Periodontal Infection Aggravates C1q-Mediated Microglial Activation and Synapse Pruning in Alzheimer's Mice.

Periodontitis is a dysbiotic infectious disease that leads to the destruction of tooth supporting tissues. There is increasing evidence that periodontitis may affect the development and severity of Alzheimer's disease (AD). However, the mechanism(s) by which periodontal infection impacts the neurodegenerative process in AD remains unclear.

Soluble Membrane Attack Complex: Biochemistry and Immunobiology.

The soluble membrane attack complex (sMAC, a.k.a.

RNASeq analysis reveals upregulation of complement C3 in the offspring gut following prenatal stress in mice.

Dysregulated activation of inflammatory signaling by the immature neonatal immune system could lead to the development of many pediatric diseases including necrotizing enterocolitis (NEC). While the mechanism(s) of pathogenesis is unknown, NEC is believed to have multifactorial causes. Microbial dysbiosis and intestinal immaturity have been implicated as potential triggers for this disease.

Epidemiology of lumbar punctures in hospitalized patients in the United States.

Objectives: Lumbar puncture (LP) is an important technique for assessing and treating neurological symptoms. The objective of this study was to describe the characteristics of diagnostic lumbar punctures performed on hospitalized patients in the United States.

Methods: We analyzed data from the 2010 National Inpatient Sample (NIS) and the National Emergency Department Survey (NEDS).

Soluble membrane attack complex in the blood and cerebrospinal fluid of HIV-infected individuals, relationship to HIV RNA, and comparison with HIV negatives.

The soluble membrane attack complex (sMAC) represents the terminal product of the complement cascade. We enrolled 47 HIV+ adults (12 of whom underwent a second visit at least 24weeks after starting therapy) as well as 11 HIV negative controls. At baseline, cerebrospinal fluid (CSF) sMAC was detectable in 27.

Therapeutic Inhibition of Complement: Well Worth the Risk.

Complement is an integral part of the immune system and protects against infection. Complement-mediated immunopathology in many autoimmune diseases and syndromes has led to the therapeutic targeting of complement and to questions around the safety of complement inhibition. Here; I examine and clarify the risks associated with complement therapeutics.

Complement peptide C3a stimulates neural plasticity after experimental brain ischaemia.

Ischaemic stroke induces endogenous repair processes that include proliferation and differentiation of neural stem cells and extensive rewiring of the remaining neural connections, yet about 50% of stroke survivors live with severe long-term disability. There is an unmet need for drug therapies to improve recovery by promoting brain plasticity in the subacute to chronic phase after ischaemic stroke. We previously showed that complement-derived peptide C3a regulates neural progenitor cell migration and differentiation in vitro and that C3a receptor signalling stimulates neurogenesis in unchallenged adult mice.

Complement: A primer for the coming therapeutic revolution.

The complement system is an important part of the innate and adaptive immune systems. Originally characterized as a single serum component contributing to the killing of bacteria, we now know that there are close to sixty complement proteins, multiple activation pathways and a wide range of effector functions mediated by complement. The system plays a critical role in host defense against bacteria, viruses, fungi and other pathogens.

Soluble membrane attack complex is diagnostic for intraventricular shunt infection in children.

Background: Children treated with cerebrospinal fluid (CSF) shunts to manage hydrocephalus frequently develop shunt failure and/or infections, conditions that present with overlapping symptoms. The potential life-threatening nature of shunt infections requires rapid diagnosis; however, traditional microbiology is time consuming, expensive, and potentially unreliable. We set out to identify a biomarker that would identify shunt infection.

C4a: An Anaphylatoxin in Name Only.

Activation of complement leads to generation of the 3 anaphylatoxins C3a, C4a, and C5a. Although all 3 peptides are structurally similar, only C3a and C5a share a similar functional profile that includes the classic inflammatory activities and, more recently, developmental homing and regenerative properties among others. In contrast, the functional profile of C4a is questionable in most cases owing to contamination of C4a preparations with physiologically relevant levels of C3a and/or C5a.

Cell surface levels of endothelial ICAM-1 influence the transcellular or paracellular T-cell diapedesis across the blood-brain barrier.

The extravasation of CD4(+) effector/memory T cells (TEM cells) across the blood-brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) or multiple sclerosis (MS). Endothelial ICAM-1 and ICAM-2 are essential for CD4(+) TEM cell crawling on the BBB prior to diapedesis. Here, we investigated the influence of cell surface levels of endothelial ICAM-1 in determining the cellular route of CD4(+) TEM -cell diapedesis across cytokine treated primary mouse BBB endothelial cells under physiological flow.

Complement C5-deficient mice are protected from seizures in experimental cerebral malaria.

Studies have demonstrated that the membrane attack complex (MAC) of complement can evoke seizures when injected directly into rodent brain. In the course of studies that examine the role of complement in the development of experimental cerebral malaria (ECM), we observed fewer seizures in mice deficient in C5, a component required for MAC formation. To determine if the MAC contributed to the tonic-clonic seizures characteristic of ECM, we performed long-term video-electroencephalography (EEG) on C5(-/-) mice with Plasmodium berghei ANKA-induced cerebral malaria and observed significantly reduced spike and seizure frequency compared to wild-type mice.

Role of complement systems in IVIG mediated attenuation of cognitive deterioration in Alzheimer's disease.

Human intravenous immunoglobulin (IVIG) has been indicated as a potential therapy for autoimmune neurological disorders, as well as in many neurodegenerative diseases, with various underlying therapeutic mechanisms such as regulation of T-cell trafficking, cytokines, Fc receptor blocking, and interruption of complement activation cascade. In Alzheimer's disease (AD), IVIG presents naturally occurring antibodies against amyloid-beta (Aβ) aggregation, thus IVIG immunotherapy may increase the clearance of Aβ and protect brain function. Recently, we and others reported that besides Aβ clearance, IVIG specifically regulates the levels of complement-derived anaphylatoxins, such as C5a and C3, which play an important role in the regulation of AMPA and NMDA receptor expression in the brain and further upregulate the AMPA-PKA-CREB signaling pathway and synaptic function in AD mouse models.

Deletion of C-reactive protein ameliorates experimental cerebral malaria?

Background: C-reactive protein (CRP) level correlates with parasitemia and severity of malaria, but whether this reflects causality remains unknown.

Methods: Using CRP-transgenic and CRP-deficient mice we compared the onset and severity of experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA (PbA).

Results: CRP-deficient mice were most resistant to ECM.

ICAM-1: isoforms and phenotypes.

ICAM-1 plays an important role in leukocyte trafficking, immunological synapse formation, and numerous cellular immune responses. Although considered a single glycoprotein, there are multiple membrane-bound and soluble ICAM-1 isoforms that arise from alternative splicing and proteolytic cleavage during inflammatory responses. The function and expression of these isoforms on various cell types are poorly understood.

Expression of a single ICAM-1 isoform on T cells is sufficient for development of experimental autoimmune encephalomyelitis.

Intercellular adhesion molecule-1 (ICAM-1) plays an important role in leukocyte trafficking, induction of cellular immune responses, and immunological synapse formation. As a member of the immunoglobulin superfamily of adhesion proteins, ICAM-1 is composed of repeating Ig-like domains, a transmembrane domain, and short cytoplasmic tail that participates in intracellular signaling events. At least seven ICAM-1 protein isoforms are generated by alternative splicing, however little is known regarding their immunobiology.

The deleterious effect of red blood cell storage on microvascular response to transfusion.

Background: The transfusion of relatively older red blood cells (RBCs) has been associated with both morbidity and mortality in trauma patients in observational studies. Although the mechanisms responsible for this phenomenon remain unclear, alterations in the microcirculation as a result of the transfusion of relatively older blood may be a causative factor. To assess this hypothesis, we evaluated microvascular perfusion in trauma patients during RBC transfusion.

The complement anaphylatoxin receptors are not required for the development of experimental autoimmune uveitis.

To determine if complement anaphylatoxin-mediated inflammation contributes to the development and progression of experimental autoimmune uveitis (EAU), we induced disease in wild type and complement anaphylatoxin receptor-deficient mice (C3a receptor(-/-), C5a receptor(-/-) and C3aR(-/-)/C5aR(-/-)) and evaluated the eyes three weeks post-induction. No differences in disease severity or in disease incidence were seen between wild type controls and anaphylatoxin receptor-deficient mice. Our data indicate that C3a and C5a-mediated functions are not critical to the development of EAU.

Carboxypeptidase N-deficient mice present with polymorphic disease phenotypes on induction of experimental autoimmune encephalomyelitis.

Carboxypeptidase N (CPN) is a member of the carboxypeptidase family of enzymes that cleave carboxy-terminal lysine and arginine residues from a large number of biologically active peptides and proteins. These enzymes are best known for their roles in modulating the activity of kinins, complement anaphylatoxins and coagulation proteins. Although CPN makes important contributions to acute inflammatory events, little is known about its role in autoimmune disease.

IVIG immunotherapy protects against synaptic dysfunction in Alzheimer's disease through complement anaphylatoxin C5a-mediated AMPA-CREB-C/EBP signaling pathway.

Background: Complement component C5-derived C5a locally generated in the brain has been shown to protect against glutamate-induced neuronal apoptosis and beta-amyloid (Aβ) toxicity, but the mechanism is not clear. In this study, we tested the hypothesis that C5a influences upstream signal transduction pathways associated with cAMP-response element-binding protein (CREB) activation, in which alterations of CREB levels are associated with cognitive deterioration in AD.

Methods: CREB signaling pathway, synaptic plasticity and cognitive function were studied in C5a receptor knockout mice (C5aR(-/-)), C5a over expressing mice (C5a/GFAP) and in Tg2576 mice, an AD mouse model.

Receptor for complement peptide C3a: a therapeutic target for neonatal hypoxic-ischemic brain injury.

Complement is an essential component of inflammation that plays a role in ischemic brain injury. Recent reports demonstrate novel functions of complement in normal and diseased CNS, such as regulation of neurogenesis and synapse elimination. Here, we examined the role of complement-derived peptide C3a in unilateral hypoxia-ischemia (HI), a model of neonatal HI encephalopathy.