Association of TNF, MBL, and VDR polymorphisms with leprosy phenotypes.

Although genetic variants in tumor necrosis factor (TNF), mannose binding lectin (MBL), and the vitamin D receptor (VDR) have been associated with leprosy clinical outcomes, these findings have not been extensively validated. We used a case-control study design with 933 patients in Nepal, which included 240 patients with type I reversal reaction (RR), and 124 patients with erythema nodosum leprosum (ENL) reactions. We compared genotype frequencies in 933 cases and 101 controls of seven polymorphisms, including a promoter region variant in TNF (G -308A), three polymorphisms in MBL (C154T, G161A and G170A), and three variants in VDR (FokI, BsmI, and TaqI). We observed an association between TNF -308A and protection from leprosy with an odds ratio of 0.52 (95% confidence interval = 0.29-0.95, p = 0.016). MBL polymorphism G161A was associated with protection from lepromatous leprosy (odds ratio = 0.33, 95% confidence interval = 0.12-0.85, p = 0.010). VDR polymorphisms were not associated with leprosy phenotypes. These results confirm previous findings of an association of TNF -308A with protection from leprosy and MBL polymorphisms with protection from lepromatous leprosy. The statistical significance was modest and will require further study for conclusive validation.

Single lesion multibacillary leprosy, a treatment enigma: a case report.

INTRODUCTION: Leprosy exhibits a wide spectrum of presentation, varying from the tuberculoid to the lepromatous pole, with immunologically unstable borderline forms in-between, depending upon the immune status of the individual. The clinical system of classification for the purpose of treatment includes the number of skin lesions and nerves involved as the basis for classifying the patients into multibacillary and paucibacillary. CASE PRESENTATION: A 20-year-old man belonging to a moderately endemic leprosy area in the Terai region of Nepal reported a large single, hypopigmented, well defined anaesthetic lesion on his left thigh extending to his knee which had been present for 2 years. There was no other nerve involvement. Clinical diagnosis was tuberculoid leprosy and immunological lateral flow test for anti-Phenolic glycolipid-I antibody was positive. Six months of paucibacillary multidrug treatment was advised immediately. However, the patient was reclassified as multibacillary on the basis of a positive skin smear and appropriate treatment of 24 months multibacillary multidrug regimen was commenced after only 1 week. Slit skin smear examination for Mycobacterium leprae from the lesion revealed a bacterial index of 4+ while it was negative from the routine sites. Histopathological examination from skin biopsy of the lesion further supported the bacterial index of the lesion granuloma which was 2+ and the patient was diagnosed as borderline tuberculoid. Bacteriological, histological, and immunological findings of this patient were borderline tuberculoid leprosy and he should have been treated with multibacillary regimen from the beginning. Five months after commencement of treatment, the patient developed a leprae reaction of Type 1 or reversal reaction with some nerve function impairment and enlargement of the lateral popliteal nerve of the left leg. This reversal reaction was managed by standard oral prednisolone whilst continuing the multibacillary multidrug regimen. CONCLUSION: This case illustrates and emphasizes the importance of slit-skin smear and biopsy as routine in all new cases to help differentiate multibacillary from paucibacillary for correct treatment. It further suggests that there are factors yet undetermined which play a significant role in determining the host response to M. leprae which is a remaining challenge in this disease.

Human TLR1 deficiency is associated with impaired mycobacterial signaling and protection from leprosy reversal reaction.

Toll-like receptors (TLRs) are important regulators of the innate immune response to pathogens, including Mycobacterium leprae, which is recognized by TLR1/2 heterodimers. We previously identified a transmembrane domain polymorphism, TLR1_T1805G, that encodes an isoleucine to serine substitution and is associated with impaired signaling. We hypothesized that this TLR1 SNP regulates the innate immune response and susceptibility to leprosy. In HEK293 cells transfected with the 1805T or 1805G variant and stimulated with extracts of M. leprae, NF-kappaB activity was impaired in cells with the 1805G polymorphism. We next stimulated PBMCs from individuals with different genotypes for this SNP and found that 1805GG individuals had significantly reduced cytokine responses to both whole irradiated M. leprae and cell wall extracts. To investigate whether TLR1 variation is associated with clinical presentations of leprosy or leprosy immune reactions, we examined 933 Nepalese leprosy patients, including 238 with reversal reaction (RR), an immune reaction characterized by a Th1 T cell cytokine response. We found that the 1805G allele was associated with protection from RR with an odds ratio (OR) of 0.51 (95% CI 0.29-0.87, p = 0.01). Individuals with 1805 genotypes GG or TG also had a reduced risk of RR in comparison to genotype TT with an OR of 0.55 (95% CI 0.31-0.97, p = 0.04). To our knowledge, this is the first association of TLR1 with a Th1-mediated immune response. Our findings suggest that TLR1 deficiency influences adaptive immunity during leprosy infection to affect clinical manifestations such as nerve damage and disability.