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Incidence of late lepra reaction among multibacillary leprosy patients after MDT.

Multidrug therapy (MDT) recommended by the World Health Organization (WHO) had been administered in 1982 to a cohort of multibacillary (MB) leprosy patients. Treatment was administered for a minimum period of 2 years or until skin-smear negativity for acid-fast bacilli was achieved (whichever was later). Among 980 MB leprosy patients who completed treatment, 11 patients (1.1%) experienced lepra reactions during surveillance. Probable predictive factors are discussed. The incidence of lepra reaction seemed to be three times more common in borderline (BL) leprosy than in lepromatous (LL) leprosy. The majority of these events occurred during the first 3 years of surveillance. All of these episodes were treated with steroids without antileprosy chemotherapy. None of these patients was confirmed as experiencing a relapse during the subsequent period of surveillance.

Colony Count, Microbial↗

Specific and nonspecific aspects of humoral immune response in leprosy.

1. We have studied some generic and specific aspects of the humoral immune response in 96 patients with leprosy (29 paucibacillary and 67 multibacillary individuals). We determined serum immunoglobulins (IgM, IgG and IgA), CH50, C1q, C3 and C4, circulating immune complexes (CIC), C-reactive protein (CRP), rheumatoid factor (RF) and antinuclear antibodies. No specific pattern of general humoral immune changes could be observed. 2. The specific immune response was studied by the detection of specific IgM anti-M. leprae antibodies. An immunoradiometric assay (IRMA) and an ELISA were compared for clinical effectiveness. IRMA showed greater sensitivity for the serodiagnosis of leprosy as compared to ELISA (88.1% vs 58.2% for multibacillary patients and 20.7% vs 10.3% for paucibacillary leprosy patients). Specificity was 96% for IRMA and 97% for ELISA. 3. Our results indicate that nonspecific changes in the humoral immune response are of little value in assessing leprosy patients and that immune assays for the detection of specific anti-M. leprae antibodies may be of value in the diagnosis, study and follow-up of these patients.

Adolescent↗

Membrane attack complex in thickened cutaneous sensory nerves of leprosy patients.

Membrane attack complex (MAC) is a terminal end product produced as a result of complement activation. The deposition of MAC, in tissues, is known to have a local tissue damaging effect in several clinical conditions. Therefore, an attempt was made to demonstrate MAC in peripheral nerve biopsies, collected from leprosy patients. Interestingly, we could demonstrate deposition of MAC in involved cutaneous sensory nerves from most of the lepromatous leprosy patients. Contrary to this, majority of nerve biopsies from tuberculoid leprosy patients did not stain for MAC. Though MAC positive sections showed reactivity for S-protein, our observations support the possibility that MAC, either acting directly or indirectly, may be implicated in nerve damage, at least, in lepromatous leprosy patients.

Antigens, Bacterial↗

A practical method of active case finding and epidemiological assessment: its origin and application in the leprosy control project in Indonesia.

Random sample surveys in the past have revealed high estimated against low registered prevalences for leprosy in several parts of Indonesia. A pilot project showed that the problem of cases that had not yet been detected could not be solved without the active participation of the local authorities, who proved able to overcome the stigma and to convince potential patients to go for examination and treatment. The pilot project was based on the principle of what are called exploration surveys, which were introduced by Sitanala in Indonesia in 1931. The Indonesian government decided to reintroduce these surveys in 1977 under the name of chase or trace surveys. They are carried out within the framework of the leprosy workers' routine duties and no additional expenses are incurred. Since then, thousands of patients of all types and with long case histories have been detected and brought under treatment. Without this "push" it is fair to assume that many would never have sought treatment voluntarily. In view of the experience in Indonesia, one wonders whether leprosy can be eliminated without emphasizing the importance of active case finding, especially in areas in which the disease is still highly endemic. Chase surveys also provide rough information about the local leprosy situation. Although of great value, they are not, in high-endemic regions, an alternative to random sample surveys which reveal, besides a wealth of additional information, the possible unknown sources of infection.

Communicable Disease Control↗

[Atypical presentations of leprosy: apropos of 2 cases].

This report describes two atypical cases of leprosy. A 48 year old male patient presented laryngeal dyspnea with adhesions of the oropharynx of which the biopsies were inconclusive. The patient was cachectic with hyperesthesia of the extremities and two subcutaneous nodules. The biopsy of one nodule evoked thesaurismosis or dyslipoidosis while the bacilloscopy was positive in nasal smears. A 14 year old female patient suffered from bullae which appeared spontaneously on erythematous skin on the legs and upper arms. Upon examination those areas were found to be hypoaesthetic, as was a very large hamartoma on the left half of the body. A biopsy of healthy skin evoked the diagnosis of leprosy. The patient then developed BT leprosy and episodes of hysteria. The first observation led to several diagnoses: while laryngeal dyspnea is unusual in LL and while cutaneous histology of regressive LL contrasted with the abundance of the bacilloscopy. The diagnosis of the second case is that of indeterminate leprosy with premonitory neurological signs associated with pathomania and evolution to a multibacillary form.

Adolescent↗

CD1 expression by dendritic cells in human leprosy lesions: correlation with effective host immunity.

A potential role for the CD1 family of lipid Ag-presenting molecules in antimicrobial immunity in vivo was investigated in human leprosy skin lesions. Strong induction of three CD1 proteins (CD1a, -b, and -c) was observed in dermal granulomas in biopsy samples of involved skin from patients with the tuberculoid form of leprosy or with reversal reactions, which represent clinical patterns of disease associated with active cellular immunity to Mycobacterium leprae. In contrast, lesions from patients with the lepromatous form of the disease who lack effective cell-mediated immunity to the pathogen did not show induction of CD1 proteins. Thus, expression of CD1 correlated directly with effective immunity to M. leprae, as assessed by the clinical course of infection. CD1a, -b, and -c could be induced to similar levels on monocytes from the blood of either tuberculoid or lepromatous leprosy patients. This suggested that the absence of expression in lepromatous lesions was most likely due to local factors at the site of infection as opposed to a primary defect of the CD1 system itself. The majority of cells expressing CD1 in leprosy lesions were identified as a population of CD83+ dendritic cells. Initial in vitro studies of the Ag-presenting function of CD1+CD83+ monocyte-derived dendritic cells showed that such cells were highly efficient APCs for CD1-restricted T cells. These results indicate that the CD1 system can be up-regulated in human infectious diseases in vivo, and may play a role in augmenting host defense against microbial pathogens.

Antibodies, Monoclonal↗

Immune reconstitution inflammatory syndrome associated with HIV and leprosy.

BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) is an unusual inflammatory reaction to an opportunistic infection that occurs in human immunodeficiency virus (HIV)-positive patients with profound immunosuppression during the reconstitution of the immune system in the initial months of highly active antiretroviral treatment. OBSERVATIONS: We describe 3 cases of leprosy occurring in patients treated with a combination of 3 antiretroviral drugs who fulfilled the criteria for IRIS. A reactional state occurred in all 3 cases. Two of the 3 patients presented an unusual ulcerous progression of the lesions not generally observed in cases of leprosy. The outcome was favorable in all 3 cases. The frequency of IRIS associated with leprosy in French Guiana and Martinique is estimated at 3 cases per 1000 HIV-positive patients receiving highly active antiretroviral treatment. CONCLUSION: Leprosy should be recognized as an IRIS-associated infection with possibility of atypical presentation.

AIDS-Related Opportunistic Infections↗

Epidemiological approach to the paleopathological diagnosis of leprosy.

In paleopathology it is usually assumed that modern diagnostic criteria can be applied to infectious diseases in the past. However, as both the human species and populations of pathogenic microorganisms undergo evolutionary changes, this assumption is not always well-founded. To get valid estimates of the frequency (the point prevalence at death) of leprosy in skeletal samples, sensitivity, specificity, and sample frequency must be estimated simultaneously. It is shown that more than three symptoms must be evaluated in at least three samples in order to reach estimates with well-described properties. The method is applied to three skeletal samples from Medieval Denmark; the samples were scored for the presence of seven osteological conditions indicating leprosy. For the osteological conditions, sensitivity varied from 0.36-0.80, and specificity from 0.58-0.98. The frequency of leprosy in the three samples was: Odense (a lepers' institution), 0.98, 95% CI 0.64-1.00; Malmö (urban cemetery), 0.02, 95% CI 0.00-0.07; and Tirup (rural cemetery), 0.36, 95% CI 0.23-0.46. It is concluded that it is indeed possible to estimate disease frequencies without reference to modern standards, and that leprosy occurred with widely differing frequencies in different segments of the Medieval population in southern Scandinavia.

Adult↗

Osteoarchaeological evidence for leprosy from western Central Asia.

Published reports of palaeopathological analyses of skeletal collections from Central Asia are, to date, scarce. During the macroscopic examination of skeletal remains dating to the early first millennium AD from the Ustyurt Plateau, Uzbekistan, diagnostic features suggestive of leprosy were found on one individual from Devkesken 6. This adult female exhibited rhinomaxillary changes indicative of leprosy: resorption of the anterior nasal spine, rounding and widening of the nasal aperture, erosion of the alveolar margin, loss of a maxillary incisor, and inflammatory changes in the hard palate. While it is unclear whether the bones of the hands and the feet from this individual were absent as a result of collection strategy or poor preservation, lesions affecting the tibia and fibula were recorded, and the ways in which they may be related to a diagnosis of leprosy are discussed. This is the first skeletal evidence of leprosy from Central Asia and raises questions not only about the spread of the disease in the past, but also about the living conditions of what traditionally were thought of as nomadic peoples.

Bone and Bones↗

T cell responses to fractionated Mycobacterium leprae antigens in leprosy. The lepromatous nonresponder defect can be overcome in vitro by stimulation with fractionated M. leprae components.

Protective immunity against Mycobacterium leprae is dependent on M. leprae-reactive T lymphocytes. M. lepare-directed T cell reactivity is high in the localized tuberculoid form of leprosy but specifically absent in the disseminated lepromatous type of the disease. Two important questions that are relevant for the understanding of the immune response in leprosy as well as for the design of rational immunoprophylaxis and -therapy strategies are: (a) what are the antigens that trigger T cell responses in tuberculoid patients and thus protect these individuals from developing lepromatous leprosy and (b) is it possible to restore T cell responsiveness to M. leprae in lepromatous patients by rechallenging the immune system with selected antigens that will trigger help but not suppression? We have addressed these question by directly probing the peripheral T cell repertoire of 10 tuberculoid and 18 lepromatous patients with large numbers of different M. leprae and BCG antigenic components that had been separated on the basis of their relative molecular mass (Mr) by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and electroblotted onto nitrocellulose. This technique allows the identification of T cell-stimulating antigens independent of the expression of B cell epitopes by these antigens. So far T cell epitopes have only been mapped on M. leprae proteins that had previously been defined by antibodies. Our results show that: (a) tuberculoid patients' T cells responded preferentially to M. leprae and BCG antigens in the lower (i.e. less than 70 kDa) Mr range with a peak in the 10-25 kDa range; (b) 6 out of 18 lepromatous patients that did not respond to whole M. leprae responded strongly to isolated M. leprae components; antigens in the lower Mr. range were recognized by five out of these six patients and thus commonly seen by both tuberculoid and lepromatous patients' T cells; however, antigens in the higher Mr range, in particular greater than 150 kDa, were only recognized by lepromatous patients' T lymphocytes; (c) furthermore, the T and B cell repertoires in leprosy patients are skewed towards different antigenic fractions.

Antibodies, Bacterial↗

Segregation analysis of leprosy in families of northern Thailand.

Sixty-three families with multiple instances of leprosy were identified through a major leprosy treatment center in northern Thailand. Complex segregation analyses for single major genes or polygenic inheritance were performed using the maximum-likelihood routine POINTER to determine the most likely etiologic model of genetic susceptibility. Liability differences between men and women were considered in these models. When individuals were considered to be affected because they had any form of leprosy, a generalized major gene model with nearly dominant parameters on the liability scale, but additive penetrances, was found to be the most likely. When only those individuals who had tuberculoid forms of leprosy were considered to be affected, a recessive model was found to be the most likely; however, the discrimination between various models was poor. Further analyses are necessary to delineate genetic mechanisms to explain these apparently divergent results. In particular, methods of testing two locus models should be considered.

Adult↗

Immunoreactivity of nerve lipid antigens in leprosy.

Neural lipid antigens, namely, galactocerebroside and ganglioside, have been implicated in demyelinating diseases. We were interested in finding the role of these antigens in leprosy neuritis. The humoral immune response to these lipid antigens was quantitated by enzyme-linked immunosorbent assay in sera from 91 leprosy patients and 18 normal individuals. Our data revealed the presence of antibodies to total nerve lipids (TNL) and galactocerebroside (GalC) and a significantly low level to ganglioside (Gg) in all the categories of leprosy. No antilipid antibodies were detected in normals. Anti-TNL and anti-GalC antibodies were highest in tuberculoid leprosy patients. Statistically significant positive correlation was observed between anti-TNL and anti-GalC antibodies in lepromatous borderline, tuberculoid, and neuritic patients.

Antibody Formation↗

An immunoperoxidase study of immunological factors in high immune and low resistance granulomas in leprosy.

The epithelioid cell granuloma in high resistant tuberculoid (TT) leprosy was contrasted with the pure macrophage granuloma of anergic lepromatous leprosy (LL) by evaluating various immunological factors operating in these lesions. The immunoperoxidase technique using antisera to immunoglobulin IgG, IgM, complement C3, C3d and C1q and other products of macrophage secretion, lysozyme, plasminogen, a1 antitrypsin and C-reactive protein and of Ia antigens revealed peak levels in tissues of most of these factors in both types of granuloma. The tuberculoid response was linked to low antigenic load and Ia-like antigen and the lepromatous response was secondary to a high antigenic load in the absence of Ia antigen. Complement and other mediators were found intracellularly in both tuberculoid and lepromatous granulomas, but extracellularly only in tuberculoid lesions. This may indicate local hypersensitivity in the tuberculoid granuloma. It is suggested that the mediators in LL macrophages remain bound to lipids of mycobacterial degenerations in the phagocytic vacuole. Secretory cells were differently sited in the two types of granulomas: peripheral in epithelioid cell lesions and central around capillaries over the whole lesion in pure macrophage granulomas of LL. In tuberculoid leprosy many of the central vessels in the granuloma were obliterated. C1q was found in fibroblasts. However, the marked absence of fibrosis in any of the lesions of leprosy, except following severe reactions, casts some doubt on the link which has been postulated between epithelioid cells and fibroblasts as an explanation of fibrosis in granulomas.

Complement System Proteins↗

A polymorphism in the toll-like receptor 2 is associated with IL-12 production from monocyte in lepromatous leprosy.

Toll-like receptor 2 (TLR2) is critical in the immune response to mycobacterial infections, and the mutations in the TLR2 have been shown to confer the susceptibility to infection with mycobacteria. We previously reported the detection of TLR2 Arg677Trp mutation in lepromatous leprosy. Here, the events triggered by TLR2 in response to cell lysate of Mycobacterium leprae(MLL), the causative agent of leprosy, were investigated. Upon stimulation with MLL, monocytes produced TNF-alpha and Interleukin-12 (IL-12), which play a role in the innate immune response to infection. Anti-TLR2 mAb blocked greater than 50% of the MLL-induced production of IL-12. We also performed the functional study on TLR2 by measurement of IL-12 production in serum and monocytes from leprosy patients with TLR2 mutation (Arg677Trp). The monocytes obtained from patients with the TLR2 mutation, in comparison to the wild-type TLR2, is significantly less responsive to MLL. It was also confirmed that patients with TLR2 mutation showed significantly lower serum levels of IL-12, in comparing with TLR2 wild-type. Our results reveal that innate immune response of monocytes against M. lepraeis mediated by TLR2, and suggest that the mutation in the intracellular domain of TLR2 gene is associated with IL-12 production in lepromatous leprosy.

Amino Acid Sequence↗

Biological, chemical, immunological and staining properties of bacteria isolated from tissues of leprosy patients.

Two kinds of microorganisms are found in tissue of leprosy patients: Mycobacterium leprae (ML) and leprosy derived corynebacteria (LDC). ML from untreated patients has an alcohol-acid-fastness, which is lost upon treatment with antibiotics and immune response (tuberculoid leprosy). Vulnerable ML thus produced can be reversibly de-stained by organic solvent: in tissue sections from tuberculoid and treated patients, more bacteria are, thus, revealed by the Wade-Fite than by the Ziehl-Neelsen procedure. Organisms of genera Corynebacterium, Mycobacterium and Nocardia (CMN group), have DNA with %GC contents of 50-70, 69-72, and 68-70 respectively. GC values of DNA from ML and LDC are close to 56%. DNA from different LDC strains display high homology among them and low homology with reference corynebacteria. CMN cell wall consists of interconnected peptidoglycan and polysaccharide-mycolate complex. Peptidoglycan of LDC (and known CMN) has the polysaccharide backbone linked to a tetrapeptide of L-Ala, D-Glu, m-DAP (meso-diaminopimelate), D-Ala. In ML, L-Ala is replaced by glycine. Mycobacterial wall polysaccharides (that of ML is unknown) are branched arabinogalactans with end arabinoses linked to C70 to C90 mycolates. LDC peripheral polysaccharides are arabinogalactomannans with arabinose and mannose lateral strands. Mycolic acids of LDC are of corynomycolic type (C32, C34 and C36 with 1-4 double bonds) and those of ML are of mycobacterial type. Components of CMN wall and cytoplasm are immunologically active as antigens (polysaccharides, proteins), haptens (lipids) and adjuvants (peptidoglycans). Strong intrageneric and weak intergenera crossreactions are observed among CMN bacteria: LDC preparations, however, crossreact strongly with ML and mycobacteria, and weakly with reference corynebacteria. LDC in leprosy tissues can, thus, be revealed as well by fluorescent anti-LDC antisera as by anti-ML antisera. The main crossreacting component is antigen M1 of LDC, which corresponds to antigens Ag 7 of ML and Ag60 of BCG, the active components of lepromin and tuberculin (known reagents for cutaneous tests). Antigen M1 has a polysaccharide moiety crossreacting with the wall polysaccharide of LDC.(ABSTRACT TRUNCATED AT 400 WORDS)

Corynebacterium↗

Ultrastructural and histophysiological studies on the blood-nerve barrier and perineurial barrier in leprosy neuropathy.

Onset and nature of ultrastructural changes in endoneurial vasa nervorum during the pathogenesis of leprosy neuropathy and possibly associated alterations in the "blood-nerve barrier" were investigated, together with perineurial barrier functioning, in mice infected 20-28 months previously with Mycobacterium leprae and in (ageing) non-infected mice. Barriers were tested by i.v. administration of markers (Trypan blue and ferritin) 1-4 days before killing the mice. Twenty-eight months after infection, histopathology of sciatic nerves was comparable to that seen in sensory nerves in clinically early human (borderline-) lepromatous leprosy. Schwann cells and endoneurial macrophages were bacillated, endothelia of endoneurial vessels not, and the perineurium rarely. Many infected mice and all (ageing) controls possessed ultrastructurally and functionally normal endoneurial vessels. Their continuous endothelium with close junctions had prevented marker passage, even when surrounding endoneurial tissue cells were quite heavily bacillated. The perineurium was also normal. By contrast, in infected mice showing hind limb paralysis serious histopathologic involvement and large globi of bacilli intrafascicularly in sciatic nerves, endoneurial blood vessels were abnormal. Open endothelial junctions, extreme attenuation, fenestrations, and luminal protrusions were all features comparable to neural microangiopathy encountered in leprosy patients (Boddingius 1977a, b). The "blood-nerve barrier" clearly had become defective allowing excessive exudation of Trypan blue and ferritin, via four pathways from the vessel lumen, deep into surrounding endoneurial tissues but halted by a normal perineurial barrier. Markers in such "blue" nerves were not found in bacillated or non-bacillated Schwann cells, thus denying significant phagocytotic and lysosomal activities of Schwann cells at this stage of neuropathy. Possible implications of barrier performances for anti-leprosy drug treatment of patients are discussed.

Age Factors↗

Thymus-dependent lymphocytes in leprosy. II. Effect of chemotherapy on T-lymphocyte subpopulations.

The basis of the immunological unresponsiveness seen in leprosy patients is unknown. Untreated lepromatous leprosy patients display an unspecific cellular anergy which disappears with treatment, leaving an anergy specific for Mycobacterium leprae. These patients suffer from a complication, erythema nodosum leprosum, characterized by a recurrent eruption of tender skin nodules disappearing in 2 to 3 days. These nodules show a histological picture reminiscent of an Arthus reaction. Erythema nodosum leprosum can occur in untreated patients but it is more frequent in those receiving effective chemotherapy, and this has been thought to be due to massive release of antigen from the bacilli. By using monoclonal antibodies detecting different subpopulations of human peripheral blood T lymphocytes, we have shown that both borderline lepromatous leprosy patients had increased circulating suppressor cells (P less than 0.001) while the total number of T cells was within the normal range. The suppressor-cell population decreased with the duration of treatment, the change being evident at as early as 21 days. Five patients developed erythema nodosum leprosum during the study period. In all these patients the number of suppressor cells was decreased prior to the complication, increasing to original values with clinical recovery from this syndrome. There was no significant effect on T-lymphocyte subpopulations during chemotherapy of borderline tuberculoid leprosy patients. It seems that antileprosy chemotherapy precipitates erythema nodosum leprosum by interfering with immunoregulatory T cells.

Antibodies, Monoclonal↗

Childhood leprosy in a rural hospital.

Sixty six cases of childhood leprosy were studied in detail. They comprised of 7.2% of the Hansen's disease cases and 0.1/1000 of the total hospital out patients. Male: female ratio was 2:1. Four cases (6%) only belonged to the multibacillary group. All the multibacillary patients had a family contact of leprosy. Twelve cases (18.2%) showed nerve involvement and 2 cases (3%) had deformities also. One patient had pure neuritic type of leprosy. Leprosy reactions were not observed in any case. Out of 42 patients adequately followed up after completion of treatment, 3 patients (7.1%) had relapse of the disease.

Adolescent↗