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Glomerular basement membrane heparan sulfate in health and disease: A regulator of local complement activation.
Borza DB
(2017) Matrix Biol 57-58: 299-310
MeSH Terms: Agrin, Animals, Collagen Type IV, Complement Activation, Complement C3b, Complement Factor H, Gene Expression Regulation, Glomerular Basement Membrane, Glomerulonephritis, Membranous, Heparitin Sulfate, Humans, Laminin, Lupus Nephritis, Membrane Glycoproteins, Signal Transduction, Static Electricity
Show Abstract · Added December 2, 2016
The glomerular basement membrane (GBM) is an essential component of the glomerular filtration barrier. Heparan sulfate proteoglycans such as agrin are major components of the GBM, along with α345(IV) collagen, laminin-521 and nidogen. A loss of GBM heparan sulfate chains is associated with proteinuria in several glomerular diseases and may contribute to the underlying pathology. As the major determinants of the anionic charge of the GBM, heparan sulfate chains have been thought to impart charge selectivity to the glomerular filtration, a view challenged by the negligible albuminuria in mice that lack heparan sulfate in the GBM. Recent studies provide increasing evidence that heparan sulfate chains modulate local complement activation by recruiting complement regulatory protein factor H, the major inhibitor of the alternative pathway in plasma. Factor H selectively inactivates C3b bound to surfaces bearing host-specific polyanions such as heparan sulfate, thus limiting complement activation on self surfaces such as the GBM, which are not protected by cell-bound complement regulators. We discuss mechanisms whereby the acquired loss of GBM heparan sulfate can impair the local regulation of the alternative pathway, exacerbating complement activation and glomerular injury in immune-mediated kidney diseases such as membranous nephropathy and lupus nephritis.
Copyright © 2016 Elsevier B.V. All rights reserved.
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16 MeSH Terms
Distinct roles for the complement regulators factor H and Crry in protection of the kidney from injury.
Laskowski J, Renner B, Le Quintrec M, Panzer S, Hannan JP, Ljubanovic D, Ruseva MM, Borza DB, Antonioli AH, Pickering MC, Holers VM, Thurman JM
(2016) Kidney Int 90: 109-22
MeSH Terms: Animals, Complement C3, Complement Factor H, Complement Pathway, Alternative, Glomerulonephritis, Kidney Glomerulus, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Receptors, Complement
Show Abstract · Added December 2, 2016
Mutations in the complement regulatory proteins are associated with several different diseases. Although these mutations cause dysregulated alternative pathway activation throughout the body, the kidneys are the most common site of injury. The susceptibility of the kidney to alternative pathway-mediated injury may be due to limited expression of complement regulatory proteins on several tissue surfaces within the kidney. To examine the roles of the complement regulatory proteins factor H and Crry in protecting distinct renal surfaces from alternative pathway mediated injury, we generated mice with targeted deletions of the genes for both proteins. Surprisingly, mice with combined genetic deletions of factor H and Crry developed significantly milder renal injury than mice deficient in only factor H. Deficiency of both factor H and Crry was associated with C3 deposition at multiple locations within the kidney, but glomerular C3 deposition was lower than that in factor H alone deficient mice. Thus, factor H and Crry are critical for regulating complement activation at distinct anatomic sites within the kidney. However, widespread activation of the alternative pathway reduces injury by depleting the pool of C3 available at any 1 location.
Copyright © 2016 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.
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12 MeSH Terms
Human and mouse neuroinflammation markers in Niemann-Pick disease, type C1.
Cologna SM, Cluzeau CV, Yanjanin NM, Blank PS, Dail MK, Siebel S, Toth CL, Wassif CA, Lieberman AP, Porter FD
(2014) J Inherit Metab Dis 37: 83-92
MeSH Terms: 1-Deoxynojirimycin, Adolescent, Alleles, Animals, Biomarkers, Brain, Cerebellum, Cerebral Cortex, Chemokine CCL3, Chemokine CXCL5, Child, Child, Preschool, Complement C3, Disease Models, Animal, Female, Gene Expression Regulation, Humans, Infant, Infant, Newborn, Inflammation, Interleukins, Male, Mice, Mice, Inbred BALB C, Mice, Transgenic, Niemann-Pick Disease, Type C, Young Adult
Show Abstract · Added March 13, 2014
Niemann-Pick disease, type C1 (NPC1) is an autosomal recessive lipid storage disorder in which a pathological cascade, including neuroinflammation occurs. While data demonstrating neuroinflammation is prevalent in mouse models, data from NPC1 patients is lacking. The current study focuses on identifying potential markers of neuroinflammation in NPC1 from both the Npc1 mouse model and NPC1 patients. We identified in the mouse model significant changes in expression of genes associated with inflammation and compared these results to the pattern of expression in human cortex and cerebellar tissue. From gene expression array analysis, complement 3 (C3) was increased in mouse and human post-mortem NPC1 brain tissues. We also characterized protein levels of inflammatory markers in cerebrospinal fluid (CSF) from NPC1 patients and controls. We found increased levels of interleukin 3, chemokine (C-X-C motif) ligand 5, interleukin 16 and chemokine ligand 3 (CCL3), and decreased levels of interleukin 4, 10, 13 and 12p40 in CSF from NPC1 patients. CSF markers were evaluated with respect to phenotypic severity. Miglustat treatment in NPC1 patients slightly decreased IL-3, IL-10 and IL-13 CSF levels; however, further studies are needed to establish a strong effect of miglustat on inflammation markers. The identification of inflammatory markers with altered levels in the cerebrospinal fluid of NPC1 patients may provide a means to follow secondary events in NPC1 disease during therapeutic trials.
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27 MeSH Terms
Murine membranous nephropathy: immunization with α3(IV) collagen fragment induces subepithelial immune complexes and FcγR-independent nephrotic syndrome.
Zhang JJ, Malekpour M, Luo W, Ge L, Olaru F, Wang XP, Bah M, Sado Y, Heidet L, Kleinau S, Fogo AB, Borza DB
(2012) J Immunol 188: 3268-77
MeSH Terms: Albuminuria, Animals, Autoantibodies, Autoantigens, Basement Membrane, Collagen Type IV, Complement C3, Disease Models, Animal, Glomerulonephritis, Membranous, Immunization, Immunoglobulin G, Kidney, Mice, Mice, Congenic, Mice, Inbred DBA, Nephrotic Syndrome, Pulmonary Alveoli, Receptors, IgG, Recombinant Fusion Proteins
Show Abstract · Added August 21, 2013
Membranous nephropathy (MN) is a leading cause of nephrotic syndrome in adults and a significant cause of end-stage renal disease, yet current therapies are nonspecific, toxic, and often ineffective. The development of novel targeted therapies requires a detailed understanding of the pathogenic mechanisms, but progress is hampered by the lack of a robust mouse model of disease. We report that DBA/1 mice as well as congenic FcγRIII(-/-) and FcRγ(-/-) mice immunized with a fragment of α3(IV) collagen developed massive albuminuria and nephrotic syndrome, because of subepithelial deposits of mouse IgG and C3 with corresponding basement membrane reaction and podocyte foot process effacement. The clinical presentation and histopathologic findings were characteristic of MN. Although immunized mice produced genuine anti-α3NC1 autoantibodies that bound to kidney and lung basement membranes, neither crescentic glomerulonephritis nor alveolitis ensued, likely because of the predominance of mouse IgG1 over IgG2a and IgG2b autoantibodies. The ablation of activating IgG Fc receptors did not ameliorate injury, implicating subepithelial deposition of immune complexes and consequent complement activation as a major effector pathway. We have thus established an active model of murine MN. This model, leveraged by the availability of genetically engineered mice and mouse-specific reagents, will be instrumental in studying the pathogenesis of MN and evaluating the efficacy of novel experimental therapies.
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19 MeSH Terms
Engineering complement activation on polypropylene sulfide vaccine nanoparticles.
Thomas SN, van der Vlies AJ, O'Neil CP, Reddy ST, Yu SS, Giorgio TD, Swartz MA, Hubbell JA
(2011) Biomaterials 32: 2194-203
MeSH Terms: Animals, Biocompatible Materials, Complement Activation, Complement C3, Complement Pathway, Alternative, Materials Testing, Mice, Mice, Inbred C57BL, Nanoparticles, Polypropylenes, Sulfides, Surface Plasmon Resonance, Surface Properties, Vaccines
Show Abstract · Added March 20, 2014
The complement system is an important regulator of both adaptive and innate immunity, implicating complement as a potential target for immunotherapeutics. We have recently presented lymph node-targeting, complement-activating nanoparticles (NPs) as a vaccine platform. Here we explore modulation of surface chemistry as a means to control complement deposition, in active or inactive forms, on polypropylene sulfide core, block copolymer Pluronic corona NPs. We found that nucleophile-containing NP surfaces activated complement and became functionalized in situ with C3 upon serum exposure via the alternative pathway. Carboxylated NPs displayed a higher degree of C3b deposition and retention relative to hydroxylated NPs, upon which deposited C3b was more substantially inactivated to iC3b. This in situ functionalization correlated with in vivo antigen-specific immune responses, including antibody production as well as T cell proliferation and IFN-γ cytokine production upon antigen restimulation. Interestingly, inactivation of C3b to iC3b on the NP surface did not correlate with NP affinity to factor H, a cofactor for protease factor I that degrades C3b into iC3b, indicating that control of complement protein C3 stability depends on architectural details in addition to factor H affinity. These data show that design of NP surface chemistry can be used to control biomaterials-associated complement activation for immunotherapeutic materials.
Copyright © 2010 Elsevier Ltd. All rights reserved.
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14 MeSH Terms
Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes.
Monsalvo AC, Batalle JP, Lopez MF, Krause JC, Klemenc J, Hernandez JZ, Maskin B, Bugna J, Rubinstein C, Aguilar L, Dalurzo L, Libster R, Savy V, Baumeister E, Aguilar L, Cabral G, Font J, Solari L, Weller KP, Johnson J, Echavarria M, Edwards KM, Chappell JD, Crowe JE, Williams JV, Melendi GA, Polack FP
(2011) Nat Med 17: 195-9
MeSH Terms: Adolescent, Adult, Age Factors, Antibodies, Viral, Antigen-Antibody Complex, Antigens, Viral, Complement C3, Cross Reactions, Cytokines, Humans, Influenza A Virus, H1N1 Subtype, Influenza, Human, Interferon-alpha, Interferon-beta, Lung, Middle Aged, Young Adult
Show Abstract · Added November 14, 2013
Pandemic influenza viruses often cause severe disease in middle-aged adults without preexisting comorbidities. The mechanism of illness associated with severe disease in this age group is not well understood. Here we find preexisting serum antibodies that cross-react with, but do not protect against, 2009 H1N1 influenza virus in middle-aged adults. Nonprotective antibody is associated with immune complex-mediated disease after infection. We detected high titers of serum antibody of low avidity for H1-2009 antigen, and low-avidity pulmonary immune complexes against the same protein, in severely ill individuals. Moreover, C4d deposition--a marker of complement activation mediated by immune complexes--was present in lung sections of fatal cases. Archived lung sections from middle-aged adults with confirmed fatal influenza 1957 H2N2 infection revealed a similar mechanism of illness. These observations provide a previously unknown biological mechanism for the unusual age distribution of severe cases during influenza pandemics.
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17 MeSH Terms
Complement component 3 polymorphisms interact with polyunsaturated fatty acids to modulate risk of metabolic syndrome.
Phillips CM, Goumidi L, Bertrais S, Ferguson JF, Field MR, Kelly ED, Peloso GM, Cupples LA, Shen J, Ordovas JM, McManus R, Hercberg S, Portugal H, Lairon D, Planells R, Roche HM
(2009) Am J Clin Nutr 90: 1665-73
MeSH Terms: Adult, Case-Control Studies, Complement C3, Dietary Fats, Fatty Acids, Unsaturated, Female, Genotype, Humans, Male, Metabolic Syndrome, Middle Aged, Polymorphism, Single Nucleotide, Prospective Studies, Risk
Show Abstract · Added January 20, 2015
BACKGROUND - Complement component 3 (C3) is a novel determinant of the metabolic syndrome (MetS). Gene-nutrient interactions with dietary fat may affect MetS risk.
OBJECTIVES - The objectives were to determine the relation between C3 polymorphisms and MetS and whether interaction with plasma polyunsaturated fatty acids (PUFAs), a biomarker of dietary PUFA, modulate this relation.
DESIGN - C3 polymorphisms (rs11569562, rs2250656, rs1047286, rs2230199, rs8107911, rs344548, rs344550, rs2241393, rs7257062, rs163913, and rs2230204), biochemical measurements, and plasma fatty acids were measured in the LIPGENE-SUpplementation en VItamines et Minéraux AntioXydants (SU.VI.MAX) study in MetS cases and matched controls (n = 1754).
RESULTS - Two single nucleotide polymorphisms were associated with MetS. rs11569562 GG homozygotes had decreased MetS risk compared with minor A allele carriers [odds ratio (OR): 0.53; 95% CI: 0.35, 0.82; P = 0.009], which was augmented by high plasma PUFA status (OR: 0.32; 95% CI: 0.11, 0.93; P = 0.04). GG homozygotes had lower C3 concentrations than those in AA homozygotes (P = 0.03) and decreased risk of hypertriglyceridemia compared with A allele carriers (OR: 0.54; 95% CI: 0.34, 0.92; P = 0.02), which was further ameliorated by an increase in long-chain n-3 (omega-3) PUFAs (OR: 0.46; 95% CI: 0.22, 0.97; P = 0.04) or a decrease in n-6 PUFAs (OR: 0.32; CI: 0.16, 0.62; P = 0.002). rs2250656 AA homozygotes had increased MetS risk relative to minor G allele carriers (OR: 1.78; CI: 1.19, 2.70; P = 0.02), which was exacerbated by low n-6 PUFA status (OR: 2.20; CI: 1.09, 4.55; P = 0.03).
CONCLUSION - Plasma PUFAs may modulate the susceptibility to MetS that is conferred by C3 polymorphisms, which suggests novel gene-nutrient interactions. This trial was registered at clinicaltrials.gov as NCT00272428.
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14 MeSH Terms
Interleukin-1beta induces complement component C3 and IL-6 production at the basolateral and apical membranes in a human intestinal epithelial cell line.
Moon MR, Parikh AA, Pritts TA, Kane C, Fischer JE, Salzman AL, Hasselgren PO
(2000) Shock 13: 374-8
MeSH Terms: Acute-Phase Reaction, Caco-2 Cells, Cell Membrane, Complement C3, Epithelial Cells, Humans, Inflammation, Interleukin-1, Interleukin-6, Intestines, NF-kappa B, RNA, Messenger
Show Abstract · Added March 5, 2014
In previous studies, stimulation of cultured enterocytes with IL-1beta resulted in production of IL-6 and complement component C3. The cellular mechanisms of these responses in the enterocyte are not fully understood. We tested the hypothesis that IL-1beta-induced C3 and IL-6 production is differentially regulated at the apical and basolateral membranes of the enterocyte. Caco-2 cells (a transformed human colonic carcinoma cell line) were grown in a 2-chamber system to full differentiation. The cells were treated with IL-1beta either at the apical or basolateral membrane, and C3 and IL-6 mRNA levels and release of C3 and IL-6 into the apical and basal chambers were determined. The release of C3 was greatest into the basal chamber regardless of whether the cells were stimulated at the apical or basolateral membrane. In contrast, the production of IL-6 was greatest at the cell membrane that was stimulated with IL-1beta. Stimulation of the Caco-2 cells with IL-1beta resulted in increased mRNA levels for C3 and IL-6 with no major differences noted when the cells were treated at the apical or basolateral membrane. The results suggest that enterocyte production and release of at least some acute phase proteins and cytokines are differentially regulated at the apical and basolateral membrane of the enterocyte after stimulation with IL-1beta.
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12 MeSH Terms
Stress response decreases the interleukin-1beta-induced production of complement component C3 in human intestinal epithelial cells.
Moon R, Pritts TA, Parikh AA, Fischer JE, Salzman AL, Ryan M, Wong HR, Hasselgren PO
(1999) Clin Sci (Lond) 97: 331-7
MeSH Terms: Arsenites, Cell Line, Complement C3, Dose-Response Relationship, Immunologic, Down-Regulation, Epithelial Cells, HSP72 Heat-Shock Proteins, Heat-Shock Proteins, Heat-Shock Response, Hot Temperature, Humans, Interleukin-1, Intestinal Mucosa, RNA, Messenger, Sodium Compounds, Sulfhydryl Reagents
Show Abstract · Added March 5, 2014
Interleukin-1beta (IL-1beta) increases the production of complement component C3 in enterocytes. Heat shock regulates the response to cytokines and other inflammatory mediators in various cell types. We tested the hypothesis that the heat-shock response regulates IL-1beta-induced C3 production in the enterocyte. Cultured Caco-2 cells, a human intestinal epithelial cell line, were treated with sodium arsenite (10-500 microM) for 1 h or subjected to hyperthermia (43 degrees C) for 1-4 h, and allowed to recover for 1 h. The cells were then treated with IL-1beta (0.5 ng/ml) for up to 24 h, whereafter C3 levels were measured by ELISA and C3 mRNA by Northern blot analysis. Heat-shock protein of 72 kDa (hsp72) was determined by Western blot analysis. Treatment of the cells with sodium arsenite or subjecting them to hyperthermia induced the expression of hsp72. The IL-1beta-induced expression of C3 mRNA and C3 production were down-regulated by hyperthermia and sodium arsenite in a dose-dependent fashion. The results suggest that the stress response induced by hyperthermia or sodium arsenite decreases IL-1beta-induced C3 production in human enterocytes.
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16 MeSH Terms
Contribution of the innate immune system to autoimmune diabetes: a role for the CR1/CR2 complement receptors.
Noorchashm H, Moore DJ, Lieu YK, Noorchashm N, Schlachterman A, Song HK, Barker CF, Naji A
(1999) Cell Immunol 195: 75-9
MeSH Terms: Animals, B-Lymphocytes, Complement C3, Diabetes Mellitus, Type 1, Immunity, Innate, Immunophenotyping, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred NOD, Receptors, Complement 3b, Receptors, Complement 3d, Spleen
Show Abstract · Added October 24, 2013
B lymphocytes are required for diabetogenesis in nonobese diabetic (NOD) mice. The complement component of the innate immune system regulates B cell activation and tolerance through complement receptors CR1/CR2. Thus, it is important to assess the contribution of complement receptors to autoimmune diabetes in NOD mice. Examination of the lymphoid compartments of NOD mice revealed striking expansion of a splenic B cell subset with high cell surface expression of CR1/CR2. This subset of B cells exhibited an enhanced C3 binding ability. Importantly, long-term in vivo blockade of C3 binding to CR1/CR2 prevented the emergence of the CR1/CR2(hi) B cells and afforded resistance to autoimmune diabetes in NOD mice. These findings implicate complement as an important regulatory element in controlling the T cell-mediated attack on islet beta cells of NOD mice.
Copyright 1999 Academic Press.
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13 MeSH Terms