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Aicardi- Goutières syndrome ( AGS) is a genetically determined disorder, affecting most particularly the brain and the skin, characterized by the inappropriate induction of a type I interferon-mediated immune response. In most, but not all, cases the condition is severe, with a high associated morbidity and mortality. A number of important recent advances have helped to elucidate the biology of the AGS-related proteins, thus providing considerable insight into disease pathology. In this study, we outline the clinical phenotype of AGS, paying particular attention to factors relevant to therapeutic intervention. We then discuss the pathogenesis of AGS from a molecular and cell biology perspective. Finally, we suggest possible treatment strategies in light of these emerging insights. [ABSTRACT FROM AUTHOR]

Deficiency of mannose-binding lectin (MBL) has been suggested to influence duration of febrile neutropenia and prognosis in paediatric oncology patients. However, there is no consensus on the definition of MBL deficiency. In a cohort of children with cancer, we investigated (i) how to determine MBL deficiency and (ii) whether MBL is a prognostic factor for disease severity. In 222 paediatric oncology patients, 92 healthy children and 194 healthy adults, MBL plasma levels and MBL2 genotype (wild-type: A, variant: O) were determined. Event-free survival (EFS), overall survival (OS) and paediatric intensive care unit (PICU) admissions were recorded prospectively. In febrile neutropenic patients admitted to the PICU, disease severity was assessed by clinical, microbiological and laboratory parameters. An optimal cut-off value for MBL deficiency was determined to be < 0·20 µg/ml. Wild-type MBL2 genotype patients, including the XA/XA haplotype, had increased MBL levels compared to healthy individuals. MBL deficiency was associated with decreased EFS ( P = 0·03), but not with need for PICU admission. A trend for a twice increased frequency of septic shock (80% versus 38%, P = 0·14), multiple organ failure (40% versus 17%, P = 0·27) and death (40% versus 21%, P = 0·27) was observed in the absence of microbiological findings. MBL deficiency was associated with decreased EFS and possibly with an increased severity of disease during PICU admission after febrile neutropenia in the absence of any association with microbiological findings. These findings suggest prognosis to be worse in MBL-deficient compared to MBL-sufficient paediatric oncology patients. [ABSTRACT FROM AUTHOR]

High-dose intravenous immunoglobulin (IVIg) preparations are used currently for the treatment of autoimmune or inflammatory diseases. Despite numerous studies demonstrating efficacy, the precise mode of action of IVIg remains unclear. Paradoxically, IgG can exert both pro- and anti-inflammatory activities, depending on its concentration. The proinflammatory activity of low-dose IVIg requires complement activation or binding of the Fc fragment of IgG to IgG-specific receptors (FcγR) on innate immune effector cells. In contrast, when administered in high concentrations, IVIg has anti-inflammatory properties. How this anti-inflammatory effect is mediated has not yet been elucidated fully, and several mutually non-exclusive mechanisms have been proposed. This paper represents the proceedings of a session entitled ‘IVIg – Understanding properties and mechanisms’ at the 6th International Immunoglobulin Symposium that was held in Interlaken on 26–28 March 2009. The presentations addressed how IgG may affect the cellular compartment, evidence for IVIg-mediated scavenging of complement fragments, the role of the dimeric fraction of IVIg, the anti-inflammatory properties of the minor fraction of sialylated IgG molecules, and the genetic organization and variation in FcγRs. These findings demonstrate the considerable progress that has been made in understanding the mechanisms of action of IVIgs, and may influence future perspectives in the field of Ig therapy. [ABSTRACT FROM AUTHOR]

We investigated whether deficiency of mannose-binding lectin (MBL), a component of innate immunity, is associated with neonatal pneumonia and sepsis during the first 72 h, i.e. early onset, and during the first month after birth. In 88 neonatal intensive care patients (71 premature), MBL2 genotype and MBL plasma levels at birth were determined prospectively by Taqman analysis and enzyme-linked immunosorbent assay, respectively. Thirty-five neonates (40%) had low, i.e. ≤ 0·7 µg/ml, MBL plasma levels at birth. Median (interquartile range) MBL plasma levels in 32 no early-onset sepsis (EOS) cases, 44 possible EOS cases and 11 EOS cases were 1·57 (0·57–2·67) µg/ml, 1·05 (0·41–1·70) µg/ml and 0·20 (0·10–0·77) µg/ml, respectively ( P < 0·01). During the first month, 28 neonates (32%) had no infection, 49 (55%) had suspected infection, five (6%) had pneumonia and six (7%) had culture-proven sepsis. Low MBL levels at birth were associated both with an increased risk of developing pneumonia (OR: 12·0; 95% CI: 1·1–126·1; P = 0·04) and culture-proven sepsis (OR: 15·0; 95% CI: 1·5–151·3; P = 0·02). These results were confirmed by genetic analysis of MBL deficiency. Low MBL levels at birth are associated with an increased risk of early-onset sepsis, culture-proven sepsis and pneumonia during the first month of life. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is an acute vasculitis occurring in young children. Its aetiology is unknown, but an infectious agent is assumed. Increased levels of proinflammatory cytokines and chemokines have been reported in KD. Genetic variation in these genes and the receptors for these genes could influence the regulation of cytokines and chemokines. In a case–control study of 170 Dutch Caucasian KD patients and 300 healthy Dutch Caucasian controls, common genetic variants in chemokine receptor genes CCR3, CCR2, CCR5, CX3CR1, CXCR1 and CXCR2 were analysed . Of the eight studied single nucleotide polymorphisms (SNPs) in the CCR3–CCR2–CCR5 gene cluster, four showed a significant association with susceptibility to KD. Moreover the CCR5-Δ32 was observed with an allele frequency of 10·7% in the control population compared to 6·5% in the KD patients ( P = 0·04). Two haplotypes of the CCR3–CCR2–CCR5 gene-cluster appear to be at risk haplotypes for KD and one a protective haplotype. No association was observed with the studied SNPs in CX3CR1, CXCR1 and CXCR2. In conclusion, in a Dutch cohort of KD patients an association of KD occurrence with common genetic variants in the chemokine receptor gene-cluster CCR3–CCR2–CCR5 was observed. [ABSTRACT FROM AUTHOR]

Mannose-binding lectin (MBL) is a component of innate immunity and thus particularly important in neonates in whom adaptive immunity is not yet completely developed. Promoter polymorphisms and structural exon-1 mutations in the MBL2 gene cause reduced or deficient MBL plasma concentrations. The aim of our study was to determine the prevalence of MBL deficiency in neonates admitted to the neonatal intensive care unit (NICU). Eighty-five NICU patients (69 premature) were included in the study. We measured MBL concentrations in umbilical cord and neonatal blood within 24 h after birth by ELISA technique. MBL2 genotypes ( n = 67) were determined by Taqman analysis. MBL concentrations were measured longitudinally during three weeks in 26 premature neonates. The association between pre- and intra-partum clinical data and MBL concentrations was investigated. At birth, 29 (42%) premature and six (38%) term neonates had MBL plasma concentrations ≤ 0·7 µg/ml which was regarded as deficient. Twenty-one (38%) premature and four (36%) term neonates had variant MBL2 haplotypes, corresponding to exon-1 mutations and the LXPA haplotype. MBL concentrations increased over time in neonates with wild-type MBL2 haplotypes, but not in neonates with variant haplotypes. Low MBL plasma concentrations were related to lower gestational age and variant MBL2 haplotypes. Umbilical cord and neonatal MBL plasma concentrations appeared to be similar. In conclusion, almost half of our NICU patients, especially the premature ones, were MBL-deficient at birth. These infants may be at increased risk of neonatal infections. MBL concentration can reliably be measured in umbilical cord blood and it is positively correlated with gestational and postnatal age. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD) is an acute febrile syndrome of childhood, characterized by vasculitis of the medium-sized arteries. White blood cell counts and the inflammatory parameter C-reactive protein (CRP) are known to be elevated in the acute phase of the disease. In this study we investigated the course of inflammatory cell type-specific parameters in KD over a longer period of time. Plasma levels of human neutrophil elastase (HNE), matrix metalloproteinases-2 and -9 (MMP2, MMP9), and neutrophil gelatinase-associated lipocalin (NGAL), macrophage neopterin and CRP were measured. Plasma samples were collected in the acute, subacute and early convalescent stage, and three months after the onset of disease. Median CRP and neopterin normalized within two weeks. In contrast, six weeks and three months after onset of disease, levels of HNE were still elevated, with median values of 163 ng/ml and 156 ng/ml, respectively (control children median< 50 ng/ml; for all time-points P < 0·0001). Values of NGAL correlated with the levels of HNE ( r = 0·39, P = 0·013). These results demonstrate a longer state of neutrophil activation in KD than was previously assumed. The potential relationship between this prolonged neutrophil activation, coronary artery lesion formation and their persistence, as well as the risk of premature atherosclerosis warrants further evaluation. [ABSTRACT FROM AUTHOR]

Chronic granulomatous disease (CGD) is a clinical syndrome of recurrent bacterial and fungal infections caused by a rare disorder of phagocytic cells. In CGD, the phagocytes are unable to generate oxygen radicals after stimulation of these cells, due to a defect in the NADPH oxidase system. This NADPH oxidase is a multicomponent enzyme of at least four subunits, of which the β-subunit of cytochrome b558, gp91-phox, is encoded by an X-linked gene (called CYBB). We report here five patients from two families; in each family we found a different mutation in the promoter region of CYBB. Both mutations prevented the expression of gp91-phox in the patients' neutrophils and thus caused inability of these cells to generate oxygen radicals. However, the mutations left the gp91-phox expression and the function of the NADPH oxidase in the patients' eosinophils intact. The relatively mild course of the CGD in these patients can probably be attributed to the fact that the eosinophils have retained their oxidative capacity. Furthermore, our results indicate that neutrophils and eosinophils differ in their regulation of gp91-phox expression. [ABSTRACT FROM AUTHOR]

Kawasaki disease (KD), an acute febrile disease in children of unknown etiology, is characterized by a vasculitis that may result in coronary artery aneurysms (CAAs). In new patients with KD, a selective and prolonged T cell unresponsiveness to activation via the T cell antigen receptor CD3 was observed, whereas proliferation to other stimuli was intact. This 'split T cell anergy' delineated KD from other pediatric infections and autoimmune diseases and correlated with CAA formation (P<.001). A transient immune dysfunction was also suggested by an incomplete responsiveness to measles-mumps-rubella (MMR) vaccination in patients with KD versus controls (P<.0001; odds ratio, 15.6; 95% confidence interval, 4.8-51.1), which was overcome by revaccination(s). The reduced responsiveness to MMR in patients with KD suggests a subtle and predetermining immune dysfunction. An inherent immaturity to clear certain antigens may be an important cause that precipitates KD and the immune dysregulation during acute disease. [ABSTRACT FROM AUTHOR]