Characterization of the cellular immune response in American cutaneous leishmaniasis

The in vitro and in vivo cellular immune reactivity of 49 patients with American cutaneous leishmaniasis (ACL) was evaluated using mitogens and parasite antigens. Patients were examined before treatment and were classified on the basis of clinical and histopathological criteria as suffering localized cutaneous leishmaniasis (LCL, 32 patients) or mucocutaneous leishmaniasis (MCL, 11 patients). A small group (6 patients) of treated diffuse cutaneous leishmaniasis (DCL) patients was also examined. The lymphocyte proliferative responses to PHA were significantly lower than those of controls (87 individuals, from either endemic or nonendemic zones) in LCL, and particularly MCL. Con A responses were, however, effectively normal in these patients. Both in vivo and in vitro cellular immune responses to leishmanial antigens were significantly greater in MCL and LCL patients than in the controls, the intensity of the reactions being by far the greatest in MCL. DCL patients demonstrated a complete absence of specific immune responsiveness both in vivo and in vitro. The significance of these results in the mechanisms leading to the resolution of the infection or production of pathologic lesions is discussed.     

American cutaneous leishmaniasis

We present 3 cases of American cutaneous leishmaniasis occurring in soldiers of a unit of US Army Rangers who parachuted into the jungles of Panama. Shortly after returning to the United States, these 3 soldiers each developed a crusted, indurated papule, which slowly enlarged during the following 6 weeks. Routine microscopy of skin biopsies revealed a dermal granulomatous inflammation and a predominantly lymphoid infiltrate. Numerous histiocytes contained small oval organisms with bar-shaped paranuclear kinetoplasts, morphologically consistent with leishmanial parasites. Cultures grew Leishmaniasis brasiliensis, subspecies panamensis. The soldiers were treated with intravenous pentavalent antimonial therapy daily for 20 days with good clinical improvement. Epidemics of leishmaniasis occur periodically in tropical regions of the world, and leishmaniasis has emerged in new settings, for example, as an acquired immunodeficiency syndrome-associated opportunistic infection. With an increasingly mobile society, it is important to be familiar with the clinical and histopathologic appearance of conditions such as leishmaniasis, which are common in tropical and subtropical regions and are increasingly significant in other regions of the world.     

Allopurinol in the treatment of American cutaneous leishmaniasis.

BACKGROUND. Pentavalent antimony, the generally accepted treatment for leishmaniasis, is given parenterally, and it is expensive and not readily available in developing countries. An inexpensive, orally administered compound would be a substantial advance in treatment. Previous studies in vitro have shown synergism between allopurinol and pentavalent antimony in tissue-culture systems. We designed this clinical study to determine whether synergism could be demonstrated in patients. METHODS. We performed a randomized, controlled study of the efficacy of allopurinol plus meglumine antimoniate (Glucantime), as compared with meglumine antimoniate alone, in patients with cutaneous leishmaniasis, who were recruited from a village in southeastern Colombia. In addition, those who declined injections were treated with allopurinol alone, and those who declined any treatment were considered controls. All the patients were followed for one year after the completion of treatment. Lesions that healed completely at three months and remained healed during follow-up were considered to be cured. RESULTS. The cure rate for patients treated with meglumine antimoniate was 36 percent; the addition of allopurinol increased the rate to 74 percent (P less than 0.001). Treatment with allopurinol alone yielded a cure rate of 80 percent (P less than 0.001). There were no cures among the untreated patients. There was no significant difference between the cure rate with allopurinol plus meglumine antimoniate and that with allopurinol alone. No major toxic effects were observed. CONCLUSIONS. For the treatment of American cutaneous leishmaniasis, the combination of allopurinol and meglumine antimoniate is significantly more effective than meglumine antimoniate alone, probably because of the efficacy of allopurinol alone, which appears to be as good as the combination.     

Demonstration of an indomethacin-sensitive mechanism regulating immune reactivity in American cutaneous leishmaniasis patients

We investigated some aspects of the regulation of the immune response that were sensitive to the effect of indomethacin (INDO), an inhibitor of prostaglandin synthesis, in 84 patients with American cutaneous leishmaniasis (ACL), and in normal controls. The patients were classified on the basis of clinical and histopathological criteria as suffering localized (LCL), mucocutaneous (MCL) or diffuse (DCL) forms of the disease. The responses in vitro to mitogens (PHA and Con A) and leishmanial antigens were evaluated in the presence or absence of INDO. It was found that the drug significantly increased in vitro the mitogenic stimulation by PHA of peripheral blood mononuclear cells from LCL, MCL and DCL patients, but the effect was less evident in the controls. Considering specific responses to leishmanial antigens, we showed that in the presence of INDO, these were significantly increased in LCL patients, but not in MCL or DCL. Also, only in LCL was an inverse correlation found between the initial response to leishmanial antigen and the increase caused by INDO. Significant correlations were found between the INDO-induced enhancement of PHA and Con A responses in the patient groups, but not in the controls. In LCL patients there was a significant correlation between the increases caused by INDO of the mitogen and antigen responses. It can be suggested that an indomethacin-sensitive (prostaglandin dependent) suppressor mechanism operates in LCL patients, that is possibly responsible for the modulation of the immune response against the parasite. In MCL, where this suppressive mechanism is apparently not functional, the response to the parasite is intense, and a possible consequence of this could be tissue damage. Our results indicate, however, that the anergy observed in DCL patients is not due to an involvement of prostaglandins in the suppression of the specific immune response.     

The in situ cellular immune response in acute herpes simplex encephalitis.

To characterize the in situ cellular immune response in acute herpes simplex encephalitis (HSE), the authors stained frozen brain specimens from 19 patients with HSE and 8 controls with a panel of monoclonal antibodies, which allowed them to identify inflammatory cell subsets and expression of activation markers and major histocompatibility complex (MHC) molecules. Parenchymal and meningeal inflammatory infiltrates were composed of T cells, with fewer natural killer and B cells, and variable numbers of granulocytes and macrophages. T4+ and T8+ cells were present in equal numbers. Inflammatory cells expressed interleukin-2 receptor, MHC Class I (HLA-alpha chain, beta-2 microglobulin), and MHC Class II (HLA-DR, HLA-DQ) molecules. There was increased MHC molecule expression in HSE on resident cells, including neurons and vascular endothelium, and vascular expression of HLA-DR was greater than that of HLA-DQ (P less than 0.01). No correlations between immune parameters with amount of corticosteroid therapy or duration of illness before biopsy was performed or outcome were found. T cell-mediated cytotoxic and delayed hypersensitivity mechanisms may contribute to tissue injury in HSE.     

Comparative study of American cutaneous leishmaniasis and diffuse cutaneous leishmaniasis in two strains of inbred mice.

Two Leishmania strains, AZV (isolated from a typical case of American cutaneous leishmaniasis) and AMP (from a case of diffuse cutaneous leishmaniasis), were studied in C57BL/6 and BALB/c mice. After infection with 10(4) amastigotes of either strain, C57BL/6 mice developed self-resolving lesions lasting 20 to 23 weeks and showed both delayed hypersensitivity response to leishmanial antigen and specific agglutinating antibodies. On the other hand, BALB/c mice infected with 10(4) AZV or AMP amastigotes developed chronic, large, ulcerated lesions and showed impaired cellular and humoral responses to the parasite. When BALB/c and C57BL/6 mice received 10(2) AMP amastigotes, patterns of infection were similar to those observed after inoculation of 10(4) amastigotes. In vitro studies revealed that spleen cells from AZV- or AMP-infected C57BL/6 mice showed an increased DNA-synthetic response to leishmanial antigen, concanavalin A, and phytohemagglutinin. Spleen cells from AZV- or AMP-infected BALB/c mice showed an increased response to concanavalin A and diminished responses to leishmanial antigen, phytohemagglutinin, and lipopolysaccharide.     

Antibodies to laminin in American cutaneous leishmaniasis

We found that serum samples from patients with different clinical forms of American cutaneous leishmaniasis (ACL) contained immunoglobulin G and immunoglobulin M antibodies which reacted with laminin but not with various other purified connective tissue components, such as collagen types I, III, IV, and V and fibronectin. Eighty-one percent of ACL patients had high antilaminin antibody levels, with a relationship existing between ACL ulcers and antibody levels. This was not, however, the case with patients having treated and healed ACL ulcers; only 34% of these patients had elevated antilaminin antibodies. Eighty-four percent of chronic Chagas' disease patients were also found to contain antilaminin antibodies that were limited to the immunoglobulin G class, but these were not detected in patients suffering from any of 11 other infectious diseases.     

Delayed-type hypersensitivity and immunoglobulin E in American cutaneous leishmaniasis.

Delayed-type hypersensitivity (DTH) and both total and specific immunoglobulin E (IgE) antibody levels were studied during an outbreak of American cutaneous leishmaniasis. Direct correlations were detected between DTH reactivity and either age or the period of evolution of the infection, and a clear association with sex (strongest response in females) was observed. Extremely high, age-dependent, total serum IgE levels were measured in the study group, probably due to concurrent intestinal helminthiasis. A low proportion of the group also had detectable levels of specific anti-Leishmania IgE antibody. Total and specific IgE levels were also sex dependent (lowest in females), and an inverse correlation was found between these levels and DTH responsiveness, possibly reflecting the intervention of regulatory influences of T-lymphocyte activity.     

Immunoglobulin E antileishmanial antibody response in cutaneous leishmaniasis.

High levels of antileishmanial immunoglobulin E (IgE) antibodies are associated with disease activity in visceral leishmaniasis. Herein, we report our observations about the relationship between antileishmanial IgE antibodies and clinical aspects of cutaneous leishmaniasis. This study was carried out with 45 patients (29 male and 16 female), with ages ranging from 11 to 48 years. All subjects were from an area to which leishmaniasis is endemic, Corte de Pedra (Bahia, Brazil), and the duration of the illness was 相似文献   

Immunopathogenesis of non-healing American cutaneous leishmaniasis and progressive visceral leishmaniasis

The outcomes of Leishmania infection are determined by host immune and nutrition status, parasite species, and co-infection with other pathogens. While subclinical infection and self-healing cutaneous leishmaniasis (CL) are common, uncontrolled parasite replication can lead to non-healing local lesions or visceral leishmaniasis (VL). It is known that infection control requires Th1-differentiation cytokines (IL-12, IL-18, and IL-27) and Th1 cell and macrophage activation. However, there is no generalized consensus for the mechanisms of host susceptibility. The recent studies on regulatory T cells and IL-17-producing cells help explain the effector T cell responses that occur independently of the known Th1/Th2 cell signaling pathways. This review focuses on the immunopathogenesis of non-healing American CL and progressive VL. We summarize recent evidence from human and animal studies that reveals the mechanisms of dysregulated, hyper-responses to Leishmania braziliensis, as well as the presence of disease-promoting or the absence of protective responses to Leishmania amazonensis and Leishmania donovani. We highlight immune-mediated parasite growth and immunopathogenesis, with an emphasis on the putative roles of IL-17 and its related cytokines as well as arginase. A better understanding of the quality and regulation of innate immunity and T cell responses triggered by Leishmania will aid in the rational control of pathology and the infection.     

Significance of cellular interactions in the immune response.

Recent investigations relevant to T and B cell cooperation in humoral immunity are discussed from the following aspects: requirement for T cells in antibody responses; T cell facilitation of B cell responsiveness; T cell suppression of B cell responsiveness; evidence for a nonspecific influence of T cells on B cell responsiveness; relevance to clinical disorders.     

Epidemiology of cutaneous leishmaniasis in Afghanistan. Part I: Zoonotic cutaneous leishmaniasis.

From June to September 1977, a preliminary epidemiological investigation was carried out in some parts of northern Afghanistan (Aqcha, Mazar-e-Sharif and Paul-e-Khombri). The disease in these areas is of zoonotic type having Rhombomys opimus as reservoir and P. caucasicus and P. papatasi as vectors.     

Mechanisms associated with immunoregulation in human American cutaneous leishmaniasis

Mechanisms possibly involved in the regulation of the immune response were evaluated in 49 patients with American cutaneous leishmaniasis (ACL). The patients were classified on the basis of clinical and histopathological criteria as suffering localized (LCL), mucocutaneous (MCL) or diffuse (DCL) forms of the disease. A significant leishmanial antigen-induced suppression of in vitro mitogen responsiveness was demonstrated in the DCL group, but not in the other two diseases states. Lack of suppressive activity was particularly evident in MCL, this being the group that presented the highest in vivo and in vitro reactivity to the parasite antigens. In fact, a significant inverse correlation was found between the degree of suppression and the antigen-induced lymphocyte proliferative response. In contrast, a mixture of mononuclear cells from MCL patients and normal subjects showed higher that expected responses to mitogen, while this increase was not observed in co-cultures of DCL and normal mononuclear cells. Due to their possible modulatory influences, circulating immune complexes were also evaluated in these patient groups, higher levels being found in MCL and DCL patients than in either LCL or controls. The possible mechanisms involved in the regulation of the immune response to the protozoan in the complex disease spectrum of ACL are discussed in relation to anergy in DCL and hyperresponsiveness in MCL.     

Atherosclerotic lesions in humans. In situ immunophenotypic analysis suggesting an immune mediated response

The immunophenotypical features of the cellular infiltrates in different types of human atherosclerotic lesions, including diffuse intimal thickening as a potential but controversial precursor lesion, have been examined using monoclonal antibodies. Special emphasis is put on monocytes/macrophages, lymphocytes, and their possible interactions. Immuno-double staining techniques have been employed to study these aspects. T lymphocytes and macrophages were detected in diffuse intimal thickening, fatty streaks, and atheromatous plaques. In some lesions a predominance of suppressor/cytotoxic lymphocytes was found, whereas in other lesions mixtures of T suppressor/cytotoxic cells and T helper/inducer cells were found in ratios varying from 1:1 to 4:1. A substantial number of T cells and macrophages was considered to be immunoactivated because of the expression of HLA-DR and, to a lesser extent, of I12 receptor molecules. The activation was particularly evident at sites of close cell-to-cell contact between monocytes/macrophages and lymphocytes. These observations suggest that a specific in situ immune mediated hypersensitivity reaction is associated with the development of atherosclerosis.     

In situ identification of idiotype-positive cells participating in the immune response to phosphorylcholine

The phosphorylcholine idiotype (Id)/anti-Id system has been used to study the role of antigen-specific cells in antigen-induced microenvironmental changes. Anti-Id staining of lymph nodes following PC immunization shows the presence of Id on follicular dendritic cells at 12 h and in plasma cells beginning at day 3. Germinal centers began to form at day 3, peaking in size and number at days 8-10. Scattered Id-positive small lymphocytes are present in germinal centers but with rare exceptions over 98% of germinal center cells are Id-negative. Idiotype-positive small lymphocytes are depleted from primary follicles adjacent to germinal centers but not from distant, unstimulated nodes. These results extend previous studies showing architectural alterations in lymph nodes following antigenic stimulation and demonstrate antigen-specific cells are a prominent component of these antigen-induced microenvironmental changes.