Lucio phenomenon mimicking antiphospholipid syndrome: The occurrence of antiphospholipid antibodies in a leprosy patient

Lucio phenomenon is an atypical reaction of leprosy, characterized by vasculitic lesions that can mimic antiphospholipid syndrome (APS) clinically. Distinguishing the two can be difficult as antiphospholipid autoantibodies may be present in patients with leprosy. We report on a 32‐year‐old female patient presenting with a sudden onset of fever, hemorrhagic bullae, and skin necrosis on her lower legs. She was treated for APS due to the presence of antiphospholipid antibodies but had an inadequate response. A skin biopsy revealed thrombotic vasculopathy and necrotizing vasculitis associated with aggregation of foam cells in the perivascular area and subcutis, with acid‐fast bacilli in the histiocytes and blood vessel walls. Direct immunofluorescence showed IgM, C3, and fibrinogen deposition in the superficial and deep dermal blood vessels. The pathology confirmed the diagnosis of Lucio phenomenon, and appropriate therapy was given. It is essential to evaluate the patient comprehensively, including clinical, serological, and pathological aspects, to obtain the correct diagnosis.     

Segregation analysis of leprosy in families of northern Thailand

Sixty-three families with multiple instances of leprosy were identified through a major leprosy treatment center in northern Thailand. Complex segregation analyses for single major genes or polygenic inheritance were performed using the maximum-likelihood routine POINTER to determine the most likely etiologic model of genetic susceptibility. Liability differences between men and women were considered in these models. When individuals were considered to be affected because they had any form of leprosy, a generalized major gene model with nearly dominant parameters on the liability scale, but additive penetrances, was found to be the most likely. When only those individuals who had tuberculoid forms of leprosy were considered to be affected, a recessive model was found to be the most likely; however, the discrimination between various models was poor. Further analyses are necessary to delineate genetic mechanisms to explain these apparently divergent results. In particular, methods of testing two locus models should be considered.     

Do human leukocyte antigens have a role to play in differential manifestation of multibacillary leprosy: A study on multibacillary leprosy patients from North India

118 multibacillary leprosy patients with differential manifestations were studied for the antigens they expressed at MHC loci to investigate the role of human leukocyte antigens in the differential response to the same causative agent. While the lepromatous leprosy (LL) patients showed a significant increase of Bw60, DR2, DRw8 and DQw1, borderline lepromatous (BL) patients had Bw52, DR9 and DQw7 significantly more often as compared to the normal controls. A comparison of LL, BL and mid-borderline (BB) patients showed a significantly higher frequency of Bw60 in LL patients as compared to the BL. However, Bw52, Bw53, DR9 and DQw7 were found significantly more often in the BL patients as compared to the LL patients but the difference failed to reach significance after pc. A comparison of HLA antigens in BB patients with those of either the LL or BL patients did not show any significant differences.     

Asymptomatic nerve hypertrophy in lepromatous leprosy: a clinical,electrophysiological and morphological study

Summary In order to learn more about early nerve lesions observed in leprosy, we performed a clinical, electrophysiological and morphological study in seven patients with untreated lepromatous leprosy, palpably enlarged radial cutaneous nerve and preserved sensation in the corresponding territory. The conduction velocity of the cutaneous radial nerve, which was decreased in all patients, did not significantly differ from that of a group of patients with lepromatous leprosy, hypertrophy of the radial cutaneous nerve and sensory loss. In contrast, the sensory action potential was significantly lower in patients with sensory loss, which demonstrates that axon loss is more important than demyelination in producing sensory loss. In all patients nerve enlargement was due to thickening of the epineurium and of the perineurium subsequent to inflammatory infiltrates and proliferation of fibroblasts and perineurial cells. In several fascicles, the inflammatory infiltrates and the infected cells infiltrated endoneurial connective tissue septa and blood vessels.Mycobacteria leprae were abundant in peri neurial cells, fibroblasts, macrophages, Schwarm cells and endothelial cells, and lymphocytic vasculitis present in all cases. The average density of myelinated fibres was 2600 SD 880 fibres/mm² (control: 7700 fibres/mm²), with marked differences between individual fascicles, versus 420 fibres/mm² in patients with nerve hypertrophy and sensory loss (range 0–2080 fibres/mm²). Single fibre preparations showed that segmental demyelination pre dominated in two patients, axonal degeneration in one, while inflammatory infiltrates and proliferation of connective tissue adhering to individual fibres were prominent in the others. Both infection of Schwann cells and secretory products released by mononuclear cells involved in the inflammatory process are likely to play a role in the lesions of nerve fibres observed in early stages of lepromatous leprosy.Presented in part at the Second Meeting of the European Neurological Society, Brighton (UK), June 1990     

Association of HLA antigens with differential responsiveness toMycobacterium w vaccine in multibacillary leprosy patients

Leprosy patients undergoing phase II trials in two hospitals of New Delhi, India, were HLA typed to see the association of HLA with differential responsiveness toMycobacterium w vaccine. The vaccine comprises an atypical, nonpathogenic mycobacterium,Mycobacterium w, which has cross-reactive antigens withM. leprae. Multibacillary patients who are lepromin negative are vaccinated at an interval of 3 months. Considerable improvement is evident in the patients in terms of a decline in bacterial indices and histopathological and immunological upgrading. But all the patients do not respond to the vaccine in the same manner; some are slow responders, while others are good responders. HLA-A28 and DQw3 (DQw8+9) were found to be associated with slow responsiveness, while DQw1 and DQw7 were found to be associated with a more rapid responsiveness to theM. w vaccine. However, these associations were not significant afterP correction for the number of antigens tested for each locus except for HLA-DQw3 (DQw8 and DQw9) and DQw7. DQw7, a new defined split of HLA-DQw3, seems to be associated with the responsiveness toM. w vaccine.     

Production of transforming growth factor-beta 1 (TGF-beta1) by blood monocytes from patients with different clinical forms of leprosy

In the present study, the concentration of TGF-beta1 secreted by adherent cells isolated from human peripheral blood mononuclear cells (PBMC) and either stimulated with PGL-1 or lipopolysaccharide (LPS) or left unstimulated was determined by ELISA. The cells were isolated from untreated patients with different clinical forms of leprosy and healthy individuals. The adherent cells exhibited spontaneous release of TGF-beta1 in all clinical forms of leprosy and in healthy individuals; however, lepromatous leprosy/borderline leprosy (LL/BL) patients presenting erythema nodosum leprosum (ENL) displayed significantly higher concentrations of TGF-beta1 than either the other patients studied or the controls. These high TGF-beta1 levels were consistently observed when LL/BL ENL cells were stimulated with phenolic glycolipid (PGL-1) or LPS, and even in the absence of a stimulus (P < 0.01). The most significant differences in TGF-beta1 levels were observed when comparing the results in the presence of PGL-1 from ENL with, in order of significance: tuberculoid leprosy (TT) patients (P < 0.001), LL/BL patients without ENL (P < 0.01), healthy individuals (P < 0.01) and borderline-borderline/borderline-tuberculoid (BB/BT) patients with reversal reaction (RR) (P < 0.01). The BB/BT patients produced equivalent levels of TGF-beta1 compared with LL/BL patients without ENL, for all types of stimuli (P > 0.05). In contrast, TT patients produced the lowest levels of TGF-beta1 among all the subjects studied (both patients and healthy controls), especially following PGL-1 stimulation (P < 0.001, and P < 0.05, respectively). In conjunction with our previous data regarding TGF-beta1 expression in dermal lesions, it appears that TGF-beta1 probably plays different roles in leprosy: (i) to mediate a suppressive action locally, associated with the presence of PGL-1, and (ii) to induce proinflammatory effects when secreted systemically by monocytes, thereby acting as a modulatory cytokine in the acute inflammatory reactions of ENL and associated with the Th2 immune response in multibacillary forms of leprosy.     

A complex component modulating immune-deficient cells in leprosy patients leading to loss of viability of Mycobacterium leprae--a possible vaccine.

Macrophages from peripheral blood of leprosy patients, both multi-bacillary and paucibacillary are unable to kill phagocytosed Mycobacterium leprae due to their inability to produce superoxide (O2-) and hydroxyl radicals (OH.). The macrophages from healthy individuals are able to kill M. leprae along with release of O2- and OH. radicals. The deficiency in the macrophages of both types of leprosy patients is removed by activation of these cells when exposed to a culture supernatant obtained after stimulation of peripheral blood mononuclear cells from the same patients with delipidified cell components of M. leprae which are most likely cell wall proteins. The activation of macrophages also leads to recognition of whole live M. leprae as an antigen by cells from lepromatous patients. This activation of the phagocytes by delipidified cell components is blocked by cyclosporin A, indicating the possible role of several steps involved in immune activation of cells. The observations thus indicate the significant ability of delipidified cell components to eliminate the deficiencies in the macrophages from leprosy patients and restore them to behave like the cells from healthy individuals. Considering all these, it is suggested that delipidified cell components could be potential modulators, and are probably capable of functioning as a vaccine for leprosy.     

Soluble adhesion molecules in sera of patients with leprosy: levels of soluble intercellular adhesion molecule-1 (sICAM-1) rapidly decrease during multi-drug therapy

The clinicopathological spectrum of leprosy is associated with an altered immunological reaction. The expression of adhesion molecules on endothelial cells directs the cellular traffic to sites of local skin and nerve inflammation. Soluble forms of adhesion molecules, which are released upon cytokine activation, can be detected in the circulation and may reflect ongoing tissue inflammation. We determined the serum levels of sICAM-1, sE-selectin and sL-selectin in 74 patients with leprosy (tuberculoid form, n = 23; lepromatous form, n = 36; acute leprous reaction, n = 16) and 15 healthy age- and sex-matched control donors. Patients with lepromatous leprosy had significantly higher levels of sICAM-1 (564 ± 174 versus 450 ± 92 versus 334 ± 57 ng/ml) and E-selectin (90 ± 31 versus 74 ± 29 versus 50 ± 10 ng/ml) than patients with tuberculoid leprosy and normal donors (P<0.01). No differences between groups were detected for L-selectin. Patients with leprous reactions had similar high levels to lepromatous patients. Twenty lepromatous patients were re-examined after 4 weeks of therapy. A significant decrease in sICAM-1 serum levels was observed after 1 month of anti-mycobacterial treatment, which was accompanied by a reduction of mycobacteria in skin biopsies (P<0.01). Patients with leprous reactions (n = 13) also demonstrated a drop in sICAM-1 after anti-inflammatory therapy. sE-selectin and sL-selectin serum values decreased only in lepromatous patients after therapy. It can be concluded that soluble adhesion molecules like sICAM-1 and sE-selectin are promising activity markers in patients with leprosy, which may be useful for treatment monitoring.     

Potential role of B7-1 and CD28 molecules in immunosuppression in leprosy

In order to understand the mechanism of unresponsiveness towards Mycobacterium leprae antigens in leprosy, we evaluated the role of M. leprae sonicate antigens in regulating the expression of the costimulatory molecules B7-1, CD28, intercellular adhesion molecule-1 (ICAM-1), LFA-1α, LFA-1β and Mac-1 on the lymphocytes of both leprosy patients and healthy subjects. It was observed that the expression of B7-1 and CD28 was significantly decreased but the levels of ICAM-1 and LFA-1α were increased in patients with untreated borderline leprosy (BL)/lepromatous leprosy (LL) disease. No remarkable change was noticed in the case of borderline tuberculoid (BT) leprosy or treated BL/LL patients. Further, a striking finding was that lymphocytes from healthy subjects cultured with a particularly high dose of M. leprae sonicate antigens down-regulated the expression of B7-1 and CD28 molecules, but up-regulated the display of ICAM-1 and LFA-1α. Furthermore, proliferation induced by M. leprae sonicate was inhibited only by anti-B7-1 antibody. Mycobacterium leprae antigen-induced suppression of the proliferation of lymphocytes of healthy volunteers and LL patients was reversed by culturing the lymphocytes with purified protein derivative (PPD). It may be concluded from the findings in this study that down regulation of B7-1 and CD28 in BL/LL leprosy patients may be responsible for a defective T cell signalling by the B7-1/CD28 pathway caused by M. leprae antigens. This may lead to clonal inactivation of M. leprae-reactive T cells, consequently the bacilli grow without restriction in macrophages.