Lymphocyte Phenotypes and HLA-DR Expression in the Lesions of Cutaneous Leishmaniasis and Their Draining Lymph Nodes
1987; King Faisal Specialist Hospital and Research Centre; Volume: 7; Issue: 3 Linguagem: Inglês
10.5144/0256-4947.1987.212
ISSN0975-4466
AutoresA.M. El-Hassan, Raj Kubba, Y. Al‐Gindan, Abdelhamid S. Omer, Methil Kannan Kutty, Mahmoud B. M. Saeed,
Tópico(s)Research on Leishmaniasis Studies
ResumoOriginal ArticlesLymphocyte Phenotypes and HLA-DR Expression in the Lesions of Cutaneous Leishmaniasis and Their Draining Lymph Nodes* Ahmed M. El-Hassan, MD, PhD, MRCP, FRCPath Raj Kubba, MB, BS, MRCP, FRCP(C) Yusuf M. Al-Gindan, MD, Facharzt/Int Med Abdelhamid S. Omer, MD, PhD, FRCP, DTM&H Methil K. Kutty, and MD, FRCPath, FRCPA Mahmoud B. M. SaeedMB, BS Ahmed M. El-Hassan Professor, Department of Pathology, College of Medicine and Medical Sciences, King Faisal University, P.O. Box 2114, Dammam 31451, Saudi Arabia , Raj Kubba Associate Professor of Dermatology, Department of Medicine, College of Medicine and Medical Sciences, King Faisal University, P.O. Box 2114, Dammam 31451, Saudi Arabia , Yusuf M. Al-Gindan Associate Professor of Internal Medicine, Department of Medicine, College of Medicine and Medical Sciences, King Faisal University, P.O. Box 2114, Dammam 31451, Saudi Arabia , Abdelhamid S. Omer Associate Professor of Internal Medicine, Department of Medicine, College of Medicine and Medical Sciences, King Faisal University, P.O. Box 2114, Dammam 31451, Saudi Arabia , Methil K. Kutty Professor of Internal Medicine, Department of Medicine, College of Medicine and Medical Sciences, King Faisal University, P.O. Box 2114, Dammam 31451, Saudi Arabia , and Mahmoud B. M. Saeed Resident Medical Officer, Leishmaniasis Clinic, Al-Jisha, College of Medicine and Medical Sciences, King Faisal University, P.O. Box 2114, Dammam 31451, Saudi Arabia Published Online:1 Jul 1987https://doi.org/10.5144/0256-4947.1987.212SectionsPDFCite ToolsAdd to favoritesTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutABSTRACTABSTRACTT-lymphocyte phenotypes and human leukocyte antigen-DR expression (HLA-DR) expression in skin lesions and draining lymph nodes of zoonotic leishmaniasis caused by Leishmania major were studied. T lymphocytes were the dominant cells in the lymphocytic preponderance type of lesion. They were lowest when the parasitized macrophage was the dominant cell or when the reaction consisted of an equal admixture of lymphocytes, macrophages and plasma cells. Both inducer/helper and suppressor/cytotoxic T cells were present in varying proportions. The latter were thought to be suppressor rather than cytotoxic cells. Their late appearance in the host reaction was believed to play a major role in halting the inflammatory response. Low levels of cells expressing the suppressor/cytotoxic phenotype and the continued presence of antigen in macrophages was associated with persistence of the lesions even when parasites were largely eliminated after specific antileishmanial therapy. Such lesions healed after local or systemic steroid therapy. The majority of cells in the dermal infiltrate were HLA-DR positive. Keratinocytes also expressed HLA-DR antigen.INTRODUCTIONCutaneous leishmaniasis (cl) is caused by different species and strains of leishmania parasites that replicate within the mononuclear phagocytes in the skin. The skin lesions heal spontaneously or with treatment but in some cases the disease persists for months or years. This is particularly so in the diffuse cutaneous leishmaniasis (DCL) where depressed cellular immunity to leishmania is associated with massive multiplication of the parasite.1 The healing process in the usual form of cutaneous leishmaniasis is considered to be primarily due to cell-mediated immune reactions.2,3 It was, therefore, considered useful to study the phenotypes of T lymphocytes and the human leukocyte antigen-DR (HLA-DR) antigens in the skin infiltrate and the lymph nodes in patients with cutaneous leishmaniasis and relate these to the clinical features, parasite load, response to treatment and the histological changes.MATERIALS AND METHODSIncluded in this study were thirteen patients with confirmed diagnosis of zoonotic CL due to Leishmania major, who were seen consecutively in our Leishmaniasis Clinic in the village of Al-Jisha which is located at the eastern edge of the oasis of Al-Hassa, a known endemic area for CL. Each patient received a complete dermatological and general physical examination, and the clinical data were recorded on special computer-coded study sheets. Clinical evaluation also included a leishmanin skin test. The test antigen, prepared from a local strain of L. major, was supplied by Burroughs-Wellcome (Berkhamsted, Hertfordshire, England). The test was performed using a standard technique: 0.1 ml of test antigen and 0.1 ml of control were injected intradermally, at least 10 cm apart, on the volar surface of a forearm. Each site was carefully marked and examined at 48 hours and 72 hours. The size of the reaction was determined by 'ball point technique.'4 Induration of 5 mm or more at the test site and no reaction at the control site was regarded as a positive test.Tissues for the study were obtained from representative skin lesions under local anesthesia using 4-mm disposable skin punches. Ulcerated and heavily encrusted areas were avoided. Lymph nodes were surgically excised under local anesthesia. Each specimen was bisected. One half was fixed in a formalin/mercuric chloride/acetic acid mixture, embedded in paraffin, and sections were stained with hematoxylin and eosin for light microscopy. The other half was embedded in OCT (Miles Laboratories, Naperville, Illinois, USA), snap frozen in liquid nitrogen, and stored at -70°C. Subsequently, five-micron sections were cut and placed on clean ungelatinized slides and processed for immunohistochemical studies.The diagnosis of CL was confirmed by demonstration of amastigotes in the paraffin sections of the tissue. The parasite load in each section was estimated and recorded according to the method of Ridley;5 a scale of 1+ to 5+ was used in which 5+ represented the heaviest load of amastigotes. The skin biopsies were further classified according to the histopathological features shown in Table 1.6Table 1. Histological classification of cutaneous leishmaniasis.Table 1. Histological classification of cutaneous leishmaniasis.The treatment responses of these patients were also included as data for this study. Eleven patients were randomly allocated to one of two ongoing treatment protocols; i.e., ketoconazole (Nizoral – Jenssen Pharmaceutica, Beerse, Belgium) 400 mg single dose daily, given on an empty stomach, with proportionally smaller doses for children, until healed; or sodium stibogluconate (Pentostam – Burroughs-Wellcome, Berkhamsted, Hertfordshire, England) 10 mg/kg intramuscularly daily for 14 injections, and repeated after four weeks if necessary. The results are graded as complete healing (H), partial healing (P) or failure of treatment (F).T-Lymphocyte Subtypes and HLA-DR Antigen in Skin Lesions and Lymph NodesA sensitive biotin avidin method was used to detect cells in frozen sections using monoclonal antibodies. Mouse monoclonal antibodies against human T lymphocytes or HLA-DR antigen (Becton-Dickinson Monoclonal Center, Mountain-view, California, USA) were used and are listed in Table 2. The staining procedure was according to the instructions provided by the manufacturer. Briefly, cryostat-cut sections were fixed in cold acetone (4°C) for ten minutes, air dried and transferred to phosphate buffered saline (PBS) 0.5 M, pH 7.4. The primary antibodies were applied for 15 minutes at 20°C. The sections were rewashed with PBS and exposed to biotinylated antimouse IgG for 15 minutes at 20°C and washed again in PBS. The sections were then exposed to avidin peroxidase for 15 minutes, washed in PBS and exposed to 3,3-diaminobenzidine-hydrogen peroxide mixture for 5 minutes. The sections were immersed in copper sulphate to enhance the color, washed in PBS, counterstained with hematoxylin, dehydrated and mounted in distrene plasticizer xylene (DPX).Table 2. Antigens detected by monoclonal antibodies.*Table 2. Antigens detected by monoclonal antibodies.*The positive cells showed a distinct dark brown rim at the periphery of the cell and/or brown cytoplasmic staining. At least five infiltrates with more than 40 cells in each focus were counted as there was some variation in the cellular composition of individual infiltrates in different areas of the section. No staining was observed in specificity control section. The total number of T cells in the section (Anti-Leu 1), expressed as a percentage of all cells in the infiltrate, was calculated as follows:7The percentage of helper/inducer cells (Anti-Leu 3a) or suppressor/cytotoxic cells (Anti-Leu 2a) was calculated as follows:Anti-Leu-4 serum gave a percentage similar to Anti-Leu-1. The controls included non-neoplastic human tonsil and/or lymph node. Controls for method specificity were performed by omission of primary antibody or its replacement with normal BALB/C mouse serum.HLA-DR positive cells were expressed as a percentage of all cells in the infiltrate.Indirect Immunofluorescence for the Detection of Leishmania Antigen in the Skin and Lymph NodesThis was performed according to the method recommended by Bray,8 modified to detect leishmania antigen in frozen sections. Frozen sections were exposed to positive antileishmania serum obtained from BALB/C mice bearing a 16-week growth of 1.5 x 107L. major promastigotes in the hind footpad. After 30 minutes the slides were washed in three changes of PBS of five minutes each, followed by application of fluorescence-labeled goat antimouse serum (Institut Pasteur, Paris, France). After thorough washing, the sections were mounted in glycerine buffered saline and examined in a Leitz epifluorescence microscope. Control sections included omission of positive primary serum or its replacement with normal BALB/C serum.RESULTSThirteen patients with CL were studied. Their demographic and clinical information is recorded in Table 3. Two patients were children, and the rest were adults. Their mean age was 29 years (range 4 months to 62 years). Nine patients were males. Three patients were native Saudis, and the others included four Egyptians, two Indians, two Bangladeshis, one Thai and one Sri Lankan. This distribution is representative of the range of clinical material in our leishmaniasis field clinic. The average duration of disease in this group at the time of evaluation was seven weeks (range 2-12 weeks). With the exception of three patients, the number of lesions per patient were few (maximum five). One patient, an Indian, had 53 lesions.Table 3. Clinical features and results of treatment.Table 3. Clinical features and results of treatment.Ten patients had classical nodulo-ulcerative lesions of CL. In the other three the lesions were smooth to irregular papules and nodules without crusting or ulceration. Patient 2 had two discrete mobile subcutaneous nodules proximal to the primary lesion on the right forearm. These subcutaneous nodules represented lymphatic dissemination of CL.9 One of these subcutaneous nodules was excised and examined pathologically and showed characteristic features of CL, along with the presence of amastigotes. Four patients in this group had painless regional lymphadenitis. Leishmanin test was carried out in ten patients, and in nine it was positive. Patient 10, a Saudi infant, had a negative leishmanin test; this patient also had the highest parasite load (4+).The parasite load for each patient is shown in Table 4. With the exception of patients 10 (see above), 11 and 13, the parasite load was 1+. In patient 11, the findings were of special interest. The skin biopsy performed for this study showed no identifiable parasites. However, our earlier skin biopsy done several weeks previously, prior to treatment with sodium stibogluconate and ketoconazole, had shown 3+ parasite load.Table 4. Histological type, parasite index and T-lymphocyte phenotypes in dermal infiltrate.Table 4. Histological type, parasite index and T-lymphocyte phenotypes in dermal infiltrate.The majority of the patients were histological type I (lymphocytic preponderance). Patient 10 was a type II (macrophage preponderance), patient 11 was a type III (mixed cellularity), and patient 7 was a type IV (plasma cell preponderance. The results of treatment in patients who completed the prescribed course were generally good (Table 3). Patient 11 responded differently.He experienced only slight regression of his lesions, even after two separate treatment programs. Although the parasite load fell from 3+ to 0, the inflammatory reaction continued and leishmania antigen was detected in the infiltrate (see below). It was decided to treat one lesion with intralesional triamcinolone (5 mg/ml). Two weeks later there was at least 25% regression in this lesion. Subsequently, he received triamcinolone 40 mg intramuscularly, with evidence of regression in all lesions. At six weeks the lesions were completely flat without induration (Figures 1 and 2).Figure 1. Nodular lesion of cutaneous leishmaniasis involving right wrist after pentostam and ketoconazole therapy. Lesion did not regress.Download FigureFigure 2. Same lesion as in Figure 1, two weeks after intralesional and systemic steroids. Note the marked regression.Download FigurePatient 13 also had multiple papulonodular lesions. He showed only partial regression of his lesions ten weeks after a course of pentostam. Rebiopsy of one of the lesions showed no parasites, a type 1a reaction and leishmania antigen in macrophages. One of the nodular lesions was treated with intralesional triamcinolone. A week later there was a marked regression of the lesion. He was completely cured after systemic steroid therapy.Phenotypes of T Lymphocytes and HLA-DR Expression in the Skin LesionsThese results are shown in Table 4. In ten patients, total T lymphocytes formed 55-85% of the infiltrate in the CL lesion. The highest percentage of T lymphocytes was scored in lesions with type I reactions (Figure 3) and the lowest in type II, III and IV (Figure 4). In six patients, the majority of the T lymphocytes were of the suppressor/cytotoxic type, in two patients the percentages of helper and suppressor/cytotoxic cells were equal, and in the remaining five patients the helper/inducer cells were more numerous. Patients 11 and 13 had the lowest percentage of suppressor/cytotoxic cells.Figure 3. Cutaneous leishmaniasis lesion stained with Leu-1 monoclonal antibody. The lymphocytic preponderance (type I) reaction. Majority of cells are Leu-1-positive.(Immunoperoxidase reaction X400)Download FigureFigure 4. Cutaneous leishmaniasis lesion of the mixed cellularity type stained with Leu-1 monoclonal antibody. Leu-1-positive cells are fewer than in Figure 3. (Immunoperoxidase reaction X400)Download FigureT lymphocytes were also seen in the epidermis. Ulcerated lesions regularly showed appreciable numbers of suppressor/cytotoxic cells. Nonulcerated nodular lesions showed very few or no suppressor/cytotoxic cells in the epidermis, the majority of lymphocytes in such cases being of the helper type. Most of the cells in the dermal infiltrate (>80%) were HLA-DR positive. The epidermis (Figure 5) hair follicles and vascular endothelium also showed a positive reaction for HLA-DR antigen.Figure 5. Epidermis in cutaneous leishmaniasis stained with HLA-DR monoclonal antibody. Keratinocytes show a positive reaction. (Immunoperoxidase reaction X400)Download FigureHistological Changes in Lymph NodesEnlarged, palpable, epitrochlear lymph nodes from three patients were available for this study. Common findings included marked follicular hyperplasia, well-developed paracortical areas, the presence of plasma cells in the medullary cords and scattered small granulomas consisting of epithelioid cells and Langhans giant cells. In one lymph node (patient 5) there was necrosis with neutrophil leukocytes in the center of the granuloma, and a Ziehl-Neelsen stain was negative for acid-fast bacilli. In all cases there was a mononuclear cell infiltrate in the capsule and surrounding fat, particularly around the afferent lymphatics. The amastigotes were scanty except in one patient, who had moderate numbers.T-lymphocyte Phenotypes and HLA-DR Antigens in the Lymph NodesThe results are shown in Table 5. In the paracortex, 78-87% of the cells were T lymphocytes. In two patients the helper/inducer cells were more numerous than the suppressor/cytotoxic cells. Suppressor/cytotoxic lymphocytes were scanty or absent in the germinal center.Table 5. Phenotype of T lymphocytes in the paracortex of lymphnodes.Table 5. Phenotype of T lymphocytes in the paracortex of lymphnodes.Distribution of Leishmania Antigen in the Skin and Lymph NodesThree untreated patients with nodulo-ulcerative disease and one patient with nodular lesions were examined. The antigen was seen in scattered macrophages in the dermal infiltrate. The lesions of two other patients (patients 11 and 13) were examined after failure of specific antileishmanial therapy. Many macrophages containing antigen were seen in the dermis. The keratinocytes also showed a positive reaction in the nodulo-ulcerative but not in the nodular lesions. Some scattered large cells showing stronger fluorescence were thought to be Langerhans cells. In the lymph nodes, strong fluorescence was seen in the dendritic cells, in the marginal sinuses and sinusoids. In one case the interdigitating cells of the paracortical zone showed antigen.DISCUSSIONPrevious studies have shown that leishmania parasites are largely eliminated by two processes.6,10,11 One is a necrotizing mechanism that destroys the macrophages along with the parasites they contain. In the second process the parasite is destroyed inside an activated macrophage. The latter is mediated by T lymphocytes.12,13 Our results show that T lymphocytes are usually abundant in cutaneous leishmaniasis, particularly in the lymphocytic preponderance type of reaction.In about half of the patients the helper T lymphocytes were more numerous or equal to the suppressor/cytotoxic lymphocytes. The latter were more numerous in the remaining patients. The exact significance of this finding is not clear since it is not possible to distinguish between suppressor and cytotoxic T cells in sections with the presently available monoclonal antibodies. It may be that the majority of cells identified as suppressor/cytotoxic are in fact suppressor cells appearing in the later stages of the inflammatory response. Their role would then appear to be to specifically suppress the antileishmanial immune response and limit the inflammatory reaction after parasites and antigen had already been eliminated. This is supported by the fact that most of the patients whose major T lymphocytes were of the suppressor/cytotoxic phenotype responded well to treatment and had a low parasite load. Patient number 10 had the highest parasite load. His total lymphocytes were low but the suppressor/cytotoxic lymphocytes were comparatively high. His leishmanin test was negative. Unfortunately, it was not possible to follow his progress. We do not know what the evolution of the disease is like in patients who have a high parasite load and a high suppressor/cytotoxic lymphocyte response. Such patients are infrequent in our area.The lesions of two patients who had the lowest numbers of suppressor/cytotoxic cells failed to heal with specific antileishmanial treatment. Patient number 11 had many parasites before antileishmanial treatment. These were largely eliminated after pentostam and ketoconazole therapy, though the lesions failed to resolve. Rebiopsy at this stage showed no parasites but there were many antigen-containing macrophages. His suppressor/cytotoxic cells at that time were low. It appears that persistence of antigen coupled perhaps with a low suppressor/cytotoxic T-cell response caused the inflammatory reaction to continue. He responded well to local and systemic steroid treatment. That steroids may have actually promoted clearance of antigen is supported by the work of Netterheim and Hamous14 who showed that corticosteroids given in vivo reduced the retention of antigen in germinal centers in lymph nodes, possibly by an effect on the surface of dentritic macrophages.Steroids also have other effects on the modulation of the immune responses including suppression of lymphocyte responses to antigens and mitogens.15 Steroids have previously been used with benefit in leishmaniasis recidivans, usually as a treatment of last resort.16 Patient 13 had the lowest number of suppressor/cytotoxic cells. He too responded poorly to pentostam therapy. Although no parasites were demonstrated ten weeks after pentostam therapy, macrophages containing antigen were present in the skin infiltrate. He was completely cured with local and systemic steroids.It is to be noted, however, that two other patients (patients 4 and 5) were cured despite the fact that their suppressor/cytotoxic cells were on the low side. We do not know if their suppressor/cytotoxic T cells had increased prior to involution of the lesions. The relative importance of low suppressor/cytotoxic cells and antigen retention by macrophages in patients responding poorly to specific antileishmanial therapy is currently under investigation.The role of cytotoxic T cells in human cutaneous leishmaniasis is not known with certainty. The work of Bryceson and coworkers17 using Leishmania enriettii infection in the guinea pig indicated that parasitized macrophages might be destroyed by specific lymphocytes through a mechanism akin to killing of target cells by cytotoxic T lymphocytes. Using L. major infection in the mouse, however, very few of the lymphocytes in immune mice expressed the Lyt-2 antigen marker of cytotoxic T lymphocytes.18 Furthermore, the mouse/L. major model immune lymphocytes had no in vitro cytotoxic effect when incubated with syngeneic, L.-major-infected macrophages.12 These observations in animal models, however, do not rule out a possible role of cytotoxic T lymphocytes in human cutaneous leishmaniasis.The majority of the cells in the skin infiltrate were HLA-DR positive. These antigens are the human equivalent of la antigen in the mouse and are a product of HLA genes.19 They facilitate communication between immunocompetent cells and have a restricted distribution in the body compared to class I histocompatibility antigens and are found mainly on the surface of B-lymphocytes, macrophages and activated T lymphocytes.20 The induction of T-helper cell activation requires the presentation of antigen by HLA-DR-positive cells. The keratinocytes normally do not express HLA-DR antigen. However, in the tuberculin reaction keratinocytes were shown to express the antigen and this was preceded by invasion of the epidermis by lymphocytes.21 Smolle22 described HLA-DR expression by keratinocytes in a variety of skin diseases. In this study we have observed lymphocytic infiltration of the epidermis and this too was associated with HLA-DR expression by the keratinocytes. The mechanism by which this happens is unknown. The lymphocyte may induce keratinocytes to express the antigen or the antigens may be adsorbed from lymphocytes and other HLA-DR positive cells in the dermal and epidermal infiltrate.In conclusion, the cure of cutaneous leishmaniasis requires the elimination of the parasite and antigen as well as an appropriate immunological response. One feature of the latter is the appearance of increased numbers of suppressor T cells which specifically suppress the antileishmanial immunological responses when parasite and antigen had already been cleared.ARTICLE REFERENCES:1. Bryceson AD. "Diffuse cutaneous leishmaniasis in Ethiopia: I. The clinical and histological features of the disease" . Trans R Soc Trop Med Hyg. 1969; 63:708–37. Google Scholar2. Garnham PC, Humphrey JH. "Problems in leishmaniasis related to immunology" . Curr Top Microbiol Immunol. 1969; 48:29–42. Google Scholar3. Pearson RD, Wheeler DA, Harrison LH, Kay HD. "The immunobiology of leishmaniasis" . Rev Infect Dis. 1983; 5(5):907–27. Google Scholar4. Sokal JE. "Measurement of delayed skin-test responses [editorial]" . N Engl J Med. 1975; 293(10):501–2. Google Scholar5. Ridley DS. "The pathogenesis of cutaneous leishmaniasis" . Trans R Soc Trop Med Hyg. 1979; 73(2): 150–60. Google Scholar6. El-Hassan AM, Kutty MK. "The pathology of cutaneous leishmaniasis" . 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Gaafar A, Fadl A, El Kadaro A, El Hassan M, Kemp M, Ismail A, Morgos S and Hassan A (1994) Sporotrichoid cutaneous leishmaniasis due to Leishmania major of different zymodemes in the Sudan and Saudi Arabia: a comparative study, Transactions of the Royal Society of Tropical Medicine and Hygiene, 10.1016/0035-9203(94)90158-9, 88:5, (552-554), Online publication date: 1-Sep-1994. Al‐Gindan Y, Kubba R, El‐Hassan A, Omer A, Kutty M and Saeed M (2007) Dissemination in Cutaneous Leishmaniasis, International Journal of Dermatology, 10.1111/j.1365-4362.1989.tb04814.x, 28:4, (248-254), Online publication date: 1-May-1989. Kubba R and Al-Gindan Y (1989) Leishmaniasis, Dermatologic Clinics, 10.1016/S0733-8635(18)30604-1, 7:2, (331-352), Online publication date: 1-Apr-1989. Peters W (1988) "The little sister" — a tale of Arabia, Transactions of the Royal Society of Tropical Medicine and Hygiene, 10.1016/0035-9203(88)90400-2, 82:2, (179-184), Online publication date: 1-Mar-1988. Volume 7, Issue 3July 1987 Metrics History Accepted12 November 1986Published online1 July 1987 KeywordsT lymphocytesLeishmaniasisPhenotypeACKNOWLEDGEMENTSThis work was supported by a grant from the King Abdul Aziz City for Science and Technology (KAACST). We are indebted to Mr. Mahmood Faqir Saeed and Mr. A. R. O. Abdul Rahim for their technical help, Mr. S. M. Zahid for typing the manuscript, and Mr. A. El-Tayeb for the photographs.InformationCopyright © 1987, Annals of Saudi MedicinePDF download
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