Cytokines in leprosy, II. Effect of treatment on serum cytokines in leprosy

Background Multidrug therapy (MDT) causes a decrease in the bacterial burden in leprosy patients. Does the decrease in the antigenic stimulation of the immune system have an effect on cytokine production? Methods The effect of treatment on serum cytokines was evaluated in 36 leprosy patients and 35 reactional leprosy patients and compared with that in 20 age- and sex-matched healthy individuals. The enzyme-linked immunosorbent assay (ELISA) technique was used to measure serum levels of interleukin-2 receptor (IL-2R), interleukin-10 (IL-10), and interleukin-1beta (IL-1β) before and after treatment. These cytokines represent T-helper 1 (TH1), T-helper 2 (TH2), and macrophage cytokines, respectively. Results The studied serum cytokines were significantly reduced after 1 year of treatment in leprosy patients. The degrees of reduction were significantly positively correlated with a reduction in the bacterial index (BI) and morphologic index (MI). After 1 year of MDT (but not 6 months), paucibacillary (PB) patients showed a significant reduction in all the studied serum cytokines to levels comparable with those of healthy controls. Multibacillary (MB) patients also showed a significant reduction in all the studied serum cytokines, but the levels were still significantly higher than those of healthy controls. Leprosy patients with high levels of serum IL-1β were more susceptible to the development of reactions after the initiation of treatment. Corticosteroid therapy of reactional patients resulted in a significant reduction in the studied serum cytokines to levels similar or lower than those of nonreactional leprosy patients. The dose of steroids showed a significant positive correlation with the amount of decrease in IL-1β. Conclusions MDT caused a reduction in serum cytokines correlated with a reduction in the bacterial burden. It is advisable to continue MDT for PB patients for 1 year. Serum IL-1β levels may have a prognostic value for the susceptibility of leprosy patients to the development of reactions.     

麻风患者血清Th1/Th2/Th17相关细胞因子检测

目的：检测麻风患者血清中Th1/Th2/Th17相关细胞因子水平,探讨其在麻风发病中的作用。方法：利用微量样本多重蛋白定量技术检测12例新发麻风患者,29例治愈麻风患者及37例正常人血清中IL-1、IL-2、IL-4、IL-6、IL-10、TNF、IFN-γ和IL-17A水平。利用Kruskal-Wallis和Nemenyi方法进行组间比较。结果：新发组患者血清IL-1和IL-2水平显著高于治愈组（P≤0.005）;新发组及治愈组患者血清IL-6水平均显著高于对照组（P＜0.005）;新发组患者血清IFN-γ 和IL-17A水平显著高于对照组（P＜0.005）。新发组、治愈组和对照组IL-4、IL-10和TNF浓度差异无统计学意义。结论：Th1/Th2/Th17某些相关细胞因子可能与麻风的发病有关。     

Circulating cytokine profiles in leprosy patients

BACKGROUND: Leprosy is a chronic infectious disease caused by Mycobacterium leprae which is an obligate intracellular pathogen. It is characterised by a broad spectrum of clinical forms dictated by the patient's immune response to the organism. The tuberculoid pole has good cell mediated immunity to M. leprae, with few lesions and bacilli while the lepromatous pole has poor immunity coupled with extensive involvement and greater bacillary load. METHODS: We studied serum levels of interferon gamma and interleukin 6 in 100 patients of untreated leprosy, compared them with 30 age and sex matched normal healthy controls and co-related them with different parts of the spectrum and reactional episodes. The purpose of this study was to delineate the role of cytokines and their clinical implications in the leprosy spectrum and during reactional episodes. RESULTS: We observed that mean cytokine levels were significantly higher in the patient group as compared to the controls. In the non reactional patient group, pure neuritic leprosy patients showed highest levels of INFgamma which were directly proportional to the extent of nerve involvement. Lepromatous leprosy patients had the highest levels of IL6. Bacteriological index demonstrated a negative and positive corelation with INFgamma and IL 6 levels respectively. Type I and Type II reactional patients had higher levels of INFgamma and IL 6 respectively as compared to nonreactional patients. CONCLUSIONS: Our results suggest that pure neuritic leprosy and borderline tuberculoid patients in type I reaction are at greatest risk for nerve and tissue damage. Thus cytokines have the potential to play a significant role in classification, prognosis and treatment of leprosy.     

Occurrence of reversal reactions in BT patients during who paucibacillary leprosy MDT (1982)

55 B.T. patients were treated with WHO Paucibacillary MDT (1982). The patients suffered from reversal reaction neither at the time of initiation of MDT nor prior to that. During the 6 months period of MDT, one patient developed reversal reaction of a skin patch, and another patient developed neuritis of a peripheral nerve trunk.     

Genetic variations in cytokines and cytokine receptors associated with psoriasis found by genome-wide association

Genetic variants have long been suspected to be important in psoriasis. Recent work has suggested that HLA-Cw6 on chromosome 6 is the risk variant in the PSORS1 [MIM 177900] susceptibility locus that confers the greatest risk for early onset of psoriasis. Although numerous minor susceptibility loci have been identified by linkage analysis, few biologically relevant candidates have been discovered within these intervals. Recent large-scale genome-wide association studies have yielded new candidates in genes encoding cytokines with functional relevance to psoriasis. Polymorphisms within the genes encoding the IL-12 p40 subunit, IL12B, and one of the IL-23 receptor subunits, IL23R, have been replicated in US and European populations and overlap with risk of Crohn's disease. Polymorphisms within the gene encoding IL-13, a Th2 cytokine, also confer risk for psoriasis. Variants of the gene IL15 encoding IL-15 have been identified that associate with psoriasis in a Chinese population. These discoveries pose the challenge of elucidating the role of common genetic variants in susceptibility to and manifestations of psoriasis.     

Cytokines in leprosy, I. Serum cytokine profile in leprosy

Background Leprosy is a chronic infectious disease characterized by a broad spectrum of clinical forms depending on the patient's immune response, in particular cell-mediated immune response. Methods Cytokines can play a role in the cell-mediated immune response. Serum levels of interferon-gamma (IFN-γ), interleukin-2 (IL-2), interleukin-2 receptor (IL-2R), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β) were measured by enzyme-linked immunosorbent assay (ELISA) in 55 untreated leprosy patients and 35 reactional leprosy patients, in addition to 20 age- and sex-matched healthy controls. Results Leprosy patients showed significantly higher serum levels of the studied cytokines (except IL-2) compared with healthy controls. When the two poles were compared, tuberculoid leprosy (TT) patients showed significantly higher levels of IFN-γ and TNF-α with significant negative correlations with the bacterial index (BI), whereas lepromatous leprosy (LL) patients showed significantly higher serum levels of IL-2R, IL-10, and IL-1β with significant positive correlations with the BI. Both type I and type II reactional patients showed significantly higher serum IFN-γ, IL-2R, and IL-1β, in addition to IL-10 in type II reactional patients, compared with nonreactional leprosy patients. When compared with each other, type I reactional patients showed increased levels of IFN-γ, whereas type II reactional patients showed increased levels of IL-10. Conclusions In leprosy patients, both IFN-γ and TNF-α are immunoprotective, whereas IL-2R, IL-10, and IL-1β are immunosuppressive. Our results indicate that type I reaction, with increased levels of IFN-γ, is a cell-mediated immune response, whereas type II reaction, with increased levels of IL-10, is essentially an immune complex disease.     

Infiltrating cells, related cytokines and chemokine receptors in lesional skin of patients with dermatomyositis

BACKGROUND: There have been only two reports on immunophenotypic characterization in the cutaneous lesions of dermatomyositis (DM) that emphasize the importance of the infiltrating CD4+ T lymphocytes. OBJECTIVES: To characterize the immunophenotype of the cells that infiltrate the lesional skin of DM and to evaluate the possible T-helper (Th) polarization Th1/Th2 through detection of specific cytokines, chemokine receptors and markers of cellular activation. METHODS: Skin biopsy specimens derived from pathognomonic lesions (Gottron's papules and Gottron's sign) of eight patients with DM were immunostained with a large panel of monoclonal antibodies to CD3, CD4, CD8, myeloperoxidase (MPO), eosinophil cationic protein, tryptase, CD40, CD40 ligand (CD40L), HLA-DR, interleukin (IL)-2, IL-4, IL-5, IL-13, interferon-gamma, tumour necrosis factor-alpha, receptor 3 for CXC chemokines (CXCR3) and receptor 3 for CC chemokines, using the alkaline phosphatase-antialkaline phosphatase method. Control specimens were obtained from five healthy subjects and from six patients with discoid lupus erythematosus. RESULTS: Activated CD4+ Th lymphocytes (HLA-DR+ CD40L+) were the principal infiltrating cells in the lesional skin of DM; the CD4/CD8 ratio was approximately 2.5. A mixed Th1/Th2 profile and higher Th1 cytokine production together with significant staining for CXCR3 were detected. Neutrophil granulocytes were the second most abundant population; eosinophil granulocytes were very poorly represented. CONCLUSIONS: Activated CD4+ T cells presumably mediate the main pathogenetic mechanisms in pathognomonic skin lesions. The interaction between CD40 and CD40L could be an important mechanism of cellular activation in cutaneous immune-mediated inflammation by induction of secretion of proinflammatory cytokines and chemokines. Neither Th1 nor Th2 clear polarization was found, although there was a slight Th1 prevalence. There was a significant quantity of MPO+ cells (neutrophil granulocytes) in the inflamed tissue, and they might have a role in sustaining the chronic inflammation.     

银屑病患者血清中新蝶呤的水平和意义

目的：探讨新蝶呤（neopterin，Npt）在银屑病血清中的水平及其意义。方法：检测37例寻常型银屑病患者不同时期及治疗前后血清Npt水平。结果：银屑病患者血清Npt水平较健康对照组显著升高（P=0．001），血清Npt水平进行期较静止期增高（P〈0．05），治疗后，明显下降（P=0．001）。银屑病患者治疗前、后血清Npt水平与PASI评分有显著正相关（P=0．01，r=0．61；P=0．01，r=0．66）。结论：血清Npt可能在银屑病的发病机制中起着重要作用，并与疾病的活动和严重程度密切相关．     

Patterns of immunoglobulins in the serum of leprosy patients

There have been considerable variations in the levels of immunoglobulins in the serum of leprosy patients which needed elucidation. An attempt has been made in this direction to find out the levels of IgG, IgM and IgA in the serum samples of 145 cases of various grades of leprosy. The patients were selected in the age group of 11 to 60 years and have received treatment with DDS from a period ranging from 6 months to 5 years. A constant increase in the levels of immunoglobulins has been noted and the effect of treatment over variation in the levels has been discussed.     

皮肌炎患者血清中细胞因子检测及临床意义

目的 探讨皮肌炎（DM）和临床无肌病性皮肌炎（CADM）患者血清细胞因子水平与疾病活动,特别是与皮损和肺间质病变之间的联系。方法 采用酶联免疫吸附测定和流式微珠阵列法检测40例DM/CADM患者血清中白细胞介素（IL）2、IL-4、IL-6、IL-10、IL-17A、IL-18、肿瘤坏死因子、γ干扰素8种细胞因子水平,分析细胞因子与皮损、炎症指标和肺间质病变严重程度的关系。结果 ①DM/CADM患者血清中,IL-6（37.8 ± 45.8 pg/ml）、IL-10（16.1 ± 7.2 pg/ml）和IL-18（492.0 ± 193.1 pg/ml）水平显著高于健康对照组IL-6（12.0 ± 2.7 pg/ml）、IL-10（7.7 ± 1.4 pg/ml）和IL-18（191.1 ± 39.2 pg/ml）水平,均P <0.001。其他5种细胞因子与健康对照组比较,差异无统计学意义;②红细胞沉降率升高患者的血清IL-6水平（49.7 ± 46.8 pg/ml）显著高于红细胞沉降率正常患者（29.1 ± 45.4 pg/ml）,P = 0.008;C反应蛋白升高患者的血清IL-6（68.7 ± 59.7 pg/ml）和IL-18（635.1 ± 232.8 pg/ml）水平显著高于C反应蛋白正常患者（IL-6为30.6 ± 40.3 pg/ml,P = 0.013;IL-18为440.2 ± 164.7 pg/ml,P = 0.020）;乳酸脱氢酶升高患者的IL-10（18.4 ± 6.9 pg/ml）、IL-17A（19.6 ± 6.7 pg/ml）和IL-18（529.4 ± 197.2 pg/ml）显著高于乳酸脱氢酶正常患者（IL-10为10.7 ± 4.8 pg/ml,P < 0.001;IL-17A为11.4 ± 6.6 pg/ml,P = 0.001;IL-18为404.9 ± 158.0 pg/ml,P = 0.037）;肌酸激酶升高组与肌酸激酶正常组之间细胞因子水平比较,差异无统计学意义;③具有Gottron丘疹/征的患者血清IL-18水平（513.7 ± 187.2 pg/ml）显著高于无Gottron丘疹/征的患者（297.1 ± 140.4 pg/ml）,P < 0.05;④DM/CADM伴肺间质病变的患者血清IL-10（18.0 ± 6.7 pg/ml）和IL-18水平（552.3 ± 192.8 pg/ml）显著高于不伴肺间质病变者（IL-10为11.6 ± 6.5 pg/ml,IL-18为351.4 ± 101.0 pg/ml）,P = 0.001。结论 皮肌炎患者血清IL-6、IL-10、IL-18等细胞因子与炎症指标、皮损和肺间质病变显著相关。     

Lepromatous leprosy and reversal reaction in a Micronesian immigrant

A 25-year-old Micronesian man from the island of Otia developed erythematous plaques on his legs. He was diagnosed with erythema nodosum and treated with systemic prednisone. Two months later, he presented with erythematous nodules on his forehead, cheeks, and chin (Fig. 1). Examination revealed scattered violaceous papules on his chest, arms, forearms, hands, and feet, and deep purple macules on his palms and soles. Laboratory evaluation included negative serologies for human immunodeficiency virus, rapid plasma reagin, and hepatitis A, B, and C. Routine histopathology revealed nodular aggregates of histiocytes, plasma cells, and lymphocytes. Histiocytes showed basophilic clusters of organisms within vacuoles, suggesting globi. Acid-fast stain revealed numerous acid-fast-positive rod-shaped organisms. The bacterial index on the Fite stain was four (bacterial index/Ridley's logarithmic scale, indicating 10-100 bacteria/high power field) (Fig. 2). An acid-fast stain obtained from a smear of tissue was positive for acid-fast bacilli, but no acid-fast bacilli were cultured. After the first day of treatment with dapsone 100 mg, rifampin 600 mg, and clofazimine 50 mg, the patient complained of burning and pain in his ankles and wrists. There was intense erythema within the lesions. Edema developed in his hands and feet. Consultation with the Gillis W. Long Hansen's Disease Center in Carville, Louisiana, recommended prompt treatment with corticosteroids. The edema of the hands and wrists was treated as a type I reversal reaction with prednisone 1 mg/kg/day. Subsequently, the edema and neuralgia quickly resolved in his distal extremities.