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PubMed1997

Value of nerve biopsy in the diagnosis and follow-up of leprosy: the role of vascular lesions and usefulness of nerve studies in the detection of persistent bacilli.

Nerve biopsy specimens from 53 patients with leprosy and neuropathy were taken from the sural, the dorsal branch of the ulnar, or the superficial radial nerves and processed for light and electron microscopy. There was inflammation in 40 cases (75%), 7 with a granulomatous reaction, various stages of fibrosis in 35 (66%), and endoneurial vascular neoformation in 7. In two cases, small focal infarcts were associated with marked endoneurial inflammation compressing the vessels, in addition to endoneurial lymphocytic vasculitis. Most had an axonal neuropathy of varying degree, some with total fibre loss, others with predominant small myelinated and unmyelinated fibre loss. Signs of demyelination and remyelination were the main findings in 9 cases (17%). Bacilli were present in endothelial, perineurial, Schwann cells and in macrophages. On two occasions, they lost their alcohol acid resistance, were suspected in semithin sections, and confirmed ultrastructurally. The biopsy was decisive for the diagnosis of leprosy in 15 cases (28%), most without skin lesions. We evaluated the effectiveness of the treatment in 20 (37.7%), 12 without and 8 with bacilli, despite negativity in the skin. The diagnosis of leprosy based on skin lesions was confirmed with the nerve biopsy in 9 cases, 6 had an inflammatory neuropathy suggestive of leprosy in the absence of bacilli, and 3 had nonspecific changes in the sural nerve since the neuropathy was in the upper limbs. We conclude that nerve biopsy is indicated for the diagnosis of leprosy in cases without clinically visible skin lesions and to evaluate the effectiveness of the treatment. In these cases the ultrastructural studies are important for recognition of the bacilli. Vascular lesions may play an important role in the progression of the nerve damage, including the occurrence of focal nerve infarcts which, to our knowledge, have not been previously reported in association with leprosy.

Biopsy↗
PubMed2005

IL-10 promoter single nucleotide polymorphisms are significantly associated with resistance to leprosy.

The minor haplotype -3575A/-2849G/-2763C in IL-10 promoter has been defined as a marker of disease resistance to leprosy and its severity in Brazilian population. Our investigation of six single-nucleotide polymorphisms (SNPs) in IL-10 promoter in 282 Indian leprosy patients and 266 healthy controls by direct PCR sequencing, however, showed that the extended haplotype: -3575T/-2849G/-2763C/-1082A/-819C/-592C was associated with resistance to leprosy per se and to the development of severe form of leprosy, using either a binomial (controls vs cases, P=0.01, OR=0.58, CI=0.37-0.89) or ordinal (controls vs paucibacillary vs multibacillary, P=0.004) model. Whereas, IL-10 haplotype -3575T/-2849G/-2763C/-1082A/-819T/-592A was associated with the risk of development of severe form of leprosy (P=0.0002) in contrast to the minor risk haplotype -3575T/-2849A/-2763C in the Brazilian population. The role of IL-10 promoter SNPs in Brazilian and Indian population strongly suggests the involvement of IL-10 locus in the outcome of leprosy.

Brazil↗
PubMed2003

Study of visual evoked potentials in the assessment of the central optic pathways in leprosy patients.

We evaluated the possible involvement of central optic pathways (COP) in leprosy patients with visual evoked potentials, an easy, sensitive and reliable noninvasive method for evaluation of COP. In 37 patients with lepromatous leprosy and in 37 age-matched controls, we measured reversal pattern visual evoked potentials (RP-VEP) and nerve conduction parameters. The mean latency value of positive peak P100 in leprosy patients was significantly delayed compared to that of controls (patients, 108.02+/-9.61 ms in left eye and 108.23+/-8.51 ms in right eye; controls, 96.22+/-4.20 ms in left eye and 95.75+/-4.03 ms in right eye; p<0.05). Abnormally delayed P100 latency was recorded in 5 of 37 leprosy patients (13.5%). The mean amplitude of P100 latency in leprosy patients was smaller than that of controls (patients, 8.7+/-5.6 micro V in left eye and 9.5+/-4.8 micro V in right eye; controls, 10.7+/-4.6 micro V in left eye and 10.5+/-5.1 micro V in right eye), but this difference was not significant. No correlation was observed between abnormalities of RP-VEP and sensorimotor nerve conduction parameters. This study suggests that involvement of COP may develop in patients with lepromatous leprosy. RP-VEP measurement, which can be easily and rapidly performed in an EMG laboratory using standard equipment, can show these alterations.

Adult↗
PubMed1987

Lepromin-induced suppressor cells in lepromatous leprosy.

The presence or absence of suppressor cells in leprosy patients was investigated by measuring peripheral blood lepromin-induced suppression of the Con A response. Significant suppressor activity was measured in 15 of 15 untreated or recently treated patients with lepromatous leprosy and 3 of 5 patients with borderline lepromatous leprosy. In addition, in patients with lepromatous leprosy, suppressor cell activity was found in 10 of 14 patients that had been under treatment for more than 1 year but in only 2 of 27 patients who had active or thalidomide controlled erythema nodosum leprosum. Suppression was observed in only 5 of 29 tuberculoid leprosy patients, 1 of 6 patient contacts, and 0 of 11 normal controls. The differences between the lepromatous or borderline lepromatous group as compared with the tuberculoid group were statistically significant (P less than 0.001). Our findings confirm the presence of lepromin-triggered suppressor cells in the peripheral blood of patients with lepromatous leprosy. These suppressor cells may contribute to the selective unresponsiveness of lepromatous patients to the antigens of Mycobacterium leprae.

Concanavalin A↗
PubMed1981

Hepatitis-B virus infection in patients with leprosy: a serological study in a leprosarium in Northern Nigeria.

The prevalence rates of hepatitis-B surface antigen (HGsAg) and its homologous antibody (anti-HBs) were determined in 62 patients in a leprosarium (42 tuberculoid and 20 lepromatous) and in 40 adults living near the locality. The exposure rate (HBsAg + anti-HBs) was high in both controls and patients, 72.5% and 70.9% respectively, The frequency of HBsAg was significantly higher in patients with lepromatous leprosy (40%) compared with controls (10%) (chi 2 = 5.7 p less than 0.025) but there was no difference in the prevalence rate of HBsAg between patients with lepromatous leprosy (40%) compared with those with tuberculoid leprosy (23.8%) (chi 2 = 1.7 p greater than 0.1). The exposure rate was higher in the lepromatous group (80%) compared with the tuberculoid group (59.5%) but the difference was not significant (chi 2 = 2.87 p greater than 0.05). It is concluded that the high rate of infection in patients with leprosy if not due to a peculiar genetic defect but the result of living in an environment where the virus is highly endemic. The observed significance increase in carriage of HBsAg in lepromatous leprosy is probably due to depressed cellular immune function characteristic of this group of patients. The slightly increased exposure rate to HBV of lepromatous versus the tuberculoid type of leprosy is probably due to increased opportunity for infections from repeated and prolonged stay in hospital.

Adult↗
PubMedDate not supplied

Epidemiology and control of leprosy--a review of progress over the last 30 years.

A review of progress in the epidemiology and control of leprosy indicates that, even though there has been only limited advancement in the epidemiological understanding of the disease, control of leprosy through chemotherapy of patients has been highly successful. Diagnostic tools using serology and other means have substantially improved, particularly in meeting research needs. There has been a reduction of more than 50% over the past decade in the leprosy case load in the world, due mainly to the vigorous implementation of multidrug therapy (MDT) in the treatment of the disease. MDT has been remarkably effective in curing patients, preventing relapse and minimizing side-effects. The progress in disease control in recent years prompted the World Health Assembly in 1991 to endorse a goal of global elimination of leprosy as a public health problem by the year 2000, defining elimination of leprosy as attaining a level of prevalence below one case per 10,000 population. The future prospects for leprosy control in general and improved MDT appear to be good.

Drug Therapy, Combination↗
PubMed1996

Significantly increased frequency of the apolipoprotein E epsilon 4 allele in elderly non-demented leprosy patients.

Apolipoprotein E (apo E) genotypes in 350 leprosy patients were examined and compared with those of 870 age-matched controls. The allelic frequencies of the apo E gene did not differ between demented patients with leprosy and controls. However, the frequency of apo E epsilon 4 allele was significantly higher in non-demented leprosy patients than in controls (P < 0.001). Of special interest is that the prevalence of E3/4 genotype in non-demented leprosy patients increased significantly with age, being 14.1%, 24.4%, and 28.3% in the 60s, 70s, and 80s, respectively (P < 0.05). These data suggest that apo E epsilon 4 is not a risk factor for senile dementia in elderly leprosy patients, and there exist factors to overcome the risk of apo E4 in leprosy patients.

Age Distribution↗
PubMed2004

Leprosy.

Leprosy remains an important health problem worldwide. The disease is caused by a chronic granulomatous infection of the skin and peripheral nerves with Mycobacterium leprae. The clinical range from tuberculoid to lepromatous leprosy is a result of variation in the cellular immune response to the mycobacterium. The resulting impairment of nerve function causes the disabilities associated with leprosy. This review summarises recent advances in understanding of the biology of leprosy, clinical features of the disease, the current diagnostic criteria, and the new approaches to treatment of the infection and the immune-mediated complications. Supervised multi-drug therapy (MDT) for fixed durations is highly effective for all forms of the disease. The widespread implementation of MDT has been associated with a fall in the prevalence of the leprosy but as yet no reduction in the case-detection rate globally. Thus, leprosy control activities must be maintained for decades to interrupt transmission of infection.

Humans↗
PubMed2003

T-cell recognition of peptides from the Mycobacterium leprae 35 kDa protein in Thai leprosy patients, healthy contacts, and non-contacts.

The objective of the study was to identify Mycobacterium leprae-specific immunogenic peptides for the development of a skin test reagent. Such a reagent is required for the detection of M. leprae infection and possibly for the diagnosis of patients with active leprosy. For this purpose, we analyzed the in vitro responses of human peripheral blood mononuclear cell (PBMCs) to peptides from the 35 kDa protein of M. leprae. This protein is of interest since it has no homologue within the Mycobacterium tuberculosis complex, although it has a homologue in Mycobacterium avium. The subjects enrolled in the study were paucibacillary (PB) and multibacillary (MB) leprosy patients, healthy contacts, and non-contacts. Seventy-three PB and 124 MB leprosy patients were recruited from four leprosy clinics in Thailand. Fifty-seven healthy contacts were household contacts. Twenty non-leprosy contacts had no family history of or exposure to leprosy. PBMCs from individuals were tested for stimulation with 12 overlapping peptides from the M. leprae 35 kDa protein using the lymphocyte proliferation assay. These peptides were located in four areas containing three to six residues which were distinct for the M. leprae product in comparison to that from M. avium. Four peptides (p60-76, p132-151, p206-224 and p267-286), which were the most permissive from each region and recognized by non-contacts with significantly lower frequencies than other subject groups, were identified. From this preliminary result, we conclude that these four peptides were likely to be M. leprae-specific.

Adult↗
PubMed1996

Does bacille Calmette-Guérin scar size have implications for protection against tuberculosis or leprosy?

SETTING: Total population study in Karonga District, northern Malawi, in which the overall vaccine efficacy of bacille Calmette-Guérin (BCG) has been found to be -7% against tuberculosis and 54% against leprosy. OBJECTIVE: To examine the relationship between BCG scar size and protection against tuberculosis and leprosy. DESIGN: Cohort study in which 85,134 individuals were screened for tuberculosis and 82,265 for leprosy between 1979 and 1984, and followed up between 1986 and 1989. RESULTS: Of the BCG scar positive individuals whose scars were measured, 31/3 2471 were later identified with tuberculosis and 81/31 879 with leprosy. In 19,114 individuals, of whom 17 developed tuberculosis, tuberculin induration was measured at first examination. Mean scar sizes increased with increasing tuberculin induration in all except the oldest individuals. Mean scar sizes were lowest in individuals aged < 10 years, highest in individuals aged 10-29 years and intermediate in older individuals. There was some evidence (P = 0.08) for an increase in tuberculosis risk with increasing scar size, which probably reflects the known correlation between scar size and tuberculin status at the time of vaccination. There was no clear association between BCG scar size and leprosy incidence. CONCLUSIONS: We find no evidence that increased BCG scar size is a correlate of vaccine-induced protective immunity against either tuberculosis or leprosy.

Adolescent↗
PubMed1992

Limiting dilution analysis in leprosy.

Peripheral blood mononuclear cells (PBM) obtained from leprosy patients and healthy controls were cultured with Mycobacterium leprae and the control antigens, BCG and SKSD. Parallel cultures were supplemented with additional interleukin-2 (IL-2). On the basis of the level of response to M. leprae, leprosy patients could be divided into low, intermediate and high responders. The addition of IL-2 resulted in enhanced proliferation to antigen only by cells from intermediate responders. This effect was neither antigen specific nor was it confined to cells from leprosy patients. When limiting dilution analyses were performed on cells from 26 patients across the leprosy spectrum, no M. leprae-reactive lymphocytes were detected in cells from subjects with lepromatous disease. The precursor frequency for cultures containing M. leprae plus IL-2 was no greater than that of cultures containing IL-2 alone, thereby excluding the possibility of clonal anergy reversible with IL-2. This was observed in both untreated patients and those on long-term treatment, which made sequestration of antigen-reactive cells within leprosy lesions an unlikely explanation. On the other hand, M. leprae-reactive lymphocytes were detected in patients with tuberculoid and borderline tuberculoid disease and in two subjects with borderline lepromatous leprosy in type I reversal reaction. IL-2 reactive cells were detected in all patients regardless of clinical classification. Three 'suppressor' curves were obtained but were not confined to cells from lepromatous patients. Taken together, these findings suggest that the non-responsiveness to M. leprae characteristic of the great majority of multibacillary patients is due to an absence of antigen-sensitive T cells.

Antigens, Bacterial↗
PubMed2004

Genome-wide scans for leprosy and tuberculosis susceptibility genes in Brazilians.

Genome-wide scans were conducted for tuberculosis and leprosy per se in Brazil. At stage 1, 405 markers (10 cM map) were typed in 16 (178 individuals) tuberculosis and 21 (173 individuals) leprosy families. Nonparametric multipoint analysis detected 8 and 9 chromosomal regions respectively with provisional evidence (P<0.05) for linkage. At stage 2, 58 markers from positive regions were typed in a second set of 22 (176 individuals) tuberculosis families, with 22 additional markers typed in all families; 42 positive markers in 50 (192 individuals) new leprosy families, and 30 additional markers in all families. Three regions (10q26.13, 11q12.3, 20p12.1) retained suggestive evidence (peak LOD scores 1.31, 1.85, 1.78; P=0.007, 0.0018, 0.0021) for linkage to tuberculosis, 3 regions (6p21.32, 17q22, 20p13) to leprosy (HLA-DQA, 3.23, P=5.8 x 10(-5); D17S1868, 2.38, P=0.0005; D20S889, 1.51, P=0.004). The peak at D20S889 for leprosy is 3.5 Mb distal to that reported at D20S115 for leprosy in India. (151 words).

Brazil↗
PubMed2004

Interleukin-10 promoter single-nucleotide polymorphisms as markers for disease susceptibility and disease severity in leprosy.

We have determined IL-10 promoter genotypes of five single-nucleotide polymorphisms (SNPs): T-3575A, A-2849G, C-2763A, -A-1082G and C-819T. The haplotype frequencies were defined in healthy subjects compared to leprosy patients, and analyzed for their occurrence in multi- (MB) vs paucibacillary (PB) as severe and mild forms of leprosy, respectively. Haplotypes defined by three SNP positions (-3575, -2849 and -2763) captured significant differences between controls and patients (P=0.04). The haplotype carrying -3575A, -2849G and -2763C was associated with resistance to leprosy and to the development of severe forms of the disease using either a binomial (controls vs cases, P=0.005, OR=0.35, CI=0.13-0.91) or ordinal (controls vs PB vs MB, P=0.006, OR=0.32, CI=0.12-0.83) model. By contrast, the IL-10 haplotype -3575T/-2849A/-2763C was found to be associated with susceptibility to leprosy per se (P=0.027, OR=2.37, CI=1.04-5.39), but not leprosy type. The data suggest that the IL-10 locus contributes to the outcome of leprosy.

Confidence Intervals↗
PubMed2004

Nitrotyrosine localization to dermal nerves in borderline leprosy.

BACKGROUND: Nerve damage is a common and disabling feature of leprosy, with unclear aetiology. It has been reported that the peroxidizing agents of myelin lipids-nitric oxide (NO) and peroxynitrite-are produced in leprosy skin lesions. OBJECTIVES: To investigate the localization of nitrotyrosine (NT)-a local end-product of peroxynitrite-in leprosy lesions where dermal nerves are affected by a granulomatous reaction. METHODS: We investigated by immunohistochemistry and immunoelectron microscopy the localization of the inducible NO synthase (iNOS) and NT in biopsies exhibiting dermal nerves from patients with untreated leprosy. RESULTS: There were abundant NT-positive and iNOS-positive macrophages in the borderline leprosy granulomas infiltrating peripheral nerves identified by light microscopy, S-100 and neurofilament immunostaining. Immunoelectron microscopy showed NT reactivity in neurofilament aggregates and in the cell wall of Mycobacterium leprae. CONCLUSIONS: Our results suggest that NO and peroxynitrite could be involved in the nerve damage following borderline leprosy.

Granuloma↗
PubMed1998

Potential role of B7-1 and CD28 molecules in immunosuppression in leprosy.

In order to understand the mechanism of unresponsiveness towards Mycobacterium leprae antigens in leprosy, we evaluated the role of M. leprae sonicate antigens in regulating the expression of the costimulatory molecules B7-1, CD28, intercellular adhesion molecule-1 (ICAM-1), LFA-1alpha, LFA-1beta and Mac-1 on the lymphocytes of both leprosy patients and healthy subjects. It was observed that the expression of B7-1 and CD28 was significantly decreased but the levels of ICAM-1 and LFA-1alpha were increased in patients with untreated borderline leprosy (BL)/lepromatous leprosy (LL) disease. No remarkable change was noticed in the case of borderline tuberculoid (BT) leprosy or treated BL/LL patients. Further, a striking finding was that lymphocytes from healthy subjects cultured with a particularly high dose of M. leprae sonicate antigens down-regulated the expression of B7-1 and CD28 molecules, but up-regulated the display of ICAM-1 and LFA-1alpha. Furthermore, proliferation induced by M. leprae sonicate was inhibited only by anti-B7-1 antibody. Mycobacterium leprae antigen-induced suppression of the proliferation of lymphocytes of healthy volunteers and LL patients was reversed by culturing the lymphocytes with purified protein derivative (PPD). It may be concluded from the findings in this study that down regulation of B7-1 and CD28 in BL/LL leprosy patients may be responsible for a defective T cell signalling by the B7-1/CD28 pathway caused by M. leprae antigens. This may lead to clonal inactivation of M. leprae-reactive T cells, consequently the bacilli grow without restriction in macrophages.

Antigens, Bacterial↗
PubMed1998

Pentoxifylline decreases in vivo and in vitro tumour necrosis factor-alpha (TNF-alpha) production in lepromatous leprosy patients with erythema nodosum leprosum (ENL).

Increasing evidence has implicated TNF-alpha as a pivotal molecule involved in the systemic inflammatory manifestations of ENL, an acute inflammatory complication that may occur in the chronic course of leprosy. In the present study, the mechanism of action of pentoxifylline (PTX) as an alternative therapy for management of leprosy reactions has been evaluated. The effect of PTX on TNF-alpha production was examined in leprosy patients at the protein level and at the transcriptional level as well. Treatment of ENL patients with PTX (1200 mg daily) ameliorated the systemic symptoms and favoured the evolution of reactional leprosy lesions. Serum TNF-alpha was assayed before and during treatment with PTX in 15 patients. The increased TNF-alpha levels seen in the circulation during the reaction were dramatically reduced within 3-7 days of therapy. No significant effect on serum IL-6 was noted. In vitro TNF-alpha production was assayed upon culture stimulation with Mycobacterium leprae. A reduction of inducible TNF-alpha in peripheral blood mononuclear cells (PBMC) was seen after 1-2 weeks of in vivo administration of PTX. Furthermore, no effect of the drug on IL-10 secretion was detected in these cultures. A kinetic analysis of the expression of TNF-alpha and IL-6 mRNA at the site of leprosy lesion was performed in six reactional patients by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). The amount of TNF-alpha mRNA was increased in the tissue during ENL compared with before the reaction, and decreased thereafter following treatment for reaction (either PTX or thalidomide). These data suggest that PTX inhibits TNF-alpha production in ENL patients both in vivo and in vitro, and it may be useful in the treatment of leprosy patients undergoing ENL.

Adolescent↗
PubMed2000

High prevalence of vitiligo in lepromatous leprosy.

BACKGROUND: Leprosy and vitiligo are common affections in the West Indies. Vitiligo frequently occurs in lepromatous patients, an observation rarely reported in the literature. METHODS: We studied the prevalence of vitiligo in patients affected by leprosy by performing a retrospective study between 1978 and 1999 in the French West Indies (Martinique). RESULTS: Eleven patients presented with vitiligo among 101 with lepromatous (multibacillary) leprosy. None presented with vitiligo among the 364 with the tuberculoid (paucibacillary) form. The mean age of the vitiligo patients was 55. 4 years at vitiligo onset. The sex ratio was 0.8. Vitiligo occurred 19 years after the diagnosis of leprosy, with a range from 3 to 42 years. The prevalence of vitiligo in lepromatous patients was 10.9%, compared to 0% in tuberculoid patients. Such an increase in prevalence compared with that in the general population (0.34%) was shown to be highly significant (P< 0.0001). CONCLUSIONS: Our data confirmed that the association of vitiligo and leprosy was not fortuitous. The physiopathology leading to this high rate of vitiligo in lepromatous leprosy is unclear, despite the fact that autoimmunity plays a major role in both diseases.

Adult↗
PubMed2000

Novel mechanisms in the immunopathogenesis of leprosy nerve damage: the role of Schwann cells, T cells and Mycobacterium leprae.

The major complication of reversal (or type 1) reactions in leprosy is peripheral nerve damage. The pathogenesis of nerve damage remains largely unresolved. In situ analyses suggest an important role for type 1 T cells. Mycobacterium leprae is known to have a remarkable tropism for Schwann cells that surround peripheral axons. Reversal reactions in leprosy are often accompanied by severe and irreversible nerve destruction and are associated with increased cellular immune reactivity against M. leprae. Thus, a likely immunopathogenic mechanism of Schwann cell and nerve damage in leprosy is that infected Schwann cells process and present antigens of M. Leprae to antigen-specific, inflammatory type 1 T cells and that these T cells subsequently damage and lyse infected Schwann cells. Previous studies using rodent CD8+ T cells and Schwann cells have revealed evidence for the existence of such a mechanism. Recently, a similar role has been suggested for human CD4+ T cells. These cells may be more important in causing leprosy nerve damage in vivo, given the predilection of M. leprae for Schwann cells and the dominant role of CD4+ serine esterase+ Th1 cells in leprosy lesions. Antagonism of molecular interactions between M. leprae, Schwann cells and inflammatory T cells may therefore provide a rational strategy to prevent Schwann cell and nerve damage in leprosy.

Antigen Presentation↗