Advances in Infectious Diseases, 2013, 3, 35-43
http://dx.doi.org/10.4236/aid.2013.31004 Published Online March 2013 (http://www.scirp.org/journal/aid) 35
Considerations for Erythema Nodosum Leprosum, with
Emphasis on Its Oral Manifestations
Antonio Carlos Vinhas1*, Roberto Meyer Nascimento2
1Interactive Processes in Organs and Systems Program, Concentration Area in Biosafety (PPGORGSISTEM), Salvador, Brazil;
2Immunology Institute of Sciences and Health (ICS-UFBA), Salvador, Brazil.
Received September 25th, 2012; revised October 28th, 2012; accepted November 29th, 2012
ABSTRACT
Leprosy is an infectious disease caused by Mycobacterium leprae, transmitted from person to person through contact
among susceptible untreated patients. It presents a broad clinical spectrum which is related to the host’s ability to mount
a specific immune response. The lesions caused by the proliferation of Mycobacterium leprae (M. leprae) were sig-
nificantly reduced in recent years with the early detection of new cases. Because they are less evident and/or study,
maxillofacial injuries and the oral mucosa may reveal important details about the transmissibility and immuno-
pathogenesis of leprosy. This article was based on a literature to verify an interrelation between oral manifestations in
virchowian patients and immuno-pathological factors. Association between the infection of oral mucosa and some
pathological findings as well as the participation of the local immune response in protection against the disease are
research topics still not fully ex ploited.
Keywords: Leprosy; Hansen Disease; Oral Manifestation
1. Introduction
Leprosy is an infectious-contagious disease caused by M.
leprae, transmitted from individual to individual through
the contact with contagious patients without treatment. It
presents a broad clinical spectrum that is related to the
ability of the host to mount an immune response. The
main local of entry of the Bacillus are the upper airways.
There is still much to learn about the cellular and mo-
lecular mechanisms responsible for the ineffectiveness of
the cellular immune response in leprosy. It is known,
however, that there are changes in the processing of an-
tigens and the production of some interleukins. Immune
response in leprosy involves all major components of the
immune response, such as macrophages, various inter-
leukins, T lymphocytes and their subpopulations, NK
cells, B lymphocytes and antibodies. The cytokines re-
leased by macrophages activated by M. leprae, perform
various effects in cells of the immune system, helping to
increase the effector mechanisms of the site of inflamma-
tion.
In leprosy, as well as in other infections where the
macrophage is the main target of the parasite, the mecha-
nism of immune response that determines cure or disease
relates to types of cytokines produced by the immune
system, where the predominance of Th1 profile deter-
mines the tuberculoid form, while Th2 profile leads to
lepromatous form. So a great difficulty for the control
and management of the disease is the occurrence of lep-
rosy reactions. The cellular responses are related to the
pathogenesis of reverse reactions. Several reactional
stages are produced by a variety of immune mechanisms
that give rise to severe tissue damage in the course of the
clinical figure of the patient. Leprosy reactions are re-
lated to the exacerbation of cellular immunity, or demon-
strate marked effects of immune-complex formation,
called reaction type 1 and type 2, respectively [1].
The identification of specific lesions in the oral cavity
in leprosy patients becomes of great importance, as well
as the relevance of an imunopathology study, considering
the scarcity on the subject in literature. There are many
reports that discuss oral lesions, however there is a di-
vergence about the region of the same.
Authors report that skin lesions are concomitant with
oral lesions. Indeed so far not found. Furthermore, were
found a few reports about the role of cytokines expressed
in the oral mucosa.
2. Series of Problem
Leprosy is considered still today one of the biggest pub-
lic health problems. The World Health Organization
*Corresponding a uthor.

Considerations for Erythema Nodosum Leprosum, with Emphasis on Its Oral Manifestations 36
(WHO), after the introduction of multidrug therapy
(MDT), had established the goal of elimination of the
disease by the year 2005, i.e. the reduction of the preva-
lence rate of 1 for every 1000 inhabitants, unfortunately
not met. Brazil continues occupying the second place in
the world in prevalence of this disease, with an estimated,
6.72 patients/10,000 inhabitants and with prevision of
45,000 new cases annually. Although b eing as the second
largest endemicity in the world, has contributed signifi-
cantly to these statistical changes. In the State of Bahia,
considered of an average prevalence in Brazil, was de-
tected an increase in incidence, preocupating fact due to
the difficulties for the low class inhabitants regarding the
diagnosis and treatment of disease [2].
Brazil, according to a study by Penna [3], provides a
downward trend statistically significant, in time for the
time series of coefficients of detection.
However, in the period 1990-2008, this coefficient
ranged from 20.0/100,000 inhabitants in 1990 and 29.4/
100,000 inhabitants in 2003, presenting a “very high”
classification according to the official parameters. How-
ever, the North, Northeast and Midwest still maintain
rates at very high levels. Brazil, according to a second
trend study, presents a decreasing tendency statistically
significant downward trend, in time for the time series of
coefficients of detection [4].
The State of Bahia, according some data, presents later
decreasing trend, statistically significant in time to the
time series of coefficients of detection. However, in the
period from 1990 to 2008, this coefficient ranged from
7.52/100,000 inhabitants in 1991 and 29.32/100,000 in-
habitants in 2003, sho wing a “high” rating for th e second
period, less than the official parameters found in Brazil
[4] (Tables 1 and 2).
The active record of the coefficient of prevalence per
10,000 inhabitants in 2000 was 1.5 (in the State) and
1.3(in the capital), increasing to 2.4 and 4.0 , respectively,
in the year 2002. While the coefficient of incidence in
this same period ranged from 1.3 to 1.2 in the State, and
from 1.2 to 0.8 in the capital [5 ].
Table 1. Leprosy situation in countries that have not yet
reached the goal of elimination of disease-prevalence and
incidence recorded during 2004, 2005 and 2006.
Prevalence
(per 10,000 inhabitants) Incidence (per 100,000 inhabitants)
Country2004 2005 2006 2004 2005 2006
Brazil 79.908
(4.6) 30.693 (1.7) 27.313 (1.5) 49.206 (28.6) 49.384 (26.9) 38.410 (20.6)
Source: Marzliak, 2006.
Table 2. Situation in Brazil early 2005.
Country Prevalence IncidenceNew Cases— Children (absolute
numbers)
Relapse (absolute
numbers)
Brazil1.7 26.9 4193 1606
Source: BRAZIL. The Ministry of health. National Leprosy Control Pro-
gramme. Availabl e in:
http://portal.saude.gov.br/portal/saúde/visualizar_texto.cfm?idtxt=21149.
Access in: Dec. 20, 2008.
The reduction of cases in children under age 15 is the
priority of the National Leprosy Control Programme
(PNCH), being an indicator of leprosy in the PAC—
More Health. The detection of cases in this age group has
to do with recent disease outbreaks and transmission as-
sets and its epidemiological monitoring are relevant to
the control of leprosy [6].
The detection coefficient in Bahia in this age group in
the period from 2001 to 2008, presented a “high” rating
(Table 3). The spatial distribution of cases in children
under 15 years old in 2008 shows that there has been
notification of children in 65 (15.6%) counties of the
State, which are surrounded by silent areas or without
cases. It is worth noting that the municipalities of this
State are entered in ten areas of increased risk of detec-
tion of leprosy cases, defined by the study of clusters.The
parameters in Priority Actions of health Surveillance
Programme (PAV) it is observed that the average per-
centage when assessed the degree of disability (GIF) in
Table 3. Epidemiological and operational indicator of leprosy in Brazil, 2001 to 2008.
2001 3.555 6.96 45.874 26.61 84.7 6.0 64.7 67.9 81.6
2002 3.862 7.47 49.438 28.33 84.2 5.9 63.1 68.0 75.8
2003 4.181 7.98 51.900 29.37 84.9 5.6 60.9 52.7 69.3
2004 4.075 7.68 50.565 28.24 84.8 5.8 60.4 43.9 67.3
2005 4.010 7.34 49.448 26.86 85.5 5.8 58.9 45.5 69.2
2006 3.444 6.22 43.642 23.37 86.6 5.7 60.6 49.7 85.5
2007 3.048 6.07 40.126 21.19 83.0 9.4 55.1 49.8 81.1
2008 2.910 5.88 38.992 20.56 88.2 7.7 67.8 54.3 79.4
Source: B RAZIL. The Ministry of he alth. National Leprosy Control Pr o gramme. Available in :
http://portal.saude.gov.br/portal/saúde/visualizar_texto.cfm?idtxt=21149. Access in: Dec. 20, 2008.

Considerations for Erythema Nodosum Leprosum, with Emphasis on Its Oral Manifestations 37
the diagnosis was 87.3% for this period, considered as
“regular”. GIF 2, important indicator of early detection,
fluctuated between 3.1% and 8.5%, showing rating of
“low” to “medium” in the period, according to parame-
ters. The evaluation of the GIF in healing was considered
“pre-carious” in the period, with an average of 47.7%
evaluated. The proportion of the examined contacts sho w-
ed an average of 40%, varying from 69.7% in 2001 and
30.2% in 2008, keeping up with the classification “pre-
carious”. The percentage of healing in cohorts showed an
average of 68.7%, considered “precarious”, oscillating
between 60% in 2003 and 80.2% in 2006 (Table 4).
3. Clinical Manifestations in Leprosy
Few diseases present a broad spectrum of pathological
and clinical forms regarding leprosy, where we can find
patients with a single injury that heal spontaneously, as
well as individuals with generalized injuries configuring
a severe and extensive form of the disease. The classifi-
cation of Madrid divided the leprosy in two polar groups:
tuberculoid and lepromatous, and other classified as in-
determinate and borderline.
In 1966, Ridley and Jopling divided the spectrum into
five groups based on clinical, pathological and immu-
nological factors, such as being: Tuberculoid (TT), bor-
derline Tuberculoid (BT), borderline-borderline (BB),
borderline Lepromatous (BL) and lepromatous-Lepro-
matous (LL). The indefinite and neural forms are off this
classification.
For outpatient work purposes in the field, WHO sim-
plified the classification of patients into paucibacillary
(PB), to individuals who presented negative baciloscopy
and/or up to 5, skin lesions, and multibacillary (MB) for
individuals with positive baciloscopy and widespread
injuries [1].
According to these authors neural lesions usually pre-
cede the skin lesions. Occur exclusively in the peripheral
nervous system (PNS). The first manifestations are the
sensitive, being the first anatomical structures committed
the neural “ramuscles” (distal components of PNS), pro-
gressing to proximal direction, affecting secondary ner-
ves, and, finally, the peripheral nerve trunks. These be-
come swollen, pain f ul to palpation or percu ssion.
Classification as indeterminate refers to the initial state
in which the histologic and clinical form is uncertain.
The cutaneous lesion presents as poorly defined macules,
hypopigmented and thermal hypoaesthesia region, can
occur changes of sens ibility tactile sensitivity an d painful.
The patient’s immune potential is not evident in the le-
sions in this form of leprosy.
At this stage of the disease the patient, according to the
potential of immune response can progress to the various
forms of the spectrum, but can also occur spontaneously
cure.
In tuberculoid form, lesions are isolated or infrequent,
macular or infiltrated. Patients present hypopigmented
lesions distributed asymmetrically.
On the face, due to the rich innervation, hypoesthesia
can be difficul t to be det ected.
In borderline or dimorphic, we find a mixture of ele-
ments of the two poles of the disease, i.e. the leproma-
tous or tuberculoid form.
Antibodies are in low concentrations, when detected,
whereas the cellular immunity remains or is exacerbated.
Most patients with Hansen’s disease develop the form
borderline, which is immunologically unstable. Accord-
ing to the clinical data, the bacteriological test among
others, these patients tend to present themselves as di-
morfotuberculi des or borderl ine-lepr o matous.
In lepromatous leprosy or wirchovian in the character-
istic form of dissemination, the lesions show no defined
Table 4. The detection coefficient in Bahia in this age group in the period 2001 to 2008.
Indicators/
Year New cases 0 - 14 age
Detection Coefficient
0 - 14 years/100
milinhabitants
New cases
total
Coefficient
Detection General by
100,000/inhabitants
% evaluated
as to GIF in
diagnosis
% of patients
with GIF 2 in
diagnosis
% Evaluate as
GIF in healing % of Contacts Examined
2001 3.555 6.96 45.874 26.61 84.7 6.0 64.7 67.9
2002 3.862 7.47 49.438 28.33 84.2 5.9 63.1 68.0
2003 4.181 7.98 51.900 29.37 84.9 5.6 60.9 52.7
2004 4.075 7,68 50.565 28.24 84.8 5.8 60.4 43.9
2005 4.010 7.34 49.448 26.86 85.5 5.8 58.9 45.5
2006 3.444 6.22 43.642 23.37 86.6 5.7 60.6 49.7
2007 3.048 6.07 40.126 21.19 83.0 9.4 55.1 49.8
2008 2.910 5.88 38.992 20.56 88.2 7.7 67.8 54.3
Source: B RAZIL. The Ministry of Health. National Leprosy Control Programme. Available in: Disponível em:
http://portal.saude.gov.br/portal/saúde/visualizar_texto.cfm?idtxt=21149. Access: Dec. 20 2008.

Considerations for Erythema Nodosum Leprosum, with Emphasis on Its Oral Manifestations 38
boundaries. Even in this form of the disease we can ob-
serve that, in particular, rhinitis occurs early and sp ecific,
by diffuse infiltration, sometimes with “hansenomas”,
later, ulceration and perforation can occur and collapse of
the nasal septum.
4. Oral Manifestations
Little emphasis was given to Oral lesions in leprosy. A
greater interest started in 1930 with Pavloff [7]. This
author published papers regarding lesions in the nose and
mouth, followed by other papers drew attention of loca-
lized lesions in the mucous membrane of the lips, cheek
and neck [8 -10].
Pavloff shows a higher frequency of lesions in the soft
palate, uvula and pillars of the fauces. There were no
elements of prominence observed in the cheek and gum.
On the lips and tongue nodu les were detected in skin an d
mucous board. This author also reported several isolated
tubers at the end and sides of the tongue, and sclerotic
glossitis, geographic tongue and increase in fungiform
papillae.
In most published papers there was always a higher
incidence of injury in the hard palate, soft palate and
uvula, in descending [7,9,11-16].
Most of these works refers to lepromatous patients, or
patients in the intermediate form tending to lepromatous
pole.
The most frequent types of lesions observed in these
studies were: infiltration, hansenomas and exulcerations.
Some studies did not correlate these lesions with M. le-
prae, and do not cite specific lesions of leprosy patients.
However, there are few studies that included an im-
munohistochemical study of the oral mucosa.
The study of positive bacilloscopy in oral mucosa in
material apparently healthy has been cited by authors in
1939, reviewing 456 lepromatous patients and other
clinical forms, found an overall frequency in the lepro-
matous, 19.1% of lesions in the oral cavity, and 2.09%
on the lips, 1.4% tongue, 11.7% in the hard palate, 5.9%
soft palate and 3.2% in the uvula.
The changes that MH may present in the oral cavity
were described in 1970 from the form of the disease and
its time evolution. A study conducted in 1973 found the
MH lesions in the oral mucosa, reporting that they only
occur in later stages of the disease, inexisting in tubercu-
loid and indeterminate forms. The majority of the authors
mention the nasal mucosa as the main site of contamina-
tion and elimination of Hansen bacilli. With the advent
of specific medication initiated at the sulphonis time, has
been admitted to the disappearance of the early disap-
pearance of these manifestations in the duration of ther-
apy. Few researchers gave emphasis on leprosy lesions in
the oral cavity, a reason why, in the prophylactic sense,
little has been done in the field of dentistry.
Regarding the involvement of the oral mucosa in lep-
rosy, few studies have been conducted on the specific
lesions in this area and, although scarce, the work fo-
cused on the field have attracted the attention of resear-
chers.
The authors call the attention of health professionals
who work with leprosy, as well as dentists, for the spe-
cific lesions of the disease in the oral mucosa [17].
5. Aspects of the Immune Response in
Leprosy
5.1. General Aspects
Little is known of these factors that defend against infec-
tion and disease after exposure to m. leprae, however,
complement activation promotes phagocytosis of m.
leprae [18]. When the bacillus is in contact with phago-
cytic cells of the host, it is phagocytosed and initiate to
conduct mechanisms of intracellular changes acting in
elimination of the parasite. The nonspecific cellular
immunity has been evaluated by several tests in leprosy
patients, however, some authors report that these results
are unconformity.
Other researchers [19] by evaluating a set of tests,
consider there is a nonspecific impairment of cellular
immunity in lepromatous patient. Work undertaken by
using parameters such as counting T and B lymphocytes
in peripheral blood blast transformation of lymphocytes,
macrophage inhibition test (MIF) and prolonged allograft
survival, according to these author s, is not totally discor-
dant, thus emphasizing the cellular immune deficiency in
lepromatous patients. Evidence suggests that the system
is mycobacterial oxygen-dependent, however, other me-
thods of intracellular killing such as the oxygen-inde-
pendent system probably involved in the killing of M.
leprae in vivo [20]. There is no evidence for defects in
natural barriers skin or mucous membranes in leprosy-
susceptible individuals, and there is no established role
for IgA in the defense against M. leprae [21].
Macrophages from tuberculoid and lepromatous pa-
tients may be inefficient in the recognition and presen-
tation of some mycobacterial antigens [22]. The cellular
hypersensitivity depends on specific T lymphocyte asso-
ciated to the macrophage. This is responsible for resis-
tance to infection by M. leprae.
The main parameter for the evaluation of cellular im-
munity is the Mitsuda test. The author of this test (1919)
found that after intradermal injection with a suspension
of ground fenicated hansenomas, presented in tubercu-
loid patients a positive reaction among the first three
weeks, whereas it was negative in wirchovian patients.
According to Modlin et al. [23], the inverse correla-
tion between cellular immunity and humoral immunity
was initially investigated in terms of the adaptive im-

Considerations for Erythema Nodosum Leprosum, with Emphasis on Its Oral Manifestations 39
mune response. Different sub-populations of T-cells cor-
related with the response against M. leprae, including
CD4 and CD8 cells and the pattern of cytokines they
produce. CD4 cells produce the pattern type 1 or Th1
cytokines, including IFN-γ predominantly in tuberculoid
lepromatous lesions, whereas CD8 T-cells that produce
the pattern type 2 or Th2 cytokines, including IL-4, also
prevalent in L-lep. In this way the leprosy provides an
excellent model for the investigation of mechanisms
through which the innate immune system determines, in
man, the beginning of infectious disease.
5.2. Aspects of Innate Immunity
The innate immune system cells are provided with a cod-
ing sequence of pattern recognition receptors (PRRs),
which recognizes the molecular receptors associated to
the pathogen (PAMPs), which are shared between groups
of pathogens.
Several toll-like receptors (TLRs) mediate the innate
immune recognition of M. tuberculosis and related spe-
cies. Basically, the activation of the heterodimer TLR2/1
by lipopeptides M. leprae induce the production of cyto-
kines such as TNF-α, as part of the acute inflammatory
response and IL-12, which mediates the role of the innate
immune response to instruct the adap tive type 1 response
or production of Th1 cytokines [24].
A number of mechanisms that regulates the function of
TLR in leprosy has been identified. Besides ability to
IL-4 downregulate the expression of TLR2/1, it also in-
hibits cytokine responses induced by TLR2/1. The IL-10
has no effect on the expression of TLR2/1 but inhibits,
intensely, the secretion of cytokine induced by TLR2/1
[24].
The polymorphism in TLR1 and TLR2 genes have
been investigated in patients with leprosy, but th ere is no
convincing data to suggest that TLR1 gene polymer-
phisms may contribute to the response TLR2/1 against
lipopeptides, and the pathogenesis of the disease [25-28].
The ability of TLRs to indu ce an anti microbial activity
is the main aspect of their role in innate immunity. There
is evidence to suggest that the microbial action of vita-
min D may contribute to the onset of the disease in lep-
rosy.
Analysis of gene expression profiling in leprosy le-
sions indicated that the genes coding for the key compo-
nents in microbial pathway of vitamin D were different-
tially expressed in T-lep lesions co mpared to L-lep [29].
Leprosy has provided an interesting model to invest-
tigate the key role of human innate immune system in
host defense in relation to the susceptibility to microbial
infection, the expectation that this knowledge may con-
tribute to new therapeutic interventions for leprosy and
other infectious diseases of connotation worldwide.
6. Cytokines and T-Cell Subsets
Cytokines are mediators of mechanisms which main
function is to modulate cellular interactions and which
are peptides synthesized by cells with the potential re-
sponse after activation. Cytokines are soluble by-pro-
ducts that are T-cells which are important in mycobacte-
rial infection. The immune response of T-cells plays an
importa n t role in Ha nsen dise ase .
Today we know that human CD4 have functionally
distinct subpopulations which differ in the pattern of
production of Th1 and Th2, cellular and humoral immu-
nity, respectively.
TNF-α is the principal mediator of host responses to
Gram-bacteria, and may also have an influence on the
response of other infectious organisms. Its main source is
the LPS-activated mononuclear phagocytes, although the
T-cell of antigen-stimulated, activated NK-cells and ac-
tivated mast cells can also secrete this protein.
The biological actions of TNF, such as the LPS, are
best understood as a function of quantity. The main ac-
tions of TNF in low concentrations range from the induc-
tion of vascular endothelial cells to express new surface
receptors (adhesion molecules) that causes the endothe-
lial cell surface to become adhesive to leukocytes, ini-
tially neutrophils, subsequently to monocytes and lym-
phocytes as well as acting on neutrophils to increase its
adhesion to endothelial cells. These actions contribute to
the accumulation of leukocytes at sites of inflammation,
and physiologically, are the most important local effects
of TNF [30].
TNF activates inflammatory leukocytes to kill the mi-
crobes, stimulates mononuclear phagocytes and other
cells to produce cytokines, including IL-1, IL-6, more
TNF and chemoki nes.
Interleukin 10, produced by the T lymphocyte, Th-1
and TH-2, Langerhans cells, macrophages and keratino-
cytes are immunosuppressors and immunostimulators. In
lymphocyte Th-1, suppresses the synthesis of their cyto-
kines, decreasing cell-mediated responses, while in B
lymphocytes, increases the proliferation and antibody
production. The antigen-presenting function and the pro-
duction of TNF-α, IL-1, IL-6, IL-8 and GM-CSF is pre-
sented decreased in macrophages.
In addition to the lymphokines produced by lympho-
cytes, there are many other cytokines that participate in
cell interactions of immune su bstrates [31]. According to
the same author, the two major activities of IL-10 is to
inhibit the production of cytokines (eg. TNF, IL-1, che-
mokine and IL-12) by macrophages and inhibit the fringe
function of macrophages in the T-cell activation. This
latter effect is due to reduced expression of MHC II CL
molecules and reduced expression of certain costimula-
tory (eg. B7). The net effect of these actions is to inhibit
immune mediated inflammation by T-cells In addition to

Considerations for Erythema Nodosum Leprosum, with Emphasis on Its Oral Manifestations 40
its inhibitory effects on macrophages, IL-10 has a stimu-
latory action on B cells. On the other hand, there are in-
terleukin-4 which has as its main physiological function
the regulation of immune responses mediated by IgE and
mast cells/eosinophils. The main sources of IL-4 are T
CD4+ lymphocytes, especially those pertaining to sub-
population Th-2.
Some T CD8 cells are also capable of producing IL-4
as well as activated mast cells and basophils. IL-4 is a
factor of growth and differentiation for T-cells, particu-
larly for cells of Th-2 subpopulation, and growth factor
for mast cell, acting synergistically with IL-3 in stimu-
lating the proliferation of these cells.
Interferon-gamma, also called immune interferon or
type II is produced by células T CD4+ aand activated
CD8+ and by NK cells. IFN is a potent activator of mo-
nonuclear phagocytes. Indirectly induces the synthesis of
enzymes that mediate the respiratory effort, allowing hu-
man macrophages kill phagocytosed microbes, it is the
main activating factor of Macroph age.
Among many functions performed by IFN-γ, we know
that amplify the recognition phase of immune response
by promoting the activation of T CD4+ helper cells re-
stricted to Class II, promotes the differentiation of T
lymphocytes and stimulates the cytolytic activity of NK
cells.
The immune system cells (eg. T-cells and monocytes)
synthesize mainly TGF-
 1. Both the T-cells activated by
antigens such as mononuclear phagocytes activated by
LPS, secrete biologically active TGF-  1.
TGF-  inhibits the growth of many cell types and
stimulates others. Many times, it may inhibit or stimulate
the growth of the same cell type. As a cytokine, TGF-  is
potentially important because it antagonizes many lym-
phocyte responses [32].
6.1. Cytokines of the Tuberculoid Type
In tuberculoid leprosy, displays manifestations related to
exacerbation of the immune response that leads to gra-
nuloma formation well defined, limiting injuries and ten-
dencies for the complete destruction of the bacilli.
Many laboratories have analyzed cytokines produced
by T-cells of tuberculous patients and healthy individuals
exposed, i.e. for those with cellular immunity to M. le-
prae.
A consistent finding is that the T-cells reactivated
from M. leprae from tuberculous patients are predomi-
nantly Th-1 phenotype. They produce high levels of IFN -γ
and reduced or non-detectab le levels of IL-4 [33].
Gilka Kaplin [13], 1989, injected typ e cytokines IFN-

and IL-2 in lepromatous lesions and observed evident
signs and significant increase in degradation of M. leprae,
suggesting a possible association among the Th-1 cyto-
kines and bacterial elimination.
6.2. Cytokines in Tuberculoid Type
The lepromatous type is characterized by a deficiency in
its imunecelular response, excessive bacillary multiplica-
tion and dissemination of bacilli to the viscera and ner-
vous tissue.
The results are still not so evident on the release of
cytokines by T-cells in this type of lepros y. The question
of whether cytokines are involved in non-responsiveness
in lepromatous is important and should be examined.
Some researchers [23] studied cytokine patterns in situ
lesions through PCR test in and found that in leproma-
tous lesions for mRNAs, Th-2 cytokine were enriched by
IL-4, IL-5 and IL-10, whereas IFN-
 and IL-12 were
absent.
Padmini Salgami [34] studied the production of cyto-
kines by T-cells in lepromatous leprosy, as well as Tuna
Mutis [35] and many other researchers, saying that there
may be other sources which originated T-cells, the me-
chanisms of non-responsiveness, and perhaps other un-
known variables that may give rise to differences ob-
served in relation to the role of certain cytokines studied.
6.3. Correlation among Cytokines and Clinical
Manifestations
In addition to the clinical features, lepromatous leprosy
patients presented during a specific treatment, lepra reac-
tions, erythematous nodules, fever, asthenia, arthralgia
and other typical findings of acute inflammatory reaction
[36].
The reaction type 2—ENH—common in HIV is an
acute inflammatory reaction, systemic, involving the for-
mation of immune complexes that circulate in the peri-
pheral blood and shows its most frequent clinical mani-
festation on erythema nodosum leprosum. It affects mul-
tibacillary patients, becoming worse when related to
leprosy, being responsible for considerable morbidity,
particularly erythema nodosum recurrent. The pathology
of ENL involves deposition of immune complexes and
change in cell-mediated immune response. The episode
of ENL is triggered by the deposition of immune com-
plexes in tissues [37].
There is an increase in TNF-α which is associated with
destruction of M. leprae, granuloma formation, elevated
C-reactive protein (CRP), stimulation of acute inflame-
matory reaction, and is involved in defense, in macro-
phage activity, and the reaction of ENL, compromising
the patient's general condition (FOSS, 1993).
In an acute inflammatory response occurs an increase
in IL-1, IL-6 and TNF-α, where IL-1 and IL-6 will act on
the hepatocyte stimulating the production of proteins of
acute inflammation. Levels of IL-1 and TNF-α increase
in HT and DT, and decrease in HD and DV patients [1].
It was also observed an increase of IL-4 in lepromatous

Considerations for Erythema Nodosum Leprosum, with Emphasis on Its Oral Manifestations 41
patients. In bacillary forms there was an increase in the
concentration of antibody anti-PGL1 [30] being associ-
ated with increased IL-4 and decreased IL-1 and TNF-α.
It was also observed that during the MDT decreased in
IL-4 and anti-PGL1 (flow bacillar) and increase in TNF - α.
Immunological changes assessed in peripheral blood, or
supernatants culture compared to immunohistochemical
results showed that in patients DV and VV increased
TGF-
 1 and CD8+ cells in the infiltrate and the absence
of TGF-
 1 and increase of CD4+ cells in patients with
TD and TT.
6.4. Reactional States
Perhaps the biggest problem in handling and controlling
leprosy is the occurrence of leprosy reactions. The im-
mune-cellular responses have been questioned regarding
to be involved in pathogenesis of reverse reactions [38].
Robert Modlin [39] analyzed the cytokine patterns in
lesions type 1 and type 2, and basically, found that the
signs of cytokines, similar the type Th-1, tended to pre-
dominate in reverse reactions, whereas those of type
Th-2 were exacerbated in erythema nodosum leprosum.
Kaplan Gilda shows that TNF-α and IL-6 increases a
lot in ENL patients [35]. However, according to Otten-
hoff [38], the immunopathology of the reactions type 1
and type 2 is associated with many different cytokine
patterns.
According to Ottenhoff studies [38], cytokines Th-1
inhibit Th-2, and vice versa. Due to cytokines are impor-
tant regulators, they can provide a new form of immuno-
therapy for leprosy reactions.
The reactional episodes are acute intercurrences that
may occur in leprosy, as manifestations of the patient’s
immune system [40] and can be of two types. Reaction
Type 1, also called Reverse, more frequent in HD and
HT, which is characterized by erythema and edema of
the lesions and/or th ickening of the nerves (neuritis). And
the reaction type 2, or ENL, where the most affected pa-
tients are lepromatous. They have painful erythematous
nodes anywhere in the body. It can progress to neuritis.
The reaction type 2 is of humoral hypersensitivity and
occurs in DV and VV. It can occur in treatment-naïve
patients, but usually occurs during treatment or after
leaving the hosp ital [31].
In the reaction type 2 occurs: increase in the level of
PCR; increase ROI (reactive intermediate of oxygen)
andcytokines TNF-α, IFN-
 , IL-1, IL-5 and anti-PGL-1,
and IL-4 and TG F-
 are reduced [4].
The Ministry of Health [41] calls attention to a very
important issue related to immune response in leproma-
tous leprosy, because it was found that patients with this
type of leprosy had an extremely small amount of T-cells
responsible for production and generation of anti-My-
cobacterium leprae clones. This change is not yet com-
pletely understood, but it is believed that there is a mal-
function in the mechanism of presentation of Mycobacte-
rium leprae to lymphocytes or even the absence of lym-
phocytes reactive to the bacillus.
7. Final Comments
Besides the epidemiological differences and knowledge
still precarious, particularly on the parasite-host rela-
tionship, particularly when the generation of oral mani-
festations, the information presented enable you to view
operational problems that reveal the need for more en-
gagement of situations in the implementation of strategic
actions provided in the Pact for Life, PAVS and PAC-
More Health, to improve the integral attention to people
with leprosy, or consequences of the disease [3].
The National Program to Combat Leprosy in Brazil
was developed in response to the commitment of the
country to eliminate the disease as a public health prob-
lem, as explained by the Ministry of Health [6]. The pro-
gram is outlined in three fundamental points: the updat-
ing of data from monitoring of p atients for reliable inter-
pretation of the magnitude of the problem in Brazil, the
idea that reducing the prevalence rate and interrupt the
chain of transmission of the disease depends on early
diagnosis and treatment MDT standard and that the re-
duction of social carrying depends on early detection and
assessment of physical disability, and treatment of dis-
abilities already.
The campaign to combat leprosy is from the federal
government provides equipping Brazilians with as much
information so they can be active in prevention. The
sooner the disease is identified, the less likely conse-
quences. Every year, Brazil has 47,000 new cases of the
disease. In the first half of this year were registered 201
cases in Salvador, less than the number recorded in the
same [6].
“Leprosy is still a public health problem in the country,
but a new survey by the Ministry of Health reveals a re-
duction of 27.5% in total new cases between 2003 and
2009, going from 51,941 to 37,610. In the same period,
the number of services to patients in treatment increased
by 45.9%. Between days 25 and 31 January, the ministry
conveys the media campaign “Health is Good to Know”,
with the focus on disease. The aim is to encourage the
population to find units that makes the diagnosis and
treatment. The sooner you identif y leprosy, the lower the
chances of sequelae” [21].
“Despite the significant reduction in the prevalence
coefficient of leprosy in Bahia, which currently is 1.9
cases/10 thousand inhabitants, the state demands intensi-
fied action to eliminate the disease, justified by a stan-
dard medium endemicity according to the parameters of
prevalence” [2].

Considerations for Erythema Nodosum Leprosum, with Emphasis on Its Oral Manifestations 42
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