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Autosomal recessive mutations in Inducible T Cell Costimulator Ligand (ICOSLG) result in a combined immunodeficiency syndrome of humans, saliently marked by recurrent respiratory tract infections and significant disease with DNA-based viruses at epithelial barriers, including human papillomavirus (HPV). These features are also seen in persons with loss of function of the complementary gene, ICOS. The infection phenotypes associated with these natural experiments disclose a critical role of the corresponding proteins, ICOSL and ICOS, in human immunity at mucocutaneous barriers. Here, we review the syndromes of ICOSL and ICOS deficiency and explore the mechanisms by which the ICOSL:ICOS axis mediates epithelial host defenses., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The binary view of inborn errors of immunity classified as either autoinflammatory conditions or primary immunodeficiency in the strict sense, that is, increased susceptibility to infection is challenged by the description of recent inborn errors of immunity (IEI) triggers leading to activation and disruption of cell death pathways, play a major part in the pathophysiology of infection and autoinflammation. In addition, molecules with a double role in the extracellular versus intracellular milieu add to the complexity. In all, in-depth study of human inborn errors of immunity will continue to instruct us on fundamental immunology and lead to novel therapeutic targets and approaches that can be used in other monogenic and polygenic/complex immune disorders., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Human germline MALT1 deficiency is an inborn error of immunity characterized by recurrent bacterial, viral, and fungal infections, periodontal disease, enteropathy, dermatitis, and failure to thrive. The number of identified MALT1-deficient patients have greatly increased in the past two years, which has significantly improved our understanding of the clinical features of this disorder. Patients frequently experience infections affecting the respiratory, skin, gastrointestinal, and blood systems. The most frequently detected pathogens are Staphylococcus aureus, Candida albicans, and cytomegalovirus. Enhanced susceptibility to S. aureus and C. albicans is likely due to impaired Th17 immunity, similar to STAT3 and IL-17 pathway deficiencies., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Drug transporters, classified in various ways like efflux transporters and influx transporters; secretory transporters and absorptive transporters; ATP-driven transporters and Solute Linked Carrier (SLC) transporters are of great importance while studying pharmacokinetics. They have impeccable roles in the drug discovery process of infectious diseases. Many of these find a pivotal role in synthetic antimicrobial peptides. The chapter briefly elucidates the varied types and their significance., (Copyright © 2021 Elsevier Inc. All rights reserved.)

This review surveys soluble Folate Receptors (FOLRs) in humans. FOLR1 and FOLR2 are equipped with cellular glycosylphosphatidylinositol (GPI) anchors. FOLR1 is secreted from epithelia with or without a micelle-encapsulated GPI-anchor into milk and other body fluids/secretions, e.g. semen where its interaction with spermatozoa indicates a role in male fertility. FOLR1 and FOLR2 serve as serum biomarkers of various diseases. FOLR3 possesses no GPI-anchor and originates from secretory granules of neutrophil granulocytes; its concentration in serum correlates to the FOLR3 content in leukocytes and rises with increased leukocyte counts (infection, malignancy and pregnancy). FOLR3 exerts anti-microbial and anti-tumor effects by depriving bacteria and tumor cells of natural folates. Megalin receptors mediate reabsorption of ultrafiltered folate-bound FOLR into cells of proximal kidney tubules and of folate-bound FOLR uptake in growing embryos. Megalin receptors overexpressed in malignant tumors could be suitable therapeutic targets for folate-conjugated cytotoxic agents utilizing soluble FOLRs as vectors., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A new study by Yang and colleagues has revealed that TNF-alpha regulates PANX1 levels through an NF-kB-dependent mechanism in human endothelial cells. PANX1 modulates Ca 2+ influx contributing to IL-1beta production independent of purinergic signaling. These novel findings expand our understanding of TNF-alpha-mediated upregulation of IL-1beta with implications for responses to tissue injury and infection., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Gastric cancer (GC) remains a serious threat to human health with a high cancer-related death rate and unsatisfactory treatment effects after curative resection, especially with advanced GC. Thus, exploration of the molecular mechanism of cisplatin (CDDP) resistance in GC is crucial. circCCDC66 (hsa_circ_0001313) expression was detected by quantitative reverse-transcription PCR in GC cell lines and tissues. The characteristics of circCCDC66 in CDDP resistance in GC were evaluated in vivo and vitro. We performed luciferin reporter assays, biotin-coupled RNA pull-downs and fluorescence in situ hybridization (FISH) to assess the relationship of miR-618 to circCCDC66. Function was determined by cytotoxicity assay, western immunoblotting and TUNEL. CircCCDC66 was overexpressed in CDDP-resistant cells and tissues. The circCCDC66 expression was significantly associated with malignancy and was an independent risk factor for disease-free survival (DFS) in GC patients treated by CDDP based chemotherapy. Data from in vitro and vivo experiments demonstrated that circCCDC66 inhibited apoptosis by targeting miR-618 and release of B-cell lymphoma-2 (BCL2). CircCCDC66 is an essential regulator in the development of CDDP resistance and may serve as a promising therapeutic target for GC patients. Otherwise, our study adds more evidence of circRNA functioning as a sequestering agent for miRNA., Competing Interests: Declaration of Competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Vancomycin is a common drug used in children with severe infection. In adults, at least 15 mg/L of the optimal vancomycin trough concentration (C trough ) is needed to generate the target 24-h area under the concentration-time curve (AUC 24 ) to the minimum inhibitory concentration (MIC) of 400 for a pathogen with the MIC ≤1 mg/L., Objectives: To determine vancomycin PK in children with severe infection and to explore the correlation between vancomycin C trough and AUC 24 in children, as well as to propose the appropriate vancomycin dosages using Monte Carlo simulation., Materials and Methods: Children aged 2-18 years who were admitted to Chiang Mai University Hospital and received intravenous vancomycin for severe infection were included in the study. Serum samples for vancomycin PK were obtained before and serially after the administration of the first dose according to the protocol. Pharmacokinetic analyses were performed using Phoenix WinNonlin® 7.0 and NLME™7.0., Results: Fourteen children with 64% males and age range from 2 to 13 years were included in this study. Non-compartmental analysis revealed the median volume of distribution, clearance, and elimination half-life of 0.58 L/kg, 2.82 mL/kg/min and 2.33 h, respectively. Vancomycin serum concentrations were best described by a two-compartmental model with first-order elimination.The observed C trough at 6 h correlated well with the AUC 24 . The median vancomycin C trough at steady state that correlated with the AUC 24 ≥ 400 and <800 were 11.18, 9.50, 7.91 and 6.55 mg/L in simulated children receiving vancomycin 40, 60, 80 and 100 mg/kg/day, respectively., Conclusion: Correlation between vancomycin C trough and AUC 24 values in children has been observed. However, the values of C trough that correlate with the target AUC 24 ≥400 in children are lower than the values observed and targeted in adults., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Enterochromaffin (EC) cell is the main cell type that responsible for 5-hydroxytryptamine (5-HT) synthesis, storage and release of the gut. Intestinal 5-HT play a key role in visceral sensation, intestinal motility and permeability, EC cell hyperplasia and increased 5-HT bioavailability in the gut have been found to be involved in the symptoms generation of irritable bowel syndrome and inflammatory bowel disease. EC cells originate from intestinal stem cells, the interaction between proliferation and differentiation signals on intestinal stem cells enable EC cell number to be regulated in a normal level. This review focuses on the impact factors, pathogenesis mechanisms, and therapeutic clues for intestinal EC cells hyperplasia, and showed that EC cell hyperplasia was observed under the condition of physiological stress, intestinal infection or intestinal inflammation, the disordered proliferation and/or differentiation of intestinal stem cells as well as their progenitor cells all contribute to the pathogenesis of intestinal EC cell hyperplasia. The altered intestinal niche, i.e. increased corticotrophin releasing factor (CRF) signal, elevated nerve growth factor (NGF) signal, and Th2-dominant cytokines production, has been found to have close correlation with intestinal EC cell hyperplasia. Currently, CRF receptor antagonist, nuclear factor-κB inhibitor, and NGF receptor neutralizing antibody have been proved useful to attenuate intestinal EC cell hyperplasia, which may provide a promising clue for the therapeutic strategy in EC cell hyperplasia related diseases., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Lectins are proteins found in all domains of life with a plethora of biological functions, especially in the infection process, immune response, and inflammation. Targeting these carbohydrate-binding proteins is challenged by the fact that usually low affinity interactions between lectin and glycoconjugate are observed. Nature often circumvents this process through multivalent display of ligand and lectin. Consequently, the vast majority of synthetic antagonists are multivalently displayed native carbohydrates. At the cost of disadvantageous pharmacokinetic properties and possibly a reduced selectivity for the target lectin, the molecules usually possess very high affinities to the respective lectin through ligand epitope avidity. Recent developments include the advent of glycomimetic or allosteric small molecule inhibitors for this important protein class and their use in chemical biology and drug research. This evolution has culminated in the transition of the small molecule GMI-1070 into clinical phase III. In this opinion article, an overview of the most important developments of lectin antagonists in the last two decades with a focus on the last five years is given., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Inflammasomes play a very important role in the host defense against multiple pathogenic microbes, including bacteria and viruses. Inflammasomes are multiprotein complex platforms that mediate the processing of the two most important inflammatory cytokines, pro-IL-1β and pro-IL-18, to their active forms. The inflammasome is formed by the apoptosis-associated speck-like protein containing a CARD (ASC), procaspase-1 and a sensor protein, either a NOD-like receptor (NLR) or an absent in melanoma 2 (AIM2)-like receptor. The sensor molecule determines inflammasome specificity by detecting specific and conserved microbial products or cell stress signals. Compared with the other inflammasomes, there is much more unknown about the activation or regulation mechanisms of the AIM2 inflammasome. In this review, we will discuss these mechanisms and the specific roles of the AIM2 inflammasome in response to diverse pathogens., (Copyright © 2019 Elsevier B.V. All rights reserved.)

When a pathogen invades the body, an acute inflammatory response is activated to eliminate the intruder. In some patients, runaway activation of the immune system may lead to collateral tissue damage and, in the extreme, organ failure and death. Experimental studies have found an association between severe infections and depletion in levels of adenosine triphosphate (ATP), increase in nitric oxide production, and accumulation of lactate, suggesting that tissue energetics is compromised. In this work we present a differential equations model that incorporates the dynamics of ATP, nitric oxide, and lactate accompanying an acute inflammatory response and employ this model to explore their roles in shaping this response. The bifurcation diagram of the model system with respect to the pathogen growth rate reveals three equilibrium states characterizing the health, aseptic and septic conditions. We explore the domains of attraction of these states to inform the instantiation of heterogeneous virtual patient populations utilized in a survival analysis. We then apply the model to study alterations in the inflammatory response and survival outcomes in metabolically altered conditions such as hypoglycemia, hyperglycemia, and hypoxia., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: To explore the expression and function of nucleotide-binding oligomerization domain (NOD) proteins NOD1 and NOD2 and provide guidance for prophylaxis and treatment of neonatal infection., Methods: Peripheral blood samples were collected from preterm infants, term infants and, healthy adult volunteers. A portion of collected blood was used to examine the expression of NOD1 and NOD2 by real-time PCR. The remaining blood was stimulated in vitro with NOD2 agonist L-Ala-D-Glu-meso (Tri-DAP) or NOD1 agonist muramyl dipeptide (MurNAc-L-Ala-D-isoGln; MDP) for 4 h. Consequently, the levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) were quantified by enzyme-linked immunosorbent assay (ELISA)., Results: NOD1 expression was found to be decreased in preterm and term newborns compared with adults. NOD2 was significantly lower in preterm infants alone in comparison with adults. After treated by Tri-DAP or MDP, the levels of IL-6 and TNF-α in peripheral blood were significantly lower in preterm and term newborns when comparing to adults., Conclusion: NOD1 and NOD2 expression and induced release of pro-inflammatory mediators were impaired in infants, contributing to the high susceptibility of infants to infection. Our results insisted on developing a new immunological approach for prophylaxis and treatment of neonatal infection., (Copyright © 2018. Published by Elsevier B.V.)

Taking an ecological perspective, this paper reports theoretical and empirical results concerning fatal bacterial infections of adult insects. Two models, each combining deterministic and stochastic elements, characterize how the pathogen's dynamics might govern an infected host's mortality rate. We analyze the models in detail for exponential pathogen growth, and apply them to observed insect mortality when the pathogen's growth is unregulated. We then allow bacteriophage to generate fluctuations in the within-host pathogen density; we demonstrate that only one of our models matches host mortality rates when pathogen growth is regulated by phage. We generalize our results on mortality hazard of individual hosts to analyze how random duration of the infectious period can combine with probabilistic transmission events to affect between-host transmission., (Copyright © 2018. Published by Elsevier Ltd.)

The growing global threat of antibiotic resistant human pathogens has coincided with improved methods for developing and using genome-scale metabolic network reconstructions. Consequently, there has been an increase in the number of high-quality reconstructions of relevant human and zoonotic pathogens. Novel biomedical applications of pathogen reconstructions focus on three key aspects of pathogen behavior: the evolution of antibiotic resistance, virulence factor production, and host-pathogen interactions. New methods using these reconstructions aim to improve understanding of microbe pathogenicity and guide the development of new therapeutic strategies. This review summarizes the latest ways that genome-scale metabolic network reconstructions have been used to study human pathogens and suggests future applications with the potential to mitigate infectious disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Ion channels and transporters move ions across membrane barriers and are essential for a host of cell functions in many organs. They conduct K + , Na + and Cl - , which are essential for regulating the membrane potential, H + to control intracellular and extracellular pH and divalent cations such as Ca 2+ , Mg 2+ and Zn 2+ , which function as second messengers and cofactors for many proteins. Inherited channelopathies due to mutations in ion channels or their accessory proteins cause a variety of diseases in the nervous, cardiovascular and other tissues, but channelopathies that affect immune function are not as well studied. Mutations in ORAI1 and STIM1 genes that encode the Ca 2+ release-activated Ca 2+ (CRAC) channel in immune cells, the Mg 2+ transporter MAGT1 and the Cl - channel LRRC8A all cause immunodeficiency with increased susceptibility to infection. Mutations in the Zn 2+ transporters SLC39A4 (ZIP4) and SLC30A2 (ZnT2) result in nutritional Zn 2+ deficiency and immune dysfunction. These channels, however, only represent a fraction of ion channels that regulate immunity as demonstrated by immune dysregulation in channel knockout mice. The immune system itself can cause acquired channelopathies that are associated with a variety of diseases of nervous, cardiovascular and endocrine systems resulting from autoantibodies binding to ion channels. These autoantibodies highlight the therapeutic potential of functional anti-ion channel antibodies that are being developed for the treatment of autoimmune, inflammatory and other diseases., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Intracellular infections are tricky to treat, the reason being the poor penetration of antibiotics/antimycotics into the microbial niche (host cell). Macrophages are primary targets of facultative and obligate intracellular bacteria/fungi to be abused as host cells. The need for drugs with better intracellular penetration led to the development of endocytosable drug carriers, which can cross the cell membrane of the host cells (macrophages) by imitating the entry path of the pathogens. Therefore, the drugs can be targeted to macrophages ensuring enhanced therapeutic effect. This review discusses the exploitation of various nanocarriers for targeted delivery of drugs to the macrophages in the last two decades., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Humoral immune responses are crucial for protection against invading pathogens and are the underlying mechanism of protection for most successful vaccines. Our understanding of how humoral immunity develops is largely based on animal models utilizing experimental immunization systems. While these studies have made enormous progress for the field and have defined many of the fundamental principles of B cell differentiation and function, we are only now beginning to appreciate the complexities of humoral immune responses induced by infection. Co-evolution of the adaptive immune system and the pathogenic world has created a diverse array of B cell responses to infections, with both shared and unique strategies. In this review, we consider the common mechanisms that regulate the development of humoral immune responses during infection and highlight recent findings demonstrating the evolution of unique strategies used by either host or pathogen for survival., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

In the cytoplasm, DNA is sensed as a universal danger signal by the innate immune system. Cyclic GMP-AMP synthase (cGAS) is a cytosolic DNA sensor/enzyme that catalyzes formation of 2'-5'-cGAMP, an atypical cyclic di-nucleotide second messenger that binds and activates the Stimulator of Interferon Genes (STING), resulting in recruitment of Tank Binding Kinase 1 (TBK1), activation of the transcription factor Interferon Regulatory Factor 3 (IRF3), and trans-activation of innate immune response genes, including type I Interferon cytokines (IFN-I). Activation of the pro-inflammatory cGAS-STING-IRF3 response is triggered by direct recognition of the DNA genomes of bacteria and viruses, but also during RNA virus infection, neoplastic transformation, tumor immunotherapy and systemic auto-inflammatory diseases. In these circumstances, the source of immuno-stimulatory DNA has often represented a fundamental yet poorly understood aspect of the response. This review focuses on recent findings related to cGAS activation by an array of self-derived DNA substrates, including endogenous retroviral elements, mitochondrial DNA (mtDNA) and micronuclei generated as a result of genotoxic stress and DNA damage. These findings emphasize the role of the cGAS axis as a cell-intrinsic innate immune response to a wide variety of genomic insults., (Copyright © 2017. Published by Elsevier Ltd.)

Current immunosuppression regimens in organ transplantation primarily inhibit T cells. However, T cells are also critical in protective immunity, especially in immune-compromised patients. In this study, we examined the association of T cell dysfunction, as marked by expression of T cell exhaustion molecules, and posttransplant infections in a cohort of liver transplant patients. We focused on Programmed Death 1 (PD-1) and T cell Ig- and mucin-domain molecule 3 (Tim-3), which are potent co-inhibitory receptors, and their persistent expression often leads to T cell dysfunction and compromised protective immunity. We found that patients with the highest expression of PD-1 +Tim-3+ T cells in the memory compartment before transplantation had increased incidence of infections after liver transplantation, especially within the first 90 days. Longitudinal analysis in the first year showed a strong association between variability of PD-1 and Tim-3 expression by T cells and infectious episodes in transplant patients. Furthermore, T cells that expressed PD-1 and Tim-3 had a significantly reduced capacity in producing interferon (IFN)-γ in vitro, and this reduced IFN-γ production could be partially reversed by blocking PD-1 and Tim-3. Interestingly, the percentage of Foxp3+ regulatory T cells in liver transplant patients was stable in the study period. We concluded that the functional status of T cells before and after liver transplantation, as shown by PD-1 and Tim-3 expression, may be valuable in prognosis and management of posttransplant infections., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Environmental enteropathy (EE) impairs the gut's absorptive capacity and immune function and causes decelerations in statural growth that manifest gradually over time. Objective: To illustrate an approach for assessing emerging biomarkers of EE, we separately assessed the associations between 3 such markers and subsequent nutritional status. Design: Stool samples were routinely collected between January 2010 and November 2014 from a cohort of 303 Peruvian infants and analyzed for concentrations of the biomarkers α-1-antitrypsin (AAT), myeloperoxidase, and neopterin. For each marker, a mixed-effects linear regression model was fitted for length-for-age z scores (LAZs) obtained from anthropometric assessments that incorporated covariate predictors, polynomial terms for age, and product interaction terms to test associations over varying lag lengths. The biomarkers' contribution to the models was assessed with the use of the likelihood ratio test and partial R 2 statistics. Results: Test statistics for the combined inclusion of the 4-model terms that involved the biomarker were highly statistically significant for AAT (28.71; P < 0.0001) and myeloperoxidase (62.79; P < 0.0001) over a 3-mo lag and moderately so for neopterin (13.97; P = 0.0074). AAT and myeloperoxidase seemed to interact strongly with age, with the magnitude and direction of the effect varying considerably over the first 3 y of life. The largest proportion of the variance explained by any biomarker (2.8%) and the largest difference in LAZ predicted between the 5th and 95th percentile (0.25) was by myeloperoxidase over a 2-mo lag. Conclusions: Of the 3 fecal biomarkers studied, 2 that related to intestinal function-AAT and myeloperoxidase-were associated with small but highly statistically significant differences in future statural growth trajectories in infants in this cohort, lending further evidence to the EE hypothesis that increased gut permeability and inflammation adversely affects subsequent nutritional status. This association exhibited a complex interaction with age. This trial was registered at clinicaltrials.gov as NCT02441426., (© 2017 American Society for Nutrition.)

An epidemic of obesity over the past three decades increases the risk of chronic and infectious diseases for adults and children alike. Within the past few years, obesity has been shown to impair the adaptive immune response to infection through alterations in T cell functioning. Growing evidence suggests that perturbations in T cell metabolism drives this stunted immune response, stemming from nutrient, hormone and adipokine dysregulation in the obese. In this review, recent findings in the fields of obesity and T cell mediated immunity demonstrate a unique relationship between altered mechanisms of T cell metabolic homeostasis and plasticity of adaptive immune responses in the obese setting., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Recent work has shown that reduction reactions at metallic biomaterial surfaces can induce significant killing of cells in proximity to the surface. To exploit this phenomenon for therapeutic purposes, for example, for cancer tumor killing or antibacterial effects (amongst other applications), magnesium metal particles, galvanically coupled to titanium by sputtering, have been evaluated for their cell-killing capability (i.e. cytotoxicity). Magnesium (Mg) particles large enough to prevent particle phagocytosis were investigated, so that only electrochemical reactions, and not particle toxicity per se, caused cytotoxic effects. Titanium (Ti) coated magnesium particles, as well as magnesium-only particles were introduced into MC3T3-E1 mouse pre-osteoblast cell cultures over a range of particle concentrations, and cells were observed to die in a dosage-dependent manner. Ti-coated magnesium particles killed more cells at lower particle concentration than magnesium alone (P<0.05), although the pH measured for magnesium and magnesium-titanium had no significant difference at similar particle concentrations. Complete cell killing occurred at 750μg/ml and 1500μg/ml for Mg-Ti and Mg, respectively. Thus, this work demonstrates that galvanically coupled Mg-Ti particles have a significant cell killing capability greater than Mg alone. In addition, when the pH associated with complete killing with particles was created using NaOH only (no particles), then the percentage of cells killed was significantly less (P<0.05). Together, these findings show that pH is not the sole factor associated with cell killing and that the electrochemical reactions, including the reduction reactions, play an important role. Reduction reactions on galvanically coupled Mg-Ti and Mg particles may generate reactive oxygen intermediates that are able to kill cells in close proximity to the particles and this approach may lead to potential therapies for infection and cancer., Statement of Significance: This paper demonstrates that during active corrosion of both Mg and Mg-Ti particles cells cultured with the particles are killed in a dose-dependent particle concentration fashion. Additionally, galvanically-coupled magnesium-titanium microparticles kill cells more effectively than magnesium particles alone. The killing effect was shown to not be due to pH shifts since no differences were seen for different particle types and pH adjusted medium without particles did not exhibit the same level of killing. The significance of this work is the recognition of this killing effect with Mg particles and the potential therapeutic applications in infection control and cancer treatment that this process may provide., (Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

All the human primary immunodeficiencies (PIDs) recognized as such in the 1950s were Mendelian traits and, whether autosomal or X-linked, displayed recessive inheritance. The first autosomal dominant (AD) PID, hereditary angioedema, was recognized in 1963. However, since the first identification of autosomal recessive (AR), X-linked recessive (XR) and AD PID-causing genes in 1985 (ADA; severe combined immunodeficiency), 1986 (CYBB, chronic granulomatous disease) and 1989 (SERPING1; hereditary angioedema), respectively, the number of genetically defined AD PIDs has increased more rapidly than that of any other type of PID. AD PIDs now account for 61 of the 260 known conditions (23%). All known AR PIDs are caused by alleles with some loss-of-function (LOF). A single XR PID is caused by gain-of-function (GOF) mutations (WASP-related neutropenia, 2001). In contrast, only 44 of 61 AD defects are caused by LOF alleles, which exert dominance by haploinsufficiency or negative dominance. Since 2003, up to 17 AD disorders of the third kind, due to GOF alleles, have been described. Remarkably, six of the 17 genes concerned also harbor monoallelic (STAT3), biallelic (C3, CFB, CARD11, PIK3R1) or both monoallelic and biallelic (STAT1) LOF alleles in patients with other clinical phenotypes. Most heterozygous GOF alleles result in auto-inflammation, auto-immunity, or both, with a wide range of immunological and clinical forms. Some also underlie infections and, fewer, allergies, by impairing or enhancing immunity to non-self. Malignancies are also rare. The enormous diversity of immunological and clinical phenotypes is thought provoking and mirrors the diversity and pleiotropy of the underlying genotypes. These experiments of nature provide a unique insight into the quantitative regulation of human immunity., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The immune system protects from infections primarily by detecting and eliminating invading pathogens. Beside neutrophils, monocytes and dendritic cells (DCs) have been recently identified as important sentinels and effectors in combating microbial pathogens. In the steady state mononuclear phagocytes like monocytes and DCs patrol the blood and the tissues. Mammalian monocytes contribute to antimicrobial defense by supplying tissues with macrophage and DC precursors. DCs recognize pathogens and are essential in presenting antigens to initiate antigen-specific adaptive immune responses, thereby bridging the innate and adaptive immune systems. Both, monocytes and DCs play distinct roles in the shaping of immune response. In this review we will focus on the contributions of monocytes and lymphoid organ DCs to immune defense against microbial pathogens in the mouse and their dynamic regulation from steady state to infection., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Recognition of pathogen derived molecules by Pattern Recognition Receptors (PRR) induces the production of cytokines (i.e. type I interferons) that stimulate the surrounding cells to transcribe and translate hundreds of genes, in order to prevent further infection and organize the immune response. Here, we report on the rising matter that metabolism sensing and gene expression control at the level of mRNA translation, allow swift responses that mobilize host defenses and coordinate innate responses to infection., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Female mice exhibit a better survival rate than males after infection, but if infection follows an ozone-induced oxidative stress, male survival exceeds that of females. Our goal was to study bronchoalveolar lavage factors that contribute to these sex differences in outcome. We studied parameters at 4, 24, and 48 h after ozone exposure and infection, including markers of inflammation, oxidative stress, and tissue damage, and surfactant phospholipids and surfactant protein A (SP-A). A multianalyte immunoassay at the 4h time point measured 59 different cytokines, chemokines, and other proteins. We found that: (1) Although some parameters studied revealed sex differences, no sex differences were observed in LDH, total protein, MIP-2, and SP-A. Males showed more intragroup significant differences in SP-A between filtered air- and ozone-exposed mice compared to females. (2) Oxidized dimeric SP-A was higher in FA-exposed female mice. (3) Surfactant phospholipids were typically higher in males. (4) The multianalyte data revealed differences in the exuberance of responses under different conditions - males in response to infection and females in response to oxidative stress. These more exuberant, and presumably less well-controlled responses associate with the poorer survival. We postulate that the collective effects of these sex differences in response patterns of lung immune cells may contribute to the clinical outcomes previously observed., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Pathogens and parasites encode a wide spectrum of multifunctional proteins interacting to and modifying proteins in host cells. However, the current lack of a reliable method to unveil the protein-protein interactions (PPI) at the host-pathogen interface is retarding our understanding of many important pathogenic processes. Thus, the identification of proteins involved in host-pathogen interactions is important for the elucidation of virulence determinants, mechanisms of infection, host susceptibility and/or disease resistance. In this sense, proteomic technologies have experienced major improvements in recent years and protein arrays are a powerful and modern method for studying PPI in a high-throughput format. This review focuses on these techniques analyzing the state-of-the-art of proteomic technologies and their possibilities to diagnose and explore host-pathogen interactions. Major technical advancements, applications and protocol concerns are presented, so readers can appreciate the immense progress achieved and the current technical options available for studying the host-pathogen interface. Finally, future uses of this kind of array-based proteomic tools in the fight against infectious and parasitic diseases are discussed., (© 2013.)

Aims/hypothesis: Patients with diabetes are more prone to bacterial infections mostly due to hyperglycemia-induced suppression of immune cells function. B lymphocytes by secreting antibodies inhibit microbial replication, but the impact of high glucose concentration on humoral immune response is not fully resolved. The aim of this work was to investigate the effect of high glucose concentration on B cells response to stimulation with a bacterial antigen and autocrine regulation., Methods: Purified human peripheral blood B cells were cultured at different glucose concentrations and stimulated in vitro with Staphylococcus aureus Cowan I (SAC) plus IL-2. B cells proliferation, differentiation and IgM expression were analyzed by flow cytometry. B cell ATP release and involvement of P2 purinergic receptors in regulation of IgM secretion was assessed., Results: B cells cultured at 25 mM glucose in response to SAC stimulation released significantly less (≈ 55%) IgM comparing to cells maintained in 5mM glucose. Under resting and stimulatory conditions B cells released significant quantities of ATP to the culture media, but ATP level decreased when B cells were maintain in high glucose. SAC-induced B cell IgM release was totally blocked by highly selective antagonist (Az11645373) of P2X7 receptor. IgM secretion increased in the presence of potent P2X7 receptor agonist (BzATP), but this effect was abolished by high glucose concentration., Conclusions/interpretation: High glucose concentration impairs B cell function by suppression of P2X7 receptor-dependent IgM release in response to in vitro bacterial antigen stimulation. This alteration may greatly contribute to the impaired humoral immune response in diabetics., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

This review describes how fever is generated as a regulated increase in body temperature. It results from an upward shift in the thermoregulatory set point, mediated by pyrogenic cytokines released from monocytes/macrophages in response to infection or trauma. Evidence will be presented that fever is part of an integrated host defense system, and that failure to generate a fever in response to infection is generally associated with a poorer prognosis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

The mammalian intestinal tract harbors a vast and diverse ecosystem of microbes that are separated from the sterile host milieu by a single layer of epithelial cells. While this bio-geographical configuration is critical for host biological processes, it imposes a risk for microbial penetration and life-threatening systemic invasion. Inflammasomes are cytosolic multi-protein platforms that sense both microbial and damage-associated molecular patterns and initiate a potent innate immune anti-microbial response. In this review, we will highlight the role of inflammasomes in the orchestration and regulation of the intestinal immune response, focusing on the roles of inflammasomes in maintenance of intestinal homeostasis, enteric infection, auto-inflammation, and tumorigenesis. We highlight the centrality of inflammasome signaling in the complex cross-talk between host mucosal immune arms and the environment, in particular the microflora, with emphasis on the spatial and temporal integration of inflammasome activation with signals from other innate signaling platforms.

Eosinophil extracellular traps (EETs) are part of the innate immune response and are seen in multiple infectious, allergic, and autoimmune eosinophilic diseases. EETs are composed of a meshwork of DNA fibers and eosinophil granule proteins, such as major basic protein (MBP) and eosinophil cationic protein (ECP). Interestingly, the DNA within the EETs appears to have its origin in the mitochondria of eosinophils, which had released most their mitochondrial DNA, but were still viable, exhibiting no evidence of a reduced life span. Multiple eosinophil activation mechanisms are represented, whereby toll-like, cytokine, chemokine, and adhesion receptors can all initiate transmembrane signal transduction processes leading to the formation of EETs. One of the key signaling events required for DNA release is the activation of the NADPH oxidase. Here, we review recent progress made in the understanding the molecular mechanisms involved in DNA and granule protein release, discuss the presence of EETs in disease, speculate on their potential role(s) in pathogenesis, and compare available data on other DNA-releasing cells, particularly neutrophils., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The syndrome of inappropriate antidiuresis (SIAD; formerly the syndrome of inappropriate secretion of antidiuretic hormone) is the most frequent cause of hyponatremia. A strong association exists between mortality and hyponatremia, which reflects the severity of the underlying disease. In SIAD, hyponatremia is associated with normovolaemia but the assessment of extracellular volume can be difficult. Clinical features are mainly neurological and can lead to death but mechanisms of adaptation can limit cerebral oedema. The notion of mild asymptomatic hyponatremia was questioned by the observation of subclinical neurocognitive impairment, a greater risk of falls and fractures. Aetiologies are classified into six groups: neurologic disorders, infections mainly cerebral, meningeal and pulmonary, drugs in particular antidepressants, tumors, genetic causes, and idiopathic. Symptomatic acute hyponatremia is a therapeutic emergency that is not specific of SIAD. When hyponatremia is asymptomatic, fluid restriction with salt intake is generally sufficient but urea can be an alternative. In chronic SIAD, there is currently no recommendation. Fluid restriction is not always feasible; urea has proved its efficacy, its good tolerance and its long-term harmlessness. Vaptans have demonstrated their good tolerance and their efficacy on the correction of hyponatremia from SIAD in studies subgroups, for moderate hyponatremia and asymptomatic patients. In the only study having compared vaptans and urea, efficacy and tolerance were similar. Because of the cost difference between vaptans and urea and while waiting for follow-up studies, urea appears at present as the first-line treatment of hyponatremia in SIAD., (Copyright © 2012 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.)

Ruminants are more vulnerable to copper deficiency than humans because rumen sulfide generation lowers copper availability from forage, increasing the risk of conditions such as swayback in lambs. Molybdenum-rich pastures promote thiomolybdate (TM) synthesis and formation of unabsorbable Cu-TM complexes, turning risk to clinical reality (hypocuprosis). Selection pressures created ruminant species with tolerance of deficiency but vulnerability to copper toxicity in alien environments, such as specific pathogen-free units. By contrast, cases of copper imbalance in humans seemed confined to rare genetic aberrations of copper metabolism. Recent descriptions of human swayback and the exploratory use of TM for the treatment of Wilson's disease, tumor growth, inflammatory diseases, and Alzheimer's disease have created unexpected common ground. The incidence of pre-hemolytic copper poisoning in specific pathogen-free lambs was reduced by an infection with Mycobacterium avium that left them more responsive to treatment with TM but vulnerable to long-term copper depletion. Copper requirements in ruminants and humans may need an extra allowance for the "copper cost" of immunity to infection. Residual cuproenzyme inhibition in TM-treated lambs and anomalies in plasma copper composition that appeared to depend on liver copper status raise this question "can chelating capacity be harnessed without inducing copper-deficiency in ruminants or humans?" A model of equilibria between exogenous (TM) and endogenous chelators (e.g., albumin, metallothionein) is used to predict risk of exposure and hypocuprosis; although risk of natural exposure in humans is remote, vulnerability to TM-induced copper deficiency may be high. Biomarkers of TM impact are needed, and copper chaperones for inhibited cuproenzymes are prime candidates.

Syndecan-1 is a cell surface heparan sulfate proteoglycan that binds to many mediators of disease pathogenesis. Through these molecular interactions, syndecan-1 can modulate leukocyte recruitment, cancer cell proliferation and invasion, angiogenesis, microbial attachment and entry, host defense mechanisms, and matrix remodeling. The significance of syndecan-1 interactions in disease is underscored by the striking pathological phenotypes seen in the syndecan-1 null mice when they are challenged with disease-instigating agents or conditions. This review discusses the key molecular functions of syndecan-1 in modulating the onset, progression, and resolution of inflammatory diseases, cancer, and infection., (Copyright © 2011 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.)

Lymphocyte homeostasis in type 2 diabetes mellitus (T2DM) is associated with increased susceptibility to infections. Mitochondrial oxidative stress is implicated primarily in the immune pathophysiology of diabetes; however, the molecular underpinnings of lymphocyte mitochondrial dysfunction and ensuing downstream cellular effects are hitherto unreported. Both in early diagnosed patients and patients with late complications, we observed an inverse correlation between mitochondrial DNA content in lymphocytes and hemoglobin A1 (HbA1c) levels. This relation established for the first time might serve as a general, yet direct, predictor or indicator for mitochondrial dysfunction in T2DM. Compared with controls, nuclear DNA damage response was higher (P ≤ 0.001) in diabetic subjects with increased accumulation of phospho-ataxia-telangiectasia (ATM), γ-H2AX, along with active recruitment of repair proteins (Mre11, Rad50, and Nbs1). A higher frequency (>2%) of stable chromosomal anomalies with loss of telomere integrity was observed in cases with late complications. A significant decrease (P ≤ 0.001) in enzyme activity of complex II, III, and IV of mitochondrial respiratory chain was evident in both diabetic groups in comparison with healthy controls. Activation in the cascade of nuclear factor kappa-beta (NF-κβ)-mediated feed-forward proinflammatory cytokine response was noted among T2DM subjects. Increased oxidative stress, mitochondrial membrane depolarization, activation of caspase-3, and PARP observed in diabetic groups indicated bax triggered mitochondrial mediated cellular apoptosis. Our results provide the first insights of lymphocyte mitochondrial dysfunction that might be helpful in explaining the clinical significance of immunologic perturbation observed in type 2 diabetic conditions. Our data also indicate that maneuvering through the mitochondrial function might be a viable, indirect method to modulate lymphocyte homeostasis in T2DM., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Inflammation is the immune system's response to infectious or noninfectious sources of danger. Danger recognition is facilitated by various innate immune receptor families including the Toll-like receptors (TLRs), which detect danger signals in extracellular and intracellular compartments. It is an evolving concept that renal damage triggers intrarenal inflammation by immune recognition of molecules that are being released by dying cells. Such danger-associated molecules act as immunostimulatory agonists to TLRs and other innate immune receptors and induce cytokine and chemokine secretion, leukocyte recruitment, and tissue remodeling. As a new entry to this concept, autophagy allows stressed cells to reduce intracellular microorganisms, protein aggregates, and cellular organelles by moving and subsequently digesting them in autophagolysosomes. Within the autophagolysosome, endogenous molecules and danger-associated molecules may be presented to TLRs or loaded onto the major histocompatibility complex and presented as autoantigens. Here we discuss the current evidence for the danger signaling concept in autoimmune kidney injury and propose that autophagy-related processing of self-proteins provides a source of immunostimulatory molecules and autoantigens. A better understanding of danger signaling should enable us to unravel yet unknown triggers for renal immunopathology and progressive kidney disease.

Human beta-defensin 1 (hBD-1) is probably the most important antimicrobial peptide in epithelial tissues. Its alleles and/or altered gene expression have been associated with at least 20 human diseases. hBD-1 is a tumor suppressor and DEFB1 is the only innate immunity gene that shows long-term balanced selection and heterozygote advantage. It is unique in its constitutive expression, but is still capable of upregulation upon inflammatory or microbial stimuli. The present minireview focuses on hBD-1 properties, biological function, its proposed pathogenic mechanisms and the potential uses of elicitors, inhibitors or the peptide itself in the treatment of hBD-1-related human diseases including allergies, infections and cancer., (Copyright 2010 Elsevier Ltd. All rights reserved.)

While the role of PD-1 in inhibiting immunity during chronic infections is well established, its functions during acute infections are much less clear. The PD-1 pathway can dampen CD8 T cell responses during some acute infections and restrain responses by 'helpless' CD8 memory T cells. An emerging role for PD-1 in innate immunity has been revealed by recent studies showing that PD-1 can limit function of DC and macrophages as well as T cell independent B cell responses. Thus, PD-1 can influence adaptive immune responses during acute infections, though precisely how this regulation occurs is only just beginning to be appreciated., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Co-morbid conditions in obese patients contribute to the incidence and severity of major complications after bariatric surgery and significantly increase the cost of the procedure. Previous publications have validated the patient factors that increase the risk of mortality; however, it is currently a rare event. The development of a metabolic acuity score (MAS) to augment the body mass index might allow for accurate preoperative assessment and optimal treatment of patients. The present study has proposed a MAS for decreasing major complications., Methods: Prospectively collected outcomes of 2416 patients undergoing Roux-en-Y gastric bypass (n = 1821) or laparoscopic adjustable gastric banding (n = 595) in a community hospital were evaluated for the incidence of major complications, readmissions, and reoperations. Beginning in August of 2006, 1072 patients were divided into MAS groups of 1-4 according to age, body mass index, weight, history of deep vein thrombosis/pulmonary embolism, sleep apnea, diabetes, hypertension, immobility, heart disease, and psychological classification. The acuity groups were compared with each other and with 1344 patients who underwent treatment before the MAS was implemented., Results: A significant decrease occurred in the readmission rates within 30 days after the MAS was put into practice (8.5% before MAS versus 1.7% after MAS, P <.001) for the Roux-en-Y gastric bypass patients. The postoperative infection rates were lower after implementing the MAS (3.5% before MAS, .7% after MAS, P <.001). After adjusting for random and fixed effects of covariates, the implementation of the MAS significantly reduced the incidence of postoperative internal hernias, infections, deep vein thrombosis, readmissions, and reoperations., Conclusion: Recognition of specific patient acuity characteristics through the implementation of MAS and aggressive preoperative and perioperative management led to lower major complication rates and decreased the incidence of readmissions and reoperations after bariatric surgery.

Tetraspanin proteins on host cells are involved in the pathogenesis of infectious diseases at different stages. In this review, we will focus on tetraspanins expressed in the immune system and the role they play in the defense to viral, bacterial, parasitic and fungal infections., (Copyright 2009 Elsevier Masson SAS. All rights reserved.)

While inflammatory phagocytosis of microbial pathogens and non-inflammatory phagocytosis of apoptotic cells have each been studied extensively, the consequences of innate immune recognition of host cells undergoing apoptosis as a direct result of infection are unclear. In this situation, the innate immune system is confronted with mixed signals, those from apoptotic cells and those from the infecting pathogen. Nuclear receptor activation has been implicated downstream of apoptotic cell recognition while Toll-like receptors are the prototypical inflammatory receptors engaged during infection. When the two signals combine, a new set of events takes place beginning with transrepression of a subset of inflammatory-response genes and ending with the induction of a T helper-17 adaptive immune response. This response is best suited for clearing the infecting pathogen and repairing the damage that occurred to the host tissue during infection., (Copyright 2010 Elsevier Ltd. All rights reserved.)

WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is an immune deficiency linked in many cases to heterozygous mutations causing truncations in the cytoplasmic tail of CXC chemokine receptor 4 (CXCR4). Leukocytes expressing truncated CXCR4 display enhanced responses to the receptor ligand CXCL12, including chemotaxis, which likely impair their trafficking and contribute to the immunohematologic clinical manifestations of the syndrome. CXCR4 desensitization and endocytosis are dependent on beta-arrestin (betaarr) recruitment to the cytoplasmic tail, so that the truncated CXCR4 are refractory to these processes and so have enhanced G protein-dependent signaling. Here, we show that the augmented responsiveness of WHIM leukocytes is also accounted for by enhanced betaarr2-dependent signaling downstream of the truncated CXCR4 receptor. Indeed, the WHIM-associated receptor CXCR4(1013) maintains association with betaarr2 and triggers augmented and prolonged betaarr2-dependent signaling, as revealed by ERK1/2 phosphorylation kinetics. Evidence is also provided that CXCR4(1013)-mediated chemotaxis critically requires betaarr2, and disrupting the SHSK motif in the third intracellular loop of CXCR4(1013) abrogates betaarr2-mediated signaling, but not coupling to G proteins, and normalizes chemotaxis. We also demonstrate that CXCR4(1013) spontaneously forms heterodimers with wild-type CXCR4. Accordingly, we propose a model where enhanced functional interactions between betaarr2 and receptor dimers account for the altered responsiveness of WHIM leukocytes to CXCL12.

Background: Although nutritionally dispensable amino acids are not essential in the diet, adequate synthesis is necessary for maintenance of good health. Whereas children with edematous severe childhood undernutrition (SCU) can maintain production rates of glycine and serine despite a slower body protein breakdown rate, it is unknown whether the same is true for the semidispensable amino acid arginine., Objective: We aimed to measure arginine flux and intravascular nitric oxide synthesis in children with SCU., Design: Arginine flux and the fractional and absolute synthesis rates of plasma nitrite plus nitrate were measured postabsorptively by using a 6-h infusion of [(15)N(2)]-arginine in 2 groups of children with edematous (n = 14) or nonedematous (n = 7) SCU when they were infected and malnourished (postadmission day approximately 3; clinical phase 1), when they were no longer infected (postadmission day approximately 15; clinical phase 2), and when they were recovered (postadmission day approximately 55; clinical phase 3)., Results: Arginine flux was slower (P < 0.01) and plasma arginine concentrations were lower in the edematous group than in the nonedematous group at clinical phase 1. At clinical phase 2, flux doubled to a value that was not significantly different from the value at clinical phase 3. There were no significant differences in the plasma concentration or fractional or absolute synthesis rate of plasma nitrite plus nitrate between the groups at any clinical phase and among clinical phases within each group., Conclusion: Whereas children with nonedematous SCU can maintain arginine flux at the same rate as when recovered, children with edematous SCU cannot. The slower arginine flux was not, however, associated with slower nitric oxide synthesis.

Ceramide generated in the cell membrane has been shown to be central for the induction of apoptosis by death receptors and many stress stimuli such as gamma-irradiation, UV-light or infection with pathogens. Ceramide reorganizes cell membranes and forms large ceramide-enriched membrane domains that serve the spatial and temporal organization of the cellular signalosome upon activation. Thus, ceramide-enriched membrane domains mediate clustering of CD95 and DR5 to facilitate apoptosis, and they are also critically involved in apoptosis after irradiation, UV-light and infection with Pseudomonas aeruginosa. Since ceramide-enriched membrane domains amplify signals, their function is not restricted to the induction of apoptosis and it was shown that ceramide-enriched membrane domains are also involved in internalization of pathogens and the control of cytokine release from infected epithelial cells. Recent studies support the notion that changes of the ceramide metabolism are also critically involved in human diseases, for instance neurological disorders, cancer, infectious diseases and Wilson's disease.

C1q binds to many non-self and altered-self-materials. These include microorganisms, immune complexes, apoptotic and necrotic cells and their breakdown products, and amyloids. C1q binding to amyloid fibrils found as extracellular deposits in tissues, and subsequent complement activation are involved in the pathology of several amyloid diseases, such as Alzheimer's disease. Prion diseases, such as scrapie also involve formation of amyloid by polymerization of the host prion protein (PrP). Complement activation is likely to contribute to neuronal damage in the end stages of prion diseases, but is also thought to participate in the initial infection, dissemination and replication stages. Infectious prion particles are likely to bind C1q and activate the complement system. Bound complement proteins may then influence the uptake and transport of prion particles by dendritic cells (DCs) and their subsequent proliferation at sites such as follicular DCs.

A heterogeneous set of cells that are commonly grouped as "myeloid cells", interacts in a complex landscape of physiological and pathological situations. In this review we attempt to trace a profile of the "myeloid connection" through different normal and pathological states, by analyzing common metabolic pathways of the amino acid l-arginine. Myeloid cells exert various, often divergent, actions on the immune response through mechanisms that exploit mediators of this peculiar metabolic pathway, ranging from l-arginine itself to its downstream metabolites, like nitric oxide and polyamines. Various pathological situations, including neoplastic and autoimmune diseases, as well as injury repair and infections are discussed here, showing how l-arginine metabolism is able to play a dual role, both as an active protector and a possible threat to the organism.

Human gC1qR/p33 is a multi-compartmental and multi-functional cellular protein expressed on a wide range of tissues and cell types including lymphocytes, endothelial cells, dendritic cells, and platelets. Although originally isolated as a receptor for C1q by virtue of its affinity (K(d)=15-50 nM), and specificity for the globular heads of this molecule, a large body of evidence has now been accumulated which shows that in addition to C1q, gC1qR can serve as a receptor for diverse proinflammatory ligands including proteins of the plasma kinin-forming system, most notably high molecular weight kininogen (HK; K(d)=9 nM). In addition, gC1qR has been reported to recognize and bind a number of functional antigens of viral and bacterial origin. It is its ability to interact with microbial antigens and its potential to serve as a cellular protein for bacterial attachment and/or entry that has been the focus of our laboratory in the past few years. On the surface of activated platelets, gC1qR has been shown to serve as a binding site for Staphylococcus aureus and this binding is mediated by protein A. Since the binding of S. aureus to platelets is postulated to play a major role in the pathogenesis of endocarditis, gC1qR may provide a suitable surface for the initial adhesion of the bacterium. Recent data also demonstrate that the exosporium of Bacillus cereus, a member of a genus of aerobic, Gram-positive, spore-forming rod-like bacilli, which includes the deadly Bacillus anthracis, contains a binding site for gC1qR. Therefore, by virtue of its ability to recognize plasma proteins such as C1q and HK, as well as bacterial and viral antigens, cell-surface gC1qR not only is able to generate proinflammatory byproducts from the complement and kinin/kallikrein systems, but also can be an efficient vehicle and platform for a plethora of pathogenic microorganisms.

Hepcidin is the presumed negative regulator of systemic iron levels; its expression is induced in iron overload, infection, and inflammation, and by cytokines, but is suppressed in hypoxia and anemia. Although the gene is exquisitely sensitive to changes in iron status in vivo, its mRNA is devoid of prototypical iron-response elements, and it is therefore not obvious how it may be regulated by iron flux. The multiplicity of effectors of its expression also suggests that the transcriptional circuitry controlling the gene may be very complex indeed. In delineating enhancer elements within both the human and mouse hepcidin gene promoters, we show here that members of the basic helix-loop-helix leucine zipper (bHLH-ZIP) family of transcriptional regulators control hepcidin expression. The upstream stimulatory factor 2 (USF2), previously linked to hepcidin through gene ablation in inbred mice, appears to exert a polar or cis-acting effect, while USF1 may act in trans to control hepcidin expression. In mice, we found variation in expression of both hepcidin genes, driven by these transcription factors. In addition, c-Myc and Max synergize to control the expression of this hormone, supporting previous findings for the role of this couple in regulating iron metabolism. Transcriptional activation by both USF1/USF2 and c-Myc/Max heterodimers occurs through E-boxes within the promoter. Site-directed mutagenesis of these elements rendered the promoter unresponsive to USF1/USF2 or c-Myc/Max. Dominant-negative mutants of USF1 and USF2 reciprocally attenuated promoter transactivation by both wild-type USF1 and USF2. Promoter occupancy by the transcription factors was confirmed by DNA-binding and chromatin immunoprecipitation assays. Taken together, it would appear that synergy between these members of the bHLH-ZIP family of transcriptional regulators may subserve an important role in iron metabolism as well as other pathways in which hepcidin may be involved.

Background: Children with edematous but not nonedematous severe childhood undernutrition (SCU) have lower plasma and erythrocyte-free concentrations of cysteine, the rate-limiting precursor of glutathione synthesis. We propose that these lower cysteine concentrations are due to reduced production secondary to slower de novo synthesis plus decreased release from protein breakdown., Objective: We aimed to measure cysteine production, de novo synthesis, and the rate of cysteine release from protein breakdown in children with SCU., Design: Cysteine flux, de novo synthesis, and release from protein breakdown were measured in 2 groups of children with edematous (n = 11) and nonedematous (n = 11) SCU when they were infected and malnourished (clinical phase 1), when they were still severely malnourished but no longer infected (clinical phase 2), and when they had recovered (clinical phase 3)., Results: In clinical phase 1, cysteine production and its release from protein breakdown were slower in both groups of children than were the values in the recovered state. These kinetic variables were significantly slower, however, in the children with edematous SCU than in those with nonedematous SCU. De novo cysteine synthesis in clinical phase 1 was faster than the rate at recovery in the edematous SCU group, and there were no significant differences between the groups at any clinical phase., Conclusion: These findings suggest that cysteine production is reduced in all children with SCU because of a decreased contribution from protein breakdown and not from decreased de novo synthesis. The magnitude of this reduction, however, is much greater in children with edematous SCU than in those with nonedematous SCU.