Glial cells are receiving much attention since they have been recognized as important regulators of many aspects of brain function and disease. Recent evidence has revealed that two different glial cells, astrocytes and microglia, control synapse elimination under normal and pathological conditions via phagocytosis. Astrocytes use the MEGF10 and MERTK phagocytic pathways, and microglia use the classical complement pathway to recognize and eliminate unwanted synapses. Notably, glial phagocytosis also contributes to the clearance of disease-specific protein aggregates, such as β-amyloid, huntingtin, and α-synuclein. Here we reivew recent findings showing that glial cells are active regulators in brain functions through phagocytosis and that changes in glial phagocytosis contribute to the pathogenesis of various neurodegenerative diseases. A better understanding of the cellular and molecular mechanisms of glial phagocytosis in healthy and diseased brains will greatly improve our current approach in treating these diseases.
Astrocytes ; Brain* ; Complement Pathway, Classical ; Microglia ; Neurodegenerative Diseases ; Neuroglia* ; Phagocytosis ; Protein Aggregates ; Synapses

Henoch-Schonlein purpura (HSP) is a systemic disorder characterized by leukocytoclastic vasculitis that can affect multiple organs predominantly the skin, joints, gastrointestinal tract and kidney. Although the specific pathogenesis of HSP is not known, there are several hypotheses. Although the importance of the complement activation in glomerular injury in HSP has been suggested, the complement levels and the blood pressure in those patients are usually normal and massive proteinuria is not common. And pathologic renal changes also have been reported to show a large variety of glomerular changes. However, to our knowledge, a membranoproliferative glomerulo-nephritis (MPGN) is a rare renal clinicopathologic manifestation of HSP. We report a 6-year-old boy with HSP who developed MPGN with hypertension, massive proteinuria, and hypo-complementemia revealed activation of the classical complement pathway, although we could not exclude the possibility of other hypocomplementemic glomerulonephritis including post-streptococcal acute glomerulonephritis.
Blood Pressure ; Child ; Complement Activation ; Complement Pathway, Classical ; Complement System Proteins ; Gastrointestinal Tract ; Glomerulonephritis ; Glomerulonephritis, Membranoproliferative* ; Humans ; Hypertension ; Joints ; Kidney ; Male ; Proteinuria ; Purpura, Schoenlein-Henoch* ; Skin ; Vasculitis

To evaluate the role of capsular polysaccharide (CPS) as a virulence factor, the interaction of V. vulnificus with mouse peritoneal macrophages and serum, which are involved in the clearance of bacteria from blood and other tissues, were examined. In this study, MO6-24/0 (wild strain; hemolysin- and capsule-positive), MO6-24/I' (acapsular spontaneous mutant), CVD 752 (acapsular transposon mutant), and CVD 707 (hemolysin-negative and capsule-positive mutant) were used. The strain with CPS (MO6-24/0 and CVD 707) were more resistant to phagocytosis by mouse peritoneal macrophages compared with acapsular strains (MO6-24/T and CVD 752), and the resistance to phagocytosis was not changed by serum opsonin in the capsular strains. Acapsular strains were more susceptible to serum bactericidal activity than the capsular strains through the classical complement pathway. MO6-24/0 strain were detected in blood, spleen, liver and lung at 4 hours after intraperitoneally infection, whereas CVD 752 were not detected. All tested strains could induced the transcription of inflammatory cytokine gene such as IL-1, IL-6, IL-10 and TNF-u, and their inductions were not decreased by cytochalasin B treatment. This results demonstrate that CPS of V. vulnificus plays an important role in V. vulnificus infection through interfering nonspecific host defense system such as blood clearance and phagocytosis.
Animals ; Bacteria ; Complement Pathway, Classical ; Cytochalasin B ; Interleukin-1 ; Interleukin-10 ; Interleukin-6 ; Liver ; Lung ; Macrophages, Peritoneal ; Mice ; Phagocytosis ; Spleen ; Vibrio vulnificus* ; Vibrio* ; Virulence*

Ehlers-Danlos syndrome (EDS) VIII is an autosomal dominant inherited connective tissue disorder characterized by intractable periodontal inflammation, absence of gingiva, pretibial plaques, skin hyperextensibility, joint hypermobility, and tissue fragility with onset in the childhood or adolescence. In a recent report, heterozygous variants of the C1R or C1S related to the classical complement pathway were identified in families with history of EDS VIII. The current report describes a Korean 34-year-old female carrying a novel missense variant of C1R c.925T>G (p.Cys309Gly) and exhibiting early severe periodontitis, skin fragility, and joint hypermobility. The patient also had frontal, parietal, and temporal white matter brain lesions without definite vascular abnormalities on brain magnetic resonance imaging, which have not been surveyed meticulously in EDS VIII. Considering the genetic alteration of classic complement pathways in this condition, it is necessary to carefully observe multisystemic inflammation processes such as changes in brain white matter.
Adolescent ; Adult ; Brain ; Complement C1r ; Complement Pathway, Classical ; Complement System Proteins ; Connective Tissue ; Ehlers-Danlos Syndrome ; Female ; Gingiva ; Humans ; Inflammation ; Joint Instability ; Magnetic Resonance Imaging ; Periodontitis ; Rabeprazole ; Skin ; White Matter

This study was designed to evaluate whether glomerular C4d deposition may be a useful marker of lupus nephritis activity. Twenty-one patients diagnosed as having lupus nephritis (WHO class III: 4 cases; IV: 12 cases; V: 5 cases) were included. Mean patient age was 29.3 +/- 13.5 years (range: 7-55 years). The presence and intensity of glomerular C4d deposition were compared with the corresponding histologic activity index for each case. Immunofluorescence for C4d showed diffusely granular staining along glomerular capillary loops, in all cases examined (1+, in 8 cases; 2+, in 7 cases; 3+, in 6cases). In eight cases, C4d deposition was found in the absence of capillary or mesangial C4 deposits. Moreover, the intensity of C4d deposits correlated with those of capillary IgG, IgA, C4, C1q, and fibrinogen deposits. However, C4d staining intensity did not correlate with the lupus nephritis activity index. Although glomerular capillary C4d deposition is a sensitive marker of classic complement pathway activation, it is not a sensitive marker for active lupus nephritis.
Adolescent ; Adult ; Biological Markers ; Child ; Complement 4/*metabolism ; Complement Pathway, Classical/*physiology ; Female ; Human ; Kidney Glomerulus/*metabolism ; Lupus Nephritis/*physiopathology ; Male ; Middle Aged ; Peptide Fragments/*metabolism ; Severity of Illness Index

Proteins of the complement system are known to interact with many charged substances. We recently characterized binding of C1q and factor H to immobilized and liposomal anionic phospholipids. Factor H inhibited C1q binding to anionic phospholipids, suggesting a role for factor H in regulating activation of the complement classical pathway by anionic phospholipids. To extend this finding, we examined interactions of C1q and factor H with lipid A, a well-characterized activator of the classical pathway. We report that C1q and factor H both bind to immobilized lipid A, lipid A liposomes and intact Escherichia coli TG1. Factor H competes with C1q for binding to these targets. Furthermore, increasing the factor H: C1q molar ratio in serum diminished C4b fixation, indicating that factor H diminishes classical pathway activation. The recombinant forms of the Cterminal, globular heads of C1q A, B and C chains bound to lipid A and E. coli in a manner qualitatively similar to native C1q, confirming that C1q interacts with these targets via its globular head region. These observations reinforce our proposal that factor H has an additional complement regulatory role of down-regulating classical pathway activation in response to certain targets. This is distinct from its role as an alternative pathway down-regulator. We suggest that under physiological conditions, factor H may serve as a downregulator of bacterially-driven inflammatory responses, thereby fine-tuning and balancing the inflammatory response in infections with Gram-negative bacteria.
Binding, Competitive ; immunology ; Complement Activation ; immunology ; Complement C1q ; chemistry ; immunology ; metabolism ; Complement C4b ; analysis ; Complement Factor H ; chemistry ; immunology ; metabolism ; Complement Pathway, Classical ; immunology ; Escherichia coli ; immunology ; metabolism ; Humans ; Iodine Radioisotopes ; Isotope Labeling ; Lipid A ; immunology ; metabolism ; Liposomes ; immunology ; metabolism ; Protein Binding ; immunology ; Recombinant Proteins ; chemistry ; immunology ; metabolism ; Substrate Specificity

Cold hemagglutinin disease is a form of immune hemolytic anemia caused by cold-reactive immunoglobulins. Cold agglutinins are autoantibodies, usually of the IgM type, that cause red blood cell agglutination at reduced temperatures. When the agglutinated antibody-covered red blood cells return to the central circulation, the classical complement pathway is activated. Complement components combine with the antibody-covered red blood cells, inducing membrane changes that result in intravascular hemolysis. Clinical manifestations of cold hemagglutinin disease, which occur only on cold exposure include acrocyanosis, purpura, Raynauds phenomenon, acral gangrene, immune complex nephritis, and hemolytic anemia. We experienced a case of 66-year-old woman with cold agglutinin disease, gastric cancer and gall bladder stone. Preoperative plasmapheresis and intraoperative forced air convective warming to minimize red blood cell agglutination and hemolysis were performed. The operating room was prewarmed to 31~32degrees C. The patient had her lower body and the upper extremities covered with warming blankets. Inspired gases were humidified at 37degrees C and intravenous fluids were warmed with a blood warmer. Peripheral body temperature was maintained above 36.5degrees C throughout the procedure. Subtotal gastrectomy and cholecystectomy were done successfully without complication. It can be concluded that the maintenance of central and peripheral body temperature above the thermal aetivity of the cold agglutinin is required during the perioperative period.
Aged ; Agglutination ; Agglutinins ; Anemia, Hemolytic ; Anemia, Hemolytic, Autoimmune ; Anesthesia, General* ; Antigen-Antibody Complex ; Autoantibodies ; Body Temperature ; Cholecystectomy ; Complement Pathway, Classical ; Complement System Proteins ; Erythrocytes ; Female ; Gangrene ; Gases ; Gastrectomy ; Hemagglutinins ; Hemolysis ; Humans ; Immunoglobulin M ; Immunoglobulins ; Membranes ; Nephritis ; Operating Rooms ; Perioperative Period ; Plasmapheresis ; Purpura ; Stomach Neoplasms ; Upper Extremity ; Urinary Bladder Calculi