Background
Patients with a previous history of hypersensitivity reaction (HSR) to iodinated contrast media (ICM) are at high risk of the development of HSR to ICM. Many studies have tried to evaluate ...the diagnostic potential of skin tests in this population but have not yet reached a common conclusion. We investigated the role of skin tests in patients with HSR to ICM in terms of positive rate, cross‐reactivity rate, and tolerability to skin test‐negative ICM according to the type of HSR.
Methods
We performed literature searches of the MEDLINE and EMBASE databases and included studies where skin tests were performed in patients with HSR to ICM, with extractable outcomes. Outcomes were pooled using a random‐effects model.
Results
Twenty‐one studies were included. Pooled per‐patient positive rates of skin tests were 17% (95% CI, 10–26%) in patients with immediate HSR, and up to 52% (95% CI, 31–72%) when confined to severe immediate HSR. Among patients with nonimmediate HSR, the positive rate was 26% (95% CI, 15–41%). The pooled per‐patient cross‐reactivity rate was higher in nonimmediate HSR (68%; 95% CI, 48–83%) than that in immediate HSR (39%; 95% CI, 29–50%). Median per‐test cross‐reactivity rates between pairs of ICM were 7% (IQR, 6–9%) in immediate HSR and 38% (IQR, 22–51%) in nonimmediate HSR. Pooled per‐patient recurrence rates of HSR to skin test‐negative ICM were 7% (95% CI, 4–14%) in immediate HSR and 35% (95% CI, 19–55%) in nonimmediate HSR.
Conclusion
Skin tests may be helpful in diagnosing and managing patients with HSR to ICM, especially in patients with severe immediate HSR.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The high specificity of antibodies for their antigen allows a fine discrimination of target conformations and post-translational modifications, making antibodies the first choice tool to interrogate ...the proteome. We describe here an approach based on a large-scale intracellular expression and selection of antibody fragments in eukaryotic cells, so-called intrabodies, and the subsequent identification of their natural target within living cell. Starting from a phenotypic trait, this integrated system allows the identification of new therapeutic targets together with their companion inhibitory intrabody. We applied this system in a model of allergy and inflammation. We first cloned a large and highly diverse intrabody library both in a plasmid and a retroviral eukaryotic expression vector. After transfection in the RBL-2H3 rat basophilic leukemia cell line, we performed seven rounds of selection to isolate cells displaying a defect in FcεRI-induced degranulation. We used high throughput sequencing to identify intrabody sequences enriched during the course of selection. Only one intrabody was common to both plasmid and retroviral selections, and was used to capture and identify its target from cell extracts. Mass spectrometry analysis identified protein RGD1311164 (C12orf4), with no previously described function. Our data demonstrate that RGD1311164 is a cytoplasmic protein implicated in the early signaling events following FcεRI-induced cell activation. This work illustrates the strength of the intrabody-based in-cell selection, which allowed the identification of a new player in mast cell activation together with its specific inhibitor intrabody.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Innate immune responses provide the host with an early protection barrier against infectious agents, including viruses, and help shape the nature and quality of the subsequent adaptive immune ...responses of the host. Expression of ISG15 (UCRP), a ubiquitin-like protein, and protein ISGylation are highly increased upon viral infection. We have identified UBP43 (USP18) as an ISG15 deconjugating protease. Protein ISGylation is enhanced in cells deficient in UBP43 (ref. 6). Here we have examined the role of UBP43, encoded by the gene Usp18, in innate immunity to virus infection. Usp18−/− mice were resistant to the fatal lymphocytic choriomeningitis and myeloencephalitis that developed in wild-type mice after intracerebral inoculation with lymphocytic choriomeningitis virus (LCMV) or vesicular stomatitis virus (VSV), respectively. Survival of Usp18−/− mice after intracerebral LCMV infection correlated with a severe inhibition of LCMV RNA replication and antigen expression in the brain and increased levels of protein ISGylation. Consistent with these findings, mouse embryonic fibroblasts (MEF) and bone marrow-derived macrophages from Usp18−/− mice showed restricted LCMV replication. Moreover, MEF from Usp18−/− mice showed enhanced interferon-mediated resistance to the cytopathic effect caused by VSV and Sindbis virus (SNV). This report provides the first direct evidence that the ISG15 protease UBP43 and possibly protein ISGylation have a role in innate immunity against viral infection.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Hepatitis C virus (HCV) is remarkably efficient at establishing persistent infection, suggesting that it has evolved one or
more strategies aimed at evading the host immune response. T cell ...responses, including interferon-γ production, are severely
suppressed in chronic HCV patients. The HCV core protein has been previously shown to circulate in the bloodstream of HCV-infected
patients and inhibit host immunity through an interaction with gC1qR. To determine the role of the HCV core-gC1qR interaction
in modulation of inflammatory cytokine production, we examined interleukin (IL)-12 production, which is critical for the induction
of interferon-γ synthesis, in lipopolysaccharide-stimulated human monocyte/macrophages. We found that core protein binds the
gC1qR displayed on the cell surface of monocyte/macrophages and inhibits the production of IL-12p70 upon lipopolysaccharide
stimulation. This inhibition was found to be selective in that HCV core failed to affect the production of IL-6, IL-8, IL-1β,
and tumor necrosis factor α. In addition, suppression of IL-12 production by core protein occurred at the transcriptional
level by inhibition of IL-12p40 mRNA synthesis. Importantly, core-induced inhibition of IL-12p40 mRNA synthesis resulted from impaired activation of AP-1 rather than enhanced IL-10 production. These results suggest that
the HCV core-gC1qR interaction may play a pivotal role in establishing persistent infection by dampening T H 1 responses.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The effects of betel nut chewing, smoking and alcohol on the occurrence of leukoplakia and its malignant transformation to oral carcinoma were quantified in a leukoplakia cohort (n = 435) from one ...medical centre between 1988 and 1998 in Taiwan. Sixty oral carcinomas were ascertained in this cohort. A case-control study within the leukoplakia cohort was used to study, risk factors. Using the Weibull survival model, the incidence of malignant transformation of leukoplakia was shown to increase with follow-up years. After adjustment for other relevant risk factors, betel nut chewing (adjusted odds ratio (OR) = 4.59; 95% confidence interval (CI) 1.25-16.86) remained a significant risk factor for malignant transformation. Results from the case-control study showed that the adjusted odds ratios for betel nut chewing and smoking on the occurrence of leukoplakia were 17.43 (95% CI 1.94-156.27) and 3.22 (95% CI 1.06-9.78), respectively. Similar findings were observed when daily frequency and duration were taken into account. This implies that cessation of smoking may reduce by 36% leukoplakia cases, while elimination of betel nuts may prevent 62% of leukoplakia and 26% of malignant transformation to oral carcinoma in the underlying population.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Opsonization of particulate pathogens by antibodies and complement can lead to their binding to the complement receptor (CR1), specific for C3b, on primate erythrocytes (E). This process of immune ...adherence may play a role in immunologic defense by immobilizing bacteria and viruses, thus preventing them from leaving the bloodstream to invade susceptible tissue and organs. Immune adherence of C3b‐opsonized and immune complexed pathogens to E may also facilitate their transfer to, and destruction by, fixed tissue macrophages. We have used mAbs specific for CR1 crosslinked with pathogen specific mAbs to generate heteropolymers (HP) which can bind a wide range of substrates to primate erythrocytes. Both prototype and bonafide pathogens bound to primate E via HP are handled in the circulation of non‐human primates in a manner which appears to be virtually identical to the mechanism by which C3b‐opsonized substrates bound to E CR1 are cleared. In this process of focused phagocytosis, Fc receptors on the phagocytic cell engage the E‐bound complex, CR1 is removed by proteolysis, and the entire immune complex and CR1 are internalized while sparing the E. It may be possible to use HP to target pathogens in the bloodstream in a wide range of therapeutic applications.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Somatic cell genetic alterations are a hallmark of tumor development and progression. Although various technologies have been developed and utilized to identify genetic aberrations, identifying ...genetic translocations at the chromosomal level is still a challenging task. High density SNP microarrays are useful to measure DNA copy number variation (CNV) across the genome. Utilizing SNP array data of cancer cell lines and patient samples, we evaluated the CNV and copy number breakpoints for several known fusion genes implicated in tumorigenesis. This analysis demonstrated the potential utility of SNP array data for the prediction of genetic aberrations via translocations based on identifying copy number breakpoints within the target genes. Genome-wide analysis was also performed to identify genes harboring copy number breakpoints across 820 cancer cell lines. Candidate oncogenes were identified that are linked to potential translocations in specific cancer cell lines.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Hepatitis C virus (HCV) is remarkable for its ability to establish persistent infection. Studies suggest that HCV core protein modulates immune responses to viral infection and can bind Fas receptor ...in vitro. To further examine the role of HCV core protein in Fas signaling, full-length (aa 1-192) and truncated (aa 1-152) HCV core proteins were expressed in Jurkat lymphocytes and cells were assayed for apoptotic response, caspase activation, and Fas activation. Jurkat expressing full-length but not truncated core protein exhibited ligand-independent apoptosis. Cytoplasmic targeting of truncated core protein recapitulated its ability to induce apoptosis. Activation of caspases 8 and 3 was necessary and sufficient for full-length core to induce apoptosis. Jurkat cells expressing full-length but not truncated core protein induced Fas receptor aggregation. HCV core activates apoptotic pathways in Jurkat via Fas and requires cytoplasmic localization of core. Infection of host lymphocytes by HCV may alter apoptotic signaling and skew host responses to acute infection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Summary
Cytotoxic T lymphocytes (CTL) recognize short antigenic peptides in association with class I MHC molecules at the cell surface. Newly synthesized viral polypeptides are processed in the ...cytoplasm and the fragments of antigen are transported into the endoplasmic reticulum (ER) via a peptide transporter where they complex with nascent class I molecules. The peptide‐MHC complex is transported to the cell surface and presented to CTL. Sequence analysis of endogenously expressed, MHC‐associated self or viral antigens indicates that the naturally processed peptides bound to class I MHC molecules are in general 9 ± 1 residues long. Peptides bound to specific class I MHC molecules have in common allele‐specific motifs of conserved residues. The motif for the class I K
d
molecules has been shown to be nine or 10 residues with the sequence X‐Tyr‐(X)6‐I/L or X‐Tyr‐(X)7‐I/L. The Tyr residue at the second position and the I/L residue at the ninth position are allele‐specific anchor residues which appear to be required for binding of the peptide to K
d
. To examine the stringency of the requirement for Tyr at the second position, we have performed saturation mutagenesis of a minigene encoding the class I K
d
‐restricted influenza HA210‐219 site at the Tyr residue 211. A series of 10 mutants was tested for effects on target‐cell sensitization. Most amino acid substitutions for the Tyr residue resulted in a loss of endogenous peptide recognition by HA210‐219 reactive CTL, consistent with the critical role of the Tyr at the second position for interaction with K
d
molecules. One mutant gene‐product encoding a His substitution for the Tyr residue was recognized by CTL. However, the corresponding synthetic peptide containing a His substitution at the dominant anchor position bound only weakly to K
d
, and target cells treated with the peptide were poorly recognized by CTL. The endogenous His‐containing peptide was also less stably associated with class I MHC K
d
molecules at the cell surface than the wild‐type Tyr peptide. These data indicate that endogenous antigenic peptides may bind newly‐synthesized class I MHC molecules in the ER more efficiently than fully formed class I molecules at the cell surface and that endogenous peptides may dissociate from class I MHC molecules at different rates. The implications of these findings for CTL recognition and epitope mapping are discussed.
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