ijd3850650

Review
Leprosy: pathogenesis updated
Jorge Abulafia, MD, and Raúl A. Vignale, MD

From the Department of Dermatology, University of Buenos Aires

School of Medicine, Buenos Aires, Argentina, and The Department of
Dermatology, University of the Republic, Montevideo, Uruguay

Correspondence
Jorge Abulafia, MD, Callao 1323, (1023) Buenos Aires, Argentina

Introduction two-way mechanism persists. In our experience, the cellular

basis may be a dual response of macrophages based on
Leprosy is a chronic infectious disease caused by
their origin. In Mitsuda-positive patients, these cells form
Mycobacterium leprae, which can express itself in different
epithelioid granulomas, but in Mitsuda-negative patients
clinico-pathologic forms, with a Mitsuda reaction-
they produce virchowcytic granulomas. In the latter, the
dependent bipolar distribution. A spherical model of
lepra cells or virchowcytes are macrophages that, having
leprosy (Fig. 1) shows two hemispheres and an equatorial
partially digested the bacillar phospholipids, lead to a
zone. The tuberculoid hemisphere, with variably positive
metabolic disease (tesaurismosis).6
Mitsuda reaction, includes polar (TT) and subpolar (Tt)
The invading M. leprae has three main targets: peripheral
tuberculoid leprosy, and macular (Tm), maculoanesthetic
neural tissues (Schwann cells), small vessels (endothelial
(Mal), and low resistant (Lrtl) tuberculoid leprosy. The
cells and pericytes), and the monocyte–macrophage system.
lepromatous hemisphere, with negative Mitsuda reaction,
includes polar (LL) and subpolar (sLL) lepromatous leprosy. The bacilli may survive and replicate within the Schwann
At the equator, intermediate variants may develop: cells and secondarily penetrate the perineural tissues (peri-
Mitsuda-positive borderline tuberculoid (BT), Mitsuda- neural granulomas). They may also thrive within endothel-
negative borderline lepromatous (BL) and borderline bor- ial cells and pericytes and be released to induce bacteremia
derline (BB) leprosy. (Fig. 2).7,8
Histopathologically, at the tuberculoid hemisphere, cell- Macrophages have always been relevant in leprosy.9 By
mediated immunity prevails and epithelioid granulomas the mid-1800s, lepra cells or virchowcytes were discovered
with scarce or no bacilli predominate. At the lepromatous and, as a result, lepromatous granulomas became the
hemisphere, a specific inflammation represented by lepro- histopathologic landmarks of lepromatous leprosy. In this
matous granulomas or virchowcytic granulomas, con- century, the epitheloid granulomas, with epithelioid cells
taining modified macrophages called lepra cells or and Langhans cells, were described; when associated with
virchowcytes, is seen. In borderline leprosy, both types of peripheral neuritis, these lesions imply tuberculoid leprosy.
granulomas may coexist, not infrequently with modified Both lepra cells and epithelioid cells are modified macro-
epithelioid or lepra cells. Indeterminate leprosy (IL) reveals phages.
lymphocytic infiltrates, perhaps related to immune mechan- Blood monocytes from Mitsuda-positive and Mitsuda-
isms that precede the development of tuberculoid granul- negative patients cultured with M. leprae have demon-
omas and epidermal lichenoid reactions, or the appearance strated that, in both instances, monocytes may phagocytose
of only a few lepra cells, with no epidermal lesions; all bacilli; however, in tuberculoid leprosy, the organisms
both types of indeterminate leprosy are associated with may be totally destroyed, while in lepromatous leprosy,
perineuritis. microvacuolated monocytes (phagocytes) with bacillar deb-
This thorough classic classification (Fig. 1) has been ris may persist.10–13
replaced by a simpler and briefer one that considers two The inoculation of M. leprae in high concentration to
polar (TT, LL) and several borderline forms. Since then, leprosy patients has shown that, although in tuberculoid
the spectrum of leprosy as a continuum, with transitions leprosy, granulomas tend to be epithelioid, in lepromatous
in either direction, has been accepted.1–5 The notion of a leprosy, only foreign-body granulomas may be seen. In 321

© 1999 Blackwell Science Ltd International Journal of Dermatology 1999, 38, 321–334
322 Review Leprosy: pathogenesis updated Abulafia and Vignale

Figure 1 (A) M. leprae with a thick cellular wall, enveloped in a phosphoglycolipid layer, as seen in degenerated or aged
bacilli, biochemically similar to the lipids of lepra cells. This material is probably related to the phenolic glycolipid-1 (specific
PGL-1 antigen) that may be detected in bacilli and Virchow cells. (B) Spherical model showing the human substrate and its
variations in the development of different clinico-pathological forms of leprosy, which may be classified in two large
hemispherical polar groups

tuberculoid leprosy, a specific response, probably related T (c-s) lymphocytes (cytotoxic suppressor) may co-operate
to cell-mediated immune mechanisms, may occur.14,15 in tuberculoid leprosy, but may play their most significant
Genetic research has confirmed the bipolarity of leprosy. role in lepromatous leprosy.
The study of human leukocyte antigens (HLAs) and proteins All cell-mediated and humoral immune response require
encoded by major histocompatibility complex (MHC)- ‘‘starting cells;’’ these antigen presenting cells (APCs)
linked genes has revealed the predominance of MHC class express the antigenic information on their surface and, in
II: HLA-DR3 in tuberculoid leprosy, and of MHC class concert with MHC, initiate the immune cascade. Several
II: HLA-DQ1 in lepromatous leprosy. In certain cases, APCs, such as Langerhans cells, follicular dendritic cells,
however, MHC class I may also be expressed and induce interdigitating dendritic cells, and normal macrophages,
CD8⫹ T-lymphocyte clones. In patients with type 2 (eryth- are related to the monocyte–phagocyte system. In leprosy,
ema nodosum leprosum) and type 3 (Lucio phenomenon) normal macrophages may be of the utmost importance, as
reactions, MHC class III: C4BQ0, may be detected.16 ‘‘Mitsuda-positive’’ or ‘‘Mitsuda-negative’’ clones of these
The phenotype analysis has shown interleukin 2 (IL-2) cells may evolve into different APCs, associated with cell-
and interferon gamma (IFN-γ) as markers of cell-mediated mediated or humoral immunity, respectively.
immunity in tuberculoid leprosy, and interleukin 4 (IL-4) In our opinion, the ultrastructure of lepra cells and
as an index of humoral immunity in lepromatous lep- epitheloid cells should be re-evaluated.19–48 Light and
rosy.17,18 All these cytokines are produced by CD4⫹ Th-1 electron microscopy findings are rather inconsistent, as
(helper-1) and Th-2 (helper-2) lymphocytes, involved in virchowcytes are often bacillar cemeteries instead of reser-
cell-mediated and humoral immunity, respectively. CD8⫹ voirs of viable organisms.

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Abulafia and Vignale Leprosy: pathogenesis updated Review 323

Figure 2 During the hematogenous spread of M. leprae on its way to the nerves, it may be captured by macrophages. In
Mitsuda-positive patients, epithelioid granulomas may be formed (tuberculoid leprosy); in Mitsuda-negative patients,
virchowcytic granulomas may develop (lepromatous leprosy). In certain cases, both granulomas may coexist (borderline
leprosy). These granulomas result from different mechanisms of killing M. leprae by ‘‘Mitsuda-positive’’ or ‘‘Mitsuda-negative’’
macrophages. All clinico-pathologic forms of leprosy may be related to the monocyte–macrophage system. Mø, macrophage;
ph, phagosome; lm, lysosome; mi, mitochondria; phlm, phagolysosomes; fs, foamy structures; ger, granular endoplasmic
reticulum; G, Golgi apparatus; Nu, nucleus

The purpose of this review is to re-examine the patho- 4 Why is dapsone effective and bactericidal rifampicin
genesis of leprosy in view of the different immunologic is not?
mechanisms involved.49–58 Combining the available clin- 5 May leprosy possibly be a disease of the macrophage
ical, histopathologic, histochemical, and ultrastructural organelles or is only immunity involved?
knowledge with the recent immunologic advances, we have
explored new hypotheses that may help to answer the
Leprosy: infectious disease
following questions.
1 How is M. leprae made up and how can a simple bacillus Mycobacterium leprae
generate so many distinctive pictures? M. leprae belongs to the Mycobacteriaceae group and
2 Why do epithelioid granulomas predominate in tubercu- shares several antigens with M. tuberculosis. It is also
loid leprosy and virchowcytic granulomas in lepromatous fuchsin-positive and acid-fast, does not release toxins, and
leprosy? Do epitheloid cells and lepra cells have any replicates every 20 or 30 days (Fig. 6).21 The bacilli are
pathogenic meaning? arranged in ‘‘packs of cigarettes’’ or ‘‘globis’’ in a lipid
3 Why may M. leprae stimulate cell-mediated immunity in magma, and are included in the cytoplasmic vacuoles of
tuberculoid leprosy and humoral immunity in lepromatous lepra cells (modified macrophages).
leprosy? Could two types of APC, resulting from dual Under electron microscopy, M. leprae consists of a
antigenicity, develop? spiraled nucleoplasm surrounded by a dense homogeneous

© 1999 Blackwell Science Ltd International Journal of Dermatology 1999, 38, 321–334
324 Review Leprosy: pathogenesis updated Abulafia and Vignale

cytoplasm lined by a plasma membrane, and a thick

bacterial cell wall with fibers, enveloped in a ‘‘lipid layer’’
that enlarges as the bacillus ages22,23 (Fig. 1A). Biochemical
studies have shown that the phosphoglycolipid composition
of M. leprae is similar to that found in the cytoplasm of
lepra cells.24–27 Specific antigenic structures have been
detected in the outer layer,28 the most significant being
the phenolic glycolipid-1 (PGL-1). Immunohistologic and
fluorescent methods using monoclonal antibodies have
revealed normal organisms as well as bacilli in different
stages of degeneration (granular, irregular, vacuolar,
amorphous).29 In lepromatous leprosy and borderline lep-
romatous leprosy, bacilli with a predominantly degenerative
vacuolar lipidic pattern are seen; in borderline leprosy, a
granular pattern is noted. Figure 3 Lepromatous granuloma secondary to hyperplasia
In epithelioid and Langhans cells, however, the antigen of ‘‘Mitsuda-negative macrophages.’’ vg, virchowcytic
is elusive. The lipoarabinoamanana is another important granuloma; n, nucleus; arrows, lepra cell; asterisks, multiple
component of the bacillar envelope that may have cross- cytoplasmic vacuoles (hematoxylin and eosin, ⫻440)
activity with other mycobacteria.
M. leprae enters the lymph and blood vessels to reach
its targets, the nerves and their Schwann cells, where it can
multiply and disseminate, begin new invasive cycles, and macrophages may also impinge on the nerves and produce
form perineural granulomas. Initially, the bacilli may be mechanical atrophy.
phagocytosed by neutrophils that may produce partial lysis.
When Schwann cells engulf the bacilli within phagocytic Monocyte–macrophage system and Mycobacterium
vacuoles (phagosomes), however, M. leprae may replicate leprae
and age. From there or through the cytoplasm of the The so-called mononuclear phagocyte system (formerly
endothelial cells, these ‘‘normal bacilli’’ may migrate to the known as the reticuloendothelial system) consists of mono-
perivascular connective tissue and be ingested by macro- cytes, macrophages, and their precursors. Circulating
phages rich in lysosomal enzymes capable of killing the monocytes live for approximately 5 days; however, these
organisms (Fig. 2). In Mitsuda-positive patients, the macro- cells may migrate to the connective tissue and persist for
phages may destroy all bacilli and obtain normal antigenic several months as fixed histiocytes. When stimulated, they
information to act as APCs, stimulate cell-mediated may differentiate into macrophages with high energetic
immunity, and eventually form epithelioid granulomas. In activity, capable of forming epithelioid cells in tuberculoid
Mitsuda-negative patients, only partial lysis may occur and leprosy, and lepra cells or virchowcytes in lepromatous
the bacterial phospholipids may persist. Lepra cells or leprosy. In addition, macrophages may act as starter cells
virchowcytes may appear, but the antigenic information is or APCs in both cell-mediated and humoral immunity.
incomplete and the cells cannot act as APCs. Experimental studies from the Brazilian School of
Leprosy have demonstrated a distinctive behavior of blood
monocytes cultured with M. leprae.10–13 In Venezuela,
Schwann cells and Mycobacterium leprae similar results were obtained, and it has been concluded
It is usually accepted that the nerve involvement character- that macrophages act differently in Mitsuda-positive or
istic of leprosy results from the invasion of Schwann cells Mitsuda-negative patients.14,15 In lepromatous leprosy,
that engulf the bacilli within their phagosomes (phagocytic macrophages may only partially destroy M. leprae, but are
vacuoles), where they may multiply protected from the capable of totally killing other acid-fast bacteria (BCG,
antibodies and macrophages. Nevertheless, M. leprae may M. lepraemurium).15 In Mitsuda-positive patients, these
leave these sanctuaries, penetrate the perineural tissues, and cells may ingest and completely annihilate the bacilli, and
eventually form epithelioid or lepromatous granulomas. obtain normal complete antigenic information (see Fig. 2).
Histopathology always shows granulomas around nerves. In Mitsuda-negative patients, they may engulf and partially
In tuberculoid leprosy, the activated macrophages may destroy the bacilli, but the phospholipid layer may remain
phagocytose intraneural bacilli.31–38 As Schwann cells do deposited as cytoplasmic droplets (lepra cells) (see Fig. 2;
not have lysosomal enzymes capable of destroying the Figs 3 and 4). Granular bacilli are mostly necrobiotic. The
bacteria, they may survive for a long time. Interstitial main antigen is PGL-1, a component of the phospholipid

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Abulafia and Vignale Leprosy: pathogenesis updated Review 325

Figure 4 Perivascular lepra cells with lipid-laden cytoplasmic Figure 5 Electron micrograph of a lepra cell cytoplasm; vg,
vacuoles; vg, virchowcytic granuloma; v, vessel; arrows, virchowcytic granuloma; phlm, phagolysosomes (fs, foamy
lepra cell (Sudan B black, ⫻440) structures)—large vesicles with small electron-lucent vacuoles
(v) containing bacterial lipids lined by a delicate network of
lysosomal material; Ml, bacilli within small phagocytic
vacuoles (phagosomes); mi, normal mitochondria; lm,
layer that envelopes M. leprae.25,28,29,51 In this early stage
normal lysosomes; dmi, degenerated vesicular mitochondria;
of lepromatous leprosy, no normal APCs develop. r, small residual phagolysosomes; asterisks, artifacts
M. leprae (⫻43,400)
↓
Macrophages
Mitsuda-positive patients Mitsuda-negative patients
↓ ↓
Epithelioid granulomas Virchowcytic granulomas
↓ ↓
Tuberculoid leprosy Lepromatous leprosy
↓ ↓
Primary immune disease Infectious-metabolic disease

Lepromatous leprosy: infectious and primary

metabolic disease

Under light microscopy, lepra cells or virchowcytes are

macrophages with an abundant cytoplasm filled with
irregular microvacuoles—a different special type of ‘‘foam
cells’’ (see Fig. 3). They may represent ‘‘Mitsuda-negative Figure 6 Ultrastructure of a lepra cell (high magnification of
macrophages’’ that provoke partial lysis of M. leprae, and Fig. 5); mi, normal mitochondria; dmi, degenerated vesicular
are associated with bacterial necrobiosis and persistence of mitochondria; Ml, viable bacilli in transverse replication
intracytoplasmic bacillar phospholipids, histochemically phase, within a phagosome (ph); phlm, phagolysosomes (fs,
detectable with Sudan B black (see Fig. 4). Within these foamy structures)—large vesicles with small electron-lucent
vacuoles, PGL-1 may be identified. vacuoles (v) containing bacterial lipids; lm, lysosome
Our ultrastructural studies have shown that macrophages adjacent to a phagolysosome (⫻67,500)
may engulf the bacilli within phagocytic vacuoles or phago-
somes, where they may replicate. Simultaneously, the
activated macrophages may produce lysosomes filled with phagolysosomes exhibit rounded membrane-bound organ-
hydrolytic enzymes, including phospholipases. These lyso- elles with electron-lucent microvacuoles (lipids) and a
somes tend to fuse with phagosomes to form phagolyso- network of electron-dense lysosomal material. These
somes (foamy structures) (see Fig. 2). When the lysosomal ‘‘foamy structures’’ must be distinguished from degenerated
enzymes reach the bacilli, partial lysis may begin. The mitochondria (Figs 5 and 6). A predominance of phago-

© 1999 Blackwell Science Ltd International Journal of Dermatology 1999, 38, 321–334
326 Review Leprosy: pathogenesis updated Abulafia and Vignale

Figure 7 Mycobacterium leprae (Ml) phagocytosed by ‘‘Mitsuda-positive macrophages’’ may be completely destroyed; normal
antigenic information may be obtained and expressed on the cell surface. In association with MHC class II, these APCs may
secrete IL-12 and stimulate CD4⫹ lymphocytes (Th-1), which, in turn, may produce IL-2 and IFN-γ. New macrophages may
then be activated and transformed into epitheloid cells. When MHC class I is involved, however, stimulated CD8⫹
lymphocytes may act on other macrophages to kill the organisms by apoptosis. Mø, macrophage; MHC, major
histocompatibility complex; NK, natural killer

somes with multiple normal bacilli and phagolysosomes negative macrophages.’’ Lepra cells are not friendly hosts,
with scarce residual bacterial lipidic vacuoles may also be as they eventually evolve into bacterial cemeteries. Lepro-
seen. This picture may erroneously suggest that lepra cells matous leprosy may be considered a phospholipid deposit
are reservoirs of viable bacteria. disease or post-bacillar tesaurismosis.6,48 Ziehl–Neelsen
Although these structures are specific macrophage cyto- stain shows that the lipid envelope reacts like lipofuchsin;
plasmic organelles, in earlier ultrastructural studies their it is diagnostic, but not specific and does not reflect the
functional significance was uncertain. The lysosomes were viability of M. leprae.
called ‘‘opaque droplets’’ or ‘‘opaque bodies,’’ and the
phagolysosomes were named ‘‘foamy structures,’’ with little
Tuberculoid leprosy: infectious and primary
or no value.42,44–46
immune disease
In ‘‘Mitsuda-negative macrophages,’’ a functional defi-
ciency of lysosomal phospholipases may exist. As in these In Mitsuda-positive patients, phagocytosis of M. leprae
cells only partial lysis of bacilli may occur, the antigenic may lead to complete bacterial lysis; macrophages may
information is incomplete. transform into normal APCs with complete bacillar
In summary, lepromatous leprosy is an infectious disease information on the surface that, in the presence of MHC
caused by M. leprae and a metabolic disorder secondary to class II, may induce IL-12 synthesis, which in turn may
the dysfunction of lysosomal phospholipases in ‘‘Mitsuda- stimulate CD4⫹ T lymphocytes (Th-1) that produce IL-2

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Abulafia and Vignale Leprosy: pathogenesis updated Review 327

(TNF-α), may be produced (see Fig. 11). All of these

cytokines may induce a type 2 leprosy reaction (ENL),68–77
and if circulating complexes exist, a leukocytoclastic vascul-
itis type 3 reaction (Lucio phenomenon) may occur.78–80
In lepromatous leprosy, the NAPCs may relate to MHC-I
and stimulate CD8⫹ T lymphocytes (Tc-s), which accelerate
the death of lepra cells. In addition to IL-4, other cytokines,
such as IL-5, IL-6, and IL-10, may also participate.56–59 In
lepromatous leprosy, tuberculoid lesions may also appear.
The activation of ‘‘Mitsuda-positive macrophage’’ clones in
areas where ‘‘Mitsuda-negative macrophages’’ predominate
may result in tuberculoid type 1 leprosy reactions
(reversal).81,82 ENL may be the first manifestation of
subclinical lepromatous leprosy.
Figure 8 Tuberculoid leprosy—epithelioid granuloma with
central necrobiosis (pyknotic nuclei). ‘‘Mitsuda-positive Dimorphous or borderline leprosy: bipolar
macrophages’’ may completely destroy the bacilli and normal clinico-pathologic forms
APCs may emerge. New macrophages may then be activated
and transformed into epithelioid cells. Stimulated CD8⫹ Borderline leprosy (BT, BB, BL) represents those cases
(Tc) lymphocytes may account for the necrobiotic area. located at the equatorial zone of the spherical model (see
Filled arrows, epithelioid cells; open arrow, apoptotic Fig. 1B). It is worth noting that the same bacterium
macrophages (hematoxylin and eosin, ⫻530) (M. leprae) may provoke special clinical and histopatho-
logic lesions with characteristics of each polar form (BT,
BL), or intermediate features (BB), not infrequently with
and IFN-γ. Other bacteria-laden macrophages may also be epithelioid and lepromatous granulomas in the same patient
activated and promote bacterial killing until epithelioid (see Fig. 14). The finding of both granulomas suggests that,
and Langhans cells develop (Figs 7 and 8). Ultrastructurally, in borderline leprosy, different clones of ‘‘Mitsuda-positive’’
the cytoplasm of the epithelioid cells shows normal lyso- and ‘‘Mitsuda-negative’’ macrophages may coexist. BT
somes and numerous swollen, degenerated mitochondria, patients usually exhibit positive reactions, while in BB and
some of them partially phagocytosed (autophagosomes). BL patients negative reactions are documented.8–13
No bacillar debris is seen (foamy structures). The Golgi
apparatus and lysosomes are normal. The mitochondrial
Subpolar leprosy: less severe clinico-
enlargement reflects the high metabolic activity of
pathologic forms
macrophages (Figs 9 and 10). CD4⫹ T lymphocytes may
participate through IL-2 and IFN-γ production. Combining In the tuberculoid hemisphere, subpolar clinico-pathologic
with MHC class I, the same APCs may stimulate CD8⫹ T forms (Tt, Tm, and others) tend to lie nearer to the equator
lymphocytes, although to a lesser extent than in lepromat- and exhibit lesions which vary according to the intensity
ous leprosy (Fig. 7).49–67 of Mitsuda reaction positivity (see Fig. 1B). Histology
reveals perineural epithelioid granulomas with T lympho-
cytes (mostly CD4⫹, but also CD8⫹). No circulating
Lepromatous leprosy: secondary humoral
antibodies are detected.
immune disease
In the lepromatous hemisphere, several subpolar forms
In the early stages of lepromatous leprosy, lepra cells are may develop (sLL, histoid nodular leprosy, diffuse leprosy,
formed; these modified macrophages may age and die, or Lazarine leprosy). Histology shows lepra cells with variable
may succumb to CD8⫹ T lymphocyte action and eventually amounts of bacilli. The presence of plasma cells suggests
be phagocytosed by other ‘‘Mitsuda-negative macrophages’’ that circulating antibodies may be produced and that
(Figs 11–13). The latter may then obtain complete neoanti- humoral immunity-induced leprosy reactions may appear.
genic information and act as new antigen presenting cells Histoid leprosy, in which fibroblastoid macrophages filled
(NAPCs); when associated with MHC class II, they may with probably undigested bacteria replace foamy lepra
secrete IL-4, which, in turn, may incite humoral immunity- cells, may represent a variant with greatly impaired cellular
linked CD4⫹ T lymphocytes (Th-2). B lymphocytes may defenses.83–87
be activated, plasma cells may develop, and anti-M. leprae After the early stages of lepromatous leprosy already
serum antibodies, IL-1 and tumor necrosis factor alpha described, the ageing lepra cells may be phagocytosed by

© 1999 Blackwell Science Ltd International Journal of Dermatology 1999, 38, 321–334
328 Review Leprosy: pathogenesis updated Abulafia and Vignale

Figure 9 Tuberculoid leprosy—electron micrograph of an Figure 10 Ultrastructure of an epithelioid cell (high

epithelioid cell. The cytoplasm shows a few intact and magnification of Fig. 9). Cytoplasm showing swollen
numerous swollen and degenerated mitochondria. No degenerated mitochondria and cristae remnants; however, no
phagolysosomes or bacilli are seen. This picture bacilli are seen. lm, lysosomes merging with degenerated
demonstrates the intense energetic effort invested by mitochondria; aph, autophagosomes; black arrows,
macrophages to destroy the organisms. nu, cell nucleus; mi, peripheral cytoplasmic projections (⫻21,700)
normal mitochondria; dmi, degenerated mitochondria; G,
Golgi apparatus (⫻17,000)
positive macrophages’’ may account for type 1 lepra
reactions (reversal) with tuberculoid lesion outbreaks.81,82
other macrophages and the virchowcyte predigested antigen In addition to antibodies implicated in type 2 and type 3
may be totally digested; in this way, NAPCs with modified reactions, other antibodies against host tissues (antilipid,
antigenic information may emerge, and stimulate humoral rheumatoid factor, cryoproteins, LE cells) may induce
immunity. This mechanism may explain secondary type autoaggressive Hansen’s disease.51,89
2 (ENL) and type 3 (Lucio phenomenon) reactions of
lepromatous leprosy (Fig. 11).
Discussion

Many attempts have been made to explain the clinico-

Leprosy: tuberculoid and lepromatous
pathologic spectrum of leprosy. Natural resistance and
reactive outbreaks
susceptibility factors, based on positive or negative Mitsuda
In tuberculoid leprosy and, to a lesser degree, in borderline reactions, were postulated.90–94 Later, it was demonstrated
leprosy, tuberculoid reactive outbreaks with exacerbation that leprosy patients may have different MHC patterns
of quiescent lesions or the development of new lesions may with HLA variability.16–18,94,95
occur. In these instances, edematous epithelioid granulomas It must be stressed that the same bacillus may induce
may be seen. It is postulated that bacteria from the neural different clinico-pathologic forms of leprosy (see Figs 1A
sanctuaries invade the bloodstream; CD4⫹ T lymphocytes and 1B). The disease tends to be bipolarly distributed in
(Th-1) release IL-2 and IFN-γ, and activated macrophages two hemispheres, one with positive Mitsuda reaction,
destroy the bacilli and become new epithelioid cells. resistance development, little or no bacillar proliferation,
On the other hand, lepromatous reactive outbreaks may and epithelioid granulomas possibly related to cell-medi-
involve humoral immunity with antibody synthesis. These ated immunity, and the other with negative Mitsuda reac-
antibodies, in concert with cytokines from the NAPCs, tion, bacillar proliferation, and lepromatous or
such as IL-1 and TNF-α, may cause ENL (type 2 reaction). virchowcytic granulomas. This clinico-pathologic bipo-
The histology of lepromatous granulomas of ENL shows larity may stem from the dual response of monocytes and
necrobiotic foci and neutrophils. Thalidomide, so effective macrophages to M. leprae (see Fig. 2). In cases located at
in ENL, may inhibit the mRNA of TNF-α.88 the tuberculoid hemisphere, these cells may destroy and
In the Lucio phenomenon (type 3 reaction), circulating eliminate all bacilli, while in cases located at the lepro-
immune complexes may be deposited in the small vessels, matous hemisphere, the bacilli may proliferate and simul-
and leukocytoclastic vasculitis may result.78 In lepromatous taneously be partially killed, and release phospholipids that
leprosy patients, the activation of heterotopic ‘‘Mitsuda- persist as tiny droplets within the virchowcyte cytoplasm.

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Abulafia and Vignale Leprosy: pathogenesis updated Review 329

Figure 11 In Mitsuda-negative patients, only partial lysis may occur and the bacterial phospholipids may persist. Lepra cells or
virchowcytes may appear and be phagocytosed by other macrophages; in this way, new antigen presenting cells (NAPCs) with
modified antigenic information may emerge, and stimulate humoral immunity. This mechanism may explain secondary type 2
(ENL) and type 3 (Lucio phenomenon) reactions of lepromatous leprosy. Mø, macrophage; MHC, major histocompatibility
complex; IL, interleukin

Consequently, this cellular bipolarity may account for the

clinico-pathologic bipolarity (see fig. 2).
In addition, immune phenomena may also be bipolar
in leprosy. At the tuberculoid hemisphere, cell-mediated
immunity predominates, while at the lepromatous hemi-
sphere, secondary humoral immunity may occur (type 2
and type 3 reactions). Both responses may depend on
APCs, represented in leprosy by macrophages. In tubercu-
loid leprosy (Mitsuda-positive), these cells may phagocytose
and annihilate the bacilli, and obtain complete antigenic
information, which in association with MHC class II, may
stimulate cell-mediated immunity (see Figs 2 and 7). In
lepromatous leprosy (Mitsuda-negative), the macrophages
may ingest M. leprae, but due to a lysosomal enzyme
defect, may produce only partial lysis, and the persisting
phospholipids may lead to a metabolic disease with no
Figure 12 Virchowcytic granuloma showing lipid-laden lepra
cell aggregates (left) and solitary pericapillary elongated immune activity. Lepra cells contain altered complete anti-
macrophages, perhaps related to the phagocytosis of ageing gens, however. When these cells age, they may be engulfed
virchowcytes (right). vg, virchowcytic granuloma; mcr, by other macrophages, and may obtain modified (predi-
macrophages (Sudan B black stain, ⫻440) gested) antigenic information, which in association with

© 1999 Blackwell Science Ltd International Journal of Dermatology 1999, 38, 321–334
330 Review Leprosy: pathogenesis updated Abulafia and Vignale

‘‘Mitsuda-negative macrophages.’’ Antigenic components

of lepra cells may act as a Freund’s adjuvant capable of
forming NAPCs, a finding that may account for the double-
standard immune response to leprosy (Fig. 15).
Indeterminate leprosy tends to be an early form of the
disease, characterized by hypopigmented or erythematous
pigmented macules. Histologically, nerves with scarce
bacilli, surrounded by lymphocytes (perineural paravascu-
lar inflammation), are found. When these cells are T
lymphocytes lichenoid inflammatory lesions with epidermal
basal depigmentation or hyperpigmentation may be seen.3,9
The efficacy of sulfones was initially attributed to their
bactericidal effect. Hypothetically, sulfones may promote
lysosomal phospholipase activity in ‘‘Mitsuda-negative
Figure 13 Ultrastructure of a virchowcytic granuloma. A macrophages.’’39–103 An antioxidant role has also been
macrophage partially engulfing another macrophage with a suggested.96–100 The abnormality may reside within the
normal nucleus and a large cytoplasmic phagosome mitochondria (oxidative phosphorylation) and lead to
containing necrobiotic material is seen. nu, nucleus; asterisk excessive release of free radicals; consequently, depression
and black arrows, necrobiotic material within a large of phospholipases may result. In lepromatous leprosy, the
phagosome; open arrows, cell membrane with sulfone mechanism of action may be as follows.
pseudodesmosomes in the resorption areas (⫻11,000 ‘‘Mitsuda-negative macrophages’’ → mitochondrial over-
production of free radicals → inhibition of lysosomal
phospholipases → persistence of bacillary phospholipids in
cytoplasmic vacuoles (lepra cells or virchowcytes) → no
immunologic stimulation is feasible (APC) → enter sulfones
→ antioxidant action with inhibition of free radicals and
release of lysosomal phospholipases → metabolization of
lepra cell lipids → involution of lepromas.
Rifampicin may be bactericidal, particularly for neural
bacilli and also in cases of bacteremia.101 Administration
of rifampicin at 30 day intervals may be related to the
replication cycle of M. leprae.21 Bacilli harbored within
the Schwann cell cytoplasm would be protected from
drug action. Clofazimine, a pigmented agent, may fuse
with the lepra cell phospholipids and facilitate their
metabolism.102–104 This drug may also promote phospho-
lipase A2 synthesis and develop activity against the
Figure 14 Borderline leprosy. An epithelioid granuloma with bacillar phospholipids.98–103
Langhans multinucleated cells (right) and a virchowcytic
granuloma with foamy lepra cells (left) are seen. This finding
Conclusions
supports the coexistence of ‘‘Mitsuda-positive’’ and
‘‘Mitsuda-negative’’ macrophage clones in the same patient 1 Leprosy is an infectious disease, caused by Mycobacter-
(hematoxylin and eosin, ⫻550) ium leprae, with multiple clinico-pathologic forms related
to a bipolar monocyte–macrophage system response, which
exhibits two genetic and phenotypic cellular patterns,
MHC class II, may stimulate humoral immunity (see Figs represented by ‘‘Mitsuda-positive’’ and ‘‘Mitsuda-negative’’
2 and 11). Azulay51 demonstrated that other macrophages macrophages.
may phagocytose ageing lepra cells, obtain neoantigenic 2 In tuberculoid leprosy (Mitsuda-positive), phagocytic
information, become NAPCs, and stimulate humoral macrophages may destroy all bacilli, obtain complete anti-
immunity. genic information expressed on their surface with MHC
In leprosy, immune mechanisms seem to be normal. The class II, transform into complete antigenic presenting cells,
supposedly humoral dysfunction may be explained by the stimulate cell-mediated immunity (CD4⫹ Th-1 lympho-
resistance of the lipid layer of M. leprae to digestion by cytes, with IL-2 and IFN-γ synthesis), and, when acting on

International Journal of Dermatology 1999, 38, 321–334 © 1999 Blackwell Science Ltd
Abulafia and Vignale Leprosy: pathogenesis updated Review 331

Figure 15 Dual immunity in leprosy. The same M. leprae may express ‘‘normal’’ and ‘‘predigested’’ antigens. The former may
act in Mitsuda-positive patients; normal APCs may be formed, primary cell-mediated immunity may develop, and,
consequently, tuberculoid leprosy may result. The latter may operate in Mitsuda-negative patients; new APCs may appears,
secondary humoral immunity may be stimulated, and type 2 (ENL) and type 3 (Lucio phenomenon) reactions may occur. In
the two mechanisms, different cytokines may be involved. Mø, macrophage; APC, antigen presenting cell; IL, interleukin; Th,
helper T lymphocytes; TNF-α, tumor necrosis factor-alpha

M. leprae-containing macrophages, induce epitheloid cell face with MHC class II, evolve into new antigenic presenting
development. Tuberculoid leprosy may therefore represent cells, release IL-4, stimulate humoral immunity (CD4⫹ Th-
a primary cell-mediated immunologic disease. 2 and CD8⫹ T lymphocytes, B lymphocytes, and IL-1 and
3 In lepromatous leprosy (Mitsuda-negative), phagocytic TNF-α synthesis) with anti-M. leprae antibody production,
macrophages may produce partial bacterial lysis; however, and facilitate type 2 (erythema nodosum leprosum) and type
the bacterial phospholipids engulfed within cytoplasmic 3 (Lucio phenomenon) leprosy reactions. The immunologic
vacuoles persist, and lepra cells or Virchow cells result. response is secondary to the metabolic disease.
During this early stage, no immune stimulation takes place. 5 In borderline leprosy, the presence of both epithelioid
The assumed mitochondrial dysfunction of ‘‘Mitsuda-nega- and virchowcytic granulomas may reflect the coexistence
tive macrophages’’ may lead to the overproduction of of ‘‘Mitsuda-positive’’ and ‘‘Mitsuda-negative’’ macrophage
free radicals and lysosomal phospholipase depression. The clones at the equatorial zone and perhaps at both tubercu-
bacteriostatic and antioxidant effects of sulfones would loid and lepromatous hemispheres.
neutralize the free radicals, causing disinhibition of 6 Type 1 leprosy reaction (reversal) may be related to the
phospholipases, metabolization of lepra cells lipids, and stimulation of ‘‘Mitsuda-positive macrophages’’ in patients
involution and disappearance of lepromas. Initially, lepro- with predominantly ‘‘Mitsuda-negative macrophages.’’
matous leprosy may therefore behave as an infectious and 7 The re-examination of lepra cells and epithelioid cell
metabolic lipidic disease. electron micrographs may be useful to demonstrate their
4 In a later stage of lepromatous leprosy, other macro- different response to M. leprae and to explain the source
phages may phagocytose the aged lepra cells, obtain of bipolarity in the pathophysiology of leprosy.
complete neoantigenic information expressed on their sur- 8 The immune bipolarity of leprosy may be the result of

© 1999 Blackwell Science Ltd International Journal of Dermatology 1999, 38, 321–334
332 Review Leprosy: pathogenesis updated Abulafia and Vignale

two antigens, one derived from ‘‘normal’’ bacilli and the 12 Barbieri TA Correa WM. Human macrophage culture.
other arising from enzymatically digested bacilli present in The leprosy prognostic test (LPT). Int J Lepr 1967; 35:
Virchow cells. Both antigens, acting independently, may 377–381.
induce the development of normal and new antigen 13 Pisani RCG, Beiguelman B, Opromolla DVA. ‘‘In vitro’’
presenting cells, respectively, with the stimulation of cell- behavior of blood derived macrophages against killed
mediated immunity in tuberculoid leprosy and humoral M. leprae. Int J Lepr 1973; 41: 12–24.
14 Convit J, Avila JL, Goihman M, et al. A test for the
immunity in lepromatous leprosy.
determination of competency in clearing bacilli in
This review attempts to open a debate and to encourage
leprosy patients. Bull WHO 1972; 46: 821–826.
new paths of research that may correct certain erroneous
15 Convit J, Pinardi ME Rodriguez Ochoa G, et al.
concepts prevalent today.
Elimination of M. leprae subsequent to local in vivo
activation of macrophages in lepromatous leprosy by
Acknowledgements other mycobacteria. Clin Exp Immunol 1974; 00:
261–265.
Meny Bergel, MD and Luis M. Baliña, MD, made scientific 16 Rodriguez Santamaria J, Campbell IT, Delfini O, et al.
contributions to the paper. Graciela Sánchez, MD, assisted HLA na dermatologia: o que existe de concreto. An
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lated the paper into English, and Alejandro González 17 Yamamura M, Uyemura K, Deans RJ, et al. Defining
Llanos provided the illustrations. protective response to pathogens: cytokine profiles in
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18 Ochoa MT, Valderrama L, Ochoa A, et al.
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