Explore the vast range of titles available.

The soluble membrane attack complex (sMAC, a.k.a., sC5b-9 or TCC) is generated on activation of complement and contains the complement proteins C5b, C6, C7, C8, C9 together with the regulatory proteins clusterin and/or vitronectin. sMAC is a member of the MACPF/cholesterol-dependent-cytolysin superfamily of pore-forming molecules that insert into lipid bilayers and disrupt cellular integrity and function. sMAC is a unique complement activation macromolecule as it is comprised of several different subunits. To date no complement-mediated function has been identified for sMAC. sMAC is present in blood and other body fluids under homeostatic conditions and there is abundant evidence documenting changes in sMAC levels during infection, autoimmune disease and trauma. Despite decades of scientific interest in sMAC, the mechanisms regulating its formation in healthy individuals and its biological functions in both health and disease remain poorly understood. Here, we review the structural differences between sMAC and its membrane counterpart, MAC, and examine sMAC immunobiology with respect to its presence in body fluids in health and disease. Finally, we discuss the diagnostic potential of sMAC for diagnostic and prognostic applications and potential utility as a companion diagnostic.

A historic case-control study on 569 SARS patients demonstrated a role of MBL gene polymorphisms in contributing to the susceptibility of viral invasion, and implied that the complement lectin pathway represents the “first line of defense” against SARS-CoV infection (31,32). The pharmacological targeting of complement activation in severe COVID-19 may attenuate the increased mortality observed in a younger cohort of patients with persistent hyperinflammation, thromboembolic complications, and cardiac arrest beyond terminal respiratory failure associated with SARS-CoV-2 pneumonia. Specifically, there is no conflict of interest whatsoever by either of the two authors related to the pharmacological agents and companies cited in this manuscript. 1.CaoYLiuXXiongLCaiK.Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2: a systematic review and meta-analysis.J Med Virol. (2020)8:475–81.10.1016/S2213-2600(20)30079-532105632 4.TianWJiangWYaoJNicholsonCJLiRHSigurslidHH.Predictors of mortality in hospitalized COVID-19 patients: a systematic review and meta-analysis.J Med Virol.

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. We analyzed data from the 2010 National Inpatient Sample (NIS) and the National Emergency Department Survey (NEDS). We included patients treated in the Emergency Department (ED) as well as those admitted to an inpatient bed through the ED. We identified patients undergoing LPs from ICD-9 procedural code 03.31 and CPT code 62270. We generated nationally weighted estimates of the total number of LPs. We also assessed patient and hospital characteristics of cases undergoing LP. Of an estimated 135 million hospitalizations (ED + admission, or ED only), there were an estimated 362,718 LPs (331,248-394,188), including 273,612 (251,850-295,375) among adults and 89,106 (71,870-106,342) among children (<18 years old). Of the 362,718 LPs, 136,764 (122,117-151,410) were performed in the ED without admission. The most common conditions associated with LP among children were fever of unknown origin, meningitis, seizures and other perinatal conditions. The most common conditions associated with LP among adults were headache and meningitis. Lumbar Puncture remains an important procedure for diagnostic and therapeutic uses in United States Hospitals.

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. In the present study, using an amyloid precursor protein (APP) knock-in ( App KI) AD mouse model, we showed that oral infection with Porphyromonas gingivalis (Pg), a keystone pathogen of periodontitis, worsened behavioral and cognitive impairment and accelerated amyloid beta (Aβ) accumulation in AD mice, thus unquestionably and significantly aggravating AD. We also provide new evidence that the neuroinflammatory status established by AD, is greatly complicated by periodontal infection and the consequential entry of Pg into the brain via Aβ-primed microglial activation, and that Pg-induced brain overactivation of complement C1q is critical for periodontitis-associated acceleration of AD progression by amplifying microglial activation, neuroinflammation, and tagging synapses for microglial engulfment. Our study renders support for the importance of periodontal infection in the innate immune regulation of AD and the possibility of targeting microbial etiology and periodontal treatment to ameliorate the clinical manifestation of AD and lower AD prevalence.

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in industrialized nations, affecting 30-50 million people worldwide. The earliest clinical hallmark of AMD is the presence of drusen, extracellular deposits that accumulate beneath the retinal pigmented epithelium. Although drusen nearly always precede and increase the risk of choroidal neovascularization (CNV), the late vision-threatening stage of AMD, it is unknown whether drusen contribute to the development of CNV. Both in patients with AMD and in a recently described mouse model of AMD, early subretinal pigmented epithelium deposition of complement components C3 and C5 occurs, suggesting a contributing role for these inflammatory proteins in the development of AMD. Here we provide evidence that bioactive fragments of these complement components (C3a and C5a) are present in drusen of patients with AMD, and that C3a and C5a induce VEGF expression in vitro and in vivo. Further, we demonstrate that C3a and C5a are generated early in the course of laser-induced CNV, an accelerated model of neovascular AMD driven by VEGF and recruitment of leukocytes into the choroid. We also show that genetic ablation of receptors for C3a or C5a reduces VEGF expression, leukocyte recruitment, and CNV formation after laser injury, and that antibody-mediated neutralization of C3a or C5a or pharmacological blockade of their receptors also reduces CNV. Collectively, these findings establish a mechanistic basis for the clinical observation that drusen predispose to CNV, revealing a role for immunological phenomena in angiogenesis and providing therapeutic targets for AMD.

CD8 T-cell responses are critical for protection against intracellular pathogens and tumors. The induction and properties of these responses are governed by a series of integrated processes that rely heavily on cell–cell interactions. Intercellular adhesion molecule (ICAM)-1 functions to enhance the strength of antigenic stimulation, extend the duration of contact with antigen-presenting cells, and augment cytokine signals, which are all factors that influence peripheral CD8 T-cell differentiation. Although previous studies suggest that ICAM-1 is essential for establishing memory T-cell populations following peptide immunization, the roles of ICAM-1 in antiviral cellular immunity are less well understood. Here we show that, following a prototypic acute viral infection, the formation and maintenance of memory-phenotype CD127 ʰⁱ, KLRG-1 ˡᵒ CD8 T cells does not require ICAM-1. Nevertheless, ICAM-1 expression on nonlymphocytes dictates the phenotypic and functional attributes of the antiviral CD8 T-cell populations that develop and promotes the gradual attrition of residual effector-like CD127 ˡᵒ, KLRG-1 ʰⁱ CD8 T cells during the memory phase of the response. Although memory T cells do emerge and are maintained if ICAM-1 expression is abolished, the secondary proliferative capacity of these T cells is severely curtailed. Collectively, these studies reveal potential dual roles for ICAM-1 in both promoting the decay of effector responses and programming the sensitivity of memory CD8 T cells to secondary stimuli.

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. Combined with the absence of an identified C4a receptor and the inability of C4a to signal through the C3a and C5a receptors, it is clear that C4a should not be included in the family of complement anaphylatoxins.

Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the proinflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. Additionally, SNPs in genes encoding complement pathway proteins have been linked to susceptibility to pneumococcal infection, although no associations with disease severity or outcome have been established. Here, we have performed a robust prospective nationwide genetic association study in patients with bacterial meningitis and found that a common nonsynonymous complement component 5 (C5) SNP (rs17611) is associated with unfavorable disease outcome. C5 fragment levels in cerebrospinal fluid (CSF) of patients with bacterial meningitis correlated with several clinical indicators of poor prognosis. Consistent with these human data, C5a receptor-deficient mice with pneumococcal meningitis had lower CSF wbc counts and decreased brain damage compared with WT mice. Adjuvant treatment with C5-specific monoclonal antibodies prevented death in all mice with pneumococcal meningitis. Thus, our results suggest C5-specific monoclonal antibodies could be a promising new antiinflammatory adjuvant therapy for pneumococcal meningitis.

Abstract INTRODUCTION: Shunt infection and failure are associated with significant medical costs and hospitalization days. Current practice relies on microbiology culture, which significantly delays definitive diagnosis. Complement activation in the cerebrospinal fluid (CSF) has been shown to be a reliable biomarker of meningitis but has not been evaluated in shunt infection or failure. A rapid diagnostic complement assay could aid in identifying patients with hydrocephalus-associated complications. METHODS: A prospective cohort of 40 pediatric neurosurgical patients with newly diagnosed hydrocephalus, shunt failure, or shunt infection were enrolled from November 2014 through February 2015 at a single tertiary-care children's hospital. CSF was acquired at the time of initial surgical intervention and, in cases of infection, serial CSF draws were performed. Complement membrane attack complex (MAC) levels in 108 CSF samples were measured by ELISA. Statistical analysis was performed using GraphPad Prism to correlate MAC levels with culture-proven CSF infection. RESULTS: Of 40 patients, median age was 4 years (range 0–23). Etiologies of hydrocephalus included intraventricular hemorrhage, myelomeningocele, congenital hydrocephalus and tumor. Three statistically distinct categories of CSF MAC levels were identified: (1) pyogenic infection (1581 ± 1218 ng/mL, mean ± SEM); (2) symptomatic ventricular enlargement (SVE) without infection (39.2 ± 8.9 ng/mL); and (3) asymptomatic/Propionibacterium acnes infection (undetectable MAC < 3.7 ng/mL at 1:7 dilution). Infected patients had significantly higher MAC levels compared with SVE patients (Mann-Whitney, P = .003). In addition, infected patients undergoing serial CSF draws demonstrated progressive decrease in MAC levels over the course of antibiotic treatment. CONCLUSION: Preliminary results show CSF MAC levels may help differentiate between pyogenic infection, symptomatic ventricular enlargement, and asymptomatic/P acnes infected children. We are currently expanding this study with respect to patient number and complement biomarkers to establish predictive values that facilitate clinical decision making in this challenging population.