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PubMed1980

HLA-linked control of susceptibility to tuberculoid leprosy and association with HLA-DR types.

In an attempt to confirm an HLA-linked effect on the course of Mycobacterium leprae infection observed in families from Surinam (South America), we conducted a similar family study in an endemic area in India. We observed a significant (P less than .05) excess of identical HLA-GLO haplotypes only from healthy parents among siblings affected with tuberculoid leprosy. Compared with healthy controls, unrelated patients with tuberculoid leprosy (n = 15) showed a significant heterogeneity at the HLA-DR locus (P less than .05). This heterogeneity was caused by an increased frequency of HLA-DRw2 (.93 versus .53, P less than .05), particularly of DRw2 homozygotes (.53 versus .11, P less than .005), and a decreased frequency of HLA-DRw6 (.07 versus .58, P less than .005). We observed a significant (P = .03) preferential segregation of DRw2 from DRw2 heterozygous parents not affected with tuberculoid leprosy to children with the tuberculoid type of the disease. These data confirm an HLA-linked control of susceptibility to tuberculoid leprosy only, and suggest a recessive inheritance of this trait for which HLA-Drw2 appears to be a genetic marker.

Female↗
PubMed1981

HLA and sporadic tuberculoid leprosy: a population study in Maharashtra, India.

A population study to test whether associations between HLA and sporadic--i.e. non-familial--tuberculoid leprosy exist was undertaken in a hyperendemic area in India. Since previous family studies in the same area had shown both non-random haplotype segregation in the family members affected with tuberculoid leprosy and the preferential segregation of HLA-DR2 into tuberculoid leprosy patients, an increased frequency of DR2 among the "sporadic" patients was expected. However, no heterogeneity for HLA was detected between patients and controls. These findings could indicate that tuberculoid leprosy is a heterogeneous disease with regard to genetic background.

Female↗
PubMed1981

Tuberculoid leprosy and HLA in Japanese.

HLA phenotypes of 54 patients with tuberculoid leprosy were compared with those of 167 healthy controls. Frequencies of HLA-A, -B and -C antigens did not differ significantly between the leprosy patients and the controls. However, an increase in the frequencies of DR1, DR2, DRW8 and MT1 antigens and a decrease in the frequencies of DR4 and MT3 antigens were observed in the leprosy patients. Statistical evidence was presented that MT1 antigens were primarily associated with tuberculoid leprosy in Japanese patients rather than DR2.

Adult↗
PubMed1984

Association of HLA specificity LB-E12 (MB1, DC1, MT1) with lepromatous leprosy in a Venezuelan population.

To investigate whether an association could be found between HLA and lepromatous leprosy a population study was performed in Tachira, Venezuela. This was done in the same endemic area in which recently both non-random parental HLA-haplotype and preferential segregation of the HLA specificity LB-E12 (MB1, DC1, MT1) was demonstrated in lepromatous leprosy patients from multicase families. In this study 32 lepromatous patients and 32 healthy controls were typed for HLA-A, -B, -C, -DR and the specificities MB and MT. The frequency of LB-E12 (MB1, DC1, MT1) showed a significant increase in lepromatous leprosy patients (p = 0.04). This is the first report concerning HLA and leprosy which confirms in the same endemic area an association observed in families on the population level.

HLA Antigens↗
PubMed1980

Babies of mothers with leprosy have small placentae, low birth weights and grow slowly.

One hundred and sixteen women with leprosy and 31 healthy controls were studied throughout 155 pregnancies, and their babies were observed for a period of up to two years. Babies of mothers with leprosy weighed less than those of healthy mothers; the placental weights and coefficients followed the same trend. The babies of the mothers with leprosy grew more slowly than those of the healthy mothers and these findings were most marked in the babies of mothers with lepromatous leprosy. The cause of the reduced feto-placental weight is thought to be related to the immune status of the mother.

Adult↗
PubMed1999

Serum neopterin as a marker for reactional states in leprosy.

Reactions, a relatively common phenomenon among leprosy patients in treatment, require early detection and proper management to prevent serious sequelae. It is generally accepted that reactional states are immunologically mediated and, as such, usually improve with immunomodulatory treatments such as corticosteroids or thalidomide. Neopterin, a product of gamma-interferon-activated macrophages, is a marker for cell-mediated immune activation and may be useful to detect reactional states in leprosy. Here, we compared neopterin levels in single serum samples from leprosy patients with and without reaction with untreated controls and, when available, serial samples among patients with and without reaction. Levels in the single sample measurements, conducted in 22 patients with a reversal reaction (mean 14.5 nmol l(-1), S.D. 8.7) and 13 with erythema nodosum leprosum (mean 16.9 nmol l(-1), S.D. 13.6), were significantly higher (P=0.02 and P=0.001, respectively) than levels in 26 untreated patients (mean 9.1 nmol l(-1), S.D. 7.3). Values above the upper limit of normal (10 nmol l(-1)) were found in seven of 26 untreated patients, 14 of the 22 reversal reaction patients (P=0.01) and 10 of the 13 ENL patients (P=0.003). Serial serum samples, obtained from six patients that developed reactions and 14 that remained free of reaction, indicated that reversal reaction or erythema nodosum leprosum paralleled a concomitant increase in the serum neopterin level. Neopterin levels generally declined upon corticosteroid therapy. Neopterin may be a useful marker for reactional states in leprosy by providing a laboratory parameter to assess the onset, progression, response to therapy and resolution.

Biomarkers↗
PubMed1984

Immunological unresponsiveness in leprosy.

The various forms of leprosy form a clinical and immunological spectrum which offers extraordinary possibilities for insight into immunoregulatory mechanisms in man. At one pole, tuberculoid leprosy, patients develop high levels of cell-mediated immunity which ultimately results in killing of bacilli in the tissues, albeit often with damage to nerves. At the lepromatous pole, patients exhibit selective immunological unresponsiveness to antigens of M. leprae. Even though all currently known protein species of M. leprae and BCG are cross-reactive, lepromatous patients unreactive to M. leprae antigens frequently respond strongly to tuberculin. In vitro experiments suggest the existence of lepromin-induced suppressor activity, mediated by both monocytes and T cells. The T suppressor cells have the T8 phenotype of which 50% express the activation markers, Ia and FcR. The one unique species of antigen of the leprosy bacillus is a phenolic glycolipid, and it appears that the TS cells largely recognize the terminal trisaccharide of this unique antigen. Depletion of the TS cells restores in vitro reactivity of lymphocytes to lepromin in a portion of lepromatous patients, and addition of IL-2-containing supernatants partially restores responsiveness to M. leprae antigens. Vaccination of lepromatous patients with a mixture of M. leprae and live BCG restores cell-mediated immunity in the majority of lepromatous patients, and concomitantly reduces the in vitro suppressor activity and number of activated T8 cells. These experiments suggest the existence of stage-of-disease related suppressor cells in leprosy which appear to block the responsiveness of TH capable of responding to either specific or cross-reactive mycobacterial antigens. The mode of action of these TS appears to be the inhibition of production of IL-2 and other lymphokines. Successful immunotherapeutic vaccination appears to overcome this block in the majority of patients.

Antigens, Bacterial↗
PubMed1983

An approach to study in vitro the expression of HLA-encoded genetic factors predisposing to tuberculoid leprosy.

The existence of HLA-encoded genetic factors controlling susceptibility to tuberculoid leprosy in humans has been firmly established. Furthermore HLA-DR2 has been recognized as a marker for tuberculoid leprosy in India. At this moment, however, the gene products involved and the mechanism by which they confer susceptibility to tuberculoid leprosy remain only speculative. In an attempt to detect in vitro the expression of these HLA-encoded factors, we studied 12 tuberculoid leprosy patients and 22 healthy family members in a lymphocyte transformation test (LTT). All individuals were derived from multi-case Indian families, previously reported to show the presence of HLA-linked susceptibility genes. Although the responder-status of the healthy contact siblings was shown to behave independently from the fact whether they were HLA-identical with the patient-siblings or not, some evidence for in vitro expression of HLA-DR2 associated factors could be obtained. Nevertheless, it is concluded that the standard LTT seems not to be a test-system of first choice to detect the in vitro expression of the genes under study.

HLA Antigens↗
PubMed1976

A preliminary report on a study of serum alpha-1-antitrypsin and immunoglobulin levels in lepromatous leprosy.

IgG, IgA, and IgM immunoglobulins and alpha-1-antitrypsin globulin in sera from 30 patients with lepromatous leprosy were determined and compared with 30 age- and sex-matched healthy controls. Mean levels of IgG, IgM, IgA, and alpha-1-antitrypsin were significantly elevated in the sera of lepromatous leprosy patients in comparison with levels found in normal subjects. Statistical analysis of the relationships between levels of alpha-1-antitrypsin and immunoglobulins in the sera of lepromatous leprosy patients and controls revealed no correlation. It is therefore concluded that factors responsible for concentrations of immunoglobulins and alpha-1-antitrypsin are independent of each other in patients with lepromatous leprosy.

Humans↗
PubMed2006

Antigen discovery: a postgenomic approach to leprosy diagnosis.

Leprosy is an infectious, neurodegenerative disease of humans caused by Mycobacterium leprae. Despite effective control programs, the incidence of leprosy remains stubbornly high, suggesting that transmission may be more common than expected. The rationale of this work was to use bioinformatics and comparative genomics to identify potentially antigenic proteins for diagnostic purposes. This approach defined three classes of proteins: those restricted to M. leprae (class I), those present in M. leprae with orthologues in other organisms besides mycobacteria (class II), and exported or surface-exposed proteins (class III). Twelve genes (two class I, four class II, and six class III proteins) were cloned in Escherichia coli, and their protein products were purified. Six of these proteins were detected in cell extracts of M. leprae by immunoblotting. The immunogenicity of each recombinant protein was then investigated in leprosy patients by measuring the reactivity of circulating antibody and gamma interferon (IFN-gamma) responses in T-cell restimulation assays. Several class II and class III proteins were recognized by circulating antibodies. Importantly, most class II proteins elicited IFN-gamma responses that were significantly stronger than those produced by previously identified antigens. Among them, two class II proteins, ML0308 and ML2498, showed marked humoral and cellular immunogenicity, therefore providing promising candidates for the diagnosis of both tuberculoid and lepromatous forms of leprosy.

Amino Acid Sequence↗
PubMed2006

Evaluation of real-time and conventional PCR targeting complex 85 genes for detection of Mycobacterium leprae DNA in skin biopsy samples from patients diagnosed with leprosy.

In spite of the decrease in the number of registered leprosy patients, the number of new cases diagnosed each year (400,000) has remained essentially unchanged. Leprosy diagnosis is difficult due to the low sensitivity of current methodologies to identify new cases. In this study, conventional and TaqMan real-time PCR assays for detection of Mycobacterium leprae DNA were compared to current classification based on clinical, bacteriological, and histological evaluation. M. leprae DNA was extracted from frozen skin biopsy specimens from 69 leprosy patients enrolled in the study and was amplified using specific primers for either the antigen 85B-coding gene or the 85A-C intergenic region by using conventional and real-time PCR. The detection rate was 100% among multibacillary (MB) patients and ranged from 62.5% to 79.2% among paucibacillary (PB) patients according to the assay used. The TaqMan system for 85B gene amplification showed the highest sensitivity, although conventional PCR using the 85A-C gene as a target was also efficient. The cycle threshold (C(T)) values obtained using the TaqMan system were able to statistically (P < 0.0001) differentiate MB (mean C(T), 28.06; standard deviation [SD], 4.51) from PB (mean C(T), 33.06; SD, 2.24) patients. Also, there was a correlation between C(T) values and the bacteriological index for MB patients (Pearson's r, -0.444; P = 0.008). Within the PB patients' group, we tested normal skin from six patients exhibiting the pure neuritic form of leprosy (PNL). Five out of six PNL patients were positive for the presence of M. leprae DNA, even in the absence of skin lesions. In conclusion, the TaqMan real-time PCR developed here seems to be a useful tool for rapidly detecting and quantifying M. leprae DNA in clinical specimens in which bacilli were undetectable by conventional histological staining.

Antigens, Bacterial↗
PubMed1986

Serodiagnosis of leprosy: relationships between antibodies to Mycobacterium leprae phenolic glycolipid I and protein antigens.

Sera from leprosy patients and controls were assayed for immunoglobulin M (IgM) and IgG antibodies to the Mycobacterium leprae-specific phenolic glycolipid I antigen (PG) by enzyme-linked immunosorbent assay, for IgG antibodies to M. leprae protein antigens by Western immunoblot, and for antibodies to a 65-kilodalton (kDa) protein antigen of M. leprae by a competition antibody binding assay. Elevated levels of anti-PG IgM were seen in lepromatous and borderline lepromatous patients, and elevated levels of anti-PG IgG were seen in borderline lepromatous patients. There was a significant correlation between the bacillary index (BI) and anti-PG IgM whether all leprosy patients or only multibacillary patients were analyzed. A significant correlation was seen between anti-PG IgG and BI when all leprosy patients were used for analysis, but not when only multibacillary patients were used. IgG antibodies to protein antigens of M. leprae, as detected by Western immunoblot, were more prevalent in lepromatous and borderline lepromatous patients than in borderline tuberculoid patients, while one of eight controls showed one weak band. There were significant correlations between the number of M. leprae protein antigens detected by the sera of patients and both BI and the level of anti-PG IgM. The 65-kDa competition antibody binding assay detected active multibacillary leprosy. Patients positive for antibody to the 65-kDa antigen had a significantly higher BI and levels of anti-PG IgM and anti-PG IgG than did patients that were negative. In addition, the level of antibody to the 65-kDa antigen correlated with both the BI and anti-PG IgM. We conclude that testing for antibodies to protein antigens of M. leprae may provide a useful adjunct to testing for antibodies to PG.

Animals↗
PubMed1987

Cellular and humoral immune response to a phenolic glycolipid antigen (PhenGL-I) in patients with leprosy.

The ability of phenolic glycolipid I (PhenGL-I) of Mycobacterium leprae to stimulate in vitro lymphocyte proliferation (LP) was tested in cultures of peripheral blood cells from 42 patients with leprosy in Chicago and Thailand, 9 individuals with household contact in Thailand, and 10 unexposed North American controls. Only 10 responders (24%) were found among the patients, and the degree of LP was small. Responders were found among patients with lepromatous (18%) or tuberculoid (30%) leprosy without relation to age, complications, duration of treatment, or lepromin responsiveness. The specificity of the response was supported by a lack of response to two other glycolipids, by responses by T cells but not B cells, and by the observation that three of four responders tested maintained their responses to PhenGL-I for at least 1 year. Serum immunoglobulin M (IgM) and IgG antibodies were measured in the same patients by using PhenGL-I or its terminal monosaccharide conjugated to a bovine serum albumin carrier in an enzyme-linked immunosorbent assay. The presence of IgM antibody correlated negatively with LP to lepromin and to PhenGL-I in patients with tuberculoid leprosy. We conclude that circulating T cells from some leprosy patients proliferate in the presence of PhenGL-I in vitro, but the response is weak, possibly due to concomitant suppression or inhibition. The predominance of IgM antibody to PhenGL-I may be related to a lack of a T-helper-cell-mediated switch to IgG antibody response.

Antibodies, Bacterial↗
PubMed1993

Detection of Mycobacterium leprae nasal carriers in populations for which leprosy is endemic.

In order to better understand the role of Mycobacterium leprae nasal carriage in the maintenance of infection reservoirs and transmission of leprosy, we applied a polymerase chain reaction (PCR) that detected a 531-bp fragment of the pra gene of M. leprae on nasal swab specimens collected through a total population survey from individuals living in an area in which leprosy is endemic. Among the total tested population of 1,228 people, 7.8% were found to be PCR positive. PCR positivity was shown to be randomly distributed among the population for which leprosy is endemic. No association was observed between PCR positivity, age, or sex. The observed distribution of PCR positivity among households of different sizes confirmed the expected values, with the exception of two households, each with three people with PCR-positive nasal swab specimens. Although nasal carriage does not necessarily imply infection or excretion of bacilli, the finding of nasal carriage supports the theory of a disseminated occurrence of M. leprae in populations for which leprosy is endemic.

Adolescent↗
PubMed2004

Genotyping of Mycobacterium leprae on the basis of the polymorphism of TTC repeats for analysis of leprosy transmission.

The polymorphism of TTC repeats in Mycobacterium leprae was examined using the bacilli obtained from residents in villages at North Maluku where M. leprae infections are highly endemic (as well as from patients at North Sulawesi of Indonesia) to elucidate the possible mode of leprosy transmission. TTC genotypes are stable for several generations of passages in nude mice footpads and, hence, are feasible for the genotyping of isolates and epidemiological analysis of leprosy transmission. It was found that bacilli with different TTC genotypes were distributed among residents at the same dwelling in villages in which leprosy is endemic and that some household contacts harbored bacilli with a different genotype from that harbored by the patient. Investigations of a father-and-son pair of patients indicated that infections of bacilli with 10 and 18 copies, respectively, had occurred. Genotypes of TTC repeats were found to differ between a son under treatment and two brothers. These results reveal the possibility that in addition to exposure via the presence of a leprosy patient with a multibacillary infection who was living with family members, there might have been some infectious sources to which the residents had been commonly exposed outside the dwellings. A limited discriminative capacity of the TTC polymorphism in the epidemiological analysis implies the need of searching other useful polymorphic loci for detailed subdivision of clinical isolates.

Animals↗
PubMed2005

Cataract surgical coverage and barriers to uptake of cataract surgery in leprosy villages of north eastern Nigeria.

AIMS: To determine the coverage, outcome, and barriers to uptake of cataract surgery in leprosy villages of north eastern Nigeria. METHODS: People 30 years and above resident in eight leprosy villages were examined. Cataract blind people were questioned about the reasons they had not been treated. Subjects who had received an operation for cataract were examined to determine the outcome and, where applicable, the causes of poor outcome. RESULTS: 480 people were examined. Cataract was the commonest cause of blindness. The cataract surgical coverage (people) was 39.2% for orthodox surgery and 29.7% for couching. After surgery, visual acuity > or =3/60 had been restored to 82.1% of eyes that had had orthodox surgery, but only 58.6% of eyes that had been couched. Cost was the commonest reason given for not seeking treatment for cataract. CONCLUSIONS: Cataract is the major cause of blindness in this population but cataract surgical needs are currently not being met. There is a need for better collaboration between leprosy control and ophthalmic services, improved education of people affected by leprosy, a commitment to improving orthodox cataract surgery outcomes, and consideration of a possible role for traditional healers as sources of referral for orthodox surgical services.

Adult↗
PubMed2006

Incidence of ocular morbidity among multibacillary leprosy patients during a 2 year course of multidrug therapy.

AIM: To evaluate the incidence of and risk factors for ocular complications in multibacillary (MB) leprosy patients during their 2 year, fixed duration, multidrug therapy (MDT). METHODS: Periodic eye examinations were conducted prospectively on a cohort of 301 consecutive newly diagnosed MB patients every 6 months during their 2 year course of MDT. Incidence of ocular pathology was calculated as the number of events per person year of event free follow up of patients who did not have the specific finding at baseline. RESULTS: 292 (97%) patients had one or more follow up visits. The incidence of lagophthalmos was 1.2%/patient year (95% CI 0.5% to 2.8%); corneal opacity was 7.4%/patient year (95% CI 5.1% to 10.6%); uveal involvement was 5.1%/patient year (95% CI 3.3% to 7.8%), and cataract that reduced vision to 6/18 or less was seen in 4.3%/patient year (95% CI 2.7% to 6.9%) of patients. Overall, 23 individuals (5.8%/patient year, 95% CI 3.9 to 8.8) developed leprosy related potentially blinding pathology during the 2 years of MDT. CONCLUSIONS: Approximately 20% of patients with MB leprosy can be expected to develop ocular complications of leprosy during a 2 year course of MDT, many (11%) of which are potentially vision threatening. Ophthalmological monitoring to detect and treat ocular complications at defined intervals during MDT is indicated.

Adult↗
PubMed2006

Incidence of ocular complications in patients with multibacillary leprosy after completion of a 2 year course of multidrug therapy.

AIM: To evaluate the incidence of and risk factors for ocular complications in multibacillary (MB) leprosy patients following completion of 2 year, fixed duration, multidrug therapy (MDT). METHODS: Biannual eye examinations were conducted prospectively on a cohort of MB patients who had completed MDT and followed up for 5 years. The incidence of ocular pathology was calculated as the number of events per person year of event free follow up of patients who did not have the specific finding before completion of MDT. RESULTS: 278 patients had one or more follow up visits after completion of MDT. The incidence of lagophthalmos was 0.24%/patient year (95% CI 0.10% to 0.37%); corneal opacity, 5.35%/patient year (95% CI 4.27% to 6.70%); uveal involvement, 3.78%/patient year (95% CI 2.96% to 4.83%); and cataract that reduced vision to 6/18 or less, 2.4%/patient year (95% CI 1.77% to 3.26%). Overall, 5.65%/patient year (95% CI 4.51% to 7.09%) developed leprosy related ocular disease and 3.86%/patient year (95% CI 3.00% to 4.95%) developed leprosy related, potentially blinding ocular pathology during the period following MDT. Age and other disability also predicted incident eye disease. CONCLUSIONS: Every year, approximately 5.6% of patients with MB who have completed MDT can be expected to develop new ocular complications of leprosy, which often (3.9%) are potentially vision threatening. Because many of these complications cannot be detected without slit lamp examination, periodic monitoring, particularly of older patients and those with other disability, is recommended, in order to detect and treat ocular complications satisfactorily.

Analysis of Variance↗