IL-10 has a protective role in experimental autoimmune uveoretinitis

The role of IL-10 in the regulation of ocular autoimmune disease was studied in experimental autoimmune uveoretinitis (EAU) elicited in mice by immunization with the retinal antigen interphotoreceptor retinoid binding protein. IL-10-deficient mice were susceptible to EAU, indicating that pathogenesis can occur without presence of IL-10. Treatment of normal mice with IL-10 for 5 days after uveitogenic immunization ameliorated subsequent EAU scores, and down-regulated antigen-specific production of tumor necrosis factor-alpha and IFN- gamma. A concomitant treatment with IL-4 further reduced disease, and resulted in emergence of antigen-specific IL-4 and IL-10 production, as well as in enhancement of the IgG1 antibody isotype. IL-4 by itself was not protective. Only IL-10, but not IL-4, was able to inhibit the function of differentiated uveitogenic T cells in culture. Expression of mRNA for Th1 and Th2 cytokines in the eye during the course of EAU showed that while a Th1 pattern predominated early, IL-10 mRNA expression coincided with down-regulation of the Th1 response and resolution of EAU. Systemic neutralization of IL-10 during the expression phase of EAU resulted in elevated disease scores. Our results suggest that endogenous IL-10 limits expression of EAU and may play a role in the natural resolution of disease. The data further suggest that exogenous IL-10 may be useful in therapeutic control of autoimmune uveitis. While IL-10 by itself is sufficient to suppress Th1 effector development and function, a concomitant administration of IL-4 is required to shift the autoimmune response towards a non-pathogenic Th2 pathway.      

Monocytoid B-cell lymphoma: its evolution and relationship to other low- grade B-cell neoplasms

Monocytoid B-cell lymphoma (MBCL) is a newly recognized B-cell neoplasm of uncertain histogenesis. The cytologic features of the neoplastic monocytoid B lymphocytes are virtually identical to those of hairy cell leukemia (HCL). As with HCL, progression of MBCL to a higher histologic grade is very unusual. However, whereas circulating leukemic cells are a characteristic feature of HCL, peripheral blood involvement has not been reported in MBCL. We recently studied a patient with MBCL of the spleen and axillary lymph nodes who developed peripheral blood involvement by MBCL cells. Unlike the cells of HCL, the circulating MBCL cells exhibited strong acid phosphatase activity that was tartrate sensitive. The leukemic cells had the antigenic phenotype IgM lambda, CD20+, CD11c+, CD5-, CD25(TAC)-, and PCA-1-. Immunogenetic studies of both lymph node and peripheral blood cells revealed identical immunoglobulin heavy-chain gene rearrangements. When compared with a series of HCL, the immunophenotype was similar except for the absence of PCA-1 and TAC. Progression of the MBCL to a large cell lymphoma, also expressing IgM lambda, was documented in an abdominal lymph node of this patient. Therefore, although rare, peripheral blood involvement by lymphoma cells may occur during the course of MBCL and should be distinguished from HCL with cytochemical and immunophenotypic studies. In addition, comparison of the clinical, pathologic, and immunologic features of MBCL with those of other low-grade B-cell neoplasms suggests that a close lineage relationship exists between MBCL and HCL.     

Thrombospondin mediates the cytoadherence of Plasmodium falciparum- infected red cells to vascular endothelium in shear flow conditions

Cerebral malaria is thought to involve specific attachment of Plasmodium falciparum-infected knobby red cells to venular endothelium. The nature of surface ligands on host endothelial cells that may mediate cytoadherence is poorly understood. We have investigated the effects of soluble thrombospondin, rabbit antiserum raised against thrombospondin, and human immune serum on cytoadherence of parasitized erythrocytes in ex vivo mesocecum vasculature. Preincubation of infected red cells with soluble thrombospondin or human immune serum inhibits binding of infected red cells to rat venular endothelium. Infusion of the microcirculatory preparation with rabbit antithrombospondin antibodies before perfusion of parasitized erythrocytes also resulted in decreased cytoadherence. In addition, incubation of infected cells with human immune sera obtained from malaria patients significantly inhibited the observed cytoadherence. Our results indicate that thrombospondin mediates binding of infected red cells to venular endothelium and may thus be involved in the pathogenesis of cerebral malaria.     

Early immunologic events in mucosal and systemic lymphoid tissues after intrarectal inoculation with simian immunodeficiency virus

The pathogenesis of human immunodeficiency virus transmission via the rectal route remains poorly understood. By use of the simian immunodeficiency virus (SIV)-rhesus macaque model and intrarectal inoculation with pathogenic SIVmac251, a significant increase was found in the percentage of CD11b(+) monocyte lineage cells expressing HLA-DR and/or B7-2 in local and peripheral immune inductive sites, but not in mucosal effector sites, as early as 7 days after inoculation and up to 50 days after inoculation. Moreover, at 21 and 50 days after inoculation, not only the gut but also the lung mucosa were depleted of CD4(+) T cells, which suggests that early loss of CD4(+) T cells may be a common feature of mucosal effector sites. These data suggest that, after intrarectal inoculation with SIV, early activation occurs within the monocyte lineage cell population at immunologic inductive sites, which is followed by a loss of CD4(+) T cells at local and distant mucosal effector sites.     

Extracellular matrix of cultured bovine aortic endothelial cells contains functionally active type 1 plasminogen activator inhibitor

The extracellular matrix (ECM) of cultured bovine aortic endothelial cells (BAEs) was analyzed by immunoblotting and reverse fibrin autography and shown to contain type 1 plasminogen activator inhibitor (PAI-1). Most PAI-1 in the ECM formed complexes with exogenously added tissue-type plasminogen activator (tPA), demonstrating that this PAI-1 was functionally active. The resulting tPA/PAI-1 complexes were recovered in the reaction solution, indicating that the PAI-1 in such complexes no longer bound to ECM. The PAI-1 could not be removed by incubating ECM in high salt (2 mol/L NaCl), sugars (1 mol/L galactose, 1 mol/L mannose), glycosaminoglycans (10 mmol/L heparin, 10 mmol/L dermatan sulfate), or epsilon-aminocaproic acid (0.1 mol/L). However, PAI-1 could be extracted from ECM by treatment with either arginine (0.5 mol/L) or potassium thiocyanate (2 mol/L), or by incubation under acidic conditions (pH 2.5). ECM depleted of PAI-1 by acid extraction was able to bind both the active and latent forms of PAI-1. In this instance, most of the bound PAI-1 did not form complexes with tPA, indicating that the latent form was not activated as a consequence of binding to ECM. Although the PAI-1 activity in conditioned medium decayed with a half-life (t 1/2) of less than 3 hours, the t 1/2 of ECM- associated PAI-1 was greater than 24 hours. These data suggest that PAI- 1 is produced by cultured BAEs in an active form and is then either released into the medium where it is rapidly inactivated or into the subendothelium where it binds to ECM. The specific binding of PAI-1 to ECM protects it from this inactivation.     

A genetic variant of NLRP1 gene is associated with asbestos body burden in patients with malignant pleural mesothelioma

The presence of asbestos bodies (ABs) in lung parenchyma is considered a histopathologic hallmark of past exposure to asbestos fibers, of which there was a population of longer fibers. The mechanisms underlying AB formation are complex, involving inflammatory responses and iron (Fe) metabolism. Thus, the responsiveness to AB formation is variable, with some individuals appearing to be poor AB formers. The aim of this study was to disclose the possible role of genetic variants of genes encoding inflammasome and iron metabolism proteins in the ability to form ABs in a population of 81 individuals from North East Italy, who died after having developed malignant pleural mesothelioma (MPM). This study included 86 genetic variants distributed in 10 genes involved in Fe metabolism and 7 genetic variants in two genes encoding for inflammasome molecules. Genotypes/haplotypes were compared according to the number of lung ABs. Data showed that the NLRP1 rs12150220 missense variant (H155L) was significantly correlated with numbers of ABs in MPM patients. Specifically, a low number of ABs was detected in individuals carrying the NLRP1 rs12150220 A/T genotype. Our findings suggest that the NLRP1 inflammasome might contribute in the development of lung ABs. It is postulated that the NLRP1 missense variant may be considered as one of the possible host genetic factors contributing to individual variability in coating efficiency, which needs to be taken when assessing occupational exposure to asbestos.     

Prognostic significance of thrombocytosis in idiopathic sideroblastic anemia

In order to determine the prognostic significance of thrombocytosis in idiopathic sideroblastic anemia, the clinical courses of 17 patients were reviewed. Six patients (36%) had thrombocytosis, and none developed acute leukemia. Nine patients (53%) had normal platelet counts, and one developed acute leukemia. Two patients (12%) were thrombocytopenic, and one died of acute leukemia. There was little correlation between survival and platelet count. Sixty-three additional case reports of idiopathic sideroblastic anemia were collected from the literature. Analysis of those patients and the patients in the present study documented transformation to acute leukemia in 5 of 9 (56%) thrombocytopenic patients, 4 of 54 (7.4%) patients with normal platelet counts, and 0 of 17 patients with thrombocytosis (p less than 0.05). Therefore patients with idiopathic sideroblastic anemia and thrombocytosis appear to have a decreased likelihood of leukemic transformation.     

脂多糖诱导体外培养骨骼肌卫星细胞表达肝细胞生长因子的变化

目的:研究证实,在众多生长因子中,肝细胞生长因子无论在体外还是体内都可以激活静止状态的肌卫星细胞,修复受损肌肉。采用脂多糖刺激体外培养的骨骼肌卫星细胞,观察肌卫星细胞产生肝细胞生长因子以及肌卫星细胞增殖分化的变化。方法:实验于2006-07/2007-05在华中科技大学同济医学院同济医院创伤外科实验室完成。①实验材料:健康SD成年雄性大鼠,体质量150～200g,由华中科技大学同济医学院实验动物中心提供。实验过程中对动物处置符合实验动物伦理学标准。②实验方法:分离SD大鼠后肢部分股四头肌肉进行骨骼肌卫星细胞的培养。取第2代细胞爬片,待细胞增殖到80%密度时,丙酮固定细胞,常规处理后进行α-sarcometricactin细胞免疫化学染色鉴定,以成纤维细胞作为阴性对照。取第3代骨骼肌卫星细胞,应用0,5,10,20mg/L脂多糖刺激体外培养的大鼠骨骼肌卫星细胞,采用ELISA方法测细胞培养液中的肝细胞生长因子的浓度。取第4代骨骼肌卫星细胞,用含体积分数为0.10胎牛血清的培养基配制成单个细胞悬液,调整浓度为5×107L-1,分成两组,一组加入10mg/L脂多糖,另一组不加任何干预。采用噻唑蓝(MTT)法测定卫星细胞的增殖率。结果:①以未经脂多糖处理的无血清培养基培养的肌肉卫星细胞培养液为对照,将对照组和5,10,20mg/L脂多糖处理组比较,各实验组肝细胞生长因子浓度明显高于对照组(P<0.05)。②5,10,20mg/L脂多糖刺激骨骼肌卫星细胞分泌的肝细胞生长因子水平差异无显著性。③肝细胞生长因子在脂多糖刺激后36h分泌浓度最高。④脂多糖刺激肌卫星细胞的增殖分化明显高于未经刺激的肌卫星细胞。结论:①脂多糖可诱导骨骼肌卫星细胞自分泌肝细胞生长因子。②不同质量浓度脂多糖培养基中肝细胞生长因子水平差异无统计学意义。③脂多糖具有促进骨骼肌卫星细胞增殖分化的效应。