Analysis of transmembrane signalling and T cell defects associated with idiopathic thrombocytopenic purpura (ITP)

Adult chronic idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease characterized by production of autoreactive antibodies to platelet antigens. It is now becoming clear that autoantibody production, in general, is regulated by T helper (Th) cells. Several recent studies have examined potential defects in T cell function in this disease and have demonstrated that patients with ITP possess abnormal lymphocyte activation and Th₁/Th₂-mediated cytokine production. Although the underlying cause(s) of aberrant T cell function in this disease are not known, studies from other models of autoimmune disease indicate that defects in T cell transmembrane signalling can be causally linked to abnormal T cell activation and cytokine production. This review will present some of the major T cell signalling pathways and discuss how altered T cell signalling may be linked to autoimmunity with an emphasis on ITP. Recent preliminary findings of a potential defect in the signal transduction apparatus in lymphocytes from three patients with ITP will also be presented.     

Mechanisms in childhood idiopathic thrombocytopenic purpura (ITP)

The concepts of the pathological mechanisms in childhood idiopathic thrombocytopenic purpura (ITP) have, to a great extent, been based on clinical experience and on data generated in adults. Studies performed in children have demonstrated that platelet antigen-specific autoantibodies are present in chronic ITP and, to a lesser extent, in acute ITP. It is, however, likely that the mechanisms initiating the production of autoantibodies are different in the two entities. In acute ITP, production of autoantibodies and immune complexes is probably linked to a transient antiviral immune response. Chronic ITP in children is an autoimmune process which eventually is reversible in many cases. The initiating factors, as in other autoimmune disorders, are yet to be elucidated.     

Childhood immune thrombocytopenic purpura: diagnosis and management

Immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by a low circulating platelet count caused by destruction of antibody-sensitized platelets in the reticuloendothelial system. ITP can be classified as childhood versus adult, acute versus chronic, and primary versus secondary. Persistence of thrombocytopenia defines the chronic form of the disorder. Secondary causes of ITP include collagen vascular disorders, immune deficiencies, and some chronic infections. This review focuses on the diagnosis and management of children who have acute and chronic ITP. Emphasis is placed on areas of controversy and new therapies.     

Interleukin-1beta exon 5 and interleukin-1 receptor antagonist in children with immune thrombocytopenic purpura

Immune thrombocytopenic purpura (ITP) is associated with cytokine response and dysregulation of the cytokine network. We investigated the polymorphisms of interleukin (IL)-1beta exon 5 and IL-1 receptor antagonist (IL-1 Ra) in 50 children with acute ITP, in 30 children with chronic ITP, and in 100 healthy children by polymerase chain reaction-based restriction analysis. No significant differences in either genotype distribution (P=0.52) or allelic frequencies (P=0.70) were found among children with acute ITP, chronic ITP, or controls for IL-1beta exon 5. However, significant differences in genotype distribution (P=0.02) and the allelic frequencies (P=0.007) were found among children with acute ITP, chronic ITP, and controls for IL-1 Ra. We found that the IL-1 Ra but not IL-1beta gene polymorphism was associated with childhood ITP. This finding suggests that the IL-1 Ra gene polymorphism is implicated in the pathophysiology of childhood ITP.     

The effects of megadose methylprednisolone therapy on the immune system in childhood immune thrombocytopenia

Immune thrombocytopenia (ITP) is a frequently encountered disease in childhood. Recent reports pointed to the benefit of high-dose steroid in ITP treatment since it resulted in a better outcome in a shorter time than IV immunoglobulin therapy. In the authors' clinic, mainly after 1984, megadose methyl prednisolone (MDMP) has been used for ITP treatment. There is no report that includes an extensive immune system examination of megadose steroid effect in childhood ITP. The purpose of this study is to determine the effects of MDMP therapy on the immune system in childhood ITP for serum immunoglobulins, absolute lymphocyte and lymphocyte subclass counts, and in vitro blastogenic responses to mitogens. The authors have demonstrated that lymphocyte subtypes (CD3, CD4, CD8, CD19) and serum immunoglobulin G, A, M increased after a short-course MDMP therapy in comparison to pretreatment values in mixed group (acute + chronic) of childhood ITP patients. Also blastic transformation function of lymphocytes with Conca-A and phytohemaglutinin showed an upward trend in 6 of the 9 patients. Steroid are thought to have a suppressive effect on the immune system but this study suggests that short-course MDMP may not be hazardous to the immune system.     

Role of the T cell receptor in idiopathic thrombocytopenic purpura (ITP)

During the past few decades a number of studies has described T cell defects and attempted to elucidate their role in the pathogenesis of idiopathic thrombocytopenic purpura (ITP). Some studies implicate T cells as potential initiators of autoantibody production in ITP. However, only a few of these have studied the role that the T cell receptor may play in the pathogenesis of ITP. In a variety of autoimmune syndromes interest has focused on the α- and β-chains of the T cell receptor. Deviations from the normal T cell receptor gene usage have been reported in rheumatoid arthritis, systemic lupus erythaematosus and multiple sclerosis. Usually, these studies have shown a restricted heterogeneity of T cell receptor variable gene usage. The studies on the T cell receptor in ITP have included a limited number of patients, which makes it difficult to evaluate the significance of the role that the T cell receptor may play in the pathogenesis of ITP. Further studies are warranted.     

Antiplatelet antibodies in chronic adult immune thrombocytopenic purpura: assays and epitopes

Chronic immune thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by thrombocytopenia due to autoantibody-induced platelet destruction. The majority of these autoantibodies are directed to epitopes on either glycoprotein (GP) IIb-IIIa or GPIb-IX. The newer antigen-specific autoantibody assays are capable of detecting both platelet-associated and plasma autoantibodies and have a definite role in the diagnosis of immune thrombocytopenia. A positive assay provides strong evidence for the presence of immune thrombocytopenia both in chronic ITP and in other diseases where immune thrombocytopenia may occur, such as collagen vascular disease and lymphoproliferative disorders. However, a negative assay does not rule out the presence of ITP. Somewhat concerning is the large number of patients who have negative assays. Several possible explanations for these observations are discussed. Recent studies have localized some ITP autoepitopes to specific regions of GPIIb-IIIa and GPIb-IX. Most autoepitopes on GPIIb-IIIa are conformational, in view of their dependence on divalent cations, and are localized to the N-terminal portion of GPIIb, while the GPIb-IX autoepitopes that have been identified are localized to GPIb amino acids 333-341.     

The emerging role of leptin in humans

Leptin is an adipocyte-secreted hormone which plays a key role in energy homeostasis. Recent advances in leptin physiology have revealed that the main role of this hormone in humans is to signal energy availability in energy-deficient states. Interventional studies in leptin deficient children and observational studies in normal girls and boys support a role for leptin as a permissive factor for the initiation of puberty in children. Moreover, recent "proof of concept" studies involving leptin administration to humans further support its critical role in regulating energy homeostasis, neuroendocrine and immune function as well as insulin resistance in states of energy/caloric deprivation. Leptin's potential role in the therapy of several disease states, including hypothalamic amenorrhea, anorexia nervosa and syndromes of insulin resistance is under intensive investigation.     

Leptin and Its Emerging Role in Children and Adolescents

Leptin is an adipocyte-secreted hormone which plays a key role in energy homeostasis. Recent “proof of concept” studies involving leptin administration to humans support its critical role in regulating energy homeostasis, neuroendocrine and immune function as well as insulin resistance in states of energy/ caloric deprivation. Moreover, interventional studies in leptin deficient children and observational studies in normal girls and boys support a role for leptin as a permissive factor for the initiation of puberty in children. The potential clinical usefulness of leptin in several disease states in children and adolescents, including hypothalamic amenorrhea, eating disorders and syndromes of insulin resistance is still under investigation.     

ITP患儿外周血T细胞T-bet/GATA-3基因的检测及意义

目的研究急慢性ITP患儿Th1、Th2类细胞因子和转录因子T-bet和GATA-3的相关性,探讨其在ITP发病机制。方法选择30例ITP患儿,运用T细胞分离富聚柱得纯化的T细胞,分别用ELISA法和RT-PCR技术检测ITP患儿血清中的IFN-γ、IL-4水平和外周血T细胞转录因子T-bet和GATA-3的表达状态,设30例健康儿童为对照组。结果慢性ITP患儿血清中IL-4水平较正常人降低,IFN-γ的水平升高,GATA-3 mRNA表达水平下降,T-be tmRNA表达水平升高;而急性ITP患儿外周血中IL-4水平较正常人升高,血清中IFN-γ水平及T-bet/GATA-3比值无显著性差异。结论慢性ITP患儿外周血Th1/Th2比例失衡,T-bet/GATA-3的表达失调,可能引起慢性ITP的免疫紊乱:而急性ITP患儿的发病机制可能与T-bet/GATA-3的表达无关。     

Th17和自身免疫性疾病相关性研究进展

Th17是一种新近发现的CD4+T细胞亚群,它是Th1、Th2家族的新成员.近年来研究发现,Th17能够产生IL-17A、IL-17F、IL-21和IL-22等因子,而这些因子在类风湿关节炎、系统性红斑狼疮、系统性硬化病、炎性肠病、自身免疫性心肌炎等自身免疫性疾病的发生发展中起重要作用.因此,加深对Th17在免疫性疾病...     

Th17和自身免疫性疾病相关性研究进展

Th17是一种新近发现的CD4+T细胞亚群,它是Th1、Th2家族的新成员.近年来研究发现,Th17能够产生IL-17A、IL-17F、IL-21和IL-22等因子,而这些因子在类风湿关节炎、系统性红斑狼疮、系统性硬化病、炎性肠病、自身免疫性心肌炎等自身免疫性疾病的发生发展中起重要作用.因此,加深对Th17在免疫性疾病进展中的认识将为今后的诊断提供新的依据,Th17及其因子也将成为人类治疗自身免疫性疾病的新靶点.     

小儿病毒性心肌炎的免疫改变观察

为探讨免疫与小儿病毒性心肌炎发病的关系,检测５４例病毒性心肌炎血清免疫球蛋白和外周血Ｔ淋巴细胞亚群,与健康对照组对比,结果：病毒性心肌炎急性期,恢复期血清免疫球蛋白无明显变化,急性期ＣＤ３、ＣＤ４和ＣＤ４／ＣＤ８均明显下降,恢复期ＣＤ８下降,ＣＤ４／ＣＤ８明显升高;１３例慢性期ＣＤ８进一步下降,ＣＤ４／ＣＤ８进一步升高,提示病毒性心肌炎的免疫改变以细胞免疫为主,存在细胞免疫功能紊乱,急性期细胞免疫功能低下,恢复期、慢性期存在免疫过强和自身免疫反应。     

Role of transforming growth factor-beta 1 gene polymorphisms in childhood idiopathic thrombocytopenic purpura

PURPOSE: To investigate whether transforming growth factor-beta 1 (TGF-beta 1) gene polymorphisms have a role in the development, clinical progress, and treatment response in children with idiopathic thrombocytopenic purpura (ITP). PATIENTS AND METHODS: Thirty-five children with acute ITP, 40 children with chronic ITP, and 97 healthy children were enrolled. After genomic DNA was extracted, TGF-beta 1 gene 509 (C-->T), codon 25 (Arg-->Pro), and codon 10 (Leu-->Pro) polymorphisms were studied using a coupled polymerase chain reaction-restriction enzyme digestion method. RESULTS: The genotype and allele frequencies of TGF-beta 1 polymorphisms between acute ITP, chronic ITP, and control group did not differ significantly. No significant association was found between TGF-beta 1 polymorphisms and therapy response. CONCLUSIONS: These results demonstrate that the frequency of TGF-beta1 gene 509 (C-->T), codon 25 (Arg-->Pro), and codon 10 (Leu-->Pro) polymorphisms and alleles do not play a role as a genetic risk factor in the development and clinical progress of ITP. Different results may be obtained with further studies involving larger patient populations and other TGF-beta 1 gene polymorphisms.     

Serum leptin and interleukin-6 levels in pediatric patients with HIV

Recent therapeutic approaches have improved the prognosis of children with HIV. Many new efforts could be involved in their quality of life and therefore could need additional diagnostic strategies. Leptin regulates pubertal development; furthermore a continuous immune stimulus, as in chronic infectious diseases, can enhance leptin's secretion by the action of cytokines such as interleukin (IL)-6. To clarify this role in patients infected with HIV, we assayed leptin and IL-6 and evaluated the influence of HIV severity on its secretion. IL-6 (380.5 +/- 257.6 pg/ml; range: 22-900 pg/ml) showed a significant correlation with leptinemia, HIV-1 RNA, and viremia related to the stage of HIV disease. The difference in leptinemia from a control group (3 +/- 3.2 ng/ml; range: 1-12 ng/ml in HIV patients; 6.72 +/- 8 ng/ml in the controls) did not reach statistical significance, nor did it correlate with pubertal stage, BMI, viremia, CD4 or anti-retroviral therapy. There was a statistically significant correlation between leptinemia and the stage of the HIV disease, and with IL-6 level. We want to stress the role of immunological factors in enhancing leptin secretion.     

急性特发性血小板减少性紫癜患儿免疫功能变化及其临床意义

目的检测特发性血小板减少性紫癜(ITP)患儿的免疫功能并探讨ITP的发病机制。方法抗血小板抗体(PAIgG)测定采用放射免疫法,IgA、IgG、IgM测定采用WL-快速免疫消浊比浊法,T淋巴细胞亚群测定采用APAAP法,血清IL-2、sIL-2R和IL-6测定采用ELISA法。结果 ITP患儿的IL-2、IL-6,IgA、IgM、CD8及IL-2R表达均明显升高(P<0.01),CD4+、CD4+/CD8+细胞均明显减少(P<0.01)。结论细胞免疫及体液免疫异常共同参与ITP致病机制,调节淋巴细胞亚群平衡有助于寻找ITP治疗的新途径。     

儿童难治性特发性血小板减少性紫癜的治疗进展

特发性血小板减少性紫癜(ITP)是一种自身免疫性疾病,是临床最常见的出血性疾病.治疗以糖皮质激素、免疫抑制剂、脾切除等非特异性手段为主,但副反应明显,且约1/3的患儿治疗无效,成为难治性ITP.儿童难治性ITP目前尚无特效根治约物及方法,治疗应个体化,治疗选择应根据血小板计数和出血状态而定.近年对ITP自身免疫发病机制的深入研究令许多新的定向免疫干预措施开始进入临床研究阶段,实施定向免疫干预将是今后ITP诊疗的方向.文章结合ITP的发病机制对这些进展作一概述.     

白细胞介素-17在子代孤独症谱系障碍中的相关研究进展北大核心CSCD

白细胞介素-17(IL-17)在机体免疫应答以及炎症性反应中起着十分重要的作用。研究发现高水平的IL-17与多种自身免疫性疾病、急慢性神经退行性疾病和精神疾病的发病有关。孤独症谱系障碍(ASD)是一组儿童时期较为常见的神经发育障碍性疾病, 近期的临床及实验研究将妊娠期母体免疫激活(MIA)与子代患ASD风险联系起来。研究发现, IL-17水平在MIA诱导的子代ASD中明显升高, 是MIA导致子代小鼠神经发育异常的关键因素。现通过阐述IL-17与子代ASD间的最新研究进展, 为ASD的预防和治疗提供新的思路。     

Soluble P-selectin,interleukin 6, and thrombopoietin levels in children with acute and chronic idiopathic thrombocytopenic purpura and their relationship with mega-dose methylprednisolone therapy: a pilot study

We observed less severe symptoms in patients with chronic idiopathic thrombocytopenic purpura (ITP) than in patients with acute ITP with similar platelet counts. Thrombopoietin (TPO), soluble P-selectin, soluble P-selectin per platelet, and interleukin 6 (IL-6) were evaluated in children with ITP before treatment in 16 acute and 22 chronic cases and after treatment in 10 acute and chronic cases who received mega-dose methylprednisolone. The levels of IL-6, soluble P-selectin, soluble P-selectin per platelet, and platelet count were similar in acute and chronic ITP (P > 0.05) but TPO in acute ITP was higher than that of the patients with chronic ITP (P < 0.05). The posttreatment IL-6 and TPO declined (P < 0.05), but soluble P-selectin and platelet count increased (P < 0.05). Posttreatment soluble P-selectin per platelet levels were higher than the normal values (P < 0.05). These results suggest that IL-6, soluble P-selectin, and soluble P-selectin per platelet are not responsible for the milder symptoms in chronic than in acute ITP. Mega-dose methylprednisolone seems to keep the soluble P-selectin levels elevated.     

Angeborene Störungen der Immunregulation

The term diseases of immune dysregulation is an umbrella term for various diseases which stand out due to autoimmunity and/or lymphoproliferation of secondary lymphoid organs. The investigation of these diseases linked to single-gene defects provides an insight into different pathomechanisms of immune dysregulation or rather autoimmune phenomena. A defect of lymphocyte apoptosis in ALPS syndromes and an impairment of cellular cytotoxicity in hemophagocytic lymphohistiocytosis syndromes lead to lymphoproliferation, hepatosplenomegaly and autoimmune cytopenia. In addition a dysfunction in the development of immune tolerance causes autoimmune disease often with the involvement of endocrine organs. The APECED syndrome is caused by a disruption of central tolerance and shows in addition to autoimmune polyendocrinopathy a chronic mucocutaneous candidiasis. The defect in the development of peripheral tolerance in IPEX syndrome leads to a severe enteropathy in early childhood. The discovery of the responsible gene defects of these diseases and studies using the corresponding mouse models make an important contribution to the understanding of immune dysregulation and can possibly help in the development of new therapeutic strategies for these patients.