Case-control study of Sichuan and Hong Kong children with melamine-associated renal stones: renal ultrasonography and urinary IL-8 and MCP-1 levels

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Use of humanised mice to study antiviral activity of human γδ-T cells against influenza A viruses

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Family History of Early Infant Death Correlates with Earlier Age at Diagnosis But Not Shorter Time to Diagnosis for Severe Combined Immunodeficiency

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Essential Role of NK Cells in IgG Therapy for Experimental Autoimmune Encephalomyelitis

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Severe mycobacterial infections in two pairs of Chinese siblings with interleukin-12 receptor β1 deficiency

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Autosomal Dominant Gain-of-function STAT1 Mutation is a Novel Genetic Etiology of Penicillium Marneffei Infection

Symposium / Free Paper 4: ImmunologyConference Theme: Inflammatory Basis of Perinatal and Childhood DiseasesBackground: Penicillium marneffei infection is indigenous to Southeast Asia. Majority of cases occur in patients with AIDS and secondary immunodeficiencies. We previously reported 4 HIV-negative children with chronic mucocutaneous candidiasis (CMC) and severe penicilliosis. Hyper-IgE syndrome was diagnosed in one of them, but extensive genetic studies on IL12-IFNγ axis, CARD9 and AIRE were unrevealing for the rest. Recently, STAT1 hyperphosphorylation causing defective Th1 and Th17 immunity is recognized as a cause of CMC. Objective: To investigate the genetic and functional defects of STAT1 signaling in children affected by penicilliosis. Methods: Targeted sequencing of STAT1 gene or total exome sequencing was performed in 3 patients with CMC and penicilliosis. PBMCs were isolated from patients and normal controls. Intracellular STAT1 phosphorylation (pSTAT1) towards interferon-α and interferon-γ stimulation was evaluated by flow cytometry. Cytokine production in PBMCs towards PMA and ionomycin stimulation was assessed. PBMCs were co-cultured with live Candida albicans and P. marneffei to evaluate interferon-γ response. Results: Heterozygous STAT1 missense mutations were identified in all 3 patients. Two mutations were located in the coiled-coil domain (P1 and P2) and one in the DNA-binding domain (P3). All 3 patients recovered from penicilliosis, but P1 eventually died of fulminant aspergillosis. The percentage of pSTAT1-positive PBMCs induced by interferon-α and interferon-γ was significantly higher in all 3 patients than normal controls, indicating that they had gain-of-function mutations. PBMCs from all patients displayed defective interferon-γ and interleukin-17 production towards PMA and PMA plus ionomycin, respectively. Interferon-γ production induced by C. albicans and P. marneffei in P2 was significantly lower than normal controls. Conclusions: For the first time, we demonstrated STAT1 gain-of-function mutation as an important and novel genetic etiology of invasive mycosis including penicilliosis and aspergillosis. Penicilliosis should be regarded as an indicator disease for primary immunodeficiencies in children without HIV infection unless proven otherwise.published_or_final_versio

Construction and evaluation of rats’ tolerogenic dendritic cells (DC) induced by NF-κB Decoy method

Aims: To construct and evaluate rats’ tolerogenic dendritic cells (DC) through induction by NF-κB Decoy method.Methods: GM-CSF and IL-4 were used to transform rats’s monocytes into DC, and DC were stimulated with LPS, NF-κB Decoy ODN, and loaded with Bovine TypeⅡCollagen. The following methods were employed to phenotype DC: 1) Observation of cell morphology; 2) Evaluation of cell viability using trypan blue staining; 3) Purity determination of DC through detection of specific markers OX-62; 4) Evaluation of mature state of DC via the determination of the expression of CD80 and CD86; 5) Determination of stimulation capability towards the proliferation of lymphocyte and the secretion of INF-r and IL-10.Results: The activity of DC was more than 92%, and the expression of OX-62 was more than 70%. Most of DC exhibited the phenotype of CD80+/CD86-. Compared with control group and LPS-stimulation group, the less mature adhered cells and hairlike DC were observed in NF-κB decoy group. Significant reduction (p<0.05) was observed for the positive expression and extension of CD80 and CD86 in cell surface. After loaded with calf type II collagen, the low expression of CD80 and CD86 remains to be existed. The stimulation capability of DC towards lymphocyte in NF-κB decoy group was lower than that in control group (p<0.05) and LPS stimulation group (p<0.05).Conclusion: NF-κB Decoy ODN method can be successfully applied for construct rats’ tolerogenic dendritic cells (DC) with stable morphology and phenotype. The tolerogenic DC exhibited immature immune phenotype, and low capability to stimulate lymphocytes.Keywords: dendritic cells (DC), NF-κB Decoy ODN, calf type II collage

Influenza Virus-Induced Lung Inflammation Was Modulated by Cigarette Smoke Exposure in Mice

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Natural killer cells become tolerogenic after interaction with apoptotic cells

NK cells are effectors in innate immunity and also participate in immunoregulation through the release of TGF-β1 and lysis of activated/autoreactive T cells. Apoptotic cells (AC) have been shown to induce tolerogenic properties in innate immune cells, including macrophages and dendritic cells, but not NK cells. In this study, we demonstrated that after interaction with AC, NK cells released TGF-β1, which in turn suppressed the production of IFN-γ by NK cells upon IL-12 and IgG activation.We further identified phosphatidylserine as a potential target on AC for the NK cells, as phosphatidylserine could stimulate NK cells to release TGF-β1, which in turn suppressed CD4+ T-cell proliferation and activation. Moreover, AC-treated NK cells displayed cytotoxicity against autologous-activated CD4 + T cells by upregulating NKp46. This lysis occurred in part through the NKp46-vimentin pathway, as activated CD4+ T cells expressed vimentin on the cell surface and blocking of vimentin or NKp46, but not other NK-cell receptors, significantly suppressed the NK-cell cytotoxicity.We report here a novel interaction between NK cells and AC, resulting in the tolerogenic properties of NK cells required for immune contraction. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.postprin

The Therapeutic Effect of Pamidronate on Lethal Avian Influenza A H7N9 Virus Infected Humanized Mice

A novel avian influenza virus H7N9 infection occurred among human populations since 2013. Although the lack of sustained human-to-human transmission limited the epidemics caused by H7N9, the late presentation of most patients and the emergence of neuraminidase-resistant strains made the development of novel antiviral strategy against H7N9 in urgent demands. In this study, we evaluated the potential of pamidronate, a pharmacological phosphoantigen that can specifically boost human Vδ2-T-cell, on treating H7N9 virus-infected humanized mice. Our results showed that intraperitoneal injection of pamidronate could potently decrease the morbidity and mortality of H7N9-infected mice through controlling both viral replication and inflammation in affected lungs. More importantly, pamidronate treatment starting from 3 days after infection could still significantly ameliorate the severity of diseases in infected mice and improve their survival chance, whereas orally oseltamivir treatment starting at the same time showed no therapeutic effects. As for the mechanisms underlying pamidronate-based therapy, our in vitro data demonstrated that its antiviral effects were partly mediated by IFN-γ secreted from human Vδ2-T cells. Meanwhile, human Vδ2-T cells could directly kill virus-infected host cells in a perforin-, granzyme B- and CD137-dependent manner. As pamidronate has been used for osteoporosis treatment for more than 20 years, pamidronate-based therapy represents for a safe and readily available option for clinical trials to treat H7N9 infection.published_or_final_versio