARCOIDOSIS,ACTINOMYCO
SIS.
Definition:
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Granulomatous inflammation is a distinctive
pattern of chronic inflammatory reaction.
It is a protective response to chronic infection or
foreign material, preventing dissemination and
restricting inflammation.
Some autoimmune diseases such as rheumatoid
arthritis and Crohns disease are also associated
with granulomas.
Granulomas
the predominant cell type is an activated macrophage
with a modified epithelial-like (epithelioid) appearance
Lymphocytes.
Occasional plasma cells.
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A granuloma is a microscopic aggregation of
macrophages that are transformed into
epithelium-like cells surrounded by a collar of
mononuclear leukocytes, principally
lymphocytes and occasionally plasma cells.
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Epithelioid cells fuse to form giant cells
containing 20 or more nuclei.
The nuclei arranged either peripherally
(Langhans-type giant cell) or
haphazardly (foreign body-type giant cell).
These giant cells can be found either at the
periphery or the center of the granuloma.
Slide 3.41
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Fibrous connective tissue often
surrounds granulomas (remodeling of
tissue)
Areas within the granuloma can
undergo necrosis (prototype: caseous
necrosis in tuberculosis). Necrosis can
lead to calcification or liquefaction
and formation of a cavern if drained.
Infectious causes:
 Bacteria
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Tuberculosis
Leprosy
Parasites
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Schistosomiasis
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Fungi
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Histoplasmosis
Blastomycosis
Metal/Dust
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Berylliosis
Silicosis
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Foreign body Granulomas:
endogenous
( keratin, necrotic bone or adipose tissue uric acid crystals)
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Exogenous
(wood, silica, asbestos, silicone,suture…)
Specific chemicals:
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Beryllium
Sarcoidosis (unknown cause)
Type of granulomas:
1.
Foreign body granulomas – form when
material such as talc, sutures, or other fibers
are large enough to preclude phagocytosis by
a single macrophage.
Immune granulomas - caused by insoluble particles that
are capable of inducing a cell-mediated response. This
type of immune response produces granulomas when
the inciting agent is poorly soluble or particulate.
Macrophages engulf the foreign material and process
and present some of it to appropriate T lymphocytes,
causing them to become activated, responding T cells
produce cytokines, such as IL-2 which activates other T
cells and IFN- which is important in transforming
macrophages into epithelioid cells and multinucleate
giant cells.
Foreign body aspiration
Berrylliosis
casea
tion
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The classic example for the immune granuloma is that
caused by the bacillus of tuberculosis. In this disease,
the granuloma is referred to as a tubercle and is
classically characterized by the presence of central
caseous necrosis. Caseating necrosis is rare in other
granulomatous diseases.
There are many atypical presentations that it is always
necessary to identify the specific etiologic agent by:
special stains for organisms (acid-fast stains for
tubercle bacilli), culture methods (tuberculosis, fungal
disease), and serologic studies (syphilis). In sarcoidosis,
the etiologic agent is unknown.
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Granuloma:
bacilli are inhaled by droplets
Bacteria are phagocytosed by alveolar
macrophages
After amassing substances that they cannot
digest, macrophages lose their motility,
accumulate at the site of injury and
transform themselves into nodular
collections; the Granuloma
A localized inflammatory response recruits
more mononuclear cells
The granuloma consists of a kernel of
infected macrophages surrounded by foamy
macrophages and a ring of lymphocytes and
a fibrous cuff (containment phase)
Containment usually fails when the
immune status of the patient changes; the
granuloma caseates, ruptures and spills into
the airway
Langhans Giant Cell
Lymphocytic
Rim
Caseous Necrosis
Epithelioid Macrophage
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Pathology of Tuberculosis
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2-10micrometer in length.
Struntrually gram positive but also
containslarge amount of lipids in the cell
wall:making them acid fast.
No toxins
No spores
Obligate Aerobic
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Elicit granulomatous inflammation.
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M. tuberculosis hominis & M. bovis
M. avium, M.intracellulare in AIDS - Atypical
TB
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Infects one third of world population..!
3 million deaths due to TB every year
Under privileged population 
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Crowding, Poverty, malnutrition,
economic burden.
Since 1985 incidence is increasing in west
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AIDS, Diabetes, Immunosuppressed
patients, Diabetes, Drug resistance.
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Tuberculosis is a chronic communicable
disease in which the lungs are the prime
target,although any organ may be infected.
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Primary TB
SecondaryTB
Progressive pulmonary TB
Miliary TB
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PATHOGENESIS
The course of tuberculosis depends on age and
immune competence AND total burden of
the organisms
Tuberculous Infection: refers to growth of the
organism in a person,whether there is
symptomatic disease or not.
Active Tuberculosis; refers to infection
manifested by tissue destruction----symptomatic disease.
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Primary tuberculosis is the form of disease that
develops in a previously unexposed and
unsensitized person.
Tuberculosis is a type of delayed tissue
hypersensitivity to the tuberculous bacillus which
elicit a cell-mediated immune response which will
resists the growth and spread of the
mycobacterium.
This hypersensitivity reaction produces the
pathologic
feature
of
tuberculosis
in
immunocompetent individuals, i.e. granulomas,
caseation, cavity formation.
The sequence of events which occur after
inhalation of infectious agent in a previously
unexposed immunocompetent individual are:
The mycobacterium will gain access to the
alveolar
macrophage through receptors.
* Once the organisms are inside the cytoplasm
of the macrophage it will inhibit the
microbicidal response of the macrophage
(ineffective phagolysosome).
Multiplication of the organism inside the alveolar
macrophage
processing& presentation of the antigen on the
surface
A clone of sensitized T-cells proliferate, produce
gamma INT.
Activation of the macrophages(augmenting
their capacity to kill mycobacteria)
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The lytic enzymes of the activated
macrophages if released, also damaged host
tissues.
This activation of macrophages and destruction
of mycobacteria comprises the cell mediated
immunity.
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M. tuberculosis enters macrophages
Once inside the macrophage, M. tuberculosis
replicates within the phagosome by blocking
fusion of the phagosome and lysosome.
Thus the earliest stage of primary tuberculosis
(<3 weeks) in the nonsensitized individual is
characterized by proliferation of bacteria in the
pulmonary alveolar macrophages and
airspaces, with resulting bacteremia and
seeding of multiple sites.
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About 3 weeks after infection, a TH1 response
against M. tuberculosis is mounted that activates
macrophages to become bactericidal.
TH1 cells are stimulated by mycobacterial
antigens drained to the lymph node.
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About 3 weeks after infection, a TH1 response
against M. tuberculosis is mounted that activates
macrophages to become bactericidal.
TH1 cells are stimulated by mycobacterial
antigens drained to the lymph node.
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Mature TH1 cells, both in lymph nodes and in
the lung, produce IFN-γ.
IFN-γ is the critical mediator which drives
macrophages to become competent to contain the M.
tuberculosis infection.
IFN-γ stimulates formation of the
phagolysosome in infected macrophages,
exposing the bacteria to an inhospitable acidic
environment.
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IFN-γ also stimulates expression of inducible
nitric oxide synthase (iNOS), which produces
nitric oxide (NO). NO helps in the destruction
of several mycobacterial constituents, from cell
wall to DNA.
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In addition to stimulating macrophages to kill
mycobacteria, the TH1 response orchestrates the
formation of granulomas and 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
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In immunocompromised persons granulomas
are poorly formed or not formed at all and the
infection progress at the primary site in the
lung ,lymph nodes or in multiple sites--------progressive primary tuberculosis.
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Is characterized by:
Ghon Focus ----lung lesion of primary
TB,involves upper segments of the lower lobes
or lower seg.of the upper lobe.
Ghon complex----- combination of a peripheral
ghon focus and involved mediastinal or hilar
lymphnode.
Microscopically the classic lesion of TB is a
caseous granuloma
Clinical and pathologic implications of primary
tuberculosis
1] Development of resistance to the infection.
2] The foci of scarring may harbor viable
bacilli for life and act as a nidus for
reactivation.
3] The
disease
may
develop
into
progressive
primary tuberculosis in
immunocompro- mised patients such as
AIDS patients,
elderly, and malnourished
children.
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In patients with progressive primary
tuberculosis, the tissue reaction is different.
No well-formed granulomatous reaction or
caseation necrosis is seen in tissue affected.
Resembles acute bacterial pneumonia with
lower and middle lobe consolidation, pleural
effusion and hilar lymphadenopathy.
Cavitary lesions are rare.
Disseminated
disease
with
tuberculous
meningitis and miliary tuberculosis.
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Is the pattern of disease that arises in a
previously sensitized host.
Is usually a reactivation of dormant primary
lesions when the host resistance is lowered.
Or exogenous reinfection by a high dose of
virulent bacilli which occur more commonly in
endemic areas.
Only 5% of patients with primary disease
develop secondary tuberculosis.
Pathologic features of secondary tuberculosis:
 In secondary pulmonary tuberculosis, the
lesions involves the apices of both lungs and
appear grossly as sharply circumscribed firm
areas with central caseation and cavitation
surrounded by fibrous wall.
 It can heal by fibrosis leaving a residual apical
scar.
 Histologically, epithelioid granulomas with
central caseation and Langhan’s type giant
cells.
Other clinicopathologic forms of secondary
tuberculosis depends on the organ involved and
Includes
Cough,low grade fever wt.loss, anorxia
Cavitaton may be accompanied by haemoptysis
Chest radiographs show unilateral or bilateral apical
cavities.
Complications of secondary TB
Scarring &calcification
Spread to other areas
Pleural fibrosis&adhesions
Rupture of caseous lesion
Implantation of bacteriain the larynx --hoarseness
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Occurs when organisms drain through
lymphatics into the lymphatic ducts, which
empty into the venous return to the right side
of the heart and thence into the pulmonary
arteries.
Individual lesions are either microscopic or
small, visible (2-mm) foci of yellow-white
consolidation scattered through the lung
parenchyma.
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Miliary lesions may expand and coalesce to
yield almost total consolidation of large regions
or even whole lobes of the lung.
With progressive pulmonary tuberculosis, the
pleural cavity is invariably involved, and
serous pleural effusions, tuberculous
empyema, or obliterative fibrous pleuritis
may develop.
Miliary tuberculosis is most prominent in :
 the liver,
 bone marrow,
 spleen,
 adrenals,
 meninges, kidneys, fallopian tubes, and
epididymis.
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May appear in any of the organs or tissues
seeded hematogenously and may be the
presenting manifestation of tuberculosis
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Organs that are typically involved include the
meninges (tuberculous meningitis), kidneys
(renal tuberculosis), adrenals (formerly an
important cause of Addison disease), bones
(osteomyelitis), and fallopian tubes
(salpingitis).
When the vertebrae are affected, the disease is
referred to as Pott's disease.
Paraspinal "cold" abscesses in these patients
may track along the tissue planes to present as
an abdominal or pelvic mass
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Lymphadenitis is the most frequent form of
extrapulmonary tuberculosis, usually occurring
in the cervical region ("scrofula").
Intestinal tuberculosis contracted by the
drinking of contaminated milk.
In developed countries today, intestinal
tuberculosis is more often a complication of
protracted advanced secondary tuberculosis,
secondary to the swallowing of coughed-up
infective material.
Adrenal TB - Addison Disease
Spinal TB - Potts Disease
Diagnosis of TB
Clinical features are not confirmatory.
Zeil Nielson Stain - 1x104/ml, 60%
sensitivity
Release of acid-fast bacilli from cavities
intermittent.
3 negative smears to assure low
infectivity*
Culture most sensitive and specific test.
Conventional Lowenstein Jensen
media 3-6 wks.
Automated techniques within 9-16
days
PCR is available, but should only be
performed by experienced laboratories
PPD for clinical activity / exposure
sometime in life.
AFB - Ziehl-Nielson stain
Colony Morphology – LJ Slant
Bacterial
Tuberculosis (Mycobacterium tuberculosis)
Leprosy (Mycobacterium leprae)
Syphilitic gumma (Treponema pallidum)
Parasitic
Schistosomiasis (Schistosoma mansoni, S. haematobium,
S. japonicum)
Fungal
Histoplasma capsulatum
Blastomycosis
Cryptococcus neoformans
Coccidiodes immitis
Inorganic Metals or Dusts
Silicosis
Berylliosis
Foreign Body
Suture, breast prosthesis, vascular graft
Unknown
Sarcoidosis
Gram stain
Acid fast stain
(modified)
Silver stains
Period acid-Schiff
Mucicarmine
Giemsa
Most bacteria
Mycobacteria, nocardiae
Antibody probes
Culture
DNA probes
Fungi, legionellae, pneymocytosis
Fungi, amebae
Cryptococci
Campylobacteria, leishmaniae, malaria,
parasites
Viruses, rickettsiae
All classes
Viruses, bacteria, protozoa
Polarizing
microscope
Foreign body
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It is a classic example of delayed
hypersensitivity.
The tuberculin reaction, is produced by the
intracutaneous injection of tuberculin, a
protein-lipopolysaccharide component of the
tubercle bacillus.
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In a previously sensitized individual,
reddening and induration of the site appear in
8 to 12 hours, reach a peak in 24 to 72 hours,
and thereafter slowly subside.
Morphologically, delayed type hypersensitivity
is characterized by the accumulation of
mononuclear cells around small veins and
venules, producing a perivascular "cuffing" .
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Plasma proteins escape, giving rise to dermal
edema and deposition of fibrin in the
interstitium.
The latter appears to be the main cause of
induration, which is characteristic of delayed
hypersensitivity skin lesions.
In fully developed lesions, the lymphocytecuffed venules show marked endothelial
hypertrophy and, in some cases, hyperplasia.
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Leprosy/Hansen disease
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M. leprae is an acid-fast obligate intracellular
organism that grows very poorly in culture.
It grows more slowly than other mycobacteria
and grows best at 32° to 34°C, the temperature
of the human skin
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Is a slowly progressive infection caused by
Mycobacterium leprae, affecting the skin and
peripheral nerves and resulting in disabling
deformities.
M. leprae is likely to be transmitted from
person to person through aerosols from lesions
in the upper respiratory tract.
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Inhaled M. leprae, like M. tuberculosis, is taken
up by alveolar macrophages and disseminates
through the blood, but grows only in tissues of
the skin and extremities.
leprosy remains endemic among an estimated
10 to 15 million people living in poor tropical
countries
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Like M. tuberculosis, M. leprae secretes no toxins,
and its virulence is based on properties of its
cell wall.
The cell wall is similar enough to that of M.
tuberculosis.
Cell-mediated immunity is reflected by
delayed type hypersensitivity reactions to
dermal injections of a bacterial extract called
lepromin
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1)
Leprosy has two strikingly different patterns of
disease.
Patients with the less severe form, tuberculoid
leprosy, have dry, scaly skin lesions that lack
sensation. They often have large, asymmetric
peripheral nerve involvement.
The more severe form of leprosy, lepromatous
leprosy, includes symmetric skin thickening and
nodules. This is also called anergic leprosy,
because of the unresponsiveness (anergy) of
the host immune system.
In lepromatous leprosy, damage to the nervous
system comes from widespread invasion of the
mycobacteria into Schwann cells and into
endoneural and perineural macrophages.
- In advanced cases of lepromatous leprosy, M.
leprae is present in sputum and blood.
3- People can also have intermediate forms of
disease, called borderline leprosy.
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Begins with localized skin lesions that are first
flat and red but enlarge and develop irregular
shapes with indurated, elevated,
hyperpigmented margins and depressed pale
centers (central healing).
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Neuronal involvement dominates tuberculoid
leprosy.
Nerves become enclosed within granulomatous
inflammatory reactions.
Nerve degeneration causes skin anesthesias
and skin and muscle atrophy that render the
patient liable to trauma of the affected parts,
with the development of indolent skin ulcers.
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Contractures, paralyses, and autoamputation
of fingers or toes may ensue.
Facial nerve involvement can lead to paralysis
of the eyelids, with keratitis and corneal
ulcerations.
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On microscopic examination, all sites of
involvement disclose granulomatous lesions
closely resembling those found in tuberculosis,
and bacilli are almost never found.
The presence of granulomas and absence of
bacteria reflect strong T-cell immunity.