Polymorphism of the 5' flanking region of the IL-12 receptor beta2 gene partially determines the clinical types of leprosy through impaired transcriptional activity.

BACKGROUND: Individual differences in T cell responsiveness to interleukin 12 (IL-12), resulting from inherited factors, may be responsible for differences in the intensity of cell mediated immune (CMI) responses in patients with leprosy, a disease with a wide clinical spectrum. AIM: Polymorphisms in the 5' flanking region of the IL12RB2 gene were analysed to determine potential immunogenetic factors affecting CMI responses, using leprosy as a model. METHODS: Polymorphisms in the 5' flanking region of IL12RB2 were examined using direct sequencing techniques, and allele frequencies between patients with lepromatous leprosy and patients with tuberculoid leprosy were compared. The effect of these single nucleotide polymorphisms (SNPs) on IL12RB2 expression was estimated using the dual luciferase reporter gene assay in Jurkat T cells. RESULTS: Several SNPs, including -1035A>G, -1023A>G, -650delG, and -465A>G, were detected within the 5' flanking region of IL12RB2. The frequency of haplotype 1 (-1035A, -1023A, -650G, -464A) was high in the general Japanese population, but was significantly lower in lepromatous patients compared with tuberculoid patients and healthy controls. Reporter gene assays using Jurkat T cells revealed that all haplotypes carrying one or more SNP exhibited a lower transcriptional activity compared with haplotype 1. CONCLUSION: SNPs within the 5' flanking region of IL12RB2 affect the degree of expression of this gene and may be implicated in individual differences in CMI responsiveness to mycobacterial antigens, leading to lepromatous or tuberculoid leprosy.

Light- and electron-microscopic study of M. leprae-infected armadillo nerves.

Lesions in peripheral nerves of armadillos experimentally infected with Mycobacterium leprae were studied by light- and electron-microscopy. Bacilli could be found clearly inside axons of unmyelinated nerve fibers. Heavily bacillated Schwann cells were seen embracing unmyelinated axons with interrupted cytoplasmic membranes. This indicated the initiation of rupture of those cells which were responsible for the liberation of bacilli into the axons. The nerve lesions were divided into three grades according to their severity: grade I showed lesions focalized in the perineurium; grade II lesions were scattered inside nerve tissue; and in grade III lesions the nerve tissues were diffusely affected. No regressive changes, such as fibrosis or scar formation, were seen in the nerve lesions. Bacillated macrophages were not as foamy as those of human lesions, indicating that these bacillated cells were younger or more easily disrupted with a higher turnover than the cells in human lesions. This would promote the spread of lesions in armadillos, and would explain the less foamy appearance of the cells. We found bacilli inside lymphatics surrounding the nerves, substantiating the opinion that lesions spread to peripheral nerves not only by a hematogenous route but also by the lymphatics.

Pathological findings on peripheral nerves, lymph nodes, and visceral organs of leprosy.

Pathological findings in a) 103 autopsies, b) biopsy material of peripheral nerve tissue from 210 tuberculoid patients, and c) inguinal lymph nodes from 106 leprosy cases are presented. Overall, lesions in peripheral nerves were most common in the ulnar (85.7% in the TT type, 98.3% in LL), peroneal (77.8% in TT, 97.9% in LL), median (80% in TT, 90.2% in LL), radial (66.6% in TT, 82% in LL), and the great auricular, tibial and supraorbital nerves. The ratio of bilateral nerve involvement in the same nerve was higher than unilateral involvement (approximately 5:1). Lesions of the peripheral nerve ganglion were seen in the LL type (22 cases, 61.1%) and the TT type (8 cases, 53.3%). These have seldom been mentioned in past literature. Superficial lymph nodes were most commonly affected in all types of leprosy. Lymph nodes in the hepatic and splenic portal areas were sometimes involved in lepromatous or borderline cases. Between the two polar types of leprosy, the lesions in the lymph nodes showed gradual transitions in a spectrum-like pattern which were similar to the changes in the lesions in the skin. In lepromatous leprosy, lesions could be found in 85.3% of the cases in the liver, 41.1% in the spleen, 86.7% in the testes, approximately 50% in the upper respiratory tract (including 36.4% in the nasopharynx), and 34.4% in the adrenal gland. Three cases had ophthalmologic lesions. In borderline leprosy, biphasic lesions of leprosy were found in various internal organs.(ABSTRACT TRUNCATED AT 250 WORDS)

Histology of indeterminate leprosy.

Skin biopsies from 20 patients with indeterminate leprosy were studied histopathologically. The most common clinical manifestation of the disease was a hypopigmented macule. In most cases, 5% to 10% of the dermis was occupied by the infiltrate. Sweat glands were involved in two thirds of the cases, and approximately half the biopsies showed involvement of arrector pili muscle and pilosebaceous glands. Ninety-five percent of the cases had involvement of the dermal nerves, with perineural infiltration being the most common finding. Twenty-five percent of the cases showed lesions of the epithelium.