Viral induction of AID is independent of the interferon and the Toll-like receptor signaling pathways but requires NF-κB

Activation-induced cytidine deaminase (AID) is expressed in germinal centers of lymphoid organs during immunoglobulin diversification, in bone marrow B cells after infection with Abelson murine leukemia retrovirus (Ab-MLV), and in human B cells after infection by hepatitis C virus. To understand how viruses signal AID induction in the host we asked whether the AID response was abrogated in cells deficient in the interferon pathway or in signaling via the Toll-like receptors. Here we show that AID is not an interferon responsive gene and abrogation of Toll-like receptor signaling does not diminish the AID response. However, we found that NF-κB was required for expression of virally induced AID. Since NF-κB binds and activates the AID promoter, these results mechanistically link viral infection with AID transcription. Thus, induction of AID by viruses could be the result of several signaling pathways that culminate in NF-κB activation, underscoring the versatility of this host defense program

A Low Frequency Electromagnetic Sensor for Indirect Measurement of Glucose Concentration: In Vitro Experiments in Different Conductive Solutions

In recent years there has been considerable interest in the study of glucose-induced dielectric property variations of human tissues as a possible approach for non-invasive glycaemia monitoring. We have developed an electromagnetic sensor, and we tested in vitro its ability to estimate variations in glucose concentration of different solutions with similarities to blood (sodium chloride and Ringer-lactate solutions), differing though in the lack of any cellular components. The sensor was able to detect the effect of glucose variations over a wide range of concentrations (∼78–5,000 mg/dL), with a sensitivity of ∼0.22 mV/(mg/dL). Our proposed system may thus be useful in a new approach for non-invasive and non-contact glucose monitoring

Plant-Derived Chimeric Virus Particles for the Diagnosis of Primary Sjögren Syndrome

Plants are ideal for the production of protein-based nanomaterials because they synthesize and assemble complex multimeric proteins that cannot be expressed efficiently using other platforms. Plant viruses can be thought of as self-replicating proteinaceous nanomaterials generally stable and easily produced in high titers. We used Potato virus X (PVX) chimeric virus particles (CVPs) and Cowpea mosaic virus (CPMV) empty virus-like particles (eVLPs) to display a linear peptide (lipo) derived from human lipocalin , which is immunodominant in Sjögren’s syndrome (SjS) and is thus recognized by autoantibodies in SjS patient serum. These virus-derived nanoparticles (VNPs) were thus used to develop a diagnostic assay for SjS based on a direct enzyme linked immunosorbent assay (ELISA) format. We found that PVX-lipo formulations were more sensitive than the chemically synthesized immunodominant peptide and equally specific when used to distinguish between healthy individuals and SjS patients. Our novel assay therefore allows the diagnosis of SjS using a simple, low-invasive serum test, contrasting with the invasive labial biopsy required for current tests. Our results demonstrate that nanomaterials based on plant viruses can be used as diagnostic reagents for SjS, and could also be developed for the diagnosis of other diseases

The antiviral factor APOBEC3G improves CTL recognition of cultured HIV-infected T cells

The cytidine deaminase APOBEC3G (A3G) enzyme exerts an intrinsic anti–human immunodeficiency virus (HIV) defense by introducing lethal G-to-A hypermutations in the viral genome. The HIV-1 viral infectivity factor (Vif) protein triggers degradation of A3G and counteracts this antiviral effect. The impact of A3G on the adaptive cellular immune response has not been characterized. We examined whether A3G-edited defective viruses, which are known to express truncated or misfolded viral proteins, activate HIV-1–specific (HS) CD8+ cytotoxic T lymphocytes (CTLs). To this end, we compared the immunogenicity of cells infected with wild-type or Vif-deleted viruses in the presence or absence of the cytidine deaminase. The inhibitory effect of A3G on HIV replication was associated with a strong activation of cocultivated HS-CTLs. CTL activation was particularly marked with Vif-deleted HIV and with viruses harboring A3G. Enzymatically inactive A3G mutants failed to enhance CTL activation. We also engineered proviruses bearing premature stop codons in their genome as scars of A3G editing. These viruses were not infectious but potently activated HS-CTLs. Therefore, the pool of defective viruses generated by A3G represents an underestimated source of viral antigens. Our results reveal a novel function for A3G, acting not only as an intrinsic antiviral factor but also as an inducer of the adaptive immune system

DNA deaminases: AIDing hormones in immunity and cancer

It is well established that hormones can cause cancer, much less known is how they induce this change in our somatic cells. This review highlights the recent finding that estrogen can exert its DNA-damaging potential by directly activating DNA deaminases. This recently discovered class of proteins deaminate cytosine to uracil in DNA, and are essential enzymes in the immune system. The enhanced production of a given DNA deaminase, induced by estrogen, can lead not only to a more active immune response, but also to an increase in mutations and oncogenic translocations. Identifying the direct molecular link between estrogen and a mutation event provides us with new targets for studying and possibly inhibiting the pathological side-effects of estrogen

AID can restrict L1 retrotransposition suggesting a dual role in innate and adaptive immunity

Retrotransposons make up over 40% of the mammalian genome. Some copies are still capable of mobilizing and new insertions promote genetic variation. Several members of the APOBEC3 family of DNA cytosine deaminases function to limit the replication of a variety of retroelements, such as the long-terminal repeat (LTR)-containing MusD and Ty1 elements, and that of the non-LTR retrotransposons, L1 and Alu. However, the APOBEC3 genes are limited to mammalian lineages, whereas retrotransposons are far more widespread. This raises the question of what cellular factors control retroelement transposition in species that lack APOBEC3 genes. A strong phylogenetic case can be made that an ancestral activation-induced deaminase (AID)-like gene duplicated and diverged to root the APOBEC3 lineage in mammals. Therefore, we tested the hypothesis that present-day AID proteins possess anti-retroelement activity. We found that AID can inhibit the retrotransposition of L1 through a DNA deamination-independent mechanism. This mechanism may manifest in the cytoplasmic compartment co- or posttranslationally. Together with evidence for AID expression in the ovary, our data combined to suggest that AID has innate immune functions in addition to its integral roles in creating antibody diversity

Estrogen directly activates AID transcription and function

The immunological targets of estrogen at the molecular, humoral, and cellular level have been well documented, as has estrogen's role in establishing a gender bias in autoimmunity and cancer. During a healthy immune response, activation-induced deaminase (AID) deaminates cytosines at immunoglobulin (Ig) loci, initiating somatic hypermutation (SHM) and class switch recombination (CSR). Protein levels of nuclear AID are tightly controlled, as unregulated expression can lead to alterations in the immune response. Furthermore, hyperactivation of AID outside the immune system leads to oncogenesis. Here, we demonstrate that the estrogen–estrogen receptor complex binds to the AID promoter, enhancing AID messenger RNA expression, leading to a direct increase in AID protein production and alterations in SHM and CSR at the Ig locus. Enhanced translocations of the c-myc oncogene showed that the genotoxicity of estrogen via AID production was not limited to the Ig locus. Outside of the immune system (e.g., breast and ovaries), estrogen induced AID expression by >20-fold. The estrogen response was also partially conserved within the DNA deaminase family (APOBEC3B, -3F, and -3G), and could be inhibited by tamoxifen, an estrogen antagonist. We therefore suggest that estrogen-induced autoimmunity and oncogenesis may be derived through AID-dependent DNA instability

Regulation of immune cell function and differentiation by the NKG2D receptor

NKG2D is one of the most intensively studied immune receptors of the past decade. Its unique binding and signaling properties, expression pattern, and functions have been attracting much interest within the field due to its potent antiviral and anti-tumor properties. As an activating receptor, NKG2D is expressed on cells of the innate and adaptive immune system. It recognizes stress-induced MHC class I-like ligands and acts as a molecular sensor for cells jeopardized by viral infections or DNA damage. Although the activating functions of NKG2D have been well documented, recent analysis of NKG2D-deficient mice suggests that this receptor may have a regulatory role during NK cell development. In this review, we will revisit known aspects of NKG2D functions and present new insights in the proposed influence of this molecule on hematopoietic differentiation