Expression of innate immune complement regulators on brain epithelial cells during human bacterial meningitis

Background  

In meningitis, the cerebrospinal fluid contains high levels of innate immune molecules (e.g. complement) which are essential to ward off the infectious challenge and to promote the infiltration of phagocytes (neutrophils, monocytes). However, epithelial cells of either the ependymal layer, one of the established niche for adult neural stem cells, or of the choroid plexus may be extremely vulnerable to bystander attack by cytotoxic and cytolytic complement components.     

Review: Could neurotransmitters influence neurogenesis and neurorepair after stroke?

Brain ischaemia and reperfusion produce alterations in the microenvironment of the parenchyma, including ATP depletion, ionic homeostasis alterations, inflammation, release of multiple cytokines and abnormal release of neurotransmitters. As a consequence, the induction of proliferation and migration of neural stem cells is redirected towards the peri‐infarct region. The success of new neurorestorative treatments for damaged brain implies the need to describe with greater accuracy the mechanisms in charge of regulating adult neurogenesis, under both physiological and pathological conditions. Recent evidence demonstrates that many neurotransmitters, glutamate in particular, control the subventricular zone (SVZ), thus being part of the complex signal network that exerts a remarkable influence on the production of new neurones. Neurotransmitters provide a link between brain activity and SVZ neurogenesis. Therefore, a deeper knowledge of the role of neurotransmitters systems, such as glutamate and its transporters, in adult neurogenesis, may prove a valuable tool to be utilized as a neurorestorative therapy in this pathology.     

Protective DNA vaccination against myelin oligodendrocyte glycoprotein is overcome by C3d in experimental autoimmune encephalomyelitis

Complement receptor 2 (CR2) and its physiological ligand, C3d, known for its molecular adjuvant property on the immune response, exhibit opposite effects with regard to autoimmunity. Although CR2 has been implicated in maintaining self-tolerance, recent studies reported a role for C3d signaling to CR2 in tolerance breakdown to self-antigens and the initiation of inflammatory autoimmune pathologies. In the present study, we have investigated the effect of C3d in a model of tolerogenic DNA vaccination encoding the myelin oligodendrocyte glycoprotein (MOG-DNA) which protected mice from the induction of an experimental autoimmune encephalomyelitis (EAE). We show that fusing two or three copies of C3d to MOG overcomes the protective effect of DNA vaccination. Multimeric C3d was able to revert the unresponsiveness state of specific T cells induced by MOG-DNA, independently of a modification in the Th1/Th2 cytokine pattern. Interestingly, the adjuvant effect of C3d was not sufficient to boost the anti-MOG antibody response after DNA vaccination. These findings suggest that C3d might be involved in self-tolerance breakdown and could contribute to the pathogenesis of central nervous system autoimmune disorders.     

Low levels of the key B cell activation marker,HLA-DR,in COVID-19 hospitalized cases are associated with disease severity,dexamethasone treatment,and circulating IL-6 levels

Immunologic Research -     

CD93 is a cell surface lectin receptor involved in the control of the inflammatory response stimulated by exogenous DNA

Bacterial DNA contains CpG oligonucleotide (ODN) motifs to trigger innate immune responses through the endosomal receptor Toll-like receptor 9 (TLR9). One of the cell surface receptors to capture and deliver microbial DNA to intracellular TLR9 is the C-type lectin molecule DEC-205 through its N-terminal C-type lectin-like domain (CTLD). CD93 is a cell surface protein and member of the lectin group XIV with a CTLD. We hypothesized that CD93 could interact with CpG motifs, and possibly serve as a novel receptor to deliver bacterial DNA to endosomal TLR9. Using ELISA and tryptophan fluorescence binding studies we observed that the soluble histidine-tagged CD93-CTLD was specifically binding to CpG ODN and bacterial DNA. Moreover, we found that CpG ODN could bind to CD93-expressing IMR32 neuroblastoma cells and induced more robust interleukin-6 secretion when compared with mock-transfected IMR32 control cells. Our data argue for a possible contribution of CD93 to control cell responsiveness to bacterial DNA in a manner reminiscent of DEC-205. We postulate that CD93 may act as a receptor at plasma membrane for DNA or CpG ODN and to grant delivery to endosomal TLR9.     

Increased Complement Biosynthesis By Microglia and Complement Activation on Neurons in Huntington's Disease

In this study complement activation and biosynthesis have been analysed in the brains of Huntington's disease (HD) (n = 9) and normal (n = 3) individuals. In HD striatum, neurons, myelin and astrocytes were strongly stained with antibodies to C1q, C4, C3, iC3b-neoepitope and C9-neoepitope. In contrast, no staining for complement components was found in the normal striatum. Marked astrogliosis and microgliosis were observed in all HD caudate and the internal capsule samples but not in normal brain. RT-PCR analysis and in-situ hybridisation were carried out to determine whether complement was synthesised locally by activated glial cells. By RT-PCR, we found that complement activators of the classical pathway C1q C chain, C1r, C4, C3, as well as the complement regulators, C1 inhibitor, clusterin, MCP, DAF, CD59, were all expressed constitutively and at much higher level in HD brains compared to normal brain. Complement anaphylatoxin receptor mRNAs (C5a receptor and C3a receptor) were strongly expressed in HD caudate. In general, we found that the level of complement mRNA in normal control brains was from 2 to 5 fold lower compared to HD striatum. Using in-situ hybridisation, we confirmed that C3 mRNA and C9 mRNA were expressed by reactive microglia in HD internal capsule. We propose that complement produced locally by reactive microglia is activated on the membranes of neurons, contributing to neuronal necrosis but also to proinflammatory activities. Complement opsonins (iC3b) and anaphylatoxins (C3a, C5a) may be involved in the recruitment and stimulation of glial cells and phagocytes bearing specific complement receptors.     

Molecular and cellular insights into the coxsackie–adenovirus receptor: role in cellular interactions in the stem cell niche

In recent years, progress has been made in characterizing the molecular and cellular elements that are responsible for the regeneration in the damaged brain and highlighting the key role of the stromal-vascular ‘environment’ to orchestrate secondary neurogenesis and repair. Indeed, the ability of the stem cells to self-renew and differentiate is tightly regulated by stromal ependymal cells and endothelial cells expressing molecular cues that constitute the extracellular stem cell ‘niche’. Several soluble growth factors such as EGF, TGFβ, FGF2, SDF-1α and Noggin are important signals for the stem cell niche but little is known about the role of membrane-bound molecules in intercellular communications between the niche and the stem cells. In this mini-review, we highlight the emerging role of a family of adhesion molecules in the control of secondary neurogenesis. The coxsackie–adenovirus receptor (CAR) is a 46 kDa transmembrane protein and a member of the immunoglobulin super family. It is close structurally and evolutionary to other adhesion molecules involved in cell–cell interactions during embryogenesis, broadly expressed in the developing central nervous system but restricted to ependymal cells in the adult brain. This unique location and its newly established signalling properties further support the role of CAR in intercellular communications. Elucidating the other signalling molecules and manipulating the stromal-vascular niche for example by adenovirus gene therapy remain important goals for future clinical applications.     

Uptake of GABA by bovine adrenal medulla slices

Summary A sodium dependent GABA uptake system has been found in bovine adrenal medulla slices. This uptake has a K _m of 83.19±38.45 M and a V _max of 9.20±1.36 pmol/min×mg of tissue. It was inhibited by nipecotic acid and 2,4-diaminobutyric acid (IC50 67 and 38.5 M, respectively) but not by -alanine at concentrations up to 5 mM, a result which is similar to those found for the neuronal GABA uptake rather than the glial uptake. It is suggested that GABA uptake together with catabolic action of GABA-transaminase, also found in this tissue, could be regulating the GABA levels disposable for the proposed modulator role on catecholamine secretion of this amino acid in adrenal medulla.     

NFL during acute spinal cord lesions in MS: a hurdle for the detection of inflammatory activity

Journal of Neurology - Levels of neuro-filament light chain (NFL) correlate with clinical and radiological activity in multiple sclerosis (MS) and have been used as a surrogate biomarker of axonal...