International Reviews of Immunology

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Immunology of leprosy

Luis Alberto Ribeiro Froes Jr , Maria Angela Bianconcini Trindade & Mirian
Nacagami Sotto

To cite this article: Luis Alberto Ribeiro Froes Jr , Maria Angela Bianconcini Trindade & Mirian
Nacagami Sotto (2020): Immunology of leprosy, International Reviews of Immunology, DOI:
10.1080/08830185.2020.1851370

To link to this article: https://doi.org/10.1080/08830185.2020.1851370

Published online: 26 Nov 2020.

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INTERNATIONAL REVIEWS OF IMMUNOLOGY
https://doi.org/10.1080/08830185.2020.1851370

REVIEW

Immunology of leprosy
Luis Alberto Ribeiro Froes Jra, Maria Angela Bianconcini Trindadea,b, and Mirian Nacagami Sottoa
a
Departamento de Patologia, University of Sao Paulo, S~ao Paulo, Brazil; bImunodermatologia, Universidade de S~ao Paulo Hospital das
Clınicas, S~ao Paulo, Brazil

ABSTRACT ARTICLE HISTORY

Leprosy is a disease caused by Mycobacterium leprae (ML) with diverse clinical manifesta- Received 10 July 2020
tions, which are strongly correlated with the host’s immune response. Skin lesions may be Accepted 9 November 2020
accompanied by peripheral neural damage, leading to sensory and motor losses, as well as
KEYWORDS
deformities of the hands and feet. Both innate and acquired immune responses are
Immunology; leprosy;
involved, but the disease has been classically described along a Th1/Th2 spectrum, where leprosy reactions;
the Th1 pole corresponds to the most limited presentations and the Th2 to the most disse- lymphocyte activation;
minated ones. We discuss this dichotomy in the light of current knowledge of cytokines, Th Mycobacterium leprae
subpopulations and regulatory T cells taking part in each leprosy presentation. Leprosy reac-
tions are associated with an increase in inflammatory activity both in limited and dissemi-
nated presentations, leading to a worsening of previous symptoms or the development of
new symptoms. Despite the efforts of many research groups around the world, there is still
no adequate serological test for diagnosis in endemic areas, hindering the eradication of
leprosy in these regions.

Introduction by hereditary traits, with variable expressiveness in sev-

Leprosy is an infectious disease caused by
Mycobacterium leprae, the main host of which is
humans. Notwithstanding the falling incidence, the
disease is still an important cause of morbidity, with
208,641 new cases recorded in the world in 2018 [1].
The stigma caused by the disease has changed in
recent years. The introduction of multidrug treat-
ment recommended by the WHO allowed a change
in the natural history of the disease, with a signifi-
cant increase in cure rates and a substantial drop in
the number of new cases. Despite these advances, the
disease still has a high disabling potential, being the
main cause of infectious neuropathy in tropical and
subtropical countries [2].
The pathophysiology of leprosy is multifactorial,
with genetic, immunological and environmental
aspects determining the individual’s susceptibility to
the bacillus [3–5]. Individuals whose skin bacilloscopic
index reveals a high concentration of bacilli are called
multibacillary. These individuals typically develop a
weak cellular immune response, unable to contain the
proliferation of M. leprae, with an intense humoral
response and high titers of specific serum antibodies
against the bacillus [6]. Susceptibility is also influenced
eral genes demonstrated, according to the clinical pres-
entation. Of particular relevance, in lepromatous leprosy
and leprosy reactions, is the fact that genes involved in
the humoral immune response are highly expressed, not-
ably genes for immunoglobulin receptors or proteins of
the classical complement pathway [7].
Whole-genome sequencing of Mycobacterium leprae
collected from different parts of the world has
revealed a low interregional genetic variability, with
99.995% of the genetic material identical among differ-
ent strains [8]. This is due, in large part, to the fact that
the genome of M. leprae contains a low percentage of
functional genes (less than 50%), with a high percentage
of pseudogenes [9]. This finding suggests that the vari-
ability in the clinical presentation of the disease among
individuals is mainly due to idiosyncratic factors of the
host, rather than to variations specific to the micro-
organism, which has also been demonstrated by studies
matching certain immunogenic variations to specific
clinical presentations [4,10–12].
It is estimated that more than 95% of infected indi-
viduals are naturally resistant to M. leprae, never devel-
oping any symptoms of the disease [13]. Among
symptomatic individuals, the disease manifests itself along
a clinical spectrum with two poles and is classically

CONTACT Luis Alberto Ribeiro Froes lulafroes@usp.br Departamento de Patologia, University of Sao Paulo, S~ao Paulo, Brazil.
ß 2020 Taylor & Francis Group, LLC
2 L. A. R. FROES ET AL.
divided into five different presentations in between these
poles. Tuberculoid leprosy lies in one of the poles, pre-
senting as well-defined annular erythematous plaques
and sensitivity loss. The anatomopathological examin-
ation of these lesions is characterized by well-defined
granulomas, formed by epithelioid cells, multinucleated
giant cells and macrophages, surrounded by a ring of
lymphocytes, with few or no bacilli inside. On the other
end of the spectrum, individuals with lepromatous lep-
rosy exhibit intense humoral immune response, abundant
production of specific anti-M. leprae antibodies and very
weak cellular immune response. Clinically, these individ-
uals present with a higher number of lesions, and no
granulomas on histological examination, but abundant
foamy macrophages full of bacilli – the so-called
Virchow cells [14]. Between the poles lie the borderline
presentations, namely: borderline-tuberculoid, borderline-
borderline and borderline-lepromatous. As the clinical
presentation moves from the tuberculoid to the leproma-
tous pole, a gradual transition occurs from a Th1 to a
Th2 immune response.
Finally, the so-called “indeterminate” leprosy is
clinically represented solely by a hypochromic macule
with reduced local sensitivity and, on histological
examination, the presence of a lymphohistiocytic infil-
trate of perineural and periadnexal location, which
can evolve with spontaneous healing or toward any of
the five classic presentations [14].
The innate response to M. leprae
M. leprae is a gram-positive, acid-fast bacillus and
obligate intracellular parasite, exhibiting a pronounced
tropism for macrophages and Schwann cells [15,16].
The leprosy bacillus is distinguished from other gram-
positive and gram-negative bacteria by its lipid-rich
cell wall, in particular mycolic acids and the phenolic
glycolipid-1 (PGL-1). PGL-1 mediates bacillus pene-
tration into macrophages by binding to the comple-
ment protein C3, via complement receptors CR1, CR3
and CR4, inducing its phagocytosis [16,17]. It is a
component that is central to the pathogenesis of the
disease and is involved in the mechanism of phagoly-
sosome escape [16].
Inside the monocyte, PGL-1 plays an immunosup-
pressive role that facilitates its survival in the cell.
Analyses of cytokines secreted by “naive” monocytes
exposed to PGL-1 and lipopolysaccharides (LPS) from
the outer membrane of gram-negative bacteria showed
that PGL-1 alone induced a very weak production of
inflammatory cytokines, such as tumor necrosis fac-
tor-alpha (TNF-a), IL-1b and IL-10, although it also
induced high levels of negative regulatory molecules,
such as the Monocyte Chemoattractant Protein-1
(MCP-1) and the Interleukin-1 Receptor Antagonist
(IL-1RA). In addition, exposure to LPS subsequent to
exposure to PGL-1 suppressed the monocyte response
to LPS, limiting the secretion of TNF-a, IL-1b and IL-
6 [18,19].
The microbicidal activity of macrophages involves
the production of reactive oxygen and nitrogen spe-
cies, through the NADPH-oxidase complex and nitric
oxide, respectively [20], and greater expression of the
enzyme nitric oxide synthase (iNOS) has been
described in skin tuberculoid lesions, in comparison
with lepromatous lesions, which might be ascribed to
the higher Th1 response in localized leprosy [21].
Macrophages are generally classified into two
groups, namely M1 and M2, according to the Th
response (Th1/Th2). M2 macrophages are associated
with Th2 responses and be highly present in leproma-
tous leprosy [22,23]. M2 macrophages from patients
with disseminated presentations have shown increased
expression of costimulatory molecules (CD68 and
CD163), Arginase 1 (an enzyme involved in mecha-
nisms regeneration and repairing of tissue) and the
anti-inflammatory cytokines IL-10 and TGF- b [24].
In addition, growing evidence suggests the existence
of a new subpopulation of macrophages known as
M4, originating from M0 macrophages that alter their
behavior in the presence of CXCL4 to produce CD68,
IL-6, TNF- a, Myeloid-Related Protein-8 (MRP8) and
Matrix Metalloproteinases (MMP) 7 and 12 [25–27].
M4 phenotype is more strongly expressed in patients
with lepromatous leprosy, suggesting that this subpo-
pulation is less effective in eliminating the bacillus,
favoring disseminated presentations [28].
IL-37 expression in the skin of leprosy patients was
measured in keratinocytes, endothelial cells, macro-
phages and lymphocytes, revealing higher secretion
than in the controls. In keratinocytes, endothelial cells
and lymphocytes, the level of IL-37 were even higher
in lepromatous than in tuberculoid leprosy. IL-37
induces inhibitory mechanisms that negatively regu-
late the production of TNF-a, IL-6 and IL-1b in mac-
rophages and T lymphocytes in the dermis [29,30].
Hence, the predominance of IL-37 expression in lep-
romatous leprosy might be related to the M2 macro-
phages phenotype, since IL-37 has already been
shown to induce differentiation into the M2 pheno-
type through production of the CD206, CD86, TGF-b,
IL-10 and Arginase 1 in studies with M. tubercu-
losis [31].

Curiously, a higher expression of genes related to
the phagocytic activity was observed in macrophages
in disseminated leprosy, whereas in limited leprosy,
genes linked to microbicidal pathways related to vita-
min D metabolism were more highly expressed [32].
Immunohistochemistry studies have also shown that
macrophages in disseminated leprosy express CD209
– a scavenger receptor with an affinity for both LDL
cholesterol and M. leprae, thus reinforcing the belief
that there is indeed more intense phagocytic activity
in lepromatous leprosy. The explanation proposed for
that apparent contradiction is that the increase in the
phagocytic capacity of macrophages might somehow
reduce their microbicidal activity, subsequently limit-
ing their ability to control the infection [32].
An important role in the immune response to M.
leprae has been attributed to the Toll-Like Receptors
(TLRs) – a type of molecular pattern recognition
receptor (PRR) found in monocytes and dendritic
cells. TLR 2 and 4 recognize the leprosy bacillus, thus
leading to secretion of IL-12 – an interleukin that
induces the production of other pro-inflammatory
cytokines and elimination of the bacillus [10,11,33].
One genetic variation, more strongly associated with
the lepromatous presentation, has been described on
the gene coding for TLR2 [34]. A functional genetic
study has shown that a loss-of-function mutation at
this receptor causes less production of IL-12 by mac-
rophages in response to M. leprae [11], suggesting
that eventual genetic polymorphisms in this receptor
might also affect the natural history of the disease.
The presence of dendritic cells in tuberculoid and
lepromatous lesions was assessed via immunohisto-
chemistry techniques using the CD1a and CD207
markers, revealing a higher number of dendritic cells
in the tuberculoid pole, therefore suggesting that the
presence of such cells favors a more efficient immune
response against M. leprae [35]. It has also been
reported that stimulation of TLR2 in limited presenta-
tions elicited both CD209þ macrophages and
CD1b þ dendritic cells, whereas, in disseminated presen-
tations, TLR2 activation elicited CD209þ macrophages,
but not CD1b þ dendritic cells. This finding suggests
that a failure in activating CD1b þ dendritic cells might
also be at the root of disease dissemination [33].
Also relevant to the response to M. leprae is the
fact that Schwann cells can process and present anti-
gens to CD4þ T cells, triggering an inflammatory
process that is harmful to Schwann cells, leading to
demyelination of peripheral nerves and neural lesions
[36,37]. M. leprae also stimulates the inflammatory
response by increasing the sensitivity of the Schwann
INTERNATIONAL REVIEWS OF IMMUNOLOGY 3
cell to the pro-inflammatory cytokine TNF-a, via
induction of the expression of transmembrane TNF-a
and the TNF-a receptor in these cells [38].
The role of the inflammasome in leprosy has also
been studied. A component of the innate immune
response, the inflammasome is a complex of cytosolic
proteins that mediate the inflammatory response
through molecular patterns associated with pathogens
(PAMPs) and molecular patterns associated with dam-
age (DAMPs), the latter being responsible for the mat-
uration of caspase 1, secretion IL-1b and IL-18, as
well as a type of cell death called pyroptosis [39–41].
Greater expression of inflammasome markers in lep-
romatous lesions has been reported, compared to
indeterminate and tuberculoid presentations, pointing
to the inefficiency of this protein complex in control-
ling the infection [42].
Certain genetic polymorphisms in the vitamin D
receptor (VDR) have been associated with limited lep-
rosy, whereas others have been seen in disseminated
cases [12]. The VDR receptor is constitutively
expressed in macrophages and dendritic cells and can
induce the secretion of IL-1 and cathelicidin (an anti-
microbial peptide), thus meaning that it plays a role
in the innate response against some bacteria [12].
Thus, it is reasonable to assume that polymorphisms
associated with greater activation of this microbicidal
pathway may favor the development of more effective
immune responses against the bacillus, whereas poly-
morphisms that cause less activation of the VDR
microbicidal pathway should favor the dissemi-
nated disease.
The T cell response to M. leprae
As a consequence of the Th1/Th2 leprosy paradigm,
the cytokine profile found at each pole differs, with a
greater expression of Th1 cytokines (such as IL-7 and
IL-15) in patients with tuberculoid leprosy, and
greater expression of Th2 cytokines (such as IL-4, IL-
5, IL-10 and the transforming growth factor [TGF-b])
in patients with disseminated presentations [43,44].
Blood measurements of leprosy patients have also
shown that, after stimulation with recombinant anti-
gens from M. leprae, there is a predominant induction
of Th1 cytokine secretion (IFN-c, IL-2 and IL-12) in
limited presentations, and Th2 cytokines (IL-4, IL-5
and IL-6) in disseminated presentations [45].
Accordingly, the expression of the transcription fac-
tors involved in Th1 cytokine signaling pathways,
such as STAT1, STAT4, JAK2 and NFjB, has been
found at higher levels in tuberculoid leprosy [46].
4 L. A. R. FROES ET AL.
Beyond the classic Th1/Th2 paradigm, studies have
shown differences along the spectrum also regarding
Th9, Th17, Th22 and Treg cells [47–51]. The role of
Th9 lymphocytes, for example, was assessed in a study
that demonstrated higher levels of IL-9 at the tubercu-
loid pole, suggesting that this cytokine has an antag-
onistic function to IL-4 and IL-10, switching the
immune response from pole Th2 to pole Th1 [52].
The potential role of T helper 25 (Th25) cells in lep-
rosy has also recently been evaluated using monoclo-
nal antibodies against cytokines typical of the Th25
response, such as IL-4, IL-13, IL-25 and IL-17E. These
cytokines, which stimulate a Th2 response, were
found in significantly higher concentrations in
patients with disseminated presentations [53].
T Helper 17 cells are similar to Th1 cells in that
they both produce pro-inflammatory cytokines, most
prominently IL-17, and have also been associated with
the development of leprosy reverse reactions [54–56].
An increase in the expression of IL-17 in tuberculoid
leprosy was also reported, contributing to the recruit-
ment of inflammatory cells, activation of endothelial
cells and maintenance of the chronic inflammatory
process [57]. It is believed that the Th17 response may
play a critical role in modulation of macrophage activ-
ity, as IL-17 can induce production of TNF-a, IL-6 and
iNOS, leading to the generation of reactive oxygen spe-
cies (ROS) that should destroy the bacillus [58,59].
T helper 22 cells (Th22) have been recognized as
an important subpopulation involved in the immune
response to infections. These cells are part of a group
of CD4þ T cells that produce isoforms of the
Fibroblast-Growth-Factor (FGF) family and cytokines
such as IL-22, TNF-a, IL-13 and IL-26 [60–64].
Studies have evaluated the existence of IL-22 in lep-
rosy lesions, revealing the presence of this cytokine in
disseminated, rather than limited, presentations
[65,66], even though IL-22 is known to act on macro-
phages stimulating phagolysosomal maturation and
fusion. The release of IL-22 in these cases might be an
alternative attempt to stimulate macrophage phago-
cytic activity, which is compromised by M. leprae’s
immune escape mechanisms [65]. Furthermore, the
increase in FGF-b in lepromatous leprosy reinforces
the crucial role of the aforementioned growth factor
in the healing response, since this clinical presentation
is associated with a higher number of lesions and
more extensive tissue damage [65,67].
Regulatory T cells (Tregs), phenotypically charac-
terized by the expression of CD4, CD25 (interleukin-2
receptor [IL-2R]) and the transcription factor FOXP3,
have been receiving particular attention. They
comprise 10% of the CD4þ T cell population in the
human peripheral blood [68] and have been shown to
suppress cellular immune responses, both through dir-
ect contact with immune effector cells and through the
production of regulatory cytokines, such as TGF-b and
IL-10, thus playing an important role in maintaining
immune self-tolerance and homeostasis [69–75].
In leprosy, Treg cells are more abundantly found in
patients with lepromatous leprosy, who also display
an increased expression of IL-10 and CTLA-4, thus
suggesting that these cells may have a pathogenic role
in disseminated presentations [69,76–81]. One single
study, however, has reported a higher frequency of
Tregs in tuberculoid leprosy than in lepromatous lep-
rosy [82], making the precise role of such cells still
unclear. It has also been shown that Tregs in local-
ized leprosy produce more IL-17 (proinflammatory
cytokine) and less IL-10 (regulatory cytokine), result-
ing in a microenvironment that favors inflammation
over-regulation and enhances tissue damage [83].
Similarly, a higher concentration of IL-17 in limited
leprosy has also been described, in association with
higher expression of TGF-b (regulatory cytokine) in
disseminated leprosy [84].
Still, with regard to Tregs, an increase in Interleukin
35 (IL-35) has been reported in leprosy patients, dir-
ectly proportional to the skin bacilloscopy index. IL-
35 is a potent immunosuppressive cytokine secreted
by Tregs, which functions as an important immuno-
suppressive factor in immune-mediated diseases,
inhibiting T cells’ proliferation and production of
IFN- c, TNF-a and IL-2. One of the suppressive
mechanisms is based on the expression of the inhibi-
tory molecule Programmed cell Death-1 (PD-1) on
the surface of Tregs, which is more evident in disse-
minated leprosy [85].
A difference has also been described between the lep-
rosy poles in terms of the expression of the adhesion mol-
ecules E-selectin and P-selectin, as well as the integrins
VCAM-1, ICAM-1 and VLA-4. Immunohistochemistry
studies have shown a greater expression of these molecules
in endothelial cells and leukocytes in tuberculoid than in
lepromatous leprosy [86,87]. The expression of these mole-
cules is mediated by Th1 cytokines such as TNF-a, IFN-
c and IL-1, thus meaning that the higher production of
the aforementioned cytokines in tuberculoid leprosy
should be accountable for the higher expression of selec-
tins in these cases. As a consequence, the deficiency of
these cytokines observed in lepromatous leprosy should
reduce the migration of T cells to the tissues [86,88].
Finally, B-cells are also found in infiltrates of
inflammatory leprosy lesions, even though their role is

poorly understood [89]. A study comparing the gene
expression profile in tuberculoid and lepromatous
lesions showed that disseminated disease was associ-
ated with increased expression of multiple pathways
and functional groups related to B-cell genes,
increased frequency of plasma cells (CD138þ), and
increased expression of IL-5 and IgM levels in the
lesions, consistent with the fact that lepromatous lep-
rosy is closer to the Th2 pole [90].
Immunology of leprosy reactions
Leprosy reactions are episodes of acute hypersensitiv-
ity presenting as aggravation of the previous lesions
or the appearance of new ones, occurring before, dur-
ing or after treatment [91,92]. Most commonly, lep-
rosy reactions happen in disseminated presentations
during the first three months of treatment and cur-
rently represent the main complication of the disease,
requiring immediate treatment to prevent permanent
neural damage [93]. They can be of two types: reverse
reaction (RR) or erythema nodosum leprosum (ENL).
RR occurs in approximately one-third of patients with
the borderline presentation, whereas ENL occurs in
around 50% of patients with lepromatous and 10% of
patients with borderline leprosy [51], especially in
those with a skin bacilloscopy index equal to, or
greater than, 4 þ [94].
RR is a type IV hypersensitivity reaction, character-
ized by an exacerbation of the cellular immune
response against M. leprae. If, on the one hand, this
reaction leads to an enhanced elimination of bacilli,
on the other hand, it causes an exacerbation of the
inflammatory process and disease symptoms, includ-
ing neural damage [51,95]. These lesions are charac-
terized by the presence of cellular infiltrate composed
predominately of CD4þ T lymphocytes, as well as
CD163þ macrophages [96]. The CD4þ T cells found
in the skin and neural lesions release TNF-a and IFN-
c, leading to the pain and edema typically observed in
RR [97,98]. A higher expression of cytokines such as
IL-12, IL-1b and IL-2 has also been described in RR,
in addition to the monocyte-1 chemotactic protein
(MCP-1), all associated with Th1 responses [99,100].
It has also been shown that, in RR, similar to tubercu-
loid leprosy, there is an increase in the expression of
genes related to the production of IFN-c, such as
genes involved in the vitamin D-mediated antimicro-
bial pathway [19].
In terms of ENL, it is characterized by a systemic
inflammatory process related to an extravascular
deposition of immune complexes (IC) and a
INTERNATIONAL REVIEWS OF IMMUNOLOGY 5
neutrophilic infiltrate. It is not yet clear whether the
IC mediates a type III hypersensitivity reaction or
whether their presence is only an epiphenomenon
[101]. Since this reaction occurs more commonly in
patients with borderline and lepromatous presenta-
tions, it is possible that a large number of antigens
and the higher production of antibodies, typical of
Th2 responses, may contribute to the formation of
these immune complexes [51,102,103].
ENL is also characterized by the presence of high
levels of TNF-a, both in lesions and in the peripheral
blood [104], in addition to the cytokines IL-2, IL-4,
IL-5, IL-6 and IL-10, typical of Th2 responses [100].
Successful use of anti-TNF therapy with infliximab
and etanercept has been reported in three patients
with ENL, providing additional evidence on the
inflammatory role of TNF-a in the process
[96,105,106]. The use of thalidomide in the treatment
of these patients is also believed to be based on TNF-
a suppression [58].
CD64 (FccRI), a high-affinity receptor for mono-
meric IgG1 and IgG3, present on the surface of neu-
trophils, was described in higher levels in ENL
patients than in patients with lepromatous or border-
line presentations, potentially serving as a biomarker
for ENL and severe disease [107]. It is believed that
the increase in CD64 expression during ENL might be
induced by cytokines such as IFN-c and GM-CSF
[108], or by intracellular antigens from bacilli
destroyed with treatment [107], consistent with the
fact that the incidence of ENL is maximal during
treatment when intense bacterial destruction is taking
place [109].
Finally, T cells also seem to play a role in ENL;
indeed, several studies have reported an increase in the
CD4/CD8 ratio both in the skin and in the peripheral
blood, with a reduction in the ratio being noted when
patients are treated, and an increase when disease
relapses [110–114]. ENL is also characterized by a
Th17 pattern of an immune response, with high
expression of the pro-inflammatory cytokine IL-17 and
marked reduction of Tregs [115], thus suggesting that
suppression of Tregs gives rise to pro-inflammatory
responses mediated by Th-17. Indeed, treatment with
thalidomide has already been shown to inhibit Th17
response [58].
Complement system in leprosy
The role of complement in leprosy has been assessed
in the past [116–118]. Complement C3 fraction levels
were found to be reduced in patients with ENL, with
6 L. A. R. FROES ET AL.
no changes in lepromatous control patients. This
reduction in C3 provides support to the theory that
ENL is an IC-related reaction, similar to diseases such
as lupus or acute glomerulonephritis, which also pre-
sent with complement consumption [17,118–120].
Moreover, it has been suggested that there is a hyper-
catabolism of complement in ENL since the C3d
metabolite levels were found to increase by 70%,
whereas only an 18% increase was seen in uncompli-
cated lepromatous patients [121,122].
A Brazilian study with 109 patients analyzed the
association between leprosy, leprosy reactions and the
complement proteins BF, C2, C4A and C4B, showing
that all patients with C4B deficiency developed ENL
[119,121]. C4 deficiency has also been associated with
lupus erythematosus, thus suggesting that this factor
might play a role in the removal of ICs from the cir-
culation [121]. Interestingly, another study reported
that M. leprae only induced activation of the comple-
ment system when its cellular integrity was lost, with
intact bacillus unable to activate the complement
[123], thus supporting the notion that the release of
antigens from destroyed bacilli during treatment
might trigger reactions.
Serological testing
The main leprosy control strategies are still based on
early diagnosis and treatment, to halt its spread and
prevent, or, at least minimize, permanent damage.
However, there is currently no serological analysis
that, in isolation, could be adopted as a reliable tool
for diagnosis of the disease [6,124–127]. In this
regard, some specific antibodies against M. leprae
have been studied as potential markers [6,124–127],
with particular attention paid to the phenolic glycoli-
pid-1 (PGL-1) [128]. Multibacillary subjects produce
large amounts of IgM-specific anti-PGL-1, and this
production is proportional to bacterial load, although
with relatively low sensitivity. The average sensitivity
for multibacillary individuals is 78% and for the pau-
cibacillary only 23% [6,129,130].
The correlation between serum levels of anti-PGL-1
IgM antibodies and reaction episodes has also been
studied. A comparative analysis between patients with
RR, ENL, uncomplicated leprosy and healthy controls
showed a significantly higher amount of anti-PGL-1
antibodies in ENL patients compared to all the others
[131]. Accordingly, another study found serum levels
of anti-PGL-1 IgM and IgG to be low or absent in RR
patients [132]. Seropositivity for anti-PGL-1 was also
higher among borderline patients who subsequently
developed RR, thus suggesting a possible predictable
role for that kind of reaction too [133]. These findings
were confirmed by another investigation with 440
patients, which also revealed that a positive PCR for
M. leprae DNA at the time of diagnosis is a risk factor
for reverse reactions. In addition, reactions were more
frequent among patients who, by the end of treat-
ment, remained positive for anti-PGL-1 serology or
M. leprae PCR [134], with a 10.4-fold increase in the
risk of reactions after treatment [135].
A large cohort of 753 patients, however, showed
divergent results. This study did report that reactions
after diagnosis were more commonly seen in individu-
als with a positive skin bacilloscopy index prior to
beginning the treatment, although with no significant
relation between anti-PGL-1 levels and leprosy reac-
tions. Also, statistical analyses in this study did not
demonstrate significant sensitivity or specificity for
anti-PGL-1 serology in the diagnosis of leprosy reac-
tions [136].
Furthermore, two antigens called ML0405 and
ML2331, originating from a fusion protein, were
developed and named “Leprosy IDRI diagnostic-1”
(LID-1), with increased sensitivity [125, 137,138].
LID-1 was fused to PGL-1, forming the NDO-LID
molecule, which also showed higher sensitivity
compared to its isolated components [139,140]. A
different study assessed anti-PGL-I, anti-LID-1 and
anti-NDO-LID antibodies as predictors of type I
reverse reaction, revealing low positive and negative
predictive values for the reaction. The same study,
however, suggested the usefulness of anti-LID-1 ser-
ology as a predictor of the development of ENL in
multibacillary patients [102,141].
Conclusion
Leprosy’s clinical manifestations are characterized by
its bipolar spectral presentation, with a strong correl-
ation between the immune system branch (Th1/Th2)
most prominently activated and the clinical picture.
The very low genetic variability found in the M. leprae
genome strongly suggests that the immunological
response depends mostly on the host, rather than on
variations in the pathogen. Indeed, some genetic stud-
ies have already demonstrated a correlation between
certain haplotypes and specific clinical manifestations,
even though the immunogenetic determinants of the
natural history of the disease are still far from being
fully known [11,12, 69,70].
The cornerstone of the elimination and control of
leprosy has primarily consisted of improving access to

health care, combined with a better ability to screen
the cases and diagnose them early. A study indicated
that Brazilian patients begin treatment, on average,
1.5–2 years after the appearance of the first symptoms,
and the delay is credited, at least in part, to the lim-
ited clinical skills of the health workers [142]. In this
regard, comprehension of the immune response to the
disease could offer new opportunities for early diagno-
sis and treatment, control of reactions and permanent
damage, prevention of physical disabilities, and block-
ing of the transmission of disease – aspects which
have been neglected in many parts of the world for
so long.
Funding
Fundo de Apoio a Dermatologia de S~ao Paulo – Sebasti~ao
Sampaio (FUNADERSP) da Sociedade Brasileira de
Dermatologia.
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