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Nutr Hosp. 2014;29(1):26-36

ISSN 0212-1611 CODEN NUHOEQ
S.V.R. 318

Revisin

Micronutrients influencing the immune response in leprosy

Ceclia Maria Passos Vzquez1, Raquel Simes Mendes Netto2, Kiriaque Barra Ferreira Barbosa2,
Tatiana Rodrigues de Moura1, Roque Pacheco de Almeida1,3, Malcolm S. Duthie4 and
Amelia Ribeiro de Jesus1,3
Laboratrio de Biologia Molecular. Hospital Universitrio. Departamento de Medicine. Universidade Federal de Sergipe.
Departamento de Nutrio.Universidade Federal de Sergipe. 3Instituto de Investigao em Imunologia. Institutos Nacionais
de Cincia e Tecnologia. CNPq. 4IDRI-Infectious Disease Research Institute. Seattle. WA 98014. USA.

1
2

Abstract
Leprosy is a chronic infectious disease caused by
Mycobacterium leprae, an intracellular bacillus of airborne
transmission. The disease affects the skin and peripheral
nerves and can cause neurological sequelae. The bacillus
multiplies slowly in the host and the disease probably
occurs due to malfunctioning in host immune response.
This review addresses the role of some specific micronutrients in the immune response, such as Vitamins A, D, E, C,
Zinc and Selenium, detailing their mechanisms of actions in
infectious diseases, and in leprosy. The immune response to
pathogens releases harmful substances, which lead to tissue
damage. This review discusses how a decreased level of
antioxidants may contribute to an increased oxidative stress
and complications of infectious diseases and leprosy. As the
nutrients have a regulatory effect in the innate and adaptative immune responses, a perfect balance in their concentrations is important to improve the immune response
against the pathogens.

(Nutr Hosp. 2014;29:26-36)

DOI:10.3305/nh.2014.29.1.6988
Key words: Nutrition. Leprosy. Oxidative stress and antioxidants.

MICRONUTRIENTES QUE INFLUYEN EN LA

RESPUESTA IMMUNE EN LA LEPRA
Resumen
La lepra es una enfermedad infecciosa crnica causada
por el Mycobacterium leprae, un bacilo intracelular de
transmisin area. La enfermedad afecta la piel y los nervios perifricos y causa secuelas neurolgicas. El bacilo se
multiplica lentamente en el hospedador y posiblemente la
enfermedad ocurre por el mal funcionamiento de la respuesta inmunitaria del hospedador. Esta revisin aborda el
papel de algunos micronutrientes especficos en la respuesta
inmunitaria, tales como las vitaminas A, D, E, C, el cinc y el
selenio, detallando sus mecanismos de accin en las enfermedades infecciosas y en la lepra. La respuesta inmunitaria
a los patgenos libera sustancias nocivas que producen
lesin tisular. Esta revisin tambin aborda cmo una
menor cantidad de antioxidantes puede contribuir a un
aumento del estrs oxidativo y a complicaciones de las
enfermedades infecciosas y la lepra. Puesto que los micronutrientes poseen un efecto regulador de la respuesta inmunitaria innata y adaptativa, es importante un equilibrio perfecto de sus concentraciones para mejorar la respuesta
inmunitaria frente a los patgenos.

(Nutr Hosp. 2014;29:26-36)

DOI:10.3305/nh.2014.29.1.6988
Palabras clave: Nutricin. Lepra. Estrs oxidativo y antioxidantes.

Abbreviations
WHO: World Health Organization.
SINAN: Information System and Reporting of
Health Problems.
IFN-: Interferon-.
TNF-: Tumor Necrosis Factor .
TL: Tuberculoid.
LL: Lepromatous Leprosy.
BB: Borderline.
BT: Borderline Tuberculoid.
BL: Borderline Lepromatous.
Correspondence: Amlia Ribeiro de Jesus.
E-mail: [email protected]
Recibido: 19-IX-2013.
Aceptado: 16-X-2013.

26

NO: Nitric Oxide.

ROS: Reactive Oxygen Species.
LPO: Lipid Peroxidation.
MDA: Malondialdehyde.
MT: Metallothionein.
SOD: Superoxide Dismutase.
HIV (+): Human Immunodeficiency Virus.
GPxs : Glutathione Peroxides.
VDR: Vitamin D Receptors.
TLR: Toll-like receptors.
Definition, epidemiology, clinical aspects
and immunopathology of leprosy
Leprosy is an infectious disease caused by the intracellular alcohol acid resistant bacillus Mycobacterium

04. MICRONUTRIENTS_01. Interaccin 28/01/14 16:47 Pgina 27

leprae (M. leprae).1 Its transmission occurs by upper

airway through the contact of susceptible individuals
with non-treated multibacillary leprosy patients. The
disease, affects mainly the skin and peripheral nerves,
the mucosa of the upper respiratory tract, and the eyes
of the infected persons, provoking severe deformities
that lead in many cases to mutilation and social stigma.2
According to the World Health Organization (WHO)
the global number of cases of leprosy decreased from
2003 to 2009; however, the prevalence of the disease is
still high in specific countries, such as India and Brazil.3
Epidemiological data from WHO show that there were
213,036 new cases in 2009. In Brazil there was a reduction in new cases from 2006 to 2011; however, the
country still has a rate of two or more cases per 10,000
inhabitants, still not reaching the goal of the WHO for
leprosy control (1 case/10,000 inhabitants). The northeast Brazil was the third area with the highest incidence
of leprosy cases. Among the northeast states of Brazil,
Maranho is the most affected by the disease
(68.4/100,000 inhabitants), being the fourth Brazilian
state most affected. According to data from Information system and reporting of health problems (SINAN
2010), the state of Sergipe presented a detection rate of
18.4/100,000 habitants in 2010.4 The WHO states that
the main intervention strategy is the identification of
cases and multidrug treatment.2 The global strategy by
the World Health Organization (2011 to 2015) aims at
reducing the rate of grade 2 of physical disability.3
In leprosy, a wide spectrum of clinical phenotypes is
seen.5 The Ridley-Jopling classification considers six
clinical forms: indeterminate, tuberculoid, lepromatous and borderline forms (borderline tuberculoid, mid
borderline, and borderline lepromatous borderline).
The indeterminate form (I) is determined by the
presence of hypopigmented lesions with sensory
disturbance, loss of hair and absence of horripilation.
There is no involvement of the nerve trunks and the
individuals are not contagious. The tuberculoid form
(TL) is defined by skin lesions such as plaques delimited with erythematous-brownish and elevated borders.
In this case there is activation of the Th1 response,
producing interferon (IFN)-, and tumor necrosis
factor (TNF)-, cytokines that activate macrophages to
kill the M. leprae. This clinical form is paucibacillary,
but can be associated with the presence of peripheral
neuropathy that may lead to physical debility.6-8 In the
lepromatous leprosy (LL), the skin injuries have imprecise limits. When there is a deep infiltration on the face,
with natural grooves are accentuation, and the condition is called leonine facies (lion face). In this form
there is activation of a Th2 response, producing interleukin IL-4, IL-3 and IL-10, which suppresses the Th1
response, facilitating the bacterial replication. This clinical form is multibacillary and is the most contagious of
the disease, with continuous infiltration in the skin and
nerves, leading also to neurological damage and physical disabilities.5 In the mid borderline (BB) clinical
form, patients present with well-defined plaques with

Micronutrients and immune response

in leprosy

areas of normal skin within the plaque, giving a Swiss

cheese appearance. This clinical form also tends to be
multibacillary and contagious. The peripheral nerves
are frequently compromised and this involvement is
intense and extensive. The peripheral neuropathy can
continue for many years after the clinical cure of the
disease resulting in physical disabilities. The borderline form can also present with lesions reminiscent of
the tuberculoid form (borderline tuberculoid-BT), or
the lepromatous form (borderline lepromatous-BL).6
M. leprae is a pathogen of low proliferation rate and
pathogenicity, and in the course of infection it can be
seen that the majority of the individuals do not develop
the disease. However, the factors that lead the individual to present with disease are unknown. It is an
imbalance between the cellular and humoral immune
responses that causes the different clinical forms of
leprosy. Individuals with the lepromatous clinical
forms have a predominance of the Th2 response, which
induces a humoral immune response, which is not efficient at destroying the bacillus. This Th2 response also
produces IL-10, which suppresses the Th1 response
(the cellular immune response), leading to a dissemination of the bacillus and to more severe multibacillary
forms of the disease (LL, BL). It is still unclear if the
IL-10 is produced only by Th2 cells, or if T regulatory
cells are also involved.9 A more recent study described
the presence of higher numbers of T regulatory cells
expressing FoxP3, CTLA-4 and IL-10 in LL patients
than in TT leprosy patients.10 Although some components present in the surface of M. leprae are known to
induce IL-10, explaining the suppression of the Th1
immune response of the host, not all individuals
develop severe clinical forms. In fact, some individuals
present an effective cellular immune response and
develop the paucibacillary clinical forms of the disease
(I, TL and BT).
The course of the infection is dependent on individual factors that influence the host immunologic
response. In its turn, the immune response can be influenced by genetic and environmental factors, including
the patient s nutritional status.7-8,11,12 Nutritional deficiencies are common in countries in which leprosy is
endemic. It is possible that the clinical presentation of
the disease is a result of nutritional deficiencies interacting with other environmental and genetic factors of
the host. Nutrition is known to influence immune
response in several aspects. Deficiency of trace
elements and vitamins affect the innate and adaptive
immune response, causing an unbalance of the host
response to pathogens.13
This review of the literature was performed using the
terms leprosy, micronutrients, immune response,
oxidative stress antioxidants. The variety of terms
used allowed a significant coverage in order to conduct
a comprehensive search on the topic. Proceeded to the
query through the databases PubMed, SciELO and
HighWire, covering the years 2000-2013, including
also articles relevant to the topic, published previously

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cited in the articles previously selected. Were included

especially intervention studies, randomized controlled
trials, and studies with experimental animals, that were
used predominantly for the development of concepts as
well as the description of mechanisms of action.
The following topics will describe specific nutrients
that influence the immune response, detailing their
mechanisms of action, and specific effects in leprosy or
in other intracellular infections.
Immunologic response to infections
and the influence of nutrition
The human organism is an environment rich in nutrients, which are maintained with an elevated and
uniform temperature and that are constantly renewed.
Thus, we are an attractive hostel for many pathogens.
Therefore all organisms are infected by some kind of
pathogen, being responsible for diseases or not. The
protection against infections is mediated by natural
boundaries and by their immune response. The natural
boundaries can be mechanical, chemical or biological.
The mechanical barriers consist of epithelial and
mucosa surfaces, skin loss and the rapid capacity of
mucosa and skin regeneration, air flux, ciliary movement, peristaltic movement, and the mucus produced
by the respiratory and digestive mucosas. Chemical
barriers include fatty acids, (skin) bactericidal
substances such as lysozyme (saliva, sweat and tears),
proteolytic enzymes (in the stomach and intestines),
acid pH, and anti-bacterial peptides (the skin and the
intestines). The biological barriers consist of the
normal bacterial flora, which compete for nutrients and
for the epithelium receptors with the pathogenic agents
and produce the microbiocidal substances.14
The immune response is activated when the
pathogen overcomes these natural barriers. The infection or pathogen control will depend on the host s
ability to produce a response against the infectious
agent, and depending on the host, the disease can be
exacerbated or controlled.15 Nutritional deficiency can
affect both natural barriers and lead to suppressed
immune response, since certain micronutrients are
important for the maintenance of the integrity of
natural barriers, and the appropriate functioning of
different components of the immune system, such as
cellular response and antibody production.16
The clinical manifestations of an infectious disease
can also be a result of intense tissue inflammation mediated by the immune response, as described in the highly
sensitive reactions. Products such as TNF-, nitric oxide
(NO) and reactive oxygen species (ROS), although
displaying important microbiocidal action, also induce
tissue damage. Thus, antioxidant substances (endogenous or nutritional) and modulating cytokines have
fundamental role for a balanced immune response,
which controls the pathogen multiplication and protects
the host tissue.17

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In different infections the malnutrition effect is variable and difficult to measure. In diseases as measles
and tuberculosis the nutritional deficiency presents a
relation with the increase in susceptibility and worsens
the disease prognosis.18 One of the consequences of the
infections from persistent pathogens is the generation
of autoimmunity and inflammatory diseases. Although
pathogens are the main trigger for the inflammatory
response, the hypothesis that nutritional factors can
have important contributions in the disease progress
cannot be excluded.19
The risk of leprosy is significantly associated with
poverty, poor education, dietetic inadequacy, related to
total caloric intake and reduced intake of vegetables,
fruits and fish.20
Studies conducted in India and Brazil demonstrated
dietetic inadequacies among individuals with leprosy
and their relatives, specially related to the lack of
vegetables and fruits intake. The observed unbalanced
diets were explained by inadequate feeding habits
mainly associated with the lack of knowledge about the
nutritional value of these foods. The economic status
was not the main predictor of the diet quality.21,22
Both low body weight and overweight individuals
are reported to have dietetic inadequacies regarded to
the quality of the foods. Overweight individuals from
Brazil and from other developing countries are
reported to have a diet based on empty calories foods.
In a study conducted in Brazil, 41.9% of individuals
with leprosy were overweight or obese, and only 3.6%
were underweight. The proportion of overweight or
obesity and underweight was similar among individuals with leprosy reaction and no reaction.23 Overweight and obesity among leprosy patients was also
reported in other studies in Brazil.22 Hipercaloric diets
seem not to protect individuals against the disease;
however, the low quality of the diet is associated with
higher risk of leprosy regardless the weight status,
mainly because the low intake of antioxidants
substances is associated with impaired immunological
defense against pathogens such as M. leprae.1,21,23,24
In a study of fifty-eight patients with leprosy
conducted in India, it was observed nutritional deficiency in different forms of leprosy, but mainly in the
lepromatous, the most aggressive clinical form. They
described a decrease of serum levels of substances with
antioxidant potential, such as retinol (vitamin A), tocopherol (vitamin E), ascorbic acid (vitamin C), zinc,
magnesium and selenium.25
Endogen substances such as reactive species of
nitrogen and oxygen are the main mechanism of
destruction of intracellular agents.26-27 In M. leprae
infection macrophage activation is important for the
control of this microorganism in which the main mechanism of destruction is mediated by ROS and NO.
However these radicals have an oxidant activity and
can contribute to tissue damage, together with other
inflammatory substances produced by the immune
system. Dietary substances with antioxidant action can

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Tabla I
Main function of micronutrients and their role in the immune system
Nutrient

Source food

Function

Role in the immune system

References

Lipid

Vegetable oils, olive oil,

almonds, walnuts, peanuts,
coconut and avocado.

Assists in the transport

and absorption of
liposoluble vitamins and
cell membrane component

Production of cytokine
IL-1 and IL-6.
Production TNF-
and inflammatory response.

Kim, 2011;
Sreekumar, 2001;
Demori, 2006;
Krause, 2002.

Iron

Liver, seafood and

lean meat.

Component of hemoglobin
and myoglobin and important
in oxygen transfer.

Involvement of Fenton reaction

with production of free radicals
with antimicrobial action.

Bogdan, 1999;
Wanasen, 2007;
Krause, 2002.

Giblets, fish, seafood,

wheatgerm and brazil nut.

Involved in the metabolism

of fat and vitamin E.

Component of glutathione
peroxides.

Fairweather-Tait,
2011; Krause, 2002.

Zinc

Meat, fish, poultry and dairy.

Acts on growth and cell

replication.

Structural and catalytic

component of the superoxide
dismutase.

Koury, 2003;
Krause, 2002.

Vitamin C

Citrus fruits, tomatoes,

peppers and leafy vegetables.

Increases the absorption

of nonheme iron.

Enzymatic cofactor with

redox properties.

Murray, 2002;
Krause, 2002.

Vitamin A

Liver, egg, milk and carrots.

Protective action on the skin

and mucous and essential role
in retinal function.

Inhibition the lipid peroxidation

and the generation of
hydroperoxides.

Sies, 1995;
Krause, 2002.

Vitamin E

Vegetable oils, olive oil,

almonds and avocados.

Protection of cell membrane

unsaturated phospholipids.

Decreased lipid peroxidation.

Vijayaraghavhan, 2005;
Vanuucchi, 1998;
Krause, 2002.

Vitamin D

Fish (oil liver), egg yolk,

butter, cheeses and meats.

Maintaining homeostasis of
calcium and phosphorus.

Expression of antimicrobial
peptides.

Santiago, 2008;
Liu, 2006;
Chocano-Bedoya, 2009;
Krause,2002.

Selenium

counterbalance these effects of the oxidative stress, and

a reduction of the antioxidant species can contribute to
complications in the treatment and associating to the
progression of the disease.28 The table I describes nutrients with oxidant and antioxidant actions, their food
sources and effects in the immune system. However,
no studies have investigated the role of iron and lipids
in the protective response against infectious agents,
although, it has been shown that lipids have a role in the
inflammation, being the inducers of metabolic alteration found in obesity.29
Thus, the antioxidant substances protect the tissue
and body lipids from the lesion caused by oxidant
produced by normal metabolism or by response to the
inflammation. Moreover, these substances reestablish
the balance and allow the organism to tolerate the
oxidative stress. In the presence of disease and/or
malnutrition, the rupture of this balance occurs and
consequently the severe stress, with alteration of the
cellular metabolism, DNA lesion and lipidic peroxidation. These events contribute to the progression of
systemic inflammation, culminating in cellular death
and multiple organ dysfunction.30
The control of a variety of socioeconomic, environmental, and behavioral risk factors associated with the
adequate implementation of multi-drug therapy would
minimize the occurrence of leprosy in an endemic

Micronutrients and immune response

in leprosy

area.20 The quality of the diet is a behavioral factor that.

should be further explored to understand the role of
micronutrients in the immune response against M.
leprae. Nutrition education would be a suitable
approach to improve the patients nutritional status
aiming to achieve better clinical outcomes related to
treatment response, inflammatory manifestations as
leprosy reactions and neurological disabilities.31
Vitamin A - The role in the immune response and
studies associating vitamin A deficiency with leprosy
Vitamin A and its precursors, retinoic acid and carotene are important antioxidants in the body. These
nutrients are capable of interacting with free radicals,
such as peroxyl, inhibiting lipid peroxidation and the
generation of hydroperoxides through the stabilization
of the peroxyl radical.32 Through their photoprotective
action, the carotenoids quench the singlet forms of the
oxygen generated in the cells, transforming them into
less reactive species. Besides this action, through its
double conjugated bond, carotenoids capture free radicals that could induce oxidative damage.33 However,
some factors in biological systems interfere in this
antioxidant capacity, -carotene acts as an antioxidant
nutrient in low partial oxygen pressures and when there

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are high oxygen concentrations, vitamin E can complement this antioxidant action.34 An increase in oxidant
stress is documented in leprosy-affected individuals.1
Vitamin A also has an important role in the regulation of several components of the immune response,
including both innate and acquired immunity (both
cellular and humoral).35,36,37 Regarding innate immunity, the deficiency of vitamin A is associated with a
decrease in phagocytosis and oxidative burst activities
of macrophages.16 A decrease in NK cells was also
reported under this condition.38 In acquired immunity,
studies evaluating the effects of vitamin A deficiency
are controversial, describing a decrease in IFN-
production, which represents the Th1 response and a
deficiency in Th2 or humoral response.13-39 In an
Indonesian study conducted in children with vitamin A
deficiency, a decrease in ex-vivo production of IFN-
was detected.13 Given the importance of IFN- for
exerting critical functions in Th1 type immunity, this
observation suggests the importance of vitamin A in
control of infections by intracellular microorganisms,
such as M. leprae. On the other hand, the addition of
retinoic acid in vitro induced the production of IL-10
and an anti-inflammatory response through the inhibition of IL-12 and TNF- production in mononuclear
umbilical cord and monocyte lineage cells. Since IL-12
is important for the induction of Th1 diferenciation, the
administration of this vitamin inhibits the Th1
response, described that vitamin A deficiency compromises also Th2 responses and decreases IgG1 and IgE
antibody production.13-39
In leprosy, a previous study reported a decrease in
serum concentrations of vitamin A, predominantly in
lepromatous leprosy (LL) patients, where there is a
depression of the Th1 immune response and replication
of M. leprae in macrophages, and a predominance of the
humoral response.1 A reduction in serum concentrations
of vitamin A was also seen in children with visceral leishmaniasis in northeastern Brazil, another intracellular
microorganism.40 These data support the findings of
Wieringa and colleagues13 that vitamin A deficiency has
more detrimental effects on the Th1 immune response. A
recent study shows that the induction of T regulatory cells
by an antigen from Schistosoma mansoni eggs, called
w1, is dependent on vitamin A. T regulatory cells can
down modulate both Th1 and Th2 responses, and are
important in the control of inflammatory and autoimmune diseases.41 Additional studies to clarify the effects
of vitamin A in the immune response to infectious agents,
such as leprosy, appear merited. This is especially valid
in countries such as Brazil, where general or specific
nutritional shortages can be found in the context of many
infectious diseases. In this review we report the data of a
nutritional study in leprosy patients and observed that
over 50% of the individuals with leprosy and controls
living in the same house present with consumption below
recommended levels for vitamin A, evaluated by the food
consumption using food records and classifications of the
DRIs adequacy, 2006.

30

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Vitamin E - Protective role in the oxidative

stress in leprosy
It was demonstrated that free radicals and lipid
peroxidation suppress immune responses. Vitamin E
most important lipid soluble antioxidant, as it is
required to protect the lipid membranes against peroxidation. Additionally, it has been demonstrated in
elderly rats that a diet rich in vitamin E increases the
production of IL-2 and IFN- induced by infected
lymphocytes in influenza. These observations suggest
that increasing vitamin E ingestion above normal
levels improves the immune response against infections.42 -tocopherol, the most active form of vitamin
E, has affinity for phospholipids of the mitochondria,
endoplasmatic reticulum and plasma membrane and
constitutes the first line of defense against the peroxidation of polyunsaturated fatty acids contained in these
phospholipid membranes. When interacting with the
cellular membranes reactive oxygen species (ROS)
break the polyunsaturated fatty acids that compose the
membrane. An example of this is when the hydroxyl
radical interacts with the fatty acid of the membrane,
holding a hydrogen atom resulting in the generation of
lipid radical (fig. 1). This lipid radical can be unpaired
incorporates rapidly the oxygen molecules in the structure and transforms itself in a peroxide radical originating an hydroperoxide, forming a new free lipid
radical; this chain reaction causes the loss of the
membrane integrity.43 The tocopherols can neutralize
these reactions via the donation of phenol hydrogen to
the peroxil free radical of the polyunsaturated fatty acid,
resulting in neutralization, as depicted in figure 2.34 The
inhibition of the lipid peroxidation by neutralizing the
peroxil radical by vitamin E can be aided by vitamin C,
reduced gluthatione and NADPH. However, a perfect
balance of the concentrations of these components is
necessary, because the isolated elevated concentrations
of vitamin E can have a pro-oxidant effect, inducing to
classical alterations of the free radicals.44
In a case-control study, untreated leprosy patients
presented with higher levels of lipid peroxidation
(LPO) than healthy individuals, demonstrating the
presence of oxidative stress in this disease. However,
the levels of LPO were not reduced after the beginning
of treatment, probably because of the increase of the
production of free radicals during the immune-mediated killing of M. leprae. A subgroup of the leprosy
patients received the conventional multidrug therapy
(dapsone, rifampicin and clofazimine) and was simultaneously treated with 400 IU of vitamin E, daily,
during 12 months. This additional vitamin E treatment
reduced LPO levels close to the normal range.45 This
vitamin E deficiency and supplementation with nutrients during treatment was also described in tuberculosis.46-47 Patients with tuberculosis showed reduced
values for vitamin C and E before treatment, and also
higher serum level of Malondialdehyde (MDA) when
compared to healthy controls.47 Interestingly, the

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Fig. 1.Reactive Oxygen Species and vitamin E precursor action in the cell membrane. The interaction of ROS with cellular membranes breaks polyunsaturated fatty acids by the successive generation of free radicals. When ROS interact with fatty acid of the membrane frees a lipid radical, that interact with oxygen, generating peroxide radical, which interacts with other molecules of fatty acid, originating a hydroperoxide, and once more, breaking the lipid structure of the cellular membrane. The active form of vitamin E, the
-tocopherol, neutralizes this chain reaction (represented by the block sign in red) because it donates hydrogen atoms to the free radicals generated in this process. In Leprosy, it was observed an increase in the lipid peroxidation (LPO), and the treatment with vitamin
E associated with polychemotherapy reduced the LPO levels.

Fig. 2.Participation of the active metabolite of Vitamin D (1,25(OH)2 VD3) in the immune response against M. leprae. The 1,25
(OH)2 VD3 increases the expression of VDR, IL-1 and the peptide cathelicidin in macrophages, contributing for the bacteria clearance
mediated by the innate immune response. However, the dissemination of mycobacteria can be associated to the action of 1,25 (OH)2
VD3 in dendritic and T cells. The 1,25(OH)2 VD3 reduces the maturation of the dendritic cells by reducing the IL-12 expression, MHC
class II, CD 40, CD80, CD60, and increases the IL-10 production and FoxP3 expression in T cells, favoring the generation of the regulatory T cell. Regulatory T cells suppresses the Th1 response and interferes in the microbicidal functions of macrophages, contributing
to the persistence of the mycobacteria in the host.

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in leprosy

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supplementation of 140 mg of vitamin E and 200 g of

selenium for two months in patients with pulmonary
TB treated with standard chemotherapy resulted in a
decrease oxidative stress and improved antioxidant
status compared to TB patients treated with standard
chemotherapy but without receiving supplementation
of nutrients.46
Vitamin C and zinc - Their role in the immune
response to infectious diseases
Vitamin C and Zinc and are essential for maintaining
our health and are important for resistance to infections. Deficiencies in vitamin C or zinc negatively
impact the immune system.48
Vitamin C participates in several metabolic processes
and acts as an enzymatic co-factor in the oxi-reduction
processes, increasing the absorption of iron and inactivation of free radicals.49,50 Vitamin C constitutes a
reduction agent that reduces some molecular oxygen
components. This oxi-reduction action occurs when
vitamin C captures the oxygen present in the medium,
through stable chemical reactions, being unavailable
for the process of auto oxidation.34
Antioxidant substances that are not enzymatic, such as
ascorbic acid (vitamin C), provide an important role in
the control of the inflammation induced by ROS. It is
known that ROS presents an essential role in the death of
intracellular bacteria such as M. leprae and other intracellular pathogens; however the immune system can also be
vulnerable to these oxidative attacks. The oxidative stress
induced by high concentrations of ROS can decrease the
integrity of the cell membrane, with resultant alterations
in the membrane flow and communication between cells
affecting the immune response.51-52 Therefore, in clinical
conditions such as infections that present with high ROS
concentrations, vitamin C deficiency can exacerbate the
clinical status of the patients.
Studies with healthy children and adults using supplementation of vitamin C of 20 mg/kg/day and 1-3 g/day,
respectively, enhance the capacity of neutrophils and
macrophages to eradicate microbes. Peritoneal
macrophages from mice treated in vivo with antioxidant vitamins, including vitamin C, have an improved
phagocytosis function.48 Although no studies have
formally evaluated the role of vitamin C in leprosy, it is
likely that vitamin C deficiency adversely affects the
disease, considering these negative effects in phagocytic cells.
A decreased in serum levels of ascorbic acid was
described in patients with tuberculosis, when
compared to healthy controls.53-54 After 1 month of
multidrug therapy, 15 patients were supplemented with
1 g of ascorbic acid and 600 mg of vitamin E, and these
patients presented an increase in plasma antioxidant
capacity.55
Studies in humans show that the zinc deficiency
provokes a deficiency of Th1 response. Inflammatory

32

Nutr Hosp. 2014;29(1):26-36

cytokines, such as IFN-, IL-2 and TNF- that are

important for the control of intracellular pathogens,
such as M. leprae, were reduced, while the production
of IL-4, IL-6 and IL-10 were not affected.56
Conversely, prolonged zinc supplementation increased
the production of IL-2 and significantly decreased the
incidence of respiratory infections.56 IL-2 is a cytokine
that induces proliferation of Th1 cells.
The possible antioxidant role of zinc can be associated with regulation of metallothionein (MT) expression, a protein with low molecular weight and rich in
cysteine residue, which has antioxidant properties in
many conditions such as radiation, drugs and heavy
metal exposures.57 Zinc is a structural and catalytic
component of the superoxide dismutase (SOD), and is
important for its activity. SOD is an antioxidant
enzyme that reduces oxidant effect of the oxygen reactive species, transforming superoxide (O2-, +O2-, +2H+)
in hydrogen peroxide (H2O2 + O2), a form that minimizes the chain reaction of the cellular injury. There
are two types of SOD, a cytoplasmic form, which
contains copper-zinc in its molecule (CuZnSOD), and
a mitocondrial form, which contains manganese
(MnSOD).58 The loss of zinc in the cellular membrane
can affect its function, flow, the sodium and calcium
transport channels and the hydro and osmotic balance
of the cell. Zinc still can stabilize the reduced form of
sulfhydryl groups, protecting against the effects of
lipid peroxidation of the cellular membranes.59
A study compared the levels of zinc in blood and
scalp hair of males infected by the human immunodeficiency virus (HIV+) with healthy males controls, and
showed that HIV+ patients had lower levels of zinc
when compared to controls (p < 0.001). The zinc deficiency may contribute to the emergence of other secondary infections in HIV + patients, increased morbidity
and mortality of these individuals.60
Selenium - The role of in the inflammatory response
Selenium is a micronutrient classified as an essential
trace element that is strongly linked with complex
enzymatic and metabolic functions. Selenium has
several biological functions, the most important being
its interaction with the glutathione peroxides (GPxs).
The glutathione catalyzes the reduction of hydrogen
peroxide and organic hydroperoxides thus it is important to protect the lipids from the membrane and other
cellular constituents against oxidative injuries.61
Selenium also affects the chemotactic and microbicidal
activities of phagocytic cells, components of the innate
immune response. Selenium modulates leukotriene
synthesis and peroxide regulation in the microenvironment of immune competent cells.61-62 However, a perfect
balance of selenium must be maintained, because, while
phagocytosis and lymphocyte activity can be stimulated
in an adequate selenium supplementation, higher doses
are inhibitory. Although clinical studies have demon-

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04. MICRONUTRIENTS_01. Interaccin 28/01/14 16:47 Pgina 33

strated selenium deficiency in patients with tuberculosis,

asthma and HIV, there are no reports regarding the selenium levels in leprosy patients.63-64
Although several studies show the oxidant and antioxidant effects of each specific nutrient, the supplementation of these nutrients must be carefully evaluated due to
the interaction of their effects. It is observed that high
doses of a single antioxidant nutrient might induce an
opposite oxidant effect. Moreover, it is important to take
into account that the biochemical, clinical and genetic
individuality of the response to the nutrients, being difficult to establish their ideal doses and specific effects in
the prevention and treatment of diseases.65
Vitamin D Immunemodulatory functions in
mycobacteria infections and specifically in leprosy
During many years it was defined that vitamin D
presents an essential role on the development of bones
mineralization, however other role for vitamin D has
been suggested after the discovery of vitamin D receptors (VDR) in tissues that are not involved in calcium
and phosphate metabolism. The VDR are also seen in
many tissues and body cells, with the capacity to
develop a great variety of biological response. The
immunomodulatory action of vitamin D happens
through direct action of T cell function and the cell
presenting antigens.50,66
Mycobacterium tuberculosis (M. tuberculosis) and
M. leprae are intracellular bacteria, so the defense
mechanisms of host against the pathogens are similar.
Interestingly, before discovering the etiological cause
for tuberculosis, it was usual to use vitamin D from cod
liver oil and exposure to sun radiation for its treatment.67-68 In fact, recent studies associate vitamin D
deficiency with the increase in development of tuberculosis.37,69,70 The biological mechanisms through
which vitamin D modulates the immune system to fight
Mycobacterium are still under study, though some are
already known. The vitamin D active metabolite, 1,
25-dihidroxivitamin D3 (1, 25-(OH)2D3), present an
in vitro antimicrobial activity in monocytes and
macrophages (fig. 2). The 1,25-(OH)2D3 acts by
improving the phagosome and lysosome fusion in
infected macrophages, reverting the ability of Mycobaterium sp. of preventing the fusion of phagosomes to
lysosomes.71 The 1,25-(OH)2D3 also promotes the
death of the Mycobacterium sp., by inducing the
production of antimicrobial peptides in the infected
macrophages and neutrophils. These peptides have
immunomodulatory activity in innate immunity. They
are divided into two families: cathelicidins and
defensins, both involved in immune response in several
infectious diseases.72 One of the studied peptides of the
cathelicidin family is the LL-3, that is involved in the
first line of defense against infections, recruiting
monocytes, T-cells and neutrophils to the infection
site. Additionally, the LL-37 activates macrophages by

Micronutrients and immune response

in leprosy

binding to Toll-like receptors (TLR), inducing the

death of M. tuberculosis. These data are corroborated
by an study which showed that serum samples from
individuals from populations known to have a high
susceptibility to develop tuberculosis present low
concentration of 25-hydroxivitamin D and low efficiency of the cathelicidin peptide.73 Matzner and colleagues, 2011 compared the levels of cathelicidin and
25OH-vitamin D3in 29 leprosy patients and 19 healthy
subjects, and showed that levels of cathelicidin in the
leprosy patient were lower than the controls group (p <
0.001), although the levels 25OH-vitamin D3 did not
differ between the groups.74
It is also known that IFN-, secreted by Th1 cells,
which have a known protective role against intracellular agents, potentiates the effect of the 1-hidroxilase
enzyme. This enzyme converts the vitamin D from
inactive to active form (1,25-(OH)2D3). Additionally,
IFN- also inhibits the induction of an enzyme which
participates in the 1,25-(OH)2D3 inactivation.75 On the
other hand, 1,25-(OH)2D3 can contribute to the
dissemination of M. leprae by affecting dendritic cells
and T-regulatory cells. In the dendritic cells, 1,25(OH)2D3 decreases maturation, inhibiting the MCH
class II, CD40, CD80, CD86 expression, decreases the
IL-12 and increases the IL-10 production. In T-cell,
1,25-(OH)2D3 can promote FoxP3 expression and the
IL-10 production, favoring the development of T regulatory cells76 (fig. 2).
As infectious diseases are multifactorial it can also
be influenced by other environmental and genetic
factors. The genetic factors can also affect the susceptibility to infections and the levels and effects of nutrients, such as of vitamin D. A polymorphism in the
vitamin D receptor gene (codon 352 C/T) was
described, which is functional and leads to a decrease
of the active metabolite of this vitamin and affects bone
mineralization. However, this receptor also affects the
Th1/Th2 immune response. Individuals who present tt
homozygous gene alleles tend to develop a Th1
response, and those who present TT homozygous gene
alleles tend to develop a Th2 response. It was shown, in
a case-control study with 2015 Africans, that genotype
tt was less frequent in tuberculosis patients.77 A study
done in India with 231 leprosy patients (107 tuberculoid and 124 lepromatous) from Calcuta, India, has
evaluated this polymorphism in the vitamin D receptor
gene (codon 352 C/T) and verified that genotype tt was
associated with tuberculoid leprosy (Odds ratio [OR] =
3.22 [95% CI 1.47-7.13]), genotype TT was associated
with lepramatous leprosy (OR 1.67 [95% CI 1.022.75]) and the resistance in developing the disease can
be associated to the heterozygous genotype (Tt) (OR
0.58 [95% CI 0.38-0.89])78.
The data above suggest that VDR and vitamin D can
have great importance in the human infection by intracellular agents such as in tuberculosis and leprosy.
Their stimulating actions to innate immune response
and down modulatory actions to the adaptive immune

Nutr Hosp. 2014;29(1):26-36

33

04. MICRONUTRIENTS_01. Interaccin 28/01/14 16:47 Pgina 34

response can be fundamental for the asymptomatic

balance of the infection. Therefore, studies evaluating
deficiency of this vitamin and the polymorphism of its
receptor can contribute to predict the clinical evolution
and its dietary reposition must be evaluated as adjuvant
for the treatment of this disease.

Development (CNPq)/ Universal, 2009, Grant No.

477935/2009-5 and by PRONEX, FAPITEC/SE/
FUNTEC/CNPq, 12/2009, Grant No. 019.203.02712/
2009-8. ARJ and RPA are scientists from CNPq.
Author contributions

Conclusions
Due to the complexity of clinical presentations, the
multitude of factors involved in the control of M. leprae,
and the complications that can occur, leprosy remains a
huge challenge for clinicians and scientists. Immunologically, leprosy is a spectral disease model that involves
components of both the innate and adaptive immune
response. These contribute not only to protection but
also to pathogenesis, with skin and neurological injuries
that can ultimately culminate in permanent disability.
Leprosy is still relatively understudied, particularly in
relation to the impact of various nutritional factors,
taking into account that the disease affects developing
countries. Leprosy patients, with different clinical
forms, but particularly in the lepromatous form, present
a reduction in potential antioxidant substances. Several
studies show familial aggregation and the influence of
genetics in disease outcome, which open the possibility
of an influence of a combination of genetic background
with environmental factors. The importance of nutritional status, specially related to micronutrients should
be investigated, mainly because the disease develops in
long term and the nutritional balance might reduce the
risk of acquiring the disease. It is also known that a
reduction in the level of antioxidant and immune modulatory nutrients can contribute for an increase in the
oxidative stress and complication in the disease and in its
treatment, since the decrease of these nutrients can be
one of the reasons for the increase of the skin and neurological injuries induced by immune response products
against the pathogen. Thus, further studies considering
the action of these antioxidant and immune modulatory
nutrients in patients infected with M. Leprae should be
designed to elucidate pathogenic mechanisms. This
knowledge is of great importance to give support for
dietary supplementation as an adjuvant for improvement
of the leprosy treatment.
Conflict of interest
The authors declare there is no conflict of interest in
the development of the study.
Acknowledgements
The research group is funded by Coordination of
Improvement of Education Personnel (CAPES) and
the Brazilian Council for Scientific and Technological

34

Nutr Hosp. 2014;29(1):26-36

CMPV: Wrote the manuscript. RSMN: Contributed

to the revision of the manuscript. TRM: Assisted the
preparation of figures and contributed to the revision of
the manuscript. RPA: Contributed to the revision of the
manuscript. MSD: Revised the manuscript. ARJ:
Helped to write and review the manuscript.
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