Role of viral RNA and lipid in the adverse events associated with the 2010 Southern Hemisphere trivalent influenza vaccine

In Australia, during the 2010 Southern Hemisphere (SH) influenza season, there was an unexpected increase in post-marketing adverse event reports of febrile seizures (FS) in children under 5 years of age shortly after vaccination with the CSL 2010 SH trivalent influenza vaccine (CSL 2010 SH TIV) compared to previous CSL TIVs and other licensed 2010 SH TIVs. In an accompanying study, we described the contribution to these adverse events of the 2010 SH influenza strains as expressed in the CSL 2010 SH TIV using in vitro cytokine/chemokine secretion from whole blood cells and induction of NF-κB activation in HEK293 reporter cells. The aim of the present study was to identify the root cause components that elicited the elevated cytokine/chemokine and NF-κB signature. Our studies demonstrated that the pyrogenic signal was associated with a heat-labile, viral-derived component(s) in the CSL 2010 SH TIV. Further, it was found that viral lipid-mediated delivery of short, fragmented viral RNA was the key trigger for the increased cytokine/chemokine secretion and NF-κB activation. It is likely that the FS reported in children <5 years were due to a combination of the new influenza strains included in the 2010 SH TIV and the CSL standard method of manufacture preserving strain-specific viral components of the new influenza strains (particularly B/Brisbane/60/2008 and to a lesser extent H1N1 A/California/07/2009). These combined to heighten immune activation of innate immune cells, which in a small proportion of children <5 years of age is associated with the occurrence of FS. The data also demonstrates that CSL TIVs formulated with increased levels of splitting agent (TDOC) for the B/Brisbane/60/2008 strain can attenuate the pro-inflammatory signals in vitro, identifying a potential path forward for generating a CSL TIV indicated for use in children <5 years.     

Hiding Lipid Presentation: Viral Interference with CD1d-Restricted Invariant Natural Killer T (iNKT) Cell Activation

The immune system plays a major role in protecting the host against viral infection. Rapid initial protection is conveyed by innate immune cells, while adaptive immunity (including T lymphocytes) requires several days to develop, yet provides high specificity and long-lasting memory. Invariant natural killer T (iNKT) cells are an unusual subset of T lymphocytes, expressing a semi-invariant T cell receptor together with markers of the innate NK cell lineage. Activated iNKT cells can exert direct cytolysis and can rapidly release a variety of immune-polarizing cytokines, thereby regulating the ensuing adaptive immune response. iNKT cells recognize lipids in the context of the antigen-presenting molecule CD1d. Intriguingly, CD1d-restricted iNKT cells appear to play a critical role in anti-viral defense: increased susceptibility to disseminated viral infections is observed both in patients with iNKT cell deficiency as well as in CD1d- and iNKT cell-deficient mice. Moreover, viruses have recently been found to use sophisticated strategies to withstand iNKT cell-mediated elimination. This review focuses on CD1d-restricted lipid presentation and the strategies viruses deploy to subvert this pathway.     

Miocardite fulminante a Legionella pneumophila – a propósito dum caso clínico

Myocarditis is defined as inflammation of the myocardium. The clinical manifestations of myocarditis vary from flu‐like symptoms to fatal fulminant forms.We report the case of a 39‐year‐old woman with a diagnosis of cardiogenic shock caused by fulminant myocarditis. Extracorporeal membrane oxygenation was used as a bridge to recovery.Etiological study revealed Legionella pneumophila serogroup 1 infection.Recovery of biventricular function was seen after treatment with azithromycin.     

Haemophilia management: time to get personal?

Summary. The possibility of alloimmunization in patients receiving protein replacement therapy depends on (at least) three risk factors, which are necessary concomitantly but insufficient alone. The first is the degree of structural difference between the therapeutic protein and the patient’s own endogenous protein, if expressed. Such differences depend on the nature of the disease mutation and the pre‐mutation endogenous protein structure as well as on post‐translational changes and sequence‐engineered alterations in the therapeutic protein. Genetic variations in the recipients’ immune systems comprise the second set of risk determinants for deleterious immune responses. For example, the limited repertoire of MHC class II isomers encoded by a given person’s collection of HLA genes may or may not be able to present a ‘foreign’ peptide(s) produced from the therapeutic protein – following its internalization and proteolytic processing – on the surface of their antigen‐presenting cells (APCs). The third (and least characterized) variable is the presence or absence of immunologic ‘danger signals’ during the display of foreign‐peptide/MHC‐complexes on APCs. A choice between existing therapeutic products or the manufacture of new proteins, which may be less immunogenic in some patients or patient populations, may require prior definition of the first two of these variables. This leads then to the possibility of developing personalized therapies for disorders due to genetic deficiencies in endogenous proteins, such as haemophilia A and B. [Correction made after online publication 11 July 2011: several critical corrections have been made to the abstract].     

A new SEMA7A variant found in Native Americans with alloantibody

Background and Objectives John Milton Hagen (JMH) antigens are carried by Semaphorin 7A that plays important roles in the nervous system and the immune responses. Its role on the erythrocytes is unclear. Over the years, few samples were referred to our Immunohaematology Reference Laboratory to elucidate their JMH status. Materials and Methods Seven blood samples with antibodies compatible with JMH1‐negative red cells were studied at the molecular level to identify polymorphisms and explain the JMH diversity observed. Four samples were of Native American background and three were Caucasians. Molecular analyses of the SEMA7A were undertaken, and soluble form of recombinant Sema7A proteins was produced to characterize the antibodies. Results Sequencing of the cDNA showed a polymorphism in SEMA7A exon 9 at position 1040 (G>T) in the four Native American samples. Caucasians had a normal sequence. This polymorphism precludes a change at position 347 where an Arg is replaced by a Leu. Plasma was assayed in ELISA on wild‐type Sema7A_Arg347 and variant Sema7A_Leu347 proteins. Results clearly indicated a specific recognition of the antibody produced by the Native Americans for the wild‐type Sema7A_Arg347 protein and not the variant one. Conclusion A new SEMA7A variant was identified in this study. The antibody present in the Native American plasma samples should be considered as an alloantibody because it recognizes the wild‐type protein.     

+49A/G polymorphism of cytotoxic T‐lymphocyte antigen 4 gene in type 1 autoimmune hepatitis and primary biliary cirrhosis: A meta‐analysis

Aim: Recently, the associations of +49A/G polymorphisms of cytotoxic T‐lymphocyte antigen 4 (CTLA‐4) gene with the susceptibility to type 1 autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) have been reported; however these associations are yet to be fully elucidated. This study aimed to identify the associations of CTLA‐4 gene +49A/G polymorphisms with the susceptibility to type 1 AIH and PBC by using a meta‐analysis. Methods: PubMed was searched by using the following keywords: “autoimmune hepatitis AND (polymorphism OR polymorphisms)” or “primary biliary cirrhosis AND (polymorphism OR polymorphisms)”. Meta‐analyses of five studies including 526 patients with type 1 AIH and 631 controls and seven studies including 1500 patients with PBC and 2345 controls were performed. Results: For type 1 AIH, the odds ratio (OR) of G allele was 1.26 [95% confidence interval (CI) 1.06–1.51] although G/G homozygosity was not associated with the susceptibility to type 1 AIH. On the other hand, the OR of A/A homozygosity for type 1 AIH was 0.66 (95% CI 0.50–0.86). For PBC, the OR of G allele was 1.20 (95% CI 1.06–1.34). Furthermore, G/G homozygosity was significantly associated with the susceptibility to PBC (OR 1.29, 95% CI 1.01–1.66). The OR of A/A homozygosity for PBC was 0.81 (95% CI 0.70–0.94). Conclusions: This study suggests that CTLA‐4 gene +49A/G polymorphisms may be associated with the susceptibility to type 1 AIH and PBC. Especially, while G/G genotype may be associated with the susceptibility to PBC, A/A genotype may be protective against type 1 AIH and PBC.     

胎膜早破患者胎儿心电图分析

目的分析孕妇胎膜早破对胎儿心脏的影响。方法根据342例孕妇胎膜早破时间不同分为3组,分别为6-12h组,〉24h组及〉36h组,再对孕妇胎儿心电图改变进行对照分析。结果胎膜早破时间越长,对胎儿影响越大,出现异常胎儿心电图改变几率越大,预后亦较差。结论孕妇胎膜早破时间不同对胎儿心脏有不同程度影响,应及早治疗,减轻胎儿及新生儿病死率。     

Removal of Polymeric Plutonium from Mice by Combined Therapy with the Calcium Chelate and Penta-ethyl Ester of DTPA

Summary

C57BL/6 mice were exposed to either ionizing radiation or actinomycin at the peak and nadir of jejunal crypt cell mitotic activity. Animals exposed at the peak were more sensitive than animals exposed at the nadir. Conversely, animals treated with actinomycin D were slightly more sensitive at the nadir. These observations suggest that studies of the combined lethal effects of ionizing radiation and actinomycin D may be complicated by the change in sensitivity of normal tissues to either treatment under the influence of a circadian variable.     

Shark variable new antigen receptor biologics – a novel technology platform for therapeutic drug development

Introduction: Biologics drugs have succeeded in achieving a commercial dominance in the global market for new therapies and large pharmaceutical companies' interest remains strong through a continued commitment to pipeline development. It is not surprising, therefore, that next-generation biologics, particularly antibody-like scaffolds that offer many of the advantages of the original biologic drugs but in simplified formats, have entered the clinic as competing substitute therapeutic products, to capture market share.

Areas covered: Specifically, this paper will position shark-derived variable new antigen receptors (VNARs) within an overview of the existing biologics landscape including the growth, diversity and success to date of alternative scaffolds. The intention is not to provide a comprehensive review of biologics as a whole but to discuss the main competing single-domain technologies and the exciting therapeutic potential of VNAR domains as clinical candidates within this context.

Expert opinion: The inherent ability to specifically bind target and intervene in disease-related biological processes, while reducing off-site toxicity, makes mAbs an effective, potent and now proven class of therapeutics. There are, however, limitations to these ‘magic bullets’. Their size and complexity can restrict their utility in certain diseases types and disease locations. In contrast, a number of so-called alternative scaffolds, derived from both immunoglobulin- and non-immunoglobulin-based sources have been developed with real potential to overcome many of the shortcomings documented for mAb treatments. Unlike competing approaches such as Darpins and Affibodies, we now know that shark VNAR domains (like camel VHH nanobody domains), are an integral part of the adaptive immune system of these animals and have evolved naturally (but from very different starting molecules) to exhibit high affinity and selectivity for target. In addition, and again influenced by the environment in which they have evolved naturally, their small size, simple architecture, high solubility and stability, deliver additional flexibility compared to classical antibodies (and many non-natural alternative scaffolds), thereby providing an attractive basis for particular clinical indications where these attributes may offer advantages.