Angiogenesis in cutaneous lesions of leprosy: implications for treatment.

OBJECTIVE: To examine the potential role of angiogenesis in leprosy. DESIGN: Immunohistochemical analysis of leprosy lesions. SETTING: Department of Dermatology, Venereology, and Leprology, Kasturba Medical College; Division of Dermatology, University of California at Los Angeles; and Departments of Dermatology and Pathology, Emory University. PATIENTS: Thirty-two cutaneous lesions that represented the spectrum of leprosy were obtained from 32 patients. MAIN OUTCOME MEASURE: CD31 microvessel counts. RESULTS: The mean CD31 microvessel count in borderline tuberculoid, midborderline, and lepromatous leprosy lesions was significantly higher than in indeterminate leprosy lesions. CONCLUSIONS: Increased bacterial load is associated with increased angiogenesis. Angiogenesis inhibitors may be of benefit in the treatment of leprosy.

A clinical and histopathological study of pityriasis lichenoides.

BACKGROUND: Pityriasis lichenoides is a papulosquamous disorder of unknown etiology with remissions and exacerbations. Histopathology helps greatly in the diagnosis of this condition. AIM: We studied clinical and histopathological features of pityriasis lichenoides in our patients. METHODS: This is a 3-year retrospective and prospective, descriptive study of all patients clinically diagnosed as pityriasis lichenoides and confirmed by histopathology. All patients were studied clinically and histopathologically. RESULTS: There were 51 (30 males and 21 females) cases of pityriasis lichenoides in the study period. The maximum number of cases, 14 (27.45%) were in their second decade of life. Pityriasis lichenoides chronica was diagnosed in 39 cases (76.47%) and pityriasis lichenoides et varioliformis acuta (PLEVA) in 12 cases (23.53%). Histopathologically, basal cell vacuolation and perivascular infiltrate were seen in all the cases. Exocytosis was seen in 45.1% of the cases. All the cases of PLEVA showed lymphocytic vasculitis albeit without fibrinoid deposition in the vessel walls. CONCLUSION: Pityriasis lichenoides is not a rare disorder, and is not a true lymphocytic vasculitis as blood vessel damage and fibrinoid deposition in the blood vessel walls were not seen in this study.

Cyclooxygenase 2 expression in vessels and nerves in reversal reaction leprosy.

Tissue expression of cyclooxygenase (COX)2, an inducible enzyme synthesizing eicosanoids in inflammation, was studied in reversal reaction (RR) leprosy in comparison with nonreactionary leprosy. COX2 was consistently expressed in cells of the mononuclear-macrophage lineage across the leprosy spectrum. Only in RR, the following two additional sites showed COX2 expression in the dermis and subcutis: 1) microvessels and 2) nerve bundles and isolated nerve fibers. The same sites also express vascular endothelial growth factor (VEGF). This is in keeping with experimental models relating VEGF to COX2 expression, with VEGF enhancing prostaglandin production through COX2 stimulation and prostaglandin synthase expression. We postulate that selective COX2 inhibitors, which are currently used in several inflammatory conditions, could be considered for RR treatment to reduce acute symptoms caused by tissue edema and possibly prevent long-term nerve damage, the main complication of RR.

Short report: Cyclooxygenase 2 expression in vessels and nerves in reversal reaction leprosy

Tissue expression of cyclooxygenase (COX)2, an inducible enzyme synthesizing eicosanoids in inflammation, was studied in reversal reaction (RR) leprosy in comparison with nonreactionary leprosy. COX2 was consistently expressed in cells of the mononuclear-macrophage lineage across the leprosy spectrum. Only in RR, the following two additional sites showed COX2 expression in the dermis and subcutis: 1) microvessels and 2) nerve bundles and isolated nerve fibers. The same sites also express vascular endothelial growth factor (VEGF). This is in keeping with experimental models relating VEGF to COX2 expression, with VEGF enhancing prostaglandin production through COX2 stimulation and prostaglandin synthase expression. We postulate that selective COX2 inhibitors, which are currently used in several inflammatory conditions, could be considered for RR treatment to reduce acute symptoms caused by tissue edema and possibly prevent long-term nerve damage, the main complication of RR.

[New pharmacological availability of thalidomide based on experience in patients with multiple myeloma].

Thalidomide was developed in the 1950s as a sedative having only a low toxicity. However, McBride and Lenz reported in 1961 a close correlation between oral administration of thalidomide by pregnant women and a particular deformity (phocomelia) of their babies. In the 1990s, the biological activities of thalidomide were determined to include the control of tumor necrosis factor-alpha production and inhibition of angiogenesis. In 1994, Folkman et al. reported that thalidomide exhibited a strong inhibition of angiogenesis in their experiments with rabbits and that this effect had a significant relationship to phocomelia. They suggested a utility of thalidomide as a therapeutic agent for diseases that involve angiogenesis, particularly tumorous diseases. Furthermore, in 1994, Vacca et al. reported that the bone marrow of multiple myeloma (MM) patients was rich in blood vessels and that there is a causal relationship between the activity of MM and marrow angiogenesis. According to these data, thalidomide was tested in many countries as a new therapeutic agent for MM. In this review, new pharmacological availability of thalidomide is described on the basis of our experiences.

Immuno-histopathology in the diagnosis of early leprosy.

The present study of 45 early leprosy cases in an endemic area in China indicates: a) Sensitivity of acid-fast bacilli (AFB) detection can be significantly improved by examining approximately 30 serial sections. AFB and/or phenolic glycolipid-I (PGL-I) were mostly detected in the infiltrates in the subepidermal zone, intraneurium, perineurium and around blood vessels. b) PGL-I antigen was positive in 10 clinically suspected, single lesion leprosy cases and AFB positive in 7 patients, AFB and/or PGL-I in nerve in 6 patients. c) Nonspecific chronic inflammation in indeterminate leprosy presented as selective perineural and/or intraneural infiltration with lymphocytes predominating. In the infiltrating mass, fragments of neural tissue were demonstrated with anti-S-100 protein staining. d) Except for 3 cases with unknown numbers of lesions, the present positive immunohistopathological findings are in direct correlation with the number of lesions at first diagnosis, namely: 41.6% (10/24) for single lesion, 66.6% (6/9) for 2 lesions, and 88.8% (8/9) for patients with > or = 3 lesions. e) Typical epithelioid or macrophage granuloma formations were not seen in early leprosy with a single lesion. In testing the immunological inclination of these patients with CD68 or tumor necrosis factor-alpha (TNF-alpha) a positive test is likely to be of prognostic value since TNF-alpha is involved in granuloma formation and nerve damage.

Nodular post-kala-azar dermal leishmaniasis: a distinct histopathological entity.

Post-kala-azar dermal leishmaniasis (PKDL) is an infrequently occurring sequel to treated visceral leishmaniasis. Diagnosis, particularly in non-endemic areas, is difficult because the clinical appearances may be subtle and simulate lepromatous leprosy. The histopathology of the condition has been a neglected subject. Nodular lesions constitute one of the large variety of lesions that can be seen in PKDL. This paper describes the histopathology of such lesions in 26 patients seen over a period of approximately 8 years in a non-endemic setting. All the biopsies had strikingly similar light microscopic features with characteristic findings: a dense lymphohistiocytic infiltrate beneath an atrophic epidermis, pronounced follicular plugging, vascular hyalinization and collagen changes and negative Fite stain. These allow a definite diagnosis of PKDL even in the absence of demonstrable Leishman-Donovan (L-D) bodies.

[Histopathology of leprosy. Study of more than 2300 biopsies]. / Réflexions sur l'histopathologie de la lèpre. Etude sur plus de 2,300 biopsies.

2,326 biopsies on Moroccan subjects suffering of leprosy had been studied in 4 years. After a critical study of histopathologic diagnosis and the classifications, the authors studied especially the lepromatous granuloma, its evolution during treatment and the lepromatous reactions. Defining histologically a reactional background, they make a certain generalisation among all the types of reactions observed in lepromatous patients.

Erythema nodosum leprosum: nature and extent of the cutaneous microvascular alterations.

Skin biopsy specimens from four patients with erythema nodosum leprosum, when examined as Epon-embedded, 1-micron sections, exhibited a necrotizing vasculitis involving capillaries, venules, and small-to-medium arteries and veins. In the superficial dermis, affected venules and capillaries showed endothelial cell enlargement and focal necrosis associated with perivascular infiltrates of lymphocytes. In the deep dermis and subcutaneous tissue, affected venules, arterioles, and arteries exhibited endothelial cell necrosis and matted fibrin in the vessel walls associated with perivascular infiltrates of neutrophils. Throughout the dermis, mononuclear phagocytes with vacuoles containing numerous fragmented organisms were observed. By electron microscopy, electron-dense material resembling immune complexes was observed in the walls of these vessels. These observations support the concept that erythema nodosum leprosum is an immune complex-mediated necrotizing vasculitis involving capillaries, arterioles, arteries, venules, and veins.

Ultrastructure of sciatic nerve of armadillo infected with Mycobacterium leprae.

Ultrastructural observation of sciatic nerves from eight Armadillos were made. Six animals had intravenous inoculation of M. leprae, one had of foot pad, while one had natural leprosy. The available nerves were biopsied at various time sequence ranging from five weeks to twenty four months. Semithin sections did not reveal any neuropathy. Ultrastructurally perineurium was thick and endoneurial collagen was increased. Initially demyelination of non-myelinated fibres was seen in all nerves irrespective of mode of infection. This was followed by demyelination of small myelinated fibres. Active remyelination was predominantly after 17 months. Schwann cell activity was increased and various stages of division were seen. Bacilli were extracellular, intraxonal, in endothelium and in perineurium. Significant observations were on blood vessels. These observations are discussed.

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.

Ultrastructure of skin in erythema nodosum leprosum.

The ultrastructural changes observed in erythema nodosum leprosum lesions were gross damage to blood vessels, particularly the endothelial cells, and deposition of immune complexes in vessel walls. Infiltrating cells and alteration of the ground substance formed a constant feature of the reaction. These changes are characteristic of an immune complex reaction.

Vascular changes in nerves in experimental leprosy--an ultrastructural study.

Ultrastructural observations made on the blood vessels of nerves in CBA/J mice with experimentally produced M. leprae infection revealed cytoplasmic filamentous structures along with large sized vacuoles in the endothelial cells and reduplication of peripericytal basement membranes in the 6-9 months of infection. In animals with late infection of 9-15 months duration, the endothelial cells presented foamy appearance caused by an increase in the number of vacuoles. These findings are suggestive of degenerative changes in the endothelial cells probably due to circulation of noxious substance in the blood stream.