Granulomatous diseases

OBJECTIVES
DEFINITION
CAUSES
TYPES
PATHOGENESIS
GRANULOMATOUS
DISEASES:TB,LEPROSY,LEISHMANIA,SCHI
STOSOMIASIS,SARCOIDOSIS,ACTINOMYCO
SIS.

Definition:

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.

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.

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

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
Tuberculosis
Leprosy

Parasites

Schistosomiasis

Fungi
Histoplasmosis
Blastomycosis

Metal/Dust
Berylliosis
Silicosis

Foreign body Granulomas:

endogenous
( keratin, necrotic bone or adipose tissue uric acid crystals)

Exogenous
(wood, silica, asbestos, silicone,suture)
Specific chemicals:

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 cellmediated 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

case
atio
n

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.

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

LanghansGiantCell
Lymphocytic
Rim
CaseousNecrosis

EpithelioidMacrophage

Pathology of
Tuberculosis

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

Elicit granulomatous inflammation.

M. tuberculosis hominis & M. bovis

M. avium, M.intracellulare in AIDS Atypical TB

Infects one third of world population..!

3 million deaths due to TB every year
Under privileged population Crowding,

Poverty, malnutrition,
economic burden.

Since 1985 incidence is increasing in west

AIDS,

Diabetes, Immunosuppressed
patients, Diabetes, Drug resistance.

Tuberculosis is a chronic communicable

disease in which the lungs are the prime
target,although any organ may be
infected.

TUBERCULOSIS

Primary TB
SecondaryTB
Progressive pulmonary TB
Miliary TB

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.

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
alveolar macrophage

organism

inside

the

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)

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.

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.

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.

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.

Mature TH1 cells, both in lymph nodes

and in the lung, produce IFN-.
IFN- is the critical mediator which drives
macrophages to become competent to
contain the M. tuberculosis infection.
IFN- stimulates formation of the
phagolysosome in infected macrophages,
exposing the bacteria to an inhospitable
acidic environment.

IFN- 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.

In addition to stimulating macrophages to

kill mycobacteria, the TH1 response
orchestrates the formation of granulomas
and caseous necrosis.
Activated macrophages, stimulated by
IFN-, produce TNF, which recruits
monocytes.
These monocytes differentiate into the
"epithelioid histiocytes" that characterize
the granulomatous response

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.

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
immunocompromised patients such as AIDS patients,
elderly, and malnourished children.

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.

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 Langhans 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

Miliary pulmonary disease

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 yellowwhite consolidation scattered through the
lung parenchyma.

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.

Isolated-organ tuberculosis

May appear in any of the organs or

tissues seeded hematogenously and may
be the presenting manifestation of
tuberculosis

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

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 Most bacteria

Acid fast stain
Mycobacteria, nocardiae (modified)
Silver stains
Fungi, legionellae, pneymocytosis
Period acid-Schiff Fungi, amebae
Mucicarmine
Cryptococci
Giemsa
Campylobacteria, leishmaniae, malaria,
parasites
Antibody probes Viruses, rickettsiae
Culture
All classes
DNA probes Viruses, bacteria, protozoa
Polarizing
microscope Foreign body

Tuberculin Test

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.

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" .

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
lymphocyte-cuffed venules show marked
endothelial hypertrophy and, in some
cases, hyperplasia.

Leprosy/Hansen disease

Pathogenesis

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
34C, the temperature of the human skin

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.

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

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

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.

Morphology of Tuberculoid
leprosy

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).

Morphology of Tuberculoid
leprosy

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.

Tuberculoid leprosy

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.

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.