c-di-GMP Enhances Protective Innate Immunity in a Murine Model of Pertussis

Innate immunity represents the first line of defense against invading pathogens in the respiratory tract. Innate immune cells such as monocytes, macrophages, dendritic cells, NK cells, and granulocytes contain specific pathogen-recognition molecules which induce the production of cytokines and subsequently activate the adaptive immune response. c-di-GMP is a ubiquitous second messenger that stimulates innate immunity and regulates biofilm formation, motility and virulence in a diverse range of bacterial species with potent immunomodulatory properties. In the present study, c-di-GMP was used to enhance the innate immune response against pertussis, a respiratory infection mainly caused by Bordetella pertussis. Intranasal treatment with c-di-GMP resulted in the induction of robust innate immune responses to infection with B. pertussis characterized by enhanced recruitment of neutrophils, macrophages, natural killer cells and dendritic cells. The immune responses were associated with an earlier and more vigorous expression of Th1-type cytokines, as well as an increase in the induction of nitric oxide in the lungs of treated animals, resulting in significant reduction of bacterial numbers in the lungs of infected mice. These results demonstrate that c-di-GMP is a potent innate immune stimulatory molecule that can be used to enhance protection against bacterial respiratory infections. In addition, our data suggest that priming of the innate immune system by c-di-GMP could further skew the immune response towards a Th1 type phenotype during subsequent infection. Thus, our data suggest that c-di-GMP might be useful as an adjuvant for the next generation of acellular pertussis vaccine to mount a more protective Th1 phenotype immune response, and also in other systems where a Th1 type immune response is required.     

Scleroderma and Primary Biliary Cirrhosis

Two cases of scleroderma and primary biliary cirrhosis are described. One had systemic sclerosis with primary biliary cirrhosis of six years'' duration at the stage of ductular proliferation. The other had the C.R.S.T. syndrome (calcinosis, Raynaud''s phenomenon, sclerodactyly, and telangiectases) with primary biliary cirrhosis at the florid stage. Several similar cases were found in a review of other reports, and it is suggested that the association may be due to a common “autoimmune” process.     

Hepatic Copper Accumulation in Primary Biliary Cirrhosis

Hepatic copper accumulation is a regular feature of primary biliary cirrhosis (PBC). The levels are directly related to the clinical stage of the disease. Since the copper values in PBC are comparable to Wilson''s disease, there is the potential for copper toxicity, although this is speculative since the two diseases differ in the binding, distribution, and intracellular localization of the copper. The involvement of copper toxicity in the progression of PBC is supported by the observation that the highest values occur in association with the hepatic failure that occurs in the advanced stage.Corticosteroid therapy appears to decrease hepatic copper levels in PBC. Although this therapy does not invariably lower the hepatic Cu content in patients with PBC, it does so in many individuals. Therapeutic trials with d-penicillamine are in progress. When results are available they will guide us in the management of individual patients with PBC. In the meantime, dietary copper should be restricted as is done in management of Wilson''s disease.     

原发性胆汁性肝硬化的药物治疗进展

原发性胆汁性肝硬化(Primary Biliary Cirrhosis,PBC)是一种以胆汁淤积及慢性非化脓性破坏性胆管炎为特点的自身免疫介导的慢性肝脏病。熊去氧胆酸(UDCA)作为PBC患者的首选治疗药物可使患者的生化指标、存活指标以及组织学等都得以改善。尽管如此,PBC的治疗仍是临床医师的一大难题,大约40%的PBC患者对UDCA的治疗仅获得了不完全应答,而肝移植则为晚期PBC患者治疗之首选。本文简要介绍近些年治疗PBC药物的新进展,包括熊去氧胆酸、布地奈德、免疫抑制剂、贝特类、6α-乙基鹅去氧胆酸、利妥昔单抗以及抗逆转录病毒药物等,期望为PBC的治疗提供帮助。     

原发性胆汁性肝硬化家系成员的发病及机制初探

目的:研究原发性胆汁性肝硬化(PBC)家系患者发病时的临床表现、生化指标及人类白细胞抗原(HLA)基因分型的特征,分析该疾病的发病机制,以提高对该病的认识。方法:分别用临床生化分析试剂盒、间接免疫荧光法、免疫印迹法和微阵列聚合酶链式反应(PCR)等技术对收集的31个家系129例一级亲属进行生化指标、自身抗体和HLAⅡ基因分型的相关检测。结果:5个家系出现免疫异常,表现在抗核抗体(ANA)阳性,但仅有一个家系的一个成员出现抗线粒体抗体(AMA)M2型阳性,可诊断为PBC。其中,发现免疫异常的5个家系中2例一级亲属出现肝功能异常,两个家系发现HLAⅡ-DRB1(*08)基因型,另外两个家系共同存在HLAⅡ-DRB1(*07)基因型。结论:PBC具有一定的家族聚集性,其发病可能与HLAⅡ-DRB1(*08)密切相关。     

Histocompatibility Antigens in Active Chronic Hepatitis and Primary Biliary Cirrhosis

The frequency of antigens HL-A 1 (48%) and HL-A 8 (52%) in 54 patients with active chronic hepatitis from south-east England was significantly higher than in 89 control subjects from the same region (22% and 17% respectively). No correlation could be detected with the age and sex of the patients or with the presence of a particular immunological abnormality but the frequency of HL-A 1 and HL-A 8 was much lower in the nine patients who were positive for HBAg than in the 45 HBAg-negative cases. These results provide further evidence of the importance of genetic factors in active chronic hepatitis. In contrast the frequency of HL-A 1 and HL-A 8 in primary biliary cirrhosis, both in 45 patients from south-east England and in 28 patients from western Scotland, was not significantly different from that found in control groups from the same regions.     

Cell-mediated Immune Response in Primary Biliary Cirrhosis to a Protein Fraction from Human Bile

Cell-mediated immune responses to a protein fraction of human bile have been demonstrated, using the leucocyte migration test, in eight out of 10 patients with primary biliary cirrhosis but in only three out of nine with active chronic hepatitis. In the latter condition sensitization to a liver-specific hepatocellular antigen was found more frequently (five out of nine patients) than in primary biliary cirrhosis (two out of 10). These results, as well as the granuloma formation observed histologically, suggest that the initial bile duct lesion in primary biliary cirrhosis may be associated with a cell-mediated response to antigens—perhaps derived from bile duct epithelial cells—which may be normal constituents of hepatic bile.     

Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells

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Interplay between Innate Immunity and Negative-Strand RNA Viruses: towards a Rational Model

Summary: The discovery of a new class of cytosolic receptors recognizing viral RNA, called the RIG-like receptors (RLRs), has revolutionized our understanding of the interplay between viruses and host cells. A tremendous amount of work has been accumulating to decipher the RNA moieties required for an RLR agonist, the signal transduction pathway leading to activation of the innate immunity orchestrated by type I interferon (IFN), the cellular and viral regulators of this pathway, and the viral inhibitors of the innate immune response. Previous reviews have focused on the RLR signaling pathway and on the negative regulation of the interferon response by viral proteins. The focus of this review is to put this knowledge in the context of the virus replication cycle within a cell. Likewise, there has been an expansion of knowledge about the role of innate immunity in the pathophysiology of viral infection. As a consequence, some discrepancies have arisen between the current models of cell-intrinsic innate immunity and current knowledge of virus biology. This holds particularly true for the nonsegmented negative-strand viruses (Mononegavirales), which paradoxically have been largely used to build presently available models. The aim of this review is to bridge the gap between the virology and innate immunity to favor the rational building of a relevant model(s) describing the interplay between Mononegavirales and the innate immune system.     

Contribution of Zinc Deficiency to Insulin Resistance in Patients with Primary Biliary Cirrhosis

The relationship between metabolic abnormalities of trace elements and insulin resistance has been established. Recent studies have revealed that insulin resistance is associated with autoimmune responses. The purpose of this study was to examine the correlation between zinc or copper metabolism and insulin resistance in patients with primary biliary cirrhosis (PBC). Sixteen patients with PBC were divided into two groups: early and advanced stage disease. The overall value of the homeostasis model assessment of insulin resistance (HOMA-IR) in patients with advanced stage PBC was significantly higher than that in patients with early stage PBC, although the mean value in advanced stage PBC was significantly lower than that in hepatitis C virus (HCV)-related liver cirrhosis. There was an inverse correlation between serum zinc concentrations and HOMA-IR values in patients with PBC, while we found no correlation between serum copper levels and HOMA-IR values. HOMA-IR values were inversely associated with peripheral platelet counts, indicating the relationship between insulin resistance and hepatic fibrosis. These results suggest that zinc deficiency plays important roles of insulin resistance and subsequent hepatic fibrosis in patients with PBC, although insulin resistance in advanced stage PBC was significantly milder than that in HCV-related liver cirrhosis.     

Meta-Analysis Assessment of GP210 and SP100 for the Diagnosis of Primary Biliary Cirrhosis

Purpose

To conduct a systematic review of included studies assessing the association of GP210 and SP100 with the risk of primary biliary cirrhosis (PBC) using meta-analysis.

Methods

Five databases, the Cochrane Library, MEDLINE, VIP, CNKI, WANFANG were used to detect the role of GP210 and SP100 in diagnosis of PBC. Approximately 13,000 participants from several countries were included in this analysis. Meta-DiSc statistical software was used for analysis.

Results

25 studies on GP210 and 21 studies on SP100 were included in the meta-analysis. The DOR, sensitivity, specificity of GP210 in diagnosis of PBC were 24.854 (11.957–51.660), 0.272 (0.257–0.288), 0.985 (0.982–0.988), respectively, and they were 9.133 (4.739–17.600), 0.231 (0.213–0.249), 0.977 (0.973–0.981) for SP100.

Conclusion

Our meta-analysis indicated both GP210 and SP100 had high specificity but low sensitivity in diagnosis of PBC.     

CD47 Promotes Protective Innate and Adaptive Immunity in a Mouse Model of Disseminated Candidiasis

CD47 is a widely expressed receptor that regulates immunity by engaging its counter-receptor SIRPα on phagocytes and its secreted ligand thrombospondin-1. Mice lacking CD47 can exhibit enhanced or impaired host responses to bacterial pathogens, but its role in fungal immunity has not been examined. cd47^-/- mice on a C57BL/6 background showed significantly increased morbidity and mortality following Candida albicans infection when compared with wild-type mice. Despite normal fungal colonization at earlier times, cd47^-/- mice at four days post-infection had increased colonization of brain and kidneys accompanied by stronger inflammatory reactions. Neutrophil and macrophage numbers were significantly elevated in kidneys and neutrophils in the brains of infected cd47^-/- mice. However, no defect in phagocytic activity towards C. albicans was observed in cd47^-/- bone-marrow-derived macrophages, and neutrophil and macrophage killing of C. albicans was not impaired. CD47-deficiency did not alter the early humoral immune response to C. albicans. Th1, Th2, and Th17 population of CD4⁺ T cells were expanded in the spleen, and gene expression profiles of spleen and kidney showed stronger pro-inflammatory signaling in infected cd47^-/- mice. The chemoattractant chemokines MIP-2α and MIP-2β were highly expressed in infected spleens of cd47^-/- mice. G-CSF, GM-CSF, and the inflammasome component NLRP3 were more highly expressed in infected cd47^-/- kidneys than in infected wild-type controls. Circulating pro- (TNF-α, IL-6) and anti-inflammatory cytokines (IL-10) were significantly elevated, but IL-17 was decreased. These data indicate that CD47 plays protective roles against disseminated candidiasis and alters pro-inflammatory and immunosuppressive pathways known to regulate innate and T cell immunity.     

Alteration of Innate Immunity by Donor IL-6 Deficiency in a Presensitized Heart Transplant Model

Engraftment of IL-6 deficient donor into wild-type recipient could significantly improve allograft survival through T cell lineage particularly regulatory T cells (Tregs) in non-sensitized transplant host. However, its effect on innate immune responses remains uncertain. Our data revealed that donor IL-6 deficiency significantly increased infiltration of two subsets of MDSCs (CD11b+Gr1+myeloid-derived suppressor cells), CD11b+Gr1^-low and CD11b+Gr1^-int with strong immunosuppression activity in the transplanted graft. It resulted in a dramatic increase of CD11b+Gr1^-low frequency and a significant decrease of the frequency of CD11b+Gr1^-high and CD4-CD8-NK1.1+ cells in the recipient’s spleen. Unexpectedly, donor IL-6 deficiency could not significantly reduce macrophage frequency irrespective of in the host’s spleen or graft. Taken together, suppression of innate immune effector cells and enhanced activity of regulatory MDSCs contributed to tolerance induction by blockade of IL-6 signaling pathway. The unveiled novel mechanism of targeting IL-6 might shed light on clinical therapeutic application in preventing accelerated allograft rejection for those pre-sensitized transplant recipients.     

The Value of MRI in the Diagnosis of Primary Biliary Cirrhosis and Assessment of Liver Fibrosis

Objectives

To evaluate MRI findings in patients with primary biliary cirrhosis (PBC) and to determine the value of MRI in the diagnosis of PBC and assessment of liver fibrosis.

Materials and Methods

This study reviewed the prevalence of MRI abnormalities seen in 45 PBC patients in the past four years, including 33 patients who underwent liver biopsy. Correlation between the MRI findings and the pathological stage was determined.

Results

There were 33 patients who underwent liver biopsy. Twenty-five patients (75.8%) had non-homogeneous changes in the liver signal intensity, 25 (75.8%) had a periportal halo sign, and 29 (87.9%) had lymphadenopathy. The short axis of the enlarged lymph nodes was a mean of 1.2±0.3 cm. A strong positive correlation was observed between histological stage and the inhomogeneity of liver signal intensity (P<0.001). There were significant differences among the four histological stages based on the periportal halo sign (P=0.034), and the grading of the periportal halo sign was found to be significantly correlated with the histological stage (P<0.001). Grading of the periportal halo sign was significantly different at stage II versus III, and stage III versus IV; no significant difference was found between stages I and II. There were also no significant differences among the four histological states in the occurrence and size of enlarged lymph nodes (P=0.674 and P=0.394).

Conclusion

MRI is valuable in the diagnosis of PBC, and the periportal halo sign and liver signal intensity help to evaluate the degree of liver fibrosis.