Chronic inflammation

By Dr. S Homathy

Chronic inflammation

• Inflammation of prolonged duration(weeks to months to year)

• In which – acute inflammation, – tissue injury and– healing • proceed simultaneously

Components of chronic inflammation

1.Acute inflammation 2.Demolition 3.Healing – repair and regeneration4.Immune response

It is characterized by

Infiltration with mononuclear (‘chronic inflammatory’) cells, including– Macrophage– Lymphocytes– Plasma cells

Tissue destruction– Largely directed by inflammatory cells

Repair – Involving new vessel proliferation( angiogenesis and fibrosis)

• 1.Acute inflammation– Evidence of acute inflammation is frequently seen

in chronic inflammationEg: pus rich in neutrophils in

osteomyelitis, pyonephrosis, chronic brain abscess: exudates rich in Eosinophils in hypersensitivity reaction

• 2.Demolition– Accomplished by macrophages derived from

emigrating monocytes of bone marrow origin

• 3.Healing – Repair • New vessel formation (angiogenesis)• Fibrosis (dense fibrosis and loss of function)

– Regeneration • Clearance of injurious stimuli• Clearance of mediators and chronic inflammatory cells • Regeneration and remodeling of damaged tissue• Normal functionEg : surface epithelia

• 4.Immune response – Very common feature is the accumulation of

lymphocytes of various types, plasma cells, and MP.

– Plasma immunoglobins levels may be elevated.

Chronic inflammation

can occur• Following acute inflamation or• Starting de novo

Differ from AI• Absence of cardinal signs• New vessel formation• No fluid exudation or oedema• Time is prolonged • Immune response • Injurious agents most often cause insidious, progressive

and often extensive tissue necrosis• Accompanied by ongoing repair by fibrosis• Specific ( immune response is activated)• Systemic response – low grade fever, weight loss, anaemia

Causes of chronic inflammation

• Viral infections – Intracellular infection of any kind require lymphocytes

and macrophages • To identify and eradicate infected cells.

• Persistent microbial infections– By some specific organismsEg: Mycobacteria, Treponema pallidum, certain fungi– Organisms are low direct pathogenicity– Typically evoke an immune response- delayed

hypersensitivity

• Persistent injury – Prolonged exposure to potentially toxic agents Eg : silica produce -silicosis of lung : chronically elevated plasma lipids- produce Atherosclerosis

• Autoimmune diseases– Immune response to self- antigen and tissuesEg: Rheumatoid arthritis / multiple sclerosis.

The Players (mononuclear phagocyte system)

• Macrophages– Scattered all over • Microglia - CNS• Kupffer cells - liver• sinus histiocytes – spleen , lymphnode• alveolar macrophages - lungs.

– Circulate as monocytes – reach site of injury within 24 – 48 hrs and

transform into large macrophages– Large MP now capable of phagocytosis

– Become activated by T cell-derived cytokines, endotoxins, and other products of inflammation

• Greater ability to kill ingested organismsLM appearance with H&E stain • Large• Flat• Pink– Similar to squamous cell ( called epithelioid

macrophages)

• After activation, MP secretes a wide variety of biologically active products

• If unchecked leads to tissue injury and fibrosis

• Mediaters from MP– Acid and neutral proteases– Complement and coagulation factors

• C1 to c5• Propedin • Coaguulation factor V and VIII

– Reactive oxygen speces and NO– AA metabolites– CK

• In CI MP accumulation persist and MP can proliferate

• lymphocytes derived factors recruit or immobilize the MP to the site of injury

• IL-4 or INF-γ– Causes MP to fuse into large, multinucleated cells • Called giant cells

• T and B lymphocytes– Antigen-activated (via macrophages and dendritic

cells)– Release macrophage-activating cytokines (in turn,

macrophages release lymphocyte-activating cytokines until inflammatory stimulus is removed)

• Plasma cells– Terminally differentiated B cells– Produce antibodies

• Eosinophils – Found especially at sites of parasitic infection, or

at– allergic (IgE-mediated) sites

• Mast cells– Participate in both acute and chronic inflammatory

responses– Armed with IgE to certain antigens

• Chronic endometritis withlymphocytes as well as plasma cells in the endometrial stroma.

• In general, the inflammatory infiltrate of chronic inflammation consists mainly of mononuclear cells ("round cells"): – lymphocytes, plasma cells, and macrophages.

Chronic cervicitis. • Prolonged acute inflammation or repeated bouts of acute inflammation may

lead to the appearance of – more mononuclear cells, – and chronic inflammation.

• In this case the inflammation is severe enough to produce mucosal damage with hemorrhage.

• Chronic inflammation can go on for a long time: – weeks to months to years.

• Seen here in the synovium from the joint of a patient with rheumatoid arthritis are– collections of dark blue lymphocytes.

Types of chronic inflammation

• Granulomatous chronic inflmmation• Non- granulomatous chronic inflammation

Granulomatous inflammation

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 Crohns disease is also associated with granulomas.

Cellular constituents of Granulomas• the predominant cell type is an activated

macrophage with a modified epithelial-like (epithelioid) appearance

• Lymphocytes.

• Occasional plasma cells

What Is A Granuloma?• 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.

– Older granulomas also develop a surrounding rim of fibroblast and connective tissue• Due to CK elaborated by the activated MP

– Frequently, but not invariably multinucleated giant cells are also found• Derived from fusion of 20 or more MP

• These are epithelioid cells around the center of a granuloma.

• They get their name from the fact that they have lots of pink cytoplasm similar to squamous epithelial cells.

• Their nuclei tend to be long and stringy

• Epithelioid cells fuse to form giant cells containing 20 or more nuclei.

• These giant cells can be found either at the periphery or the center of the granuloma

Types of giant cells

• The nuclei arranged either – Peripherally• Langhans-type giant cell(Reaction to certain organism)

– haphazardly • foreign body-type giant cell(reaction to insoluble materials)

– Nuclei enclose the central part of the homogeneous eosinophilic cytoplasm and the peripheral part of the cytoplasm is vacuolated due to its lipid content• Touton giant cell (found in xanthomas)

• MP found in Rheumatic heart disease also called caterpillar cells, as they have a large amount of clear cytoplasm surrounding a rod-shaped nucleus that to some resembles a caterpillar.

•  Larger Anitschkow cells may coalesce to form multinucleated Aschoff giant cells

• Nuclears appears as amirror image of one another– Reed-sternberg giant cell found in Hodgkin’s

lymphoma

• Fibrous connective tissue often surrounds granulomas (remodeling of tissue)

• Areas within the granuloma can undergo necrosis– prototype: caseous necrosis in tuberculosis. • Granular, cheesy

– Necrosis can lead to calcification or liquefaction and formation of a cavern if drained.

CAUSES OF GRANULOMATOUS DISEASES

Infectious causes:• Bacteria

– Tuberculosis– Leprosy(tuberculod type)– Trepanema pallidum– Brucella species

• Rickttsial organism– Coxiella burnetii

• Parasites– Schistosomiasis

• Fungi• Histoplasmosis• Blastomycosis• coccidioidomycosis

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

• unknown cause– Sarcoidosis– Crohn’s disease

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.

2. Epithelioid granuloma (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.

•Here is a foreign body type giant cell at the upper left of center •adjacent to a segment of vegetable material aspirated into the lung.• Such foreign body giant cells have nuclei scattered haphazardly about the cell

•Two foreign body giant cells are seen

•just to the right of center

•where there is a bluish strand of suture material from a previous operation

• Granulomatous disease can become quite extensive.

• Here are numerous confluent granulomas in upper lung fields in a case of active pulmonary tuberculosis.

Grossly, • a granuloma tends to be a focal lesion.• Seen here in a hilar lymph node is a granuloma. • Granulomas due to infectious agents such as

mycobacteria are often described as "caseating" when they have prominent caseous necrosis.

• The focal nature of granulomatous inflammation of lung• in which there are scattered granulomas in the

parenchyma. • This is why the chest radiograph with tuberculosis or other

granulomatous diseases is often described as "reticulonodular".

• A biopsy could miss such lesions from sampling error, too.

• Giant cells are a "committee" of epithelioid macrophages.

• Seen here are two Langhans type giant cells in which the nuclei are lined up around the periphery of the cell.

• Additional pink epithelioid macrophages compose most of the rest of the granuloma

• This is a caseating granuloma.• Epithelioid cells surround a central area of necrosis that

appears– irregular, – amorphous, and pink.

• Grossly, areas of caseation appear cheese-like

Granulomas caused by • tuberculosis and • pathogenic fungi such as 

– Histoplasma capsulatum or Cryptococcus neoformans • are often caseating.• Here, the area of caseation is seen at the upper right.

• With a poor immune response to the agents producing granulomatous inflammation,

• there can be extensive spread of infection • with the production of a "miliary" pattern of granulomas, • as seen here in the lung of a patient with miliary tuberculosis.• The 1 to 2 mm granulomas are scattered around like millet seeds

(millet is a type of cereal grain).

Types of chronic inflammation

• Granulomatous chronic inflmmation• Non- granulomatous chronic inflammation

Non- granulomatous chronic inflammation

• Characterized by the accumulation of – sensitized lymphocytes (activated by antigen)– Plasma cells– MP • In the injured area

• These cells are scattered diffusely throughout the tissue.

• Do not form granuloma.

• Scattered tissue necrosis and fibrosis are common.

Causes of non- granulomatous chronic inflammation

1. Characterized by lymphocytes and plasma cell infiltration of tissues with cell necrosis and fibrosis– Chronic viral infection• Chronic viral hepatitis• Chronic viral infection of CNS

– Autoimmune diseases• Chronic ulcerative colitis• Hashimoto’s thyroiditis

– Chronic alcoholic liver disease and pancretitis

2. Characterized by diffuse accumulation of MP with intracytoplasmic microorganisms, deficient T cell response– Lepromatous leprosy– Leishmaniasis

3.Characterized by presence of numerous eosinophils in conjuction with other inflammatory cells– Type I hypersensitivity reactions• BA• Atopic dermatitis

• Certain etiologic agents such as viruses are more likely to lead to chronic inflammation,

• as seen here in the lung of a patient with influenza A.• the inflammatory infiltrates of chronic inflammation are more likely to be

interstitial (within tissues)• rather than exudative (above surfaces or in spaces) like acute inflammation.

• You can find both acute and chronic inflammation here. • This type of mixed inflammation is typical of repeated or recurrent

inflammation.• Examples

– "acute and chronic cholecystitis" or – "acute and chronic cervicitis".

• The best possible outcome following an inflammatory process is complete resolution, – leaving the tissues intact and undamaged.

• However, chronic inflammation may occur in conjunction with some degree of scarring.

• Here, chronic inflammation of the bronchi has led to dilation and scarringwith increased tan to white collagenous tissue.

• Chronic inflammation with destruction of the bronchial wall is seen here.

• An inflammatory infiltrate extends from the lumen to the left.

• An abscess may have elements of chronic inflammation if it persists for some time.

• Thus, it is possible to have a "chronic abscess" with elements of both acute and chronic inflammation.

• Seen here in the right middle lung lobe is just such a chronic abscess.

Healing

Repair • By formation of granulation tissue• Contain variety of cells– Endothelial cells forming blood and lymphatic

vessels–Myofibroblast (fibroblast )forming collagen– Astrocytes forming a glial scar in the CNS– Small round cells- lymphocytes and plasma cells

• Healing of inflammation often involves in growth of capillaries and fibroblasts.

• This forms granulation tissue.• Here, an acute myocardial infarction is seen healing. • There are numerous capillaries, and collagen is being laid

down to form a scar.• Non-infarcted myocardium is present at the far left.

• These features are all seen in chronic inflammation

• In chronic suppuration the puss-filled cavity is lined by acutely inflamed granulation tissue.– This is the pyogenic membrane

• Vascularity of the granulations predisposes to haemorrhage

Eg: repeated haemorrhage is frequent in chronic peptic ulcer

Microscopically,• this abscess has a mixture of inflammatory cells,

• but the wall of the abscess is "organizing" with ingrowth of capillaries (filled with red blood cells) and fibroblasts.

• As organization continues there is resolution with decreasing size of the abscess, until only a scar remains.

• If the body's defensive systems cannot contain the agent causing the abscess, then the process may continue and even spread

• The wall of an abscess that is organizing has granulation tissue, at the left.

• The purulent exudate with some hemorrhage is seen at the right in the abscess center.

• At high magnification, granulation tissue has–  capillaries,fibroblasts, and a variable amount of

inflammatory cells (mostly mononuclear, but with the possibility of some PMN's still being present).

• Fibrosis is a salient features of chronic inflamation

• The resulting cicatrisation leads to many of the importanat complications of CI

Eg: MS and MR following chronic rheumatic valvulitis

: Pyloric stenosis chronic gastric ulcer

• The end result of inflammation can be scarring. • The alveolar walls are thickened and filled

with pink collagen following an autoimmune disease lasting for decades.

• This is a healing biopsy site on the skin seen a week following the excision,

• The skin surface has re-epithelialized, and• below this is granulation tissue with

– small capillaries and fibroblasts forming collagen.• After a month, just a small collagenous scar will remain.

Effects of chronic inflammation

General effects• Hyperplasia of mononuclear phagocytic

system Eg : lymph nodehyperplasia : hepatomegaly :spleenomegaly – in chronic malaria, SAIE

:marrow hyperplasia

Systemic immune response• Antibody production is a feature of most

chronic inflammatory disease– Demonstration of specific immunogloulins is a

useful diagnostic procedure • Cell – mediated immune response– Delayed hypersensitivity reactionEg : tuberculin, lepromin, Frei are based upon this.

• Cell- mediated hypersensitivity itself results in tissue damage.

• Long –continued stress on the antibody producing mechanism may be associated amyloid disease.

Changes in the blood • Anaemia- normochromic, normocytic type.• Reduction of plasma albumin• Increase gamma globulin• Increase ESR

Mechanism Of granuloma formation

• 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),– 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

Pathology of Tuberculosis

Etiology and incidenceCharacteristics of mycobacteria• 2-10micrometer in length.• Structurally gram positive but also contains large 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, Drug resistance.

• Tuberculosis is a chronic communicable disease in which the lungs are the prime target,

• although any organ may be infected.

• 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

• 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)

• The lytic enzymes of the activated macrophages is released, also damaged host tissues.

• This activation of macrophages and destruction of mycobacteria comprises the cell mediated immunity.

• 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.

• 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.

• 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

• 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

• 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

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

• With progressive pulmonary tuberculosis,– the pleural cavity is invariably involved, and • serous pleural effusions, • tuberculous empyema, • obliterative fibrous pleuritis may develop.

Secondary 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 Langhan’s type giant cells.

• Other clinicopathologic forms of secondarytuberculosis depends on the organ involved• 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 bacteria in the larynx ---

– hoarseness

Miliary tuberculosis

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 yellow-white 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.

Miliary tuberculosis is most prominent in :• the liver,• bone marrow,• spleen, • adrenals, • meninges,• kidneys, • fallopian tubes, • epididymis

Isolated-organ tuberculosis

• May appear in any of the organs or tissues seeded hematogenously and

• may be the presenting manifestation of tuberculosis

• 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

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.

Special technique for diagnosing infectious agents

Gram stain Most bacteriaAcid fast stainMycobacteria, nocardiae (modified)Silver stains Fungi, legionellae, pneymocytosisPeriod acid-Schiff Fungi, amebaeMucicarmine CryptococciGiemsa Campylobacteria, leishmaniae, malaria, parasitesAntibody probes Viruses, rickettsiaeCulture All classesDNA probes Viruses, bacteria, protozoa

Polarizingmicroscope 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

• 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

• 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

• Leprosy has two strikingly different patterns of disease.

1)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.

• 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).

• 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.

• 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.