Tumor necrosis factor-alpha promoter polymorphism TNF2 is associated with a stronger delayed-type hypersensitivity reaction in the skin of borderline tuberculoid leprosy patients.
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ABSTRACT: Several host and environmental factors contribute to tuberculosis outcome, interestingly single nucleotide polymorphisms (SNPs) in candidate genes have been evaluated in populations with different ethnicities and TB infection. In the present study we focused on SNPs in cytokine and inflammatory mediator genes: tumor necrosis factor (TNF) -308G>A (rs1800629), interleukin-10 (IL10) -819C>T (rs1800871), interferon-gamma (IFNG) +874T>A (rs2430561), and leukotriene A4 hydrolase (LTA4H) rs1978331, rs17525495 and rs2660898 in a case-control study involving 102 pulmonary tuberculosis patients and 456 controls from Mozambique. LTA4H, IL10 and IFNG SNPs showed no associations with pulmonary tuberculosis. However, distribution of the TNF -308A allele, genotype and carrier frequencies showed a significant risk association with tuberculosis that was maintained after adjustment for non-genetic variables and Bonferroni correction (AA genotype, OR = 1.9, p Bonf < 0.001; A allele OR = 2.9, p Bonf = 0.005 and GA/AA carrier OR = 2.6, p Bonf = 0.035). Interestingly, this association has not been reported in a sub-Saharan African population before. Our results suggest a role of -308 TNF polymorphism and tuberculosis susceptibility.Molecular Biology Reports 09/2014; · 1.96 Impact Factor
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ABSTRACT: FUNDAMENTOS: A hanseníase persiste como problema de saúde pública, e episódios de ENH são eventos agudos que ocorrem antes, durante e após PQT. Na última década, o uso da talidomida como agente imunomodulador foi expandido a outras doenças. OBJETIVOS: realizar revisão sistemática dos ensaios clínicos publicados sobre a eficácia e efeitos colaterais da talidomida no ENH. Descrever metodologia e resultados da triagem para recrutamento de ensaio clínico visando avaliar dose-resposta da talidomida seguida de desmame no ENH moderado e grave, realizado no Brasil. MÉTODOS: Analisaram-se ensaios publicados sobre talidomida no ENH. Foi delineado um ensaio clínico duplo-cego randomizado para avaliar dose de 100 thalid 300mg/dia de talidomida durante fase aguda de ENH, seguida de desmame da talidomida, thalid placebo. Para este ensaio clínico descreve-se metodologia e dados de recrutamento de pacientes, com ênfase na gravidade dos episódios de ENH. RESULTADOS: Os seis ensaios clínicos publicados nas décadas de 1960 e 1970 apontam para o benefício da talidomida no ENH, embora diferenças metodológicas dificultem a comparação. Na fase de recrutamento do ensaio brasileiro, dos 143 pacientes de ENH triados, 65% eram potencialmente elegíveis. A associação com neurite em 56,4% dos ENH moderados e graves exigiu co-intervenção com corticosteróide. CONCLUSÃO: O padrão de recrutamento dos pacientes evidenciou alta freqüência de neurite nos episódios de ENH. O esquema de talidomida isolada no ENH foi avaliado como infreqüente na prática clínica brasileira. O desafio atual é acumular evidências sobre a eficácia e efeitos colaterais da talidomida em associação com corticosteróides.Anais Brasileiros de Dermatologia 10/2005; 80(5):511-522. · 0.87 Impact Factor
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ABSTRACT: Considering that variability in immune response genes has been associated with susceptibility to leprosy and with disease severity, leprosy presents clinicopathological variants that are highly associated with the immune response, HLA-G has a well-recognized role in the modulation of the immune response, and polymorphisms at the 3' untranslated region (UTR) of the HLA-G gene may influence HLA-G production, we studied the polymorphic sites at the 3' UTR of the HLA-G gene in leprosy and their association with disease severity. We evaluated by sequencing analysis the allele, genotype, and haplotype frequencies of the 3' UTR HLA-G polymorphic sites (14-bpINDEL/+3003C-T/+3010C-G/+3027A-C/+3035C-T/+3142C-G/+3187A-G/+3196C-G) in 146 individuals presenting reactive leprosy from a highly endemic area, and associated with bacillary load and the type of reactive leprosy. A total of 128 healthy subjects were also studied. Allele, genotype, and haplotype frequencies for the 3' UTR HLA-G polymorphisms in leprosy patients did not differ from those observed in healthy donors. The +3187A allele was responsible for protection against the development of multibacillary leprosy in a dominant model (AA + AG)/GG, OR = 0.11, P = 0.018), and the +3187A allele and +3187A-A genotype were overrepresented in type II reactive leprosy reaction. The effect of genetic factors on leprosy susceptibility may be hidden by environmental components in highly endemic areas. The HLA-G + 3187A polymorphic site, which is related to unstable mRNA production, was associated with the development of polar forms of leprosy and reactive leprosy reaction.Molecular genetics & genomic medicine. 09/2013; 1(3):123-30.
Tumor Necrosis Factor Promoter Polymorphism (TNF2)
Seems to Protect Against Development of Severe Forms
of Leprosy in a Pilot Study in Brazilian Patients
To THE EDITOR:
Leprosy is a chronic infectious disease
characterized by clinicai forms which are
associated to the immune response devei-
oped by the host against the bacteria. Polar
forms are either paucibacillary (PB; tuber-
culoid leprosy) with a pronounced cell-me-
diated immune response (CMI) or multi-
bacillary (MB; lepromatous leprosy), which
lacks CMI. Believed to be an important
protection mediator against infections, tu-
mor necrosis factor-alpha (TNF-a), one of
the key cytokines in CMI, is an inducible
factor covering a wide range of proinflam-
matory and immunostimulatory activities
(3). Moreover, depending on the quantity
and the time period over which its produc-
tion is sustained, TNF-a may exert a bene-
ficiai or a deleterious effect. For example,
in leprosy, enhanced production of TNF-a
has been associated with the development
of such immunopathological states as nerve
damage ('°) and inflammatory reactional
episodes C) as well as with the develop-
ment of the more benign tuberculoid form
of the disease (12). High TNF-a leveis were
detected in the serum during reaction (")
and in vitro, following stimulation of the
peripheral blood mononuclear cells, both in
tuberculoid and reactional patients (').
It has been suggested that development
of a particular type of leprosy may be genet-
ically determined (2) and could be responsi-
ble for the inter-individual differences in the
immune response during the disease. Ex-
pression of TNF-a is tightly controlled at the
transcriptional and post-transcriptional lev-
els, and a particular single nucleotide poly-
morphism at the —308 position within the
regulatory region of the TNE-oc gene gener-
ates the allelic TNF2 form shown to be as-
sociated with enhanced TNF-a production
(15) and to severe forms of some inflamma-
tory and auto-immune diseases (7). In this
connection, Roy, et al. (9) have recently de-
scribed the significant association between
TNF2 alicie frequency and polar leproma-
tous-type leprosy in an Indian population.
In a study carried out in the Leprosy
Laboratory at the Oswaldo Cruz Founda-
tion, Rio de Janeiro, Brazil, TNF2 alicie
frequency was determined in 92 healthy
control individuais and in 300 leprosy pa-
tients classified on the basis of their clinicai
and histologic features (8) as suffering from
PB (BI negative patients, N = 90; 2 BT, 63
TT, 15 pure neural form and 10 indetermi-
326^International Journal of Leprosy^ 2000
THE TABLE. Distribution of –308 TNF-a
mutant alicie in leprosy patients and healthy
GA. AA. frequency (%)
210 31 04
GA and AA = Heterozygous and homozygous indi-
viduais typed for the —308 polymorphism.
Indicates significant differences when compared to
leprosy patients (p = 0.005; x2 = 7.55) and to MB pa-
tients (p = 0.001; x2= 9.63).
MB and PB are multibacillary and paucibacillary
leprosy according to the presence or absence of sys-
temic bacterial load (BI), respectively.
nate) or MB leprosy (BI positive patients, N
= 210; 85 BL, 70 LL, and 55 BB). Genomic
DNA was prepared from frozen whole
blood (300111) by a commercially available
DNA extraction kit (Gibco BRL, Gaithers-
burg, Maryland, U.S.A.) and typing of the
TNF-ot promoter region (107 bp fragment)
for analysis of polymorphisms at the –308
position was performed with use of specific
primers through a single polymerase chain
reaction (PCR) step and further digestion
with Ncol (14). Comparison of genotype fre-
quencies among the groups was determined
by means of the chi-squared test.
The results presented as allelic frequen-
cies are shown in The Table. Our present
data indicate that the presence of TNF2 pro-
tects against the development of the more
severe form(s) of leprosy. A significant (x2
= 7.55, p 0.005) higher frequency of the
mutant allele was observed in the control
group (16.3%) when compared to the lep-
rosy patients as a whole (10.8%). In addi-
tion, the TNF2 frequency rates, while simi-
lar for the controls and the PB patients
(14.4%), were significantly (x2 = 9.63, p
<0.005) higher than that observed for the
MB group (9.3%). Nevertheless, the pro-
portion of TNF2, albeit enhanced in the PB
versus MB patients, was not statistically
significant (x2 = 2.48, p >0.05).
The significant association of TNF2 to
the control group described herein supports
the idea that the presence of TNF2 could be
a predisposing genetic factor against devel-
opment of the disease. This observation is
in contrast to the findings of Roy, et al. (9),
who reported a noteworthy association be-
tween MB leprosy and TNF2.
As is well known, the protective role of
TNF-a in mycobacterial disease has been
suggested in earlier studies by demonstrat-
ing that a) immunization against TNF-a
blocked granuloma formation in mice in re-
sponse to Mycobacterium bovis (BCG) in-
fection (6); b) it reduced the survival time of
animais following infection with virulent
M. tuberculosis or Listeria monocyto genes
(4); and c) TNF-a increased the resistance
against M. avium infection (13).
Another difference between our study re-
sults and those of Roy, et al. is that the al-
lele frequency values observed in the
Brazilian control group were 5.5 times
higher than those found among the Indian
population which, while not due to a higher
frequency rate of the homozygous TNF2
genotype, could be related to differences in
the ethnic composition of each group asso-
ciated with HLA haplotypes in each popula-
tion. Rio de Janeiro is also highly endemic
for leprosy with a prevalence rate of 4.4/
10,000 (WHO, 1999). Nonetheless, whereas
the Indian population is seen as being over-
ali homogeneous, the Brazilian population
is characterized by its mixed racial and eth-
nic components, which might at least par-
tially explain the opposing results.
In conclusion, the data provided by our
study strongly point to the TNF2 allele's
protective role in defense against the devei-
opment of leprosy. It is also important to
mention that in future studies of this nature,
the particular features of a certain popula-
tion group must always be taken into ac-
count in study design and analysis.
Adalberto R. Santos, Ph.D.
Alexandre S. Almeida, Ms.C.
—Philip N. Suffys, Ph.D.
Laboratory of Molecular Biology and
Dia gnosis of Infectious Disease
—Milton O. Moraes, Ph.D.
Valcemir F. S. Filho
Oswaldo Cruz Institute
Rio de Janeiro, Brazil
^-Haroldo J. Mattos, M.D., Ph.D.^5.
Faculty of Medical Science
State University of Rio de Janeiro
Rio de Janeiro, Brazil
-Jose A. C. Nery, M.D., Ms.C.
-Pedro H. Cabello, Ph.D.
Laboratoty of Genetics^7.
-Elizabeth P. Sampaio, M.D., Ph.D.
Euzenir N. Sarno, M.D., Ph.D.
Oswaldo Cruz Institute
Av. Brasil 4365, Manguinhos^8.
21045-900 Rio de Janeiro, RJ, Brazil
^Reprint requests to Dr. Sarno at the^9.
above address or FAX 55-21-270-9997.
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Acknowledgment. We would like to thank A. M.
Sales, D. M. Vieira and L. M. M. Vieira for clinicai^10.
follow up on the patients and data information. A. S.
Almeida is supported by a grant from CNPq, Brazil.
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