Treatment of immune thrombocytopenia associated with interferon therapy of hepatitis C with the anti-CD20 monoclonal antibody, rituximab

This case report describes a patient with hepatitis C virus infection responding to pegylated INF/ribaviron therapy, who developed immune thrombocytopenia. The severe thrombocytopenia failed to resolve with cessation of the peg-IFN/ribaviron. Because of rising hepatitis C virus RNA levels and evidence of rising serum transaminases, the patient was treated with rituximab, anti-CD20 humanized monoclonal antibody. After treatment with rituximab, the patient's platelet count normalized and the patient was able to resume the pegylated IFN/ribaviron. The patient's hepatitis C virus RNA levels decreased, and the serum transaminases normalized without impairment of hepatic function or recurrence of the thrombocytopenia.     

固有免疫在慢性阻塞性肺疾病发病机制中的作用

慢性阻塞性肺疾病(COPD)是气道慢性炎症性疾病,在炎症的启动及持续过程中,固有免疫的重要组成部分模式识别受体(PRRs)起到了重要作用.PRRs主要包括Toll样受体、NOD样受体、RIG-Ⅰ样受体.香烟烟雾、病原菌可以直接或间接通过损伤相关分子模式及病原体相关分子模式激活PRRs,使NF-κB依赖的促炎症基因表达,导致气道慢性炎症的形成及持续;此外,PRRs的先天情况也决定了 COPD的易感性.固有免疫反应产生的炎症介质与慢性支气管炎、COPD中肺泡的破坏、基质成分的降解及组织的重塑有关.本文主要讨论PRRs在COPD发生发展中的作用.     

The immune system and cancer evasion strategies: therapeutic concepts

The complicated interplay between cancer and the host immune system has been studied for decades. New insights into the human immune system as well as the mechanisms by which tumours evade immune control have led to the new and innovative therapeutic strategies that are considered amongst the medical breakthroughs of the last few years. Here, we will review the current understanding of cancer immunology in general, including immune surveillance and immunoediting, with a detailed look at immune cells (T cells, B cells, natural killer cells, macrophages and dendritic cells), immune checkpoints and regulators, sialic acid‐binding immunoglobulin‐like lectins (Siglecs) and other mechanisms. We will also present examples of new immune therapies able to reverse immune evasion strategies of tumour cells. Finally, we will focus on therapies that are already used in daily oncological practice such as the blockade of immune checkpoints cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) and programmed death‐1 (PD‐1) in patients with metastatic melanoma or advanced lung cancer, or therapies currently being tested in clinical trials such as adoptive T‐cell transfer.     

Avian bornaviruses escape recognition by the innate immune system

Like other pathogens that readily persist in animal hosts, members of the Bornaviridae family have evolved effective mechanisms to evade the innate immune response. The prototype of this virus family, Borna disease virus employs an unusual replication strategy that removes the triphosphates from the 5' termini of the viral RNA genome. This strategy allows the virus to avoid activation of RIG-I and other innate immune response receptors in infected cells. Here we determined whether the newly discovered avian bornaviruses (ABV) might use a similar strategy to evade the interferon response. We found that de novo infection of QM7 and CEC32 quail cells with two different ABV strains was efficiently inhibited by exogenous chicken IFN-α. IFN-α also reduced the viral load in QM7 and CEC32 cells persistently infected with both ABV strains, suggesting that ABV is highly sensitive to type I IFN. Although quail cells persistently infected with ABV contained high levels of viral RNA, the supernatants of infected cultures did not contain detectable levels of biologically active type I IFN. RNA from cells infected with ABV failed to induce IFN-β synthesis if transfected into human cells. Furthermore, genomic RNA of ABV was susceptible to 5'-monophosphate-specific RNase, suggesting that it lacks 5'-triphospates like BDV. These results indicate that bornaviruses of mammals and birds use similar strategies to evade the host immune response.     

SIgA在肠道免疫中的作用

分泌性免疫球蛋白A(SIgA)是由J链连接成的双聚IgA与SC(分泌片段)结合后形成的复合物,其分子量约为400kD。组成SIgA的三者之间互有作用,共同确保作为整体的SIgA能有效发挥免疫作用。此文就SIgA各组成部分的生成、调节及其在肠道发挥免疫保护作用的方式作一综述。     

The effect of clotting factor concentrates on the immune system in HIV-negative haemophilics

Immune abnormalities have been reported in patients with haemophilia. Although infections with HIV and hepatitis viruses contribute to these abnormalities, chronic exposure to extraneous proteins in clotting factor concentrates (CFC) may also play a role. A number of studies suggest that the degree of immunological abnormalities correlates with the amount of intermediate purity CFC administered over time. The purpose of this study was to investigate whether there were cellular and humoral immunological abnormalities in haemophilics receiving intensive factor replacement therapy with intermediate purity CFC. For this purpose 48 severe haemophilics and 33 healthy controls were enrolled in this study. T and B lymphocytes, CD4+ and CD8+ cell counts, CD4/CD8 ratio, natural killer cells, active T cells were studied in prophylaxis group, on-demand therapy group and healthy controls. In the percentages and absolute counts of lymphocyte subgroups, no significant difference was found between three groups. We also investigated serum antitetanus IgG levels in these 48 haemophilics and the controls to evaluate the specific antibody response. Antitetanus IgG levels were significantly lower in haemophilics compared to healthy controls (P < 0.001). Additionally we evaluated the response to tuberculin skin test in 45 of 48 haemophilics vaccinated with BCG. The response to PPD test was significantly lower in haemophilics compared to the controls (P = 0.037). There was no response to tuberculin test, which is the best marker of delayed type hypersensitivity (DTH) reactions in 24% of haemophilics. In conclusion, although there was no significant change in the ratio of CD4/CD8 and lymphocyte subgroups, specific antibody responses and DTH tests were partially impaired in haemophilic patients receiving intermediate purity CFC.     

肠道微生物群组与肠道免疫的关系

人类肠道是一个生态系统,存在大量的微生物。肠道微生物群与肠道天然免疫及获得性免疫之间存在动态的相互作用,影响着肠道免疫系统的形成和功能。当这种相互作用中的一步或多步失效时,自身免疫性疾病和炎症性疾病就会发生。回顾肠道微生物群组与肠道免疫功能的关系,有助于提高微生物对免疫系统失调相关的肠道疾病治疗应用的认识。     

The activated immune system and the renin–angiotensin–aldosterone system in congestive heart failure

Samsonov M, Lopatin J, Tilz G, Artner-Dworzak E, Nassonov E, Mareev V, Belenkov J, Wachter H, Fuchs D, (Cardiology Research Centre, Moscow, Russia; University of Graz, and the University of Innsbruck, Austria). Activated immune system and the renin–angiotensin–aldosterone system in congestive heart failure. J Intern Med 1998; 243 : 93–98.

Objects

The aim of the study was to investigate a possible relationship between plasma renin activity, angiotensin II, serum levels of angiotensin-converting enzyme, aldosterone and markers of immune activation in congestive heart failure (CHF).

Patients and Methods

Fifty-three patients (50 male, three female, mean age 46 ± 16 years) with congestive heart failure were studied. Twenty-eight patients had I or II NYHA class of CHF and 25 patients had III or IV NYHA class (NYHA class, mean ± SD : 2.3 ± 0.9). Serum neopterin concentration and hormones were measured by commercial radioimmunoassays. Serum soluble receptors of tumour necrosis factor and interleukin-2 were determined by ELISA.

Results

All analytes significantly correlated with NYHA classes (P < 0.05). There existed correlations between neopterin and angiotensin-converting enzyme or aldosterone (rs= 0.35 and rs= 0.36, P < 0.05). The soluble tumour necrosis factor receptor concentrations correlated with plasma renin activity (rs= 0.38, P < 0.05).

Conclusion

The result of our study suggest that there exists some relationship between the renin–angiotensin–aldosterone system and immune activation in severe congestive heart failure, however, the associations found are rather weak.

     

拉米夫定、α-2b干扰素治疗HBeAg(+)慢性乙型肝炎疗效与基因型相关性研究

目的 探索乙型肝炎病毒(HBV)基因型与拉米夫定、α-2b干扰素序贯治疗及单独予拉米夫定、α-2b干扰素治疗HBeAg阳性慢性乙型肝炎患者的疗效的相关性.方法 HBeAg阳性慢乙肝患者,来自北京等四城市.分别拉米夫定、干扰素序贯治疗48周、拉米夫定48周或干扰素24周.停药后随访24周.评价HBV基因型与抗病毒治疗应答的关系.PCR-RFLP方法检测HBV基因型、基因亚型.结果 225例患者中C基因型184例,其中C2亚型165例;B基因型41例,均为Ba亚型.治疗结束、随访结束时,各治疗组B型与C型间病毒学应答、血清学应答及完全应答率差异均无显著性.结论 该四城市HBeAg阳性慢乙肝患者HBV基因型以B型和C型为主,亚型以Ba和C2亚型为主.治疗结束、随访结束时,各治疗组B型与C型间疗效无差异.     

肝功能与病毒性肝炎免疫及病毒复制的关系

研究肝功能与病毒性肝炎免疫状态、病毒复制的关系.淋巴细胞亚群用碱性磷酸酶法检测.聚合人血清白蛋白受体（PHSA-R）用固相放射免疫法检测.ALT与CD20呈正相关关系;TBil与CD20呈正相关关系,与CD3/CD20呈负相关关系;AST/ALT与CD8呈负相关关系;TBil/ALT与CD8、CD3呈负相关关系.AST/ALT比值与PHSA-R滴度呈正相关.AST/ALT比值升高提示细胞免疫底下及病毒复制活跃,反之提示细胞免疫增高及病毒复制受抑制;ALT体现着免疫对肝细胞膜的损伤,AST体现了病毒复制对肝细胞的破坏.酶胆比值的增高与细胞免疫的相对降低及体液免疫的过度亢进有关.因此,临床研究中应同时参照ALT、AST的值及它们的相对值.     

Effect of photoperiod on the fish innate immune system: a link between fish pineal gland and the immune system

The pineal gland via its secretory product, melatonin, influences the light-dark rhythm in most vertebrates including fish. Apart from the information concerning this circadian rhythm, the interrelation of the melatonin with other physiological processes has not been considered in fish. Thus, we evaluated the changes in the humoral innate immune system of seabream (Sparus aurata L.) and sea bass (Dicentrarchus labrax L.) specimens exposed to a constant light-dark photoperiod (12 hr L:12 hr D). Serum was obtained from blood samples collected at 02:00, 08:00 hr (light-on), 14:00, 20:00 hr (light-off) and at 08:00 hr again. Among the humoral innate immune responses, complement, lysozyme and peroxidase activities were determined. Complement activity was higher during the day than during the night in both fish species. Seabream lysozyme activity reached its maximum at 20:00 and 02:00 hr but was hardly affected in sea bass. Finally, the peroxidase activity of seabream was significantly higher at 08:00 hr than during the rest of the cycle while, in sea bass, it showed little variation. The present results demonstrate that the humoral innate immune system has a circadian rhythm based on the light-dark cycle and that this cycle might be affected by the pineal gland.     

The role of vitronectin as multifunctional regulator in the hemostatic and immune systems

Summary Vitronectin (= complement S-protein) belongs to the group of structurally and functionally homologous adhesive proteins (fibrinogen, fibronectin, von Willebrand factor) which are essential in the procoagulant phase of the hemostatic system, interacting with platelets and the vessel wall. In addition to a structural motif in vitronectin responsible for this interaction (cell attachment domain) other functional domains in the protein molecule exist that contribute to its multifunctional role as regulator in the immune system (complement) as well as in fibrinolysis. These various activities and the ubiquitous distribution of vitronectin in the organism are discussed with regard to structurefunction relationships of the protein molecule. Vitronectin may thus provide a conceptual molecular link between cell adhesion, humoral immune response and the hemostatic system, particularly at the blood-vessel wall interphase.     

Virus induced diabetes and the immune system

Summary The participation of immune reactions in the EMC virus induced diabetes of the mouse was studied by immunosuppression with 500 R sublethal X-irradiation or 120 mg/kg Asta 5122, a cyclophosphamide derivative. Average glucose levels after X-irradiation and infection remained normal, while virus infected, otherwise untreated mice, had significantly higher mean glucose levels, indicating that immune reactions are necessary for the development of virus induced diabetes. Immune suppression by the cyclophosphamide derivative led, in contrast, to a significantly increased mean glucose level and increased insulitis in comparison with the controls only infected. This indicates an important role of the cellular immune reaction, insulitis, in the destruction of the islets.Partially presented on colloquium S.F.B.-Diabetes, Nov. 1976, Düsseldorf     

MicroRNA‐130a inhibits HCV replication by restoring the innate immune response

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis and hepatocellular carcinoma. Currently pegylated interferon (IFN) combined with ribavirin remains the best therapeutic approach, although patients infected with HCV genotype I may benefit from adding protease inhibitors as ‘triple therapy’. MicroRNAs (miRNAs) are endogenous small noncoding RNAs that regulate gene expression and have recently been shown to play an important role in human innate immune response and as an antiviral in chimpanzees. We studied the effect of miR‐130a on the HCV replication. We found that miR‐130a significantly inhibits HCV replication in both HCV replicon and J6‐/JFH1‐infected cells. Over expression of miR‐130a upregulated the expression of type I IFN (IFN‐α/IFN ‐β), ISG15, USP18 and MxA, which are involved in innate immune response and decreased expression of miR‐122, a well‐defined miRNA promoting HCV production. In conclusion, miR‐130a inhibits HCV replication/production by restoring host innate immune responses and/or downregulating pro‐HCV miR‐122. miR‐130a might be a potential drug target by modulating host innate immune responses to combat HCV infection.     

Virus-induced diabetes mellitus in mice and the thymus-dependent immune system

Summary The present study concerns the effect of the experimental diabetogenic encephalomyocarditis (EMC) virus on normal and athymic nude mice of BALB/c origin. The effect of simultaneous immunosuppressive pharmacological treatment with a derivative of cyclophosphamide in a relatively low dose (3 mg/mouse) was also studied. After inoculation with EMC virus, 36% of the normal mice, but none of the nude mice, developed diabetes mellitus and 93% of the normal mice, but none of the nude mice, developed paresis of one or more leg(s). When lower doses of EMC virus were given, few or none of the normal mice developed diabetes or paresis. After treatment with a cyclophosphamide-derivative, the number of paralysed mice increased. EMC virus in abundant amounts could be isolated from the pancreas and heart of all virus-inoculated mice, including the non-diabetic nude mice. Antibodies against EMC virus were found in all groups of virus-inoculated mice, although only in small amounts in nude and immunosuppressed normal mice. Histological examination revealed no significant differences between the islets of Langerhans of the experimental mice, diabetic as well as non-diabetic, and the control mice with respect to lymphocytic infiltration.It is concluded that the thymus-dependent immune system seems to be of decisive importance for the development of diabetes in this virus model.     

Is Type II diabetes mellitus a disease of the innate immune system?

Summary Type II (non-insulin-dependent) diabetes mellitus is associated with increased blood concentrations of markers of the acute-phase response, including sialic acid, α-1 acid glycoprotein, serum amyloid A, C-reactive protein and cortisol, and the main cytokine mediator of the response, interleukin-6. The dyslipidaemia common in Type II diabetes (hypertriglyceridaemia and low serum levels of HDL cholesterol) is also a feature of natural and experimental acute-phase reactions. We review evidence that a long-term cytokine-mediated acute-phase reaction occurs in Type II diabetes and is part of a wide-ranging innate immune response. Through the action of cytokines on the brain, liver, endothelium, adipose tissue and elsewhere, this process could be a major contributor to the biochemical and clinical features of metabolic syndrome X (glucose intolerance, dyslipidaemia, insulin resistance, hypertension, central obesity, accelerated atherosclerosis) but also provides a mechanism for many other abnormalities seen in Type II diabetes, including those in blood clotting, the reproductive system, metal ion metabolism, psychological behaviour and capillary permeability. In the short-term, the innate immune system restores homeostasis after environmental threats; we suggest that in Type II diabetes and impaired glucose tolerance long-term lifestyle and environmental stimulants, probably in those with an innately hypersensitive acute-phase response, produce disease instead of repair. [Diabetologia (1998) 41: 1241–1248]