The Cutaneous Infiltrates of Leprosy

The epidermal changes that occur in human cutaneous immune responses have been investigated in the tuberculin reaction and in the lesions of tuberculoid and lepromatous leprosy and cutaneous leishmaniasis. In each situation, there was a dermal accumulation of monocytes and T cells, and the epidermis exhibited thickening. In the tuberculin response, the thickness of the epidermis sometimes doubled in 48-72 hr, and this was attributed to increases in both size and number of keratinocytes. In addition, the phenotype of the keratinocytes changed from la-to Ia'.Similar changes in keratinocyte Ia-antigen expression occurred in the epidermis overlying untreated tuberculoid leprosy and cutaneous leishmaniasis lesions, but not in lepromatous leprosy. We suggest that one or more epidermal growth factors may be generated in the course of a delayed immune reaction in the dermis.The cutaneous lesions of lepromatous leprosy are characterized by a sparse lymphocytic infiltrate and foamy macrophages laden with Mycobacteria leprae. In contrast, tuberculoid leprosy lesions exhibit large numbers of lymphocytes, granuloma formation, and the absence of appreciable numbers of intracellular bacteria (1, 2). Monoclonal antibodies to human leukocytes and their subsets have been used to determine the phenotype of the cells in dermal infiltrates (3-6). These studies showed that in lepromatous lesions there is not only a marked reduction in the numbers of T cells (compared to tuberculoid lesions) but also a selective absence of T lymphocytes of the OKT4+ subset.We wanted to establish whether this represented a specific unresponsiveness to M. leprae antigens or a more general defect in the emigration and accumulation of OKT4+ T cells. For this purpose we generated tuberculin reactions in the dermis of lepromatous patients by use of the purified protein derivative of tuberculin (PPD). During the course of these studies, we observed striking changes in the thickness and Ia-antigen expression of the epidermis overlying the PPDinduced delayed-type hypersensitivity (DTH) lesions. Similar changes also occur in the epidermis overlying the lesions of patients with tuberculoid leprosy and cutaneous leishmaniasis. MATERIALS AND METHODSThe Generation of DTH Response to PPD. After informed consent was obtained, we evaluated the DTH response to 5 units of PPD in 90 Indian leprosy patients from New Delhi (a highly endemic area for tuberculosis). The study group included 25 lepromatous (LL) (see diagnosis below), 10 borderline lepromatous (BL), and 55 tuberculoid (BT and TT) patients and 50 non-leprosy control individuals. Sex and age distribution were as follows: BL and LL patients, 3 female and 32 male, ages 16-68 (median 30) years; BT and TT patients, 12 female and 43 male, ages 11-68 (median 30) years; non-leprosy controls, 15 female and 35 male, ages 15-65 (median 28) years. The leprosy patients were examined in collaboration with A. K. Sharma and R. S. Mishra (Department of Dermatology, Safdarjung Hospital, New Delhi). Antigen was injected i...

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

Influence of delayed immune reactions on human epidermal keratinocytes.

Kaplan¹,

Witmer²,

Nath³

et al. 1986

“…Immunohistological studies using monoclonal antibodies to characterize T-lymphocyte subsets in granulomas revealed striking differences in the various types of leprosy (2,3). Tuberculoid (TT and BT) lesions contain a predominance of T cells of the CD4+ helper/inducer subset, whereas lepromatous lesions contain mainly T cells of the CD8+ suppressor/cytotoxic subset in proportions quite distinct from the normal peripheral blood CD4+/CD8+ ratio (4).…”

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confidence: 99%

Learning from lesions: patterns of tissue inflammation in leprosy.

Modlin

Melancon-Kaplan²,

Young³

et al. 1988

179

The clinical forms of leprosy constitute a spectrum that correlates closely with the degree of cellmediated immunity. Patients with tuberculoid leprosy develop strong cell-mediated responses and have only a few, localized lesions, whereas patients with multibacillary lepromatous leprosy are specifically unresponsive to antigens of Myobacterium leprae. T cells of the CD4+ subset predominate in tuberculoid lesions, whereas CD8+ cells predominate in lepromatous lesions. Monoclonal antibodies that distinguish subpopulations of CD4+ and CD8+ cells were used to analyze the distribution of T cells infiltrating lesions across the disease spectrum. In lepromatous lesions, T cells of T-suppressor phenotype (9.3-) were the predominant CD8+ cells and suppressor/inducer cells (2H4+, Leu-8+) represented half of the CD4+ subset. In tuberculoid lesions, helper T cells (CD4+4B4+) outnumbered suppressor/inducer T cells by 14:1, compared with a ratio of 1.2:1 in peripheral blood. Analysis of the precursor frequency of antigen-reactive T cells permitted us to estimate that there was a 100-fold enrichment of T cells able to proliferate in response to M. leprae antigens in tuberculoid lesions (2/100), when compared with blood from the same patients. The methods used here to characterize the T-lymphocyte subsets and frequency of antigen-reactive T cells in leprosy may be useful in analyzing imunological reactions occurring in lesions of other inflammatory and autoimmune diseases.There are at least two compelling reasons to study leprosy. The disease itself, affecting 10-15 million people worldwide, poses a significant health and economic burden on thirdworld countries. Second, because leprosy is a spectral disease in which pathology and immunology are inextricably related, it provides a unique critical model for investigating immunoregulatory mechanisms in humans.Leprosy is not a single critical entity but rather comprises a spectrum of clinical manifestations that correlate remarkably well with immunological responses to the organism (1). Patients with tuberculoid leprosy have a few localized lesions with rare organisms and a strong cell-mediated immune response directed against Myobacterium leprae antigens that ultimately kills and clears the bacilli, although often with concomitant injury to nerves. In contrast, lepromatous leprosy patients have numerous skin lesions containing extraordinarily high numbers of acid-fast bacilli and show specific immunological unresponsiveness to antigens of M. leprae in vivo and in vitro.The selective mechanisms of accumulation of lymphocytes, their antigen specificity, and immunological functions in inflammatory lesions of human infectious or autoimmune diseases remain largely unknown. Since the focal point of the immune response to M. leprae is the tissue granuloma, consisting of a collection of lymphocytes and macrophages, some of these questions can be approached directly through the study of cells infiltrating the lesions across the spectrum of leprosy.Immunohistological studies using m...

“…1). In association with this defect, helper T cells fail to migrate and to accumulate in the dermal lesions, and adequate amounts of lymphokines are not synthesized and released locally (2,3). This absence of local lymphokines leads to a failure of macrophage activation, and these cells serve as permissive hosts for the bacilli (4).…”

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confidence: 99%

Efficacy of a cell-mediated reaction to the purified protein derivative of tuberculin in the disposal of Mycobacterium leprae from human skin.

Kaplan¹,

Sheftel²,

Job³

et al. 1988

The purpose of this study was to evaluate the effects of a delayed-type cell-mediated immune response to Mycobacterium tuberculosis antigen on the Mycobacterium leprae load in the skin of leprosy patients. Twelve patients with the lepromatous form of leprosy have been injected intradermally with 5 units of the purified protein derivative of tuberculin (PPD). Ten individuals responded with areas of induration ranging from 12 to 21 mm in diameter, and two were unresponsive (<10 mm). Twenty-one days thereafter, the injected and control sites were blopsied, and the histology, number of acid-fast bacilli, nature and phenotype of the emigrant cells, and ultrastructural characteristics of the lesions were evaluated. Eight of the 10 responding patients showed reductions in the number of acid-fast bacilli by factors ranging from 5 to 10,000. Two responders and both nonresponders exhibited no discernible decline in the number of organisms. The reduction in bacillary load was correlated with an intense mononuclear cell infiltrate, the maintenance of a high CD4' T-cell/CD8' T-cell ratio, the formation of granulomata, and the extensive destruction of previously parasitized macrophages.Lepromatous leprosy is characterized by a selective inability of T cells to respond to Mycobacterium leprae antigens and to generate a cell-mediated immune response (reviewed in ref. 1). In association with this defect, helper T cells fail to migrate and to accumulate in the dermal lesions, and adequate amounts of lymphokines are not synthesized and released locally (2, 3). This absence of local lymphokines leads to a failure of macrophage activation, and these cells serve as permissive hosts for the bacilli (4). M. leprae then multiply within the secondary lysosomes of the vacuolar apparatus to levels as high as 109 organisms per g of skin (reviewed in ref. 5).Patients with lepromatous leprosy do react, however, to other mycobacterial antigens, including those contained in the purified protein derivative of tuberculin (PPD) with a delayed-type cell-mediated response (6). We suspected that the generation of a tuberculin reaction in the dermal leprosy lesions might supply the deficient cell subsets and cytokines and have a beneficial effect on the clearance of organisms.Our initial observations on the response to PPD in the skin of lepromatous leprosy patients have been reported. These include the emigration of large numbers of helper T cells into the dermis (7), the local production of the macrophageactivating lymphokine 'y interferon and its induced product IP-10 (8), the induction of HLA class II (Ia) antigens on the cells of the dermis and epidermis (7), and the accumulation of dermal Langerhans cells (9)-an important accessory cell for T-cell responses (10). We now have extended these studies and have evaluated the effectiveness of this second-party, cell-mediated reaction to influence the disposal of M. leprae. Our results indicate a striking reduction in the local bacillary load, which may be by a factor as large as 10,000. MATERI...