LEPROSY

Diagnosis, Diagnostics, Immunodiagnosis & Immunodiagnostics:

 

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 January 2003

 

6102.  Abbot NC, Beck JS, Feval F, Weiss F, Mobayen MH, Ghazi-Saidi K, Dowlati Y, Velayati AA, Stanford JL.  Immunotherapy with Mycobacterium vaccae and peripheral blood flow in long-treated leprosy patients, a randomised, placebo-controlled trial. Eur J Vasc Endovasc Surg. 2002 Sep;24(3):202-8.

 

OBJECTIVE: to evaluate immunotherapy as a means of improving peripheral blood flow in chronic leprosy patients. DESIGN: this was a double-blind, randomised, placebo-controlled, clinical trial. MATERIALS: heat-killed Mycobacterium vaccae 1mg plus 0.02 microg Tuberculin protein per 0.1 ml dose in borate buffer, with saline as placebo. Those studied were 92 long-treated residents of a leprosy  centre in Iran, 10 of their healthy children and 10 staff members. Evaluation employed the Perimed PF2, Laser-Doppler Flowmeter, a platinum skin thermistor, and a thermal sensibility tester. METHODS: single intradermal injections of test or placebo were given to 103 patients 18 months before the blinded evaluation. Fingerpulp blood flux was measured in controlled conditions and vasomotor reflexes and skin sensation to touch, pain and heat were evaluated in 45 and 47 patients in the placebo and M. vaccae groups, respectively, and in 20 healthy control persons. RESULTS: Laser-Doppler flux, skin temperature, vasomotor reflexes and sensation were impaired in leprosy patients. Immunotherapy improved (p < 0.05) Laser-Doppler flux, skin temperature and temperature sensation. CONCLUSIONS: immunotherapy, given 18 months earlier, significantly improved blood flow and temperature sensation, in fully-treated, chronic, leprosy patients. The same principles might be employed in other conditions of reduced peripheral blood flow.

 

6103.  Bakker MI, Hatta M, Kwenang A, Klatser PR, Oskam L. Epidemiology of leprosy on five isolated islands in the Flores Sea, Indonesia. Trop Med Int Health. 2002 Sep;7(9):780-7.

 

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.

 

6104.  Dhar S; Dhar S Department of Dermatopathology Clinic AMRI- Apollo Hospital, Kolkatta. Histopathological features of granulomatous skin diseases : an analysis of 22 skin biopsies Indian Journal of Dermatology . 2002; 47(2): 88-90

 

ABSTRACT: In the present study, skin biopsies were analysed for histopathological (HP) changes in 22 patients with various granulomatous dermatoses. In 6 specimens, HP features were diagnostic of BT leprosy, in 1 each of BB, BL and histoid LL. The diagnosis was lupus vulgaris (LV) in 6 biopsies, tuberculosis verrucosa cutis (TBVC) in 2, sarcoidosis in 3 and sporotrichosis in remaining 2. The study reiterated the usefulness of HP examination of all suspected cases of granulomatous skin diseases.

 

6105.  Halder Biswas A, Mundle M, Bhadra U K, Mishra R, Mahapatra B S. Study of leprosy cases among contacts in West Bengal. Indian J Commun Med 2001; 26(2), 76-9.

 

Finds out the infectivity of leprosy cases to their household contacts. Investigates the susceptibility or immunity of contacts towards leprosy. Intradermal lepromin test was done for all members of both the groups. Z test for difference of proportions was applied. No lepromatous secondary case developed from lepromatous index case. Among the contacts of index cases, secondary cases were mostly tuberculoid (73.0%). Average lepromin negativity among cases was 35.3%, among non-affected contacts was 15.3% and among controls was 7.8%, clearl showing that immunity was highest among controls and least among cases. 74 lepromatous and 8 borderline cases were lepromin negative but the rest were lepromin positive. Family contacts of cases were less immune to leprosy than the controls, hence there lies the importance of finding means to improve CMI for lepromine negative persons.

 

6106.  Nanavaty M A, Nanavaty A J, Lakhani J D, Lakhani S J, Vasavada A R. Subconjunctival adult bancroftian filaria worm. Indian J Opthal 2001; 49(3), 985-6.

 

Report a case of live adult Bancroftian Filarial nematode removed from the sub conjunctival tissue of a 58-year-old woman from the temporal limbus of her left eye.

 

6107.  Ottenhoff TH. Mycobacterium leprae and demyelination. Science. 2002 Aug 30;297(5586):1475-6; discussion 1475-6.  No abstract.

6108.  Siddiqui MR, Moreira AL, Negesse Y, Taye GA, Hanekom WA, Haslett PA, Britton S, Kaplan G. Local nerve damage in leprosy does not lead to an impaired cellular immune response or decreased wound healing in the skin. J Infect Dis. 2002 Jul 15;186(2):260-5.

 

This study investigated whether peripheral nerve damage in patients with leprosy impairs local cellular immune responses, thereby reducing wound healing and leading to chronic skin ulceration. Anesthetic and contralateral sensitive skin sites in 42 patients with leprosy were compared for delayed-type hypersensitivity responses to purified protein derivative (PPD) of tuberculin. Leukocyte recruitment, epidermal activation, keratinocyte proliferation, and rates of wound healing after skin biopsy were compared. No significant differences in PPD-induced induration, epidermal activation and thickening or numbers of total T cells, CD8+ T cells, CD1a+ Langerhans cells, and proliferating Ki67+ keratinocytes were observed between anesthetic and sensitive skin sites. Similarly, rates of wound healing over 5 days after skin biopsy did not differ significantly. Thus, local leprosy-associated anesthesia does not appear to contribute to local immune compromise or impaired wound healing. Rather, chronic cutaneous ulceration in leprosy most likely results from repeated trauma associated with loss of sensation.

6109.  Singh N, Arora VK, Jain A, Bhattacharya SN, Bhatia A. Cytology of testicular changes in leprosy. Acta Cytol. 2002 Jul-Aug;46(4):659-63.

 

OBJECTIVE: To study the changes in testicular aspirates and semen of patients with leprosy. STUDY DESIGN: A prospective study of 56 patients in the reproductive-age group, with no record of treatment for leprosy. Both Ridley-Jopling and WHO classification systems were used. Skin and/or nerve biopsies were performed for documentation of the diagnosis. Semen analysis and fine needle aspirates of the testes were performed. Smears from the testicular aspirates were stained with May-Grunwald-Giemsa and Ziehl-Neelsen stain. RESULTS: Five patients were unable to produce an ejaculate. Abnormal semen analysis and/or testicular aspirates were seen in 24 (42.8%) patients. Eleven had oligospermia and eight azoospermia. Abnormalities in testicular aspirates ranged from hypospermatogenesis (4) through maturation arrest (1) and atrophy (11). Two patients had hydrocoele, and two had associated microfilariae. Three patients with multibacillary leprosy had type 2 reaction. Mycobacterium lepre was demonstrable in testicular aspirates from all patients with multibacillary and in three with paucibacillary leprosy. CONCLUSION: Abnormal semen analysis and/or testicular aspirates occur in a very high percentage of patients with leprosy. While this is expected for multibacillary disease, the high incidence in the paucibacillary form was surprising. With the rapid elimination of leprosy, fertility-related disability might emerge as a major problem in these people.

Pathogenesis:

6110.  Maeda Y, Makino M, Crick DC, Mahapatra S, Srisungnam S, Takii T, Kashiwabara Y, Brennan PJ. Novel 33-kilodalton lipoprotein from Mycobacterium leprae. Infect Immun. 2002 Aug;70(8):4106-11.

 

A novel Mycobacterium leprae lipoprotein LpK (accession no. ML0603) was identified from the genomic database. The 1,116-bp open reading frame encodes a 371-amino-acid precursor protein with an N-terminal signal sequence and a consensus motif for lipid conjugation. Expression of the protein, LpK, in Escherichia coli revealed a 33-kDa protein, and metabolic labeling experiments and globomycin treatment proved that the protein was lipidated. Fractionation of M. leprae demonstrated that this lipoprotein was a membrane protein of M. leprae. The purified lipoprotein was found to induce production of interleukin-12 in human peripheral blood monocytes. The studies imply that M. leprae LpK is involved in protective immunity against leprosy and may be a candidate for vaccine design.

6111.      Wibawa T, Soebono H, Matsuo M. Association of a missense mutation of the laminin alpha2 gene with tuberculoid type of leprosy in Indonesian patients. Trop Med Int Health. 2002 Jul;7(7):631-6.

 

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.

 

Therapy:

6112.  Baughman RP, Judson MA, Teirstein AS, Moller DR, Lower EE. Thalidomide for chronic sarcoidosis. Chest  2002 Jul;122(1):227-32

 

STUDY OBJECTIVES: Thalidomide therapy has been shown to modify granulomatous diseases, such as tuberculosis and leprosy. Lupus pernio is a skin manifestation of sarcoidosis that does not remit spontaneously, and was used as a marker of efficacy of thalidomide for sarcoidosis. DESIGN: An open-label, dose-escalation trial of thalidomide. SETTING: Patients were seen at one of four specialized sarcoidosis clinics in the United States. PATIENTS: Fifteen patients with lupus pernio and other manifestations of sarcoidosis unresponsive to prior therapy were enrolled. INTERVENTIONS: Skin lesions were assessed with visual examination by the treating physician, and photographic evaluation by a blinded panel of physicians reviewing photographs of the lesions before and after therapy. MEASUREMENTS AND RESULTS: Fourteen patients completed 4 months of therapy. All patients experienced some improvement in their skin lesions subjectively, and 10 of 12 evaluable patients showed improvement using photograph scoring. Five patients were better after 1 month (treated with 50 mg/d of thalidomide), seven more patients improved after 2 months (treated with 100 mg/d of thalidomide in the second month), and two patients required an additional month of 200 mg of thalidomide to achieve a response. Patients reported increased somnolence (n = 9), numbness (n = 7), dizziness (n = 2), constipation (n = 6), rash (n = 1), and increasing shortness of breath (n = 1). One patient discontinued therapy because of new-onset dyspnea, due to probably unrelated new-onset congestive heart failure. CONCLUSION: Thalidomide was an effective form of treatment for chronic cutaneous sarcoidosis. The drug was well tolerated and may be a useful alternative to systemic corticosteroids.

6113.      Silverman WA. The schizophrenic career of a "monster drug". Pediatrics  2002 Aug;110(2 Pt 1):404-6  No abstract.

6114.      Tomimori-Yamashita J, Maeda SM, Sunderkotter C, Kaminsky SK, Michalany NS, Rotta O, Castro RM. Leukomelanodermic leprosy. Int J Dermatol  2002 Aug;41(8):513-5  No abstract.

 

April 2003  

 

6772.  Belliappa AD, Bhat RM, Martis J. Leprosy in type I reaction and diabetes mellitus in a patient with HIV infection. Int J Dermatol  2002 Oct;41(10):694-5. No abstract.

6773.  Dhar S; Dhar S. Histopathological features of granulomatous skin diseases : an analysis of 22 skin biopsies  Indian Journal of Dermatology . 2002; 47(2): 88-90.

ABSTRACT: In the present study, skin biopsies were analysed for histopathological (HP) changes in 22 patients with various granulomatous dermatoses. In 6 specimens, HP features were diagnostic of BT leprosy, in 1 each of BB, BL and histoid LL. The diagnosis was lupus vulgaris (LV) in 6 biopsies, tuberculosis verrucosa cutis (TBVC) in 2, sarcoidosis in 3 and sporotrichosis in remaining 2. The study reiterated the usefulness of HP examination of all suspected cases of granulomatous skin diseases.

6774.  Ghosh A K ,Ghosal A M ,Gangopadhyay D N,Bhattacharjee K,Roy M Dutta R N .Status of leprosy  patients after W.H.O. MDT- a Surviellance Study .Indian J Derm 2001, 46(1),30-2. (ISA 014378, Vol 38 No14 ,16 July 2002)

Pathogenesis:

6775.  Santos AR, Suffys PN, Vanderborght PR, Moraes MO, Vieira LM, Cabello PH, Bakker AM, Matos HJ, Huizinga TW, Ottenhoff TH, Sampaio EP, Sarno EN. Role of tumor necrosis factor-alpha and interleukin-10 promoter gene polymorphisms in leprosy. J Infect Dis  2002 Dec 1;186(11):1687-91.

Single-nucleotide polymorphisms within the genes coding for tumor necrosis factor (TNF)-alpha and interleukin (IL)-10 have been associated with several infectious diseases. To determine whether such polymorphisms are associated with leprosy, genotyping was performed at the -308 and -238 positions of the promoter of the TNF-alpha gene in 210 and 191 patients with multibacillary (MB) leprosy, respectively; 90 and 79 patients with paucibacillary (PB) leprosy; and 92 control subjects. For the -592 and -819 positions within the promoter of the IL-10 gene, 143 patients with MB leprosy, 79 patients with PB leprosy, and 62 control subjects were included in the analysis. TNF2 allele frequency was significantly higher among control subjects than among all patients with leprosy or in the MB group (P<.05 and P<.01). For the IL-10 gene, the frequency of the homozygous -819TT genotype was significantly higher among patients than among control subjects. These data indicate that a relationship exists between TNF-alpha and IL-10 promoter polymorphisms and the development of PB leprosy.

July 2003

 

7294. De Carsalade GY, Achirafi A, Flageul B.  Pentoxifylline in the treatment of erythema nodosum leprosum. J Dermatol. 2003 Jan;30(1):64-8.

      Erythema nodosum leprosum (ENL) is a well-known serious complication affecting 10% of lepromatous multibacillary leprosy patients. In the chronic form, its morbidity may be considerable. Thalidomide and systemic steroids are the two current effective drugs for the management of ENL. However, their use in endemic countries is often difficult and hazardous, and a search for new therapies is needed. We report our experience on the effects of pentoxifylline, a methylxanthine derivative, which has recently been suggested as a possible effective treatment for ENL attacks.

7295.Franco-Paredes C, Guarner J, Mehrabi D, McCall C, del Rio C. Clinical and pathological recognition of leprosy. Am J Med. 2003 Feb 15;114(3):246-7.No abstract available

7296. Ishii N.  Recent advances in the treatment of leprosy. Dermatol Online J. 2003 Mar;9(2):5.

      Leprosy, a chronic infectious disease caused by Mycobacterium leprae, was identified by G. H. A. Hansen in 1873. The different clinical presentations of the disease are determined by the quality of the host immune response. The bacteria have affinity for the peripheral nerves and are likely the cause of neuropathy, a cardinal manifestation of the disease. WHO recommends a protocol of multidrug therapy (MDT), which effectively controls the disease, hence contributing to the global elimination program. Early detection of leprosy and treatment by MDT are the most important steps in preventing deformity and disability.

7297. Lawn SD, Wood C, Lockwood DN.  Borderline tuberculoid leprosy: an immune reconstitution

            phenomenon in a human immunodeficiency virus-infected person. Clin Infect Dis. 2003 Jan 1;36(1):e5-6.

       Two months after starting highly active antiretroviral treatment (HAART), an individual with human immunodeficiency virus type 1 (HIV-1) infection and profound CD4+ T lymphocytopenia developed several erythematous plaques on his face, which were due to borderline tuberculoid leprosy with reversal reaction. The temporal association between the development of these lesions and changes in blood CD4+ lymphocyte count and plasma HIV-1 load observed during HAART strongly suggests that the presentation of leprosy resulted from immune reconstitution.

7298.  Murray CK, Joyce MP, Longfield RN.  Short report: Treatment failure in Hansen's disease. Am J Trop Med Hyg. 2003 Feb;68(2):233-4.

      Areas of low endemicity of Hansen's disease, such as Texas, California, and Hawaii, exist due to immigration and rare autochthonous infections. Managing this disease in these areas of low endemicity is difficult, especially in observing for relapse. The accurate diagnosis of relapse is imperative so that appropriate therapy can be promptly reinstituted and unnecessary treatment can be avoided. To assess treatment failures in an area of low endemicity, we retrospectively evaluated 113 patients with Hansen's disease treated in southern Texas. Of 57 patients who completed therapy, 11 were later restarted on medications for this disease for presumed relapse. However, nine of the 11 were found not to have true relapses of Hansen's disease. The accurate diagnosis of relapse of this disease is essential not only in the individual patient but also for prospective treatment trials to establish best practices.

7299.  Rajesh M, Sulochana KN, Sundaram AL, Krishnakumar S, Biswas J, Ramakrishnan S.  Presence of a 88 kDa Eales protein in uveitis, tuberculosis, leprosy and rheumatoid arthritis. Med Sci Monit. 2003 Feb;9(2):CR95-9.

7300. Thomas R, Thomas S, Muliyil J. Prevalence of glaucoma in treated multibacillary Hansen disease. J Glaucoma. 2003 Feb;12(1):16-22.

    PURPOSE: To determine the prevalence of glaucoma in a population of patients with multibacillary Hansen disease who had completed treatment. PATIENTS AND METHODS: The authors examined 386 of 446 patients with treated multibacillary Hansen disease residing in a geographically limited area. A complete ophthalmic examination including slit-lamp, applanation tonometry, gonioscopy, ophthalmoscopy, and stereobiomicroscopic examination of the optic disc was performed in all subjects. Glaucoma suspects were invited to the base hospital for further examination including automated perimetry. RESULTS: The overall prevalence of glaucoma was 3.6% (CI 1.9-5.3); 1.3% had primary open-angle glaucoma, 7% were primary angle-closure suspects (occludable angles), 1.8% had primary angle-closure glaucoma, and 0.5% had secondary glaucoma. CONCLUSION: The prevalence of primary glaucoma in patients with treated multibacillary Hansen disease was similar to that in the general population, and secondary glaucoma was rare.

7301.  Turkof E, Richard B, Assadian O, Khatri B, Knolle E, Lucas S.  Leprosy affects facial nerves in a scattered distribution from the main trunk to all peripheral branches and neurolysis improves muscle function of the face. Am J Trop Med Hyg. 2003 Jan;68(1):81-8.

      Current literature rejects nerve release in leprous facial neuropathy and states that lesions are restricted to the peripheral zygomatic branches. Since there are approximately 500,000 patients with this disease throughout the world, we wanted to clarify the precise location of facial nerve's affection and the benefit of neurolysis. Our study showed that in patients with leprosy, the facial nerve's main trunk, the peripheral zygomatic branches, and all other branches were affected. Follow-up showed improvement in lagophthalmos and in misreinnervation, with no improvement in the control cohort. Nerve release Improves muscle function in leprous facial neuropathy, provided surgery is performed on all affected segments. Intraoperative electroneurodiagnostics is an effective tool for detecting the most proximal site of lesion and ensuring effective surgery.

7302. Ulvi H, Yoldas T, Yigiter R, Mungen B. R-R interval variation and the sympathetic skin response in the assessment of the autonomic nervous system in leprosy patients. Acta Neurol Scand. 2003 Jan;107(1):42-9.

        OBJECTIVES: The aim of this study was to evaluate possible autonomic nervous system (ANS) dysfunction in leprosy patients with the sympathetic skin response (SSR) and the heart rate (R-R) interval variation (RRIV) measurements which are easy and reliable methods for evaluation of autonomic functions. MATERIAL AND METHODS: We studied 37 lepromatous leprosy patients (mean age: 38 +/- 17 years, range 23-62 years, 20 females and 17 males) and 35 age-matched healthy subjects (mean age: 34.19 +/- 12.74 years, range 24-48 years, 20 females and 15 males). Non-invasive bedside tests (orthostatic test, Valsalva ratio), R-R interval variation (RRIV) during at rest and deep breathing, the SSR latency and amplitude from both palms, and nerve conduction parameters were studied in all the subjects. RESULTS: The mean values of RRIV in leprosy patients during at rest [mean RRIV in patients, 17.42 +/- 8.64% vs controls, 22.71 +/- 3.77% (P < 0.05)] and during deep breathing [mean RRIV in patients, 21.64 +/- 9.08% vs controls, 30.70 +/- 5.99% (P < 0.005)] was significantly lower compared with the controls. The mean latency of SSR in leprosy patients [mean SSR latency in patients, 1.72 +/- 1.13 ms vs controls, 1.30 +/- 0.41 ms (P < 0.05)] was significantly prolonged compared with the controls. The mean amplitude of SSR in leprosy patients [mean SSR amplitude in patients, 0.54 +/- 0.57 microV vs controls, 1.02 +/- 0.56 microV (P > 0.05)] was smaller compared with the controls, but this difference was not significant. The mean Valsalva ratio in leprosy patients [mean in patients, 1.11 +/- 0.13 vs controls, 1.16 +/- 0.07 (P > 0.05)] was smaller compared with the controls, but not statistically significant. The mean difference of systolic and diastolic blood pressure between supine rest and during standing in leprosy patients were higher compared with the controls [mean systolic pressure in patients, 7 +/- 6 mmHg vs controls, 6 +/- 8 mmHg (P > 0.05) and mean diastolic pressure in patients, 3 +/- 3 mmHg vs controls, 3 +/- 2 mmHg (P > 0.05)], but they did not reach statistical significance. Furthermore, lower RRIV and the prolonged SSR latencies in leprosy patients were closely correlated to some parameters of sensorimotor nerve conduction and each other [median nerve distal latency and RRIV, r = -0.67 (P < 0.05), ulnar nerve distal latency and RRIV, r = -0.59 (P < 0.05), RRIV and SSR latency, r = -0.33 (P < 0.02)]. These data indicate that leprosy patients have the functional abnormalities of ANS. CONCLUSION: We conclude that combined use of these two tests, both of which can be easily and rapidly performed in the electromyogram (EMG) laboratory using standard equipment, allows separate testing of parasympathetic and sympathetic function, and are very sensitive methods in assessing of ANS function in peripheral neuropathy in leprosy patients.

 

    Pathogenesis:

 

7303.      Kiszewski CA, Becerril E, Baquera J, Aguilar LD, Hernandez-Pando R. Expression of transforming growth factor-beta isoforms and their receptors in lepromatous and tuberculoid leprosy. Scand J Immunol  2003 Mar;57(3):279-85 

       Leprosy is an infectious disease with two polar forms, tuberculoid leprosy (TT) and lepromatous leprosy (LL), that are characterized by strong cell-mediated immunity (CMI) and CMI anergy, respectively. Transforming growth factor-beta  (TGF-beta) belongs to a family of pleiotropic cytokines (TGF-beta1, TGF-beta2 and TGF-beta3) that participate in the control of cell differentiation and proliferation, as well as tissue repair. This cytokine family is unique because it suppresses CMI. In this study, we compared the expression of the three TGF-beta isoforms and their receptors in skin biopsies from LL and TT patients (LL = 20; TT = 20) using immunohistochemistry and automated morphometry. The percentage of cells immunostained for the three TGF-beta isoforms and cells positive for the three TGF-beta receptors in the inflammatory infiltrate located in the papillary dermis, reticular dermis and periadnexal tissue were  significantly higher in LL than that in TT, with macrophages being the most common and strongest immunoreactive cells. Some lymphocytes, fibroblasts, keratinocytes and epithelial cells from sweat glands and hair roots were also positive. In situ reverse-transcription polymerase chain reaction corroborated the capacity of these cells to synthesize TGF-beta1 and TGF-beta receptor 2. This high expression of TGF-beta isoforms and their receptors could contribute to CMI anergy and other clinical characteristic features of leprosy, like skin atrophy.

7304. Mira MT, Alcais A, Van Thuc N, Thai VH, Huong NT, Ba NN, Verner A, Hudson TJ, Abel L, Schurr E. Chromosome 6q25 is linked to susceptibility to leprosy in a Vietnamese population. Nat Genet  2003 Mar;33(3):412-5

      Leprosy, a chronic infectious disease caused by Mycobacterium leprae, affects an estimated 700,000 persons each year. Clinically, leprosy can be categorized as paucibacillary or multibacillary disease. These clinical forms develop in persons that are intrinsically susceptible to leprosy per se, that is, leprosy independent of its specific clinical manifestation. We report here on a genome-wide search for loci controlling susceptibility to leprosy per se in a panel of 86 families including 205 siblings affected with leprosy from Southern Vietnam. Using model-free linkage analysis, we found significant evidence for a susceptibility gene on chromosome region 6q25 (maximum likelihood binomial (MLB) lod score 4.31; P = 5 x 10(-6)). We confirmed this by family-based association analysis in an independent panel of 208 Vietnamese leprosy simplex families. Of seven microsatellite markers underlying the linkage peak, alleles of two markers (D6S1035 and D6S305) showed strong evidence for association with leprosy (P = 6.7 x 10(-4) and P = 5.9 x 10(-5), respectively).

7305.Oliveira RB, Ochoa MT, Sieling PA, Rea TH, Rambukkana A, Sarno EN, Modlin RL. Expression of Toll-like receptor 2 on human Schwann cells: a mechanism of nerve damage in leprosy. Infect Immun  2003 Mar;71(3):1427-33

       Nerve damage is a clinical hallmark of leprosy and a major source of patient morbidity. We investigated the possibility that human Schwann cells are susceptible to cell death through the activation of Toll-like receptor 2 (TLR2), a pattern recognition receptor of the innate immune system. TLR2 was detected on the surface of human Schwann cell line ST88-14 and on cultured primary human Schwann cells. Activation of the human Schwann cell line and primary human Schwann cell cultures with a TLR2 agonist, a synthetic lipopeptide comprising the N-terminal portion of the putative Mycobacterium leprae 19-kDa lipoprotein, triggered an increase in the number of apoptotic cells. The lipopeptide-induced apoptosis of Schwann cells could be blocked by an anti-TLR2 monoclonal antibody. Schwann cells in skin lesions from leprosy patients were found to express TLR2. It was possible to identify in the lesions Schwann cells that had undergone apoptosis in vivo. The ability of M. leprae ligands to induce the apoptosis of Schwann cells through TLR2 provides a mechanism by which activation of the innate immune response contributes to nerve injury in leprosy.

 

Therapy:

 

7306. Cheadle EJ, Selby PJ, Jackson AM.Mycobacterium bovis bacillus Calmette-Guerin-infected dendritic cells potently activate autologous T cells via a B7 and interleukin-12-dependent mechanism. Immunology  2003 Jan;108(1):79-88

       Mycobacteria are potent adjuvants, can survive intracellularly and have been safely used for many years as vaccines against tuberculosis and leprosy. They are thus important potential vectors for recombinant vaccines. Many of their adjuvant properties are mediated following phagocytosis by dendritic cells (DC), which are in turn critical for priming naive T cells. Although the maturation of DC in response to mycobacteria, such as Mycobacterium bovis bacillus Calmette-Guerin (BCG), is well described the subsequent responses of autologous T cells to mycobacterium-infected DC remains uncharacterized. In our experiments DC infected with BCG expressed more co-stimulatory molecules than tumour-necrosis factor-alpha (TNF-alpha) -treated DC and stimulated more potent mixed leucocyte reactions. When autologous T cells were co-cultured with BCG-exposed DC they became highly activated, as determined by display of CD25, CD54 and CD71 on both CD4+ and CD8+ cells. In contrast, the response of T cells to TNF-alpha-matured DC was significantly less. Cytokine production from T cells cultured with BCG-exposed DC was enhanced with elevated secretion of  interleukin-2 (IL-2), IL-10 and interferon-gamma (IFN-gamma) and was produced by both CD4+ and CD8+ lymphocytes as determined by intracellular staining. In particular, IFN-gamma secretion was increased from 50 pg/ml to 25 000 pg/ml and IL-10 secretion increased from 20 pg/ml to 300 pg/ml in BCG-exposed DC co-cultures. Blocking antibodies to B7.1 and B7.2 or IL-12 significantly reduced the secretion of IFN-gamma and reductions were also seen in the expression of CD25 and CD71 by CD4+ cells. These data demonstrate that mycobacterially infected DC are particularly potent activators of autologous T cells compared to TNF-alpha-exposed DC and that the resultant T cells are functionally superior.

 

 

    October 2003 

8032.  Ang P, Tay YK, Ng SK, Seow CS. Fatal Lucio's phenomenon in 2 patients with previously undiagnosed leprosy. J Am Acad Dermatol. 2003 Jun;48(6):958-61. 

 

We report 2 cases of Lucio's phenomenon, a rare, aggressive, occasionally fatal type 2 reaction occurring in the diffuse nonnodular type of lepromatous leprosy. The clinical diagnosis of Lucio's phenomenon is difficult, and there are no known predictive or prognostic factors. Despite institution of aggressive treatment after diagnosis, our 2 cases had fatal outcomes.

8033.  Hernandez MO, Neves I, Sales JS, Carvalho DS, Sarno EN, Sampaio EP. Induction of apoptosis in monocytes by Mycobacterium leprae in vitro: a possible role for tumour necrosis factor-alpha. Immunology. 2003 May;109(1):156-64. 

 

A diverse range of infectious organisms, including mycobacteria, have been reported to induce cell death in vivo and in vitro. Although morphological features of apoptosis have been identified in leprosy lesions, it has not yet been determined whether Mycobacterium leprae modulates programmed cell death. For that purpose, peripheral blood mononuclear cells obtained from leprosy patients were stimulated with different concentrations of this pathogen. Following analysis by flow cytometry on 7AAD/CD14+ cells, it was observed that M. leprae induced apoptosis of monocyte-derived macrophages in a dose-dependent manner in both leprosy patients and healthy individuals, but still with lower efficiency as compared to M. tuberculosis. Expression of tumour necrosis factor-alpha (TNF-alpha), Bax-alpha, Bak mRNA and TNF-alpha protein was also detected in these cultures; in addition, an enhancement in the rate of apoptotic cells (and of TNF-alpha release) was noted when interferon-gamma was added to the wells. On the other hand, incubation of the cells with pentoxifylline impaired mycobacterium-induced cell death, the secretion of TNF-alpha, and gene expression in vitro. In addition, diminished bacterial entry decreased both TNF-alpha levels and the death of CD14+ cells, albeit to a different extent. When investigating leprosy reactions, an enhanced rate of spontaneous apoptosis was detected as compared to the unreactive lepromatous patients. The results demonstrated that M. leprae can lead to apoptosis of macrophages through a mechanism that could be at least partially related to the expression ofpro-apoptotic members of the Bcl-2  protein family and of TNF-alpha. Moreover, while phagocytosis may be necessary, it seems not to be crucial to the induction of cell death by the mycobacteria.

 

8034.  Mehdi G, Maheshwari V, Gaur S, Sharma R. Histoid leprosy: diagnosis by fine needle aspiration cytology. Acta Cytol. 2003 May-Jun;47(3):529-31. No abstract.

8035.  Singh N, Malik A, Arora VK, Bhatia A. Fine needle aspiration cytology of leprous neuritis. Acta Cytol. 2003 May-Jun;47(3):368-72. 

 

OBJECTIVE: To document the cytomorphologic features of leprous neuritis and their correlation with bacterial density. STUDY DESIGN: A partly retrospective, partly prospective study of the fine needle aspiration cytology of enlarged nerves in leprosy. Cytomorphologic features of nerve aspirates from 28 patients were studied. May-Grunwald-Geimsa and Ziehl-Neelsen staining methods were employed. RESULTS: Five cytomorphologic patterns were observed in smears of nerve aspirates in 19 group I patients with concurrent skin and nerve lesions: (1) inflammation composed of epithelioid cell granulomas (5), bacillary index (BI) = 0; (2) epithelioid cell granulomas with necrosis (5), BI = 0-1+; (3) acellular necrosis (5), BI = 0-4+; (4) macrophage granuloma (3), BI = 5-6+; and (5) granulation tissue (1), BI = 1+. In 9 group II patients with pure neuritic leprosy, 3 patterns were seen: (1) epithelioid cell granulomas (5), BI 0-6+; (2) epithelioid granulomas with necrosis (1), BI = 0; and (3) acellular necrosis (3), BI = 0-6+. CONCLUSION: The entire spectrum of leprosy is seen in nerve aspirates. Necrosis is often a prominent feature. Recognition of the range of cytomorphologic patterns and their correlation with BI contribute to accurate calibration of the disease in nerves, resulting in appropriate choice of treatment.

 

Pathogenesis:

8036.  Bochud PY, Hawn TR, Aderem A. Cutting edge: a Toll-like receptor 2 polymorphism that is associated with lepromatous leprosy is unable to mediate mycobacterial signaling. J Immunol. 2003 Apr 1;170(7):3451-4. 

 

Toll-like receptors (TLRs) are key mediators of the innate immune response to microbial pathogens. We investigated the role of TLRs in the recognition of Mycobacterium leprae and the significance of TLR2Arg(677)Trp, a recently discovered human polymorphism that is associated with lepromatous leprosy. In mice, TNF-alpha production in response to M. leprae was essentially absent in TLR2-deficient macrophages. Similarly, human TLR2 mediated M.  leprae-dependent activation of NF-kappaB in transfected Chinese hamster ovary and human embryonic kidney 293 cells, with enhancement of this signaling in the presence of CD14. In contrast, activation of NF-kappaB by human TLR2Arg(677)Trp was abolished in response to M. leprae and Mycobacterium tuberculosis. The impaired function of this TLR2 variant provides a molecular mechanism for the poor cellular immune response associated with lepromatous leprosy and may have important implications for understanding the pathogenesis of other mycobacterial infections.

Therapy:

8037.  Durrheim DN, Speare R. Global leprosy elimination: time to change more than the elimination target date. J Epidemiol Community Health. 2003 May;57(5):316-7. No abstract.

 

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