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PubMed2004

Expression of costimulatory molecules (CD80, CD86, CD28, CD152), accessory molecules (TCR alphabeta, TCR gammadelta) and T cell lineage molecules (CD4+, CD8+) in PBMC of leprosy patients using Mycobacterium leprae antigen (MLCWA) with murabutide and T cell peptide of Trat protein.

In leprosy, cell-mediated immunity (CMI) is more significant than humoral response to eliminate intracellular pathogen. T cell defect is a common feature in lepromatous leprosy (LL) patients as compared to tuberculoid type (TT) patients. For efficient initiation of CD4+, T cell response requires T cell receptor (TCR) activation and costimulation provided by molecules on antigen-presenting cells (APC) and their counter receptors on T cells. In our previous study, the defective T cell function in LL patients was restored to a proliferating state with the release of TH1 type cytokines using mycobacterial antigen(s) with two immunomodulators (Murabutide (MDP-BE) and T cell epitope of Trat protein of Escherichia coli) by presenting the antigen in particulate form in vitro to PBMC derived from leprosy patients. This observation prompted us to study the expression of the costimulatory molecules (CD80, CD86, CD28, CD152), other accessory molecules (TCR alphabeta/gammadelta) and T cell lineage molecules (CD4+ and CD8+) during constitutive and activated state of peripheral blood mononuclear cells (PBMC) derived from normal and leprosy individuals using different formulations of Mycobacterium leprae total cell wall antigen (MLCWA), Trat and MDP-BE using flow cytometric analysis. An increased surface expression of CD80, CD86 and CD28 but decreased CD152 expression was observed when PBMC of normal, BT/TT (tuberculoid) and BL/LL (lepromatous) patients were stimulated in vitro with MLCWA+MDP-BE+Trat peptide using liposomal mode of antigen delivery, while opposite results were obtained with the antigen alone. Antibody inhibition study using antihuman CD80 or CD86 completely abolished the T cell lymphoproliferation, thereby reconfirming the importance of these costimulatory molecules during T cell activation/differentiation. Though the liposome-entrapped antigen formulation has no effect on expression of alphabeta/gammadelta T cell receptor, the constitutive levels of TCR gammadelta were high in lepromatous patients. Thus, TCR bearing gammadelta appears to have a negligible regulatory role in peripheral blood of leprosy patients. The percentage of cells positive for CD4+ are increased in inducible state in all the three groups, while CD8+-positive cells were decreased in LL patients, thereby reconfirming the fact that priming of CD4+ cells are necessary for producing final effector functions. Lastly, intracellular cytokine staining experiment indicated that CD4+ cells are the major producers of IFN-gamma but not NK cells. The study highlights the reversal of T cell anergy especially in lepromatous patients through the modulation of costimulatory molecule expression under the influence of Th1 cytokines, i.e., IL-2 and IFNgamma.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed2006

Towards an immunodiagnostic test for leprosy.

In addition to multidrug therapy, elimination of leprosy requires improved diagnostic methods. Using a comparative genomics approach, 17 potential protein antigens (MLP) that are restricted to Mycobacterium leprae, or of limited distribution, were produced and tested for antigen-specific immune responses on leprosy patients, healthy contacts of leprosy patients, and tuberculosis patients in Mali and Bangladesh, as well as on non-endemic controls. T-cell antigenicity of MLP was confirmed by IFN-gamma production in whole-blood assays with the highest responses observed in paucibacillary leprosy patients and healthy contacts. Four MLP behaved well in both countries and induced significantly different responses between the study groups. Peptides carrying T cell epitopes from one of the antigens gave promising results in restimulation assays in mice and immune responses were not influenced by prior exposure to BCG or environmental mycobacteria. This study provides the immunological framework for the development of a specific, peptide-based immunodiagnostic test for leprosy.

Amino Acid Sequence↗
PubMed2000

Comparison of the T cell patterns in leprous and cutaneous sarcoid granulomas. Presence of Valpha24-invariant natural killer T cells in T-cell-reactive leprosy together with a highly biased T cell receptor Valpha repertoire.

The T-cell-reactive (eg, tuberculoid and reversal) forms of leprosy represent a well-defined granulomatous reaction pattern against an invading pathogen. The immune response in cutaneous sarcoidosis is a granulomatous condition that pathologically is very similar to T-cell reactive leprosy. However, it lacks a defined causative agent. In view of the role of NKT cells in murine granulomas induced by mycobacterial cell walls, we have searched for the presence of NKT cells in the cutaneous lesions of both leprosy and sarcoidosis. These cells were present in T-cell-reactive leprosy but were undetectable in cutaneous sarcoidosis. We have also studied the TCR Valpha repertoire in the two diseases. In addition to Valpha24(+) NKT cells, all patients with T-cell-reactive leprosy showed a very restricted T-cell-reactive Valpha repertoire with a strong bias toward the use of the Valpha6 and Valpha14 segments. Valpha6 and Valpha14(+) T cells were polyclonal in terms of CDR3 length and Jalpha usage. In contrast, most sarcoidosis patients showed a diverse usage of Valpha chains associated with clonal or oligoclonal expansions reminiscent of antigen-driven activation of conventional T cells. Thus the origin and perpetuation of the two kinds of granulomatous lesions appear to depend on altogether distinct T-cell recruiting mechanisms.

Adolescent↗
PubMed1996

Histological findings of human leprosy periapical granulomas.

Histological analysis of human leprosy periapical granulomas was conducted to study the histological responses to Mycobacterium leprae. Many Langhans-type giant cells and epithelioid cell tubercles were observed, although M. leprae were not detected in leprosy periapical granulomas. Although numerous T- and B-cells were infiltrated in leprosy periapical granuloma, the T-/B-cell ratio of leprosy is not changed to that of periapical granulomas isolated from normal patients. These findings suggested that human leprosy periapical granulomas develop as a result of immunological responses to M. leprae.

B-Lymphocytes↗
PubMed1975

Sulphone resistance in leprosy. A review of one hundred proven clinical cases.

An account is given of the first hundred consecutive proven cases of sulphone resistance in leprosy, detected in Malaysia between 1963 and 1974. Proof of resistance was clinical in eighty patients and was obtained by drug-sensitivity testing in mice in ninety-six patients; 76 cases were proved both clinically and experimentally, and there was no discrepancy between the two methods. Sulphone resistance was confined to patients with lepromatous-type leprosy--i.e., patients with a large bacterial population. Clinical evidence of relapse due to drug resistance appeared 5-24 years after the start of sulphone treatment. Low dosage favoured the appearance of resistance; therefore regular treatment of lepromatous leprosy with dapsone in full dosage is recommended. The attainment of "skin smears negative for leprosy bacilli" is no test of cure of lepromatous leprosy.

Adolescent↗
PubMed1999

Leprosy.

Leprosy is an ancient disease which is still poorly understood and often feared by the general public and even by some healthcare professionals. Fortunately, improvements in the management of leprosy over the past three decades have diminished the stigma and greatly altered the outlook for patients. Public understanding of the disease has benefited from WHO's goal of eliminating leprosy as a public health problem by the year 2000. Unfortunately that goal has also led many to believe that leprosy has been or will soon be eradicated. This will not happen in the near future because, despite a fall in registered cases, the incidence of the disease has changed very little, and eradication of a bacterial infectious disease such as this is unlikely with chemotherapy alone. Nevertheless, as a result of the WHO's efforts, patients nearly everywhere should have access to care, and the incidence may begin to diminish if adequate control efforts are maintained beyond the year 2000. Given the mobility of patients today a physician anywhere may occasionally see a case or be asked about the disease so a basic understanding of leprosy and its management should prove useful.

Drug Administration Schedule↗
PubMedDate not supplied

The placenta in leprosy.

Eighty-one placentae from women with leprosy and 17 placentae from healthy controls were subjected to a detailed macroscopic, light microscopic, ultrastructural, immunopathological, microbiological and biochemical study. The placental morphology and immunohistology were normal, and there was no morphological evidence of infection of the placenta due to M. leprae. No acid-fast bacilli or acid-fast bacillary granules were seen on light microscopy of any of the placentae from leprous women, although homogenates from two out of seven placentae from women with very active lepromatous leprosy contained acid-fast bacilli in very small numbers. The small placental size of women with leprosy, most marked in those with lepromatous leprosy, appears to be due to a decrease in placental cell size, rather than to a reduced number of cells in the placenta. It is postulated that the small placenta and reduced fetal birth weight observed in lepromatous leprosy are a consequence of depressed maternal immune reactivity.

Complement System Proteins↗
PubMed2000

Detection of disease related immune complexes in the serum of leprosy patients. A novel single step method.

Mycobacterium leprae antigen and antibody complexes could be detected in the serum of leprosy patients using monoclonal antibody ML34 and anti-BCG antibodies by enzyme-linked immunosorbent assay. This simplified system detects disease related complexes without the need for isolating and purifying them from the serum. Immune complexes captured using monoclonal antibody ML34 revealed positivity in seven out of eight neuritic, two out of nine tuberculoid (TT), five out of ten borderline tuberculoid (BT), four out of ten borderline lepromatous (BL) and four out of ten lepromatous (LL), leprosy cases. One of the controls also showed immune complex of an IgM type. Anti-BCG based IgG immune complexes assay revealed positivity in six out of eight neuritic, one out of nine TT, four out of ten BT, two out of ten BL, four out of ten LL leprosy cases, and two out of 24 healthy controls. IgM type of mycobacterial immune complexes were almost negligible. Capture of complexes using monoclonal antibody ML34 which is against lipoarabinomannan of M. leprae seems to work better than polyclonal anti-BCG antibody. The probable role of immune complexes in nerve damage needs to be evaluated, as very high levels of immune complexes are found in neuritic leprosy by both the assays. The above test would be useful in immunodiagnosis of neuritic leprosy and also in cases where antibody response is not detectable because of the formation of immune complexes.

Antigen-Antibody Complex↗
PubMed1986

Characterization of the anti-neural antibodies in the sera of leprosy patients.

Sera from 43 leprosy patients were tested for antibodies that bound to normal human nerve. Thirty-eight percent showed positive staining as demonstrated by indirect immunofluorescence. Only 1 out of 30 control sera tested displayed similar staining. Western blots of myelin and neural intermediate filament (IF) proteins were tested with patient sera. Two of the anti-neural antibody (ANeAb)-positive leprosy sera bound to the P0 protein of PNS myelin. All 17 ANeAb-positive leprosy sera displayed 2 or more bands in the molecular weight range of Mr 45 000-55 000, when tested against IF proteins. One explanation for these findings is that leprosy patients produce antibodies to intermediate filament (IF) proteins released subsequent to the bacterial invasion of the peripheral nerves. The importance of these autoantibodies in the pathogenesis of leprosy is discussed.

Antibodies, Antinuclear↗
PubMed1989

Leprosy and glomerulonephritis: case report and review of the literature.

Membranoproliferative glomerulonephritis (MPGN) is a common form of glomerulonephritis and frequently is associated with chronic infections. Leprosy, one of the most common infections worldwide, was found in conjunction with MPGN, type I, in a patient. Serological abnormalities typical of MPGN, improvement in renal function with therapy of acute complications of leprosy, and long-term renal improvement with antileprosy therapy all occurred in this patient. Others have found that MPGN is found in 11% to 43% of leprosy patients undergoing renal biopsy. Serological abnormalities typical of MPGN frequently are found in patients with lepromatous leprosy. The associations of MPGN and leprosy, and the susceptibility of the glomerulonephritis to therapy, should be emphasized.

Glomerulonephritis, Membranoproliferative↗
PubMed2006

The role of BCG in prevention of leprosy: a meta-analysis.

The present meta-analysis investigates the role of BCG-a widely used yet controversial vaccine-in the prevention of leprosy. The electronic databases Medline, Embase, the Cochrane Library, and LILACS were searched to identify studies assessing the protective effect of BCG against leprosy. We included seven experimental studies and 19 observational studies. The experimental studies demonstrated an overall protective effect of 26% (95% CI 14-37%). At 61% (95% CI 51-70%), the observational studies overestimated the protective effect. The age at vaccination did not predict the protective effect of BCG. An additional dose of BCG was more protective in the prevention of leprosy compared with a single dose. An additional dose of BCG may be warranted for contacts of leprosy patients in areas where leprosy continues to be a public-health problem.

Adolescent↗
PubMed2002

Advances in the diagnosis and treatment of leprosy.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae that mainly affects the skin and peripheral nerves. Over recent years, many important advances have been made in developing molecular diagnostics, in identifying highly effective drugs and designing multidrug regimens for treatment, and in unravelling the genomic structure and functions of the leprosy bacillus. Using the new information about specific sequences of M. leprae, several gene probes and gene amplification systems for confirming diagnosis and monitoring treatment have been developed. Among these, polymerase chain reaction (PCR)-based methods have been useful in confirming the diagnosis in paucibacillary leprosy (where few bacilli are present). RNA-targeting systems for monitoring the progress of treatment, in situ hybridisation techniques for analysing specimens with nonspecific histological features, and molecular methods for direct detection of rifampicin/dapsone resistance are other major technological advances with immense applied value. Several effective regimens for the treatment of leprosy have been developed, which include rifampicin, clofazimine and dapsone as core drugs. Although these regimens are generally satisfactory, limitations in terms of persisting activity and late reactions/relapses in paucibacillary leprosy, and persistence of dead and/or live organisms in multibacillary forms of the disease, have been observed.

Animals↗
PubMed2004

Linkage analysis of susceptibility to leprosy type using an IBD regression method.

Leprosy is a chronic disease caused by infection with Mycobacterium leprae, which is manifested across a wide clinical spectrum. There is evidence that susceptibility both to leprosy per se and to the clinical type of leprosy is influenced by host genetic factors. This paper describes the application of an identity by descent regression search for genetic determinants of leprosy type among families from Karonga District, Northern Malawi. Suggestive evidence was found for linkage to leprosy type on chr 21q22 (P<0.001). The methodological implications of the approach and the findings are discussed.

Chromosomes, Human, Pair 21↗
PubMed1997

Characterization of circulating immune complexes in leprosy patients and their correlation with specific antibodies against Mycobacterium leprae.

Circulating immune complex (CIC) levels and their antibody and antigenic composition were evaluated in patients with leprosy as well as in any individuals living with them; they were precipitated with 3.5% polyethylene glycol (PEG) and, after affinity chromatography isolation and purification, analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblot with monoclonal antibodies (Mabs). The presence of CICs was demonstrated throughout the clinical and immunopathological leprosy spectrum at levels related to bacterial load, and in leprosy patients they showed a positive correlation with specific anti-PGL and anti-65 kDa antibodies. The isolation and analysis, however, failed to identify any Mycobacterium leprae antigenic components; although two specific antibodies anti-PGL-1 and anti-65 kDa were identified as possible CIC constituents and may be potentially useful in the follow-up of leprosy patients, especially to check bacterial load evolution, PGL-1 being an authentic antigen of this mycobacterium. Also, the involvement of 65 kDa in CICs, being homologous with the human heat shock protein (HSP) 60 kDa family, suggests an autoimmune mechanism in leprosy pathogenesis. Furthermore, those results support the inclusion of CIC antibody reactivity studies to enhance the sensitivity of serology.

Adolescent↗
PubMed1996

Soluble adhesion molecules in sera of patients with leprosy: levels of soluble intercellular adhesion molecule-1 (sICAM-1) rapidly decrease during multi-drug therapy.

The clinicopathological spectrum of leprosy is associated with an altered immunological reaction. The expression of adhesion molecules on endothelial cells directs the cellular traffic to sites of local skin and nerve inflammation. Soluble forms of adhesion molecules, which are released upon cytokine activation, can be detected in the circulation and may reflect ongoing tissue inflammation. We determined the serum levels of sICAM-1, sE-selectin and sL-selectin in 74 patients with leprosy (tuberculoid form, n = 23; lepromatous form, n = 36; acute leprous reaction, n = 16) and 15 healthy age- and sex-matched control donors. Patients with lepromatous leprosy had significantly higher levels of sICAM-1 (564 +/- 174 versus 450 +/- 92 versus 334 +/- 57 ng/ml) and E-selectin (90 +/- 31 versus 74 +/- 29 versus 50 +/- 10 ng/ml) than patients with tuberculoid leprosy and normal donors (P < 0.01). No differences between groups were detected for L-selectin. Patients with leprous reactions had similar high levels to lepromatous patients. Twenty lepromatous patients were re-examined after 4 weeks of therapy. A significant decrease in sICAM-1 serum levels was observed after 1 month of anti-mycobacterial treatment, which was accompanied by a reduction of mycobacteria in skin biopsies (P < 0.01). Patients with leprous reactions (n = 13) also demonstrated a drop in sICAM-1 after anti-inflammatory therapy. sE-selectin and sL-selectin serum values decreased only in lepromatous patients after therapy. It can be concluded that soluble adhesion molecules like sICAM-1 and sE-selectin are promising activity markers in patients with leprosy, which may be useful for treatment monitoring.

Adult↗
PubMed2002

Association of a missense mutation of the laminin alpha2 gene with tuberculoid type of leprosy in Indonesian patients.

Leprosy, an infection caused by Mycobacterium leprae, has a specific tropism for the myelinating Schwann cells of peripheral nerves. Recently, the G domain of laminin alpha2 has been shown to be a mediator for M. leprae to bind to alpha-dystroglycan in Schwann cells. In order to analyse the association of leprosy with the mediator, three genetic polymorphisms encoding the G domain of the laminin alpha2 chain were analysed by direct sequencing in 53 leprosy patients and 58 healthy contact individuals from Indonesia. There was no significant difference in the incidence of the polymorphisms between patients and non-patients. Remarkably, it was found that a missense mutation (T7809C) substituting valine with alanine (V2587A) was found to be more frequent in the tuberculoid type than in the lepromatous type leprosy. It is supposed that this missense mutation is one of the determinant factors in the early onset of peripheral nerve damage in Indonesian tuberculoid leprosy patients.

Alleles↗
PubMed2002

Epidemiology of leprosy on five isolated islands in the Flores Sea, Indonesia.

We conducted a population-based survey on five small islands in South Sulawesi Province (Indonesia) to collect baseline data previous to a chemoprophylactic intervention study aiming at interrupting the transmission of Mycobacterium leprae. Here we describe the present leprosy epidemiology on these geographically isolated islands. Of the 4774 inhabitants living in the study area 4140 were screened for leprosy (coverage: 87%). We identified 96 leprosy patients (85 new and 11 old patients), representing a new case detection rate (CDR) of 205/10 000 and a prevalence rate of 195/10 000. CDRs were similar for males and females. Male patients were more often classified as multibacillary (MB) than women. Of the new patients, 33 (39%) were classified as MB, 16 (19%) as paucibacillary (PB) 2-5 lesions and 36 (42%) as PB single lesion. In this area of high leprosy endemicity leprosy patients were extensively clustered, i.e. not equally distributed among the islands and within the islands among the houses.

Adolescent↗
PubMed1998

Recurrent scleritis in lepromatous leprosy.

BACKGROUND: Recurrent immune-mediated scleritis after adequate treatment of leprosy is not well documented in the literature. We describe an Australian resident with unilateral intra-ocular lepromatous leprosy who had persistent non-infectious scleritis. METHODS: A man of Anglo-Indian ancestry initially presented with lepromatous leprosy and unilateral ocular involvement. The affected eye had an interstitial keratitis and a granulomatous anterior uveitis that responded to antileprotics and anti-inflammatory agents. Despite systemic cure with triple antileprotic therapy, he developed recurrent scleritis that required multiple scleral patch grafts for scleral thinning and, subsequently, an enucleation. Histology failed to demonstrate persistent infection, rather a chronic non-granulomatous scleritis, which was probably immune mediated. RESULTS/CONCLUSIONS: This case demonstrates an ocular complication of leprosy that is infrequently reported. Patients with ocular involvement by leprosy are at risk of developing recurrent scleritis despite systemic cure with antileprotics.

Anterior Chamber↗