MASP-3 and its association with distinct complexes of the mannan-binding lectin complement activation pathway. Immunity ; 15 — MASP-1, a promiscuous complement protease: structure of its catalytic region reveals the basis of its broad specificity.
Hourcade DE. Properdin and complement activation: a fresh perspective. Curr Drug Targets ; 9 — Purification and crystallization of human anaphylatoxin, C3a. Hoppe Seylers Z Physiol Chem ; — X-ray crystal structure of C3d: a C3 fragment and ligand for complement receptor 2.
Structures of complement component C3 provide insights into the function and evolution of immunity. Nature ; — Factor B structure provides insights into activation of the central protease of the complement system.
Nat Struct Mol Biol ; 14 — The crystal structure of C2a, the catalytic fragment of classical pathway C3 and C5 convertase of human complement.
The role of properdin in the assembly of the alternative pathway C3 convertases of complement. Properdin can initiate complement activation by binding specific target surfaces and providing a platform for de novo convertase assembly. Activator-specific requirement of properdin in the initiation and amplification of the alternative pathway complement.
Blood ; — Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med ; 12 — Complement and coagulation: strangers or partners in crime? Trends Immunol ; 28 — Control of the complement system. Adv Immunol ; 61 — Complement factor I and cofactors in control of complement system convertase enzymes. Methods Enzymol ; — Turnberg D, Botto M. The regulation of the complement system: insights from genetically-engineered mice. Mol Immunol ; 40 — Identification of three physically and functionally distinct binding sites for C3b in human complement factor H by deletion mutagenesis.
Int J Biochem Cell Biol ; 31 — Structure of complement fragment C3b-factor H and implications for host protection by complement regulators. Nat Immunol ; 10 — Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor. Identification of the second heparin-binding domain in human complement factor H.
Human protectin CD59 , an 18,—20, MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers. Immunology ; 71 :1—9. Esser AF. The membrane attack complex of complement. Assembly, structure and cytotoxic activity.
Toxicology ; 87 — Quantitative analysis of adenine nucleotides during the prelytic phase of cell death mediated by C5b Complement mediated cell death is associated with DNA fragmentation. Cell Death Differ ; 7 — Frank MM. Annihilating host defense. Nat Med ; 7 — Anaphylatoxins: C3a and C5a. Adv Immunol ; 26 :1— Evolution of anaphylatoxins, their diversity and novel roles in innate immunity: insights from the study of fish complement. Vet Immunol Immunopathol ; — Complement factors and their receptors.
Immunopharmacology ; 38 :3— Human anaphylatoxin C4a is a potent agonist of the guinea pig but not the human C3a receptor. Haas PJ, van Strijp J. Anaphylatoxins: their role in bacterial infection and inflammation. Immunol Res ; 37 — Wetsel RA. Structure, function and cellular expression of complement anaphylatoxin receptors. Curr Opin Immunol ; 7 — Cloning and functional characterization of the mouse C3a anaphylatoxin receptor gene.
Immunogenetics ; 47 — Cloning, expression, sequence determination, and chromosome localization of the mouse complement C3a anaphylatoxin receptor gene. Mol Immunol ; 35 — Article Google Scholar. Genomics ; 13 — Cellular expression of the C5a anaphylatoxin receptor C5aR : demonstration of C5aR on nonmyeloid cells of the liver and lung.
Function, structure and therapeutic potential of complement C5a receptors. Br J Pharmacol ; — The N-formyl peptide receptors and the anaphylatoxin C5a receptors: an overview. Biochimie ; 89 — Eur J Biochem ; — Eur J Immunol ; 27 — Mol Pharmacol ; 46 — Specific interactions of chemoattractant factor receptors with G-proteins.
Mapping of the C5a receptor signal transduction network in human neutrophils. The receptor for complement anaphylatoxin C3a is expressed by myeloid cells and nonmyeloid cells in inflamed human central nervous system: analysis in multiple sclerosis and bacterial meningitis.
Expression of a functional anaphylatoxin C3a receptor by astrocytes. J Neurochem ; 71 — Receptors for the anaphylatoxins C3a and C5a are expressed in human atherosclerotic coronary plaques. Atherosclerosis ; — High levels of complement C3a receptor in the glomeruli in lupus nephritis. Am J Kidney Dis ; 49 — Receptors for complement C5a.
The importance of C5aR and the enigmatic role of C5L2. Immunol Cell Biol ; 86 — Human plasmacytoid dendritic cells express receptors for anaphylatoxins C3a and C5a and are chemoattracted to C3a and C5a. J Invest Dermatol ; — Characterization of C5aR expression on murine myeloid and lymphoid cells by the use of a novel monoclonal antibody. Immunol Lett ; 88 — Expression of the anaphylatoxin C5a receptor in non-myeloid cells. Mol Immunol ; 36 — Membrane complement receptors specific for bound fragments of C3.
Adv Immunol ; 37 — Macrophage complement receptors and pathogen clearance. Cell Microbiol ; 9 — Fearon DT. Identification of the membrane glycoprotein that is the C3b receptor of the human erythrocyte, polymorphonuclear leukocyte, B lymphocyte, and monocyte.
J Exp Med ; — Immunity ; 7 — Structure-function relationships of complement receptor type 1. Immunol Rev ; — Ross GD.
Crit Rev Immunol ; 20 — CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Progress in Immunology. New York: Academic, Pepys MB. Role of complement in induction of the allergic response.
Nat New Biol ; — Complement, membrane glycoproteins, and complement receptors: their role in regulation of the immune response. Clin Immunol Immunopathol ; 40 — Role of C3 in humoral immunity. Defective antibody production in C3-deficient dogs. Complement dependence of localisation of aggregated IgG in germinal centres.
Scand J Immunol ; 4 — Carroll MC. The complement system in B cell regulation. Complement and humoral immunity. Vaccine ; 26 Suppl 8 :I28— Characterization of murine complement receptor type 2 and its immunological cross-reactivity with type 1 receptor. Int Immunol ; 2 — Expression of complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response.
CD lowering the threshold for antigen receptor stimulation of B lymphocytes. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Transitional B cells are the target of negative selection in the B cell compartment. Mice deficient in complement receptors 1 and 2 lack a tissue injury-inducing subset of the natural antibody repertoire.
Functional activity of natural antibody is altered in Cr2-deficient mice. Essentially all upregulated genes and pathways returned to baseline expression levels at resolution of TA-TMA after eculizumab therapy, supporting the clinical practice of discontinuing complement blockade after resolution of TA-TMA.
In summary, we observed activation of multiple complement pathways in TA-TMA, in contrast to atypical hemolytic uremic syndrome aHUS , where complement activation occurs largely via the alternative pathway.
Our data also suggest a key relationship between increased interferon signaling, complement activation, and TA-TMA. These findings open opportunities to study novel complement blockers and combined anti-complement and anti-interferon therapies in patients with TA-TMA and other microangiopathies like aHUS and lupus-associated TMAs.
Here, we present novel evidence using gene expression analysis of complement activation via all complement pathways-alternative, classical, and lectin. Our data indicate important roles for activation of both complement and interferon pathways in patients with TA-TMA and offer potential new therapeutic targets for TA-TMA and other disorders presenting with thrombotic microangiopathies, especially in patients with lack of response to eculizumab therapy.
Patients are consented before transplant, prospectively enrolled, and blood samples are collected and stored starting before transplant and continuing weekly until day after HSCT. Cases and time-matched controls had available peripheral blood mononuclear cells PBMCs samples stored within 1 week before transplant conditioning chemotherapy baseline , at the time of TA-TMA diagnosis, and when eculizumab was discontinued or equivalent timepoints in controls supplemental Figure 1.
Patient demographics and disease characteristics were captured from the clinical database. A baseline sample was not used because it represents recipient PBMCs.
To accurately quantify the library concentration for the clustering, the library was diluted in dilution buffer 10 mM Tris-HCl, pH 8. Individually indexed libraries were proportionally pooled million reads per sample for clustering in the cBot system Illumina, San Diego, CA. Libraries at the final concentration of Sequence reads were aligned to the human reference genome hg19 using the TopHat2 aligner 16 and reads aligning to each known transcript were counted using Bioconductor packages for NGS data analysis.
Statistical significance of differential expressions was established for false discovery rate FDR —adjusted P values. The gene list enrichment analysis was performed in 2 steps.
A stringent Bonferroni adjustment was used for P value adjustment in this analysis. Second, the Random Set 25 enrichment analysis, as implemented in the CLEAN package, 26 of upregulated genes against all MSigDB gene sets 27 was performed to identify additional complement and interferon-related categories. Standard FDR P value adjustment was also used in this analysis. We selected 7 autologous HSCT recipients range, years old with neuroblastoma who all received identical high-dose chemotherapy conditioning with carboplatin, etoposide, and melphalan, a regimen reported to be associated with a high-risk of TA-TMA and had stored samples available for this study.
All 4 cases were treated with eculizumab and received 7 to 19 doses, after which they all had resolution of TA-TMA and normalization of their blood sC5b-9 concentration and recovery of organ function.
Eculizumab was successfully discontinued in all treated cases without any evidence of TA-TMA recurrence. All 4 cases were alive and well at 1 year after transplant.
Demographics and disease characteristics are summarized in supplemental Table 2. Demographics and relevant disease characteristic are listed in supplemental Table 3.
An enrichment analysis of KEGG pathways, 21 transcription factor targets, 22,23 and MSigDB hallmark gene sets 24 identified significant activation of complement, complement-related genes, and interferon-responsive genes Table 1. The involvement of differentially expressed genes in upregulated complement and interferon-related pathways, including signal transducer and activator of transcription 1 and 2 STAT1 and STAT2 targets, is illustrated in supplemental Figure 2. The comprehensive analysis of MSigDB identified additional complement and interferon-related gene sets enriched for upregulated genes Table 2.
Upregulated pathways and transcription factor targets at the time of TA-TMA diagnosis as compared with pretransplant baseline. Focused analysis of gene expression levels of complement and interferon-related genes showed significant changes in expression of 76 complement and interferon-related genes Figure 1. The genes that were still upregulated after resolution of TA-TMA were related to proliferation, and increased expression is likely appropriate during stem cell engraftment and blood count recovery.
The figure shows a section of the heatmap that illustrates the change in complement and interferon gene expression profiles in patients with TA-TMA. Pathway analyses confirmed significant upregulation of multiple complement pathways, including upregulation of the alternative, classical, and lectin pathways at TA-TMA diagnosis as compared with pretransplant baseline.
No complement pathways were downregulated. Specifically, the data showed a marked upregulation of expression of the complement component C1Q C chain Upregulation of C2 elevated 2.
Factor D was also upregulated 1. Additional changes in expression of key genes in the alternative, classical, and lectin pathways of complement activation are displayed in Figure 2.
This figure illustrates gene expression in alternative, classical, and lectin complement pathways among cases with TA-TMA at the time of clinical diagnosis but before initiation of complement-blocking therapy with eculizumab. Red letters and red outlines indicate statistically significant changes in gene expression from pretransplant baseline to the time of TA-TMA clinical diagnosis.
Because of our interest in identifying new targetable endothelial injury pathways, we investigated if interferon activation was associated with TA-TMA, or just with the transplantation process itself, by comparing gene expression profiles at TA-TMA diagnosis and resolution in cases with TA-TMA and at equivalent timepoints in controls without TA-TMA.
Most of the genes in interferon related pathways were not significantly upregulated in controls without TA-TMA at equivalent timepoints posttransplant. Green bars indicate statistically significant differences between time points.
Interferon pathways are not upregulated in controls without TA-TMA at matched time points after transplant. Expression of C2, a key component of the classical pathway, was significantly elevated in cases with TA-TMA, as was CFD, a promoter of rapid activation of complement via the alternative pathway. CFI, a negative regulator of complement, was significantly upregulated more than eightfold in controls without TA-TMA and was nonsignificantly upregulated 3.
We examined only TA-TMA diagnosis and TA-TMA resolution timepoints and not the pretransplant baseline sample in these subjects because in the allogeneic HSCT setting the host genome is present before transplant and the donor genome at the latter 2 timepoints. HSCT is a planned procedure and TA-TMA is frequent in our patient population so biological samples can be collected before, during, and after TA-TMA, allowing mechanistic studies that are impossible with less predictable forms of thrombotic microangiopathies, like atypical hemolytic uremic syndrome aHUS.
The cause of endothelial injury in patients with neuroblastoma and TA-TMA is likely related to high-dose chemotherapy, and we were able to study children receiving exactly the same chemotherapy regimen to eliminate another potential source of heterogeneity.
We considered at length the suitability of PBMC as a source of RNA for this study, rather than liver, traditionally thought to be the major source of complement components. PBMC have the important advantage of being accessible for serial collection, a strategy that would not be possible with liver tissue from human patients.
Enzymes called granzymes are also stored in, and released from, the granules. Granzymes enter target cells through the holes made by perforin.
Once inside the target cell, they initiate a process known as programmed cell death or apoptosis, causing the target cell to die. Another released cytotoxic factor is granulysin , which directly attacks the outer membrane of the target cell, destroying it by lysis. Cytotoxic cells also newly synthesise and release other proteins, called cytokines , after making contact with infected cells.
Cytokines include interferon-g and tumour necrosis factor-a , and transfer a signal from the T cell to the infected, or other neighbouring cells, to enhance the killing mechanisms. Virally infected cells produce and release small proteins called interferons , which play a role in immune protection against viruses.
Interferons prevent replication of viruses, by directly interfering with their ability to replicate within an infected cell. They also act as signalling molecules that allow infected cells to warn nearby cells of a viral presence — this signal makes neighbouring cells increase the numbers of MHC class I molecules upon their surfaces, so that T cells surveying the area can identify and eliminate the viral infection as described above.
Viruses can also be removed from the body by antibodies before they get the chance to infect a cell. Antibodies are proteins that specifically recognise invading pathogens and bind stick to them. This binding serves many purposes in the eradication of the virus:. Register Log in. Immune responses to viruses Download Immune responses to viruses. Release from monocytes of protein which inhibits monocyte chemotaxis. Am J Pathol — Complement anaphylatoxin C4a inhibits C5a-induced neointima formation following arterial injury.
Mol Med Rep 10 — Barnum SR. C4a: an anaphylatoxin in name only. J Innate Immun Inactivation of C3a and C5a octapeptides by carboxypeptidase R and carboxypeptidase N. Microbiol Immunol 46 —4. Carboxypeptidase N: a pleiotropic regulator of inflammation.
Mol Immunol 40 — Targeted disruption of the gene encoding the murine small subunit of carboxypeptidase N CPN1 causes susceptibility to C5a anaphylatoxin-mediated shock. Carboxypeptidase B2 deficiency reveals opposite effects of complement C3a and C5a in a murine polymicrobial sepsis model. J Thromb Haemost Two different transduction pathways are activated by C3a and C5a anaphylatoxins on astrocytes. Brain Res Mol Brain Res — Structural and functional characterization of human and murine C5a anaphylatoxins.
Acta Crystallogr D Biol Crystallogr 70 — Expression cloning of the human C3a anaphylatoxin receptor C3aR from differentiated U cells. Eur J Immunol 26 — C3a desArg does not bind to and signal through the human C3a receptor. Immunol Lett 67 —5. Mol Immunol 42 —7. C3a and C5a stimulate chemotaxis of human mast cells. Blood 89 — Local production and activation of complement up-regulates the allostimulatory function of dendritic cells through C3a-C3aR interaction.
Mol Immunol 58 — Heeger PS, Kemper C. Novel roles of complement in T effector cell regulation. Immunobiology — Weibel-Palade bodies — sentinels of acute stress. Nat Rev Nephrol 5 —6. Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 67 — Platelet activation leads to activation and propagation of the complement system. J Exp Med —9. Alternative pathway activation of complement by shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis.
Gerard NP, Gerard C. The chemotactic receptor for human C5a anaphylatoxin. C5a delays apoptosis of human neutrophils by a phosphatidylinositol 3-kinase-signaling pathway. Kidney Int 61 — Roles of phospholipase C beta2 in chemoattractant-elicited responses.
Complement C5a activation of phospholipase D in human neutrophils. A major route to the production of phosphatidates and diglycerides.
Mapping of the C5a receptor signal transduction network in human neutrophils. Chemotaxis by mouse macrophage cell lines. Activation of human neutrophils by C3a and C5A.
Comparison of the effects on shape changes, chemotaxis, secretion, and respiratory burst. FEBS Lett —4. Histamine-induced inhibition of normal human basophil chemotaxis to C5a. Modulation of the antitumor immune response by complement. Nat Immunol 9 — Human T cells express the C5a receptor and are chemoattracted to C5a. J Immunol —7. Decay accelerating factor can control T cell differentiation into IFN-gamma-producing effector cells via regulating local C5a-induced IL production.
Protective effects of C5a blockade in sepsis. Nat Med 5 — Curr Eye Res 34 — The orphan receptor C5L2 has high affinity binding sites for complement fragments C5a and C5a des-Arg C5L2, a nonsignaling C5A binding protein. Biochemistry 42 — Disruption of the complement anaphylatoxin receptor C5L2 exacerbates inflammation in allergic contact dermatitis.
An anti-inflammatory function for the complement anaphylatoxin C5a-binding protein, C5L2. High expression of C5L2 correlates with high proinflammatory cytokine expression in advanced human atherosclerotic plaques.
C5L2 and C5aR interaction in adipocytes and macrophages: insights into adipoimmunology. Cell Signal 25 —8. Cell Signal 26 — J Cell Biol — Annu Rev Physiol 69 — Regulation of toll-like receptor-mediated inflammatory response by complement in vivo. TLR2 transmodulates monocyte adhesion and transmigration via Rac1- and PI3K-mediated inside-out signaling in response to Porphyromonas gingivalis fimbriae. Kagan JC, Medzhitov R. Phosphoinositide-mediated adaptor recruitment controls toll-like receptor signaling.
Cell — Induction of anaphylatoxin C5a receptors in rat hepatocytes by lipopolysaccharide in vivo: mediation by interleukin-6 from kupffer cells. Gastroenterology — C5a negatively regulates toll-like receptor 4-induced immune responses. Immunity 22 — Combination of a TLR4 ligand and anaphylatoxin C5a for the induction of antigen-specific cytotoxic T cell responses.
Vaccine 30 — Crosstalk between toll like receptors and C5a receptor in human monocyte derived DCs suppress inflammatory cytokine production. Pepys MB. Role of complement in induction of antibody production in vivo effect of cobra factor and other C3-reactive agents on thymus-dependent and thymus-independent antibody responses.
Inhibition by C3 fragments of C3-dependent rosette formation and antigen-induced lymphocyte transformation. Clin Exp Immunol 18 — A re-evaluation of the role of C3 in B-cell activation.
Immunol Today 7 —5. Expression of complement receptors 1 and 2 on follicular dendritic cells is necessary for the generation of a strong antigen-specific IgG response. C3d of complement as a molecular adjuvant: bridging innate and acquired immunity. Science — Immunity 18 — Complement C4 maintains peripheral B-cell tolerance in a myeloid cell dependent manner.
Eur J Immunol 43 — Cutting edge: complement C3d -linked antigens break B cell anergy. The complement system contributes to the pathology of experimental autoimmune encephalomyelitis by triggering demyelination and modifying the antigen-specific T and B cell response.
Clin Immunol — Kemper C, Atkinson JP. T-cell regulation: with complements from innate immunity. Nat Rev Immunol 7 :9— Nature — Complement: central to innate immunity and bridging to adaptive responses. Immunol Lett 97 —9. C3 opsonization regulates endocytic handling of apoptotic cells resulting in enhanced T-cell responses to cargo-derived antigens.
The receptor for the complement C3a anaphylatoxin C3aR provides host protection against Listeria monocytogenes-induced apoptosis. Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells.
Nat Immunol 14 — Nat Immunol 13 — Human C3 deficiency associated with impairments in dendritic cell differentiation, memory B cells, and regulatory T cells. Semin Immunol 25 —9. Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells. Decay-accelerating factor modulates induction of T cell immunity.
Complement and its role in innate and adaptive immune responses. Cell Res 20 — PLoS One 9 :e Mol Immunol 43 — Intracellular sensing of complement C3 activates cell autonomous immunity. Science Complement evasion by human pathogens. Nat Rev Microbiol 6 — Complement evasion of pathogens: common strategies are shared by diverse organisms.
Mol Immunol 44 —7. Functional significance of factor H binding to Neisseria meningitidis. Bordetella pertussis binds the human complement regulator C4BP: role of filamentous hemagglutinin.
Infect Immun 65 — Yersinia pestis ail recruitment of C4b-binding protein leads to factor I-mediated inactivation of covalently and noncovalently bound C4b: immunity to infection. Eur J Immunol 44 — The meningococcal vaccine candidate neisserial surface protein A NspA binds to factor H and enhances meningococcal resistance to complement. PLoS Pathog 6 :e Binding of complement inhibitor C4b-binding protein to a highly virulent Streptococcus pyogenes M1 strain is mediated by protein H and enhances adhesion to and invasion of endothelial cells.
Structural basis for complement evasion by lyme disease pathogen Borrelia burgdorferi. Microbes bind complement inhibitor factor H via a common site. PLoS Pathog 9 :e Human factor H interacts selectively with Neisseria gonorrhoeae and results in species-specific complement evasion. Neisseria meningitidis recruits factor H using protein mimicry of host carbohydrates. Nature —3. Foster TJ. Immune evasion by Staphylococci. Nat Rev Microbiol 3 — Results Immunol 3 — Staphylococcus aureus surface protein SdrE binds complement regulator factor H as an immune evasion tactic.
PLoS One 7 :e Structure and regulatory profile of the monkeypox inhibitor of complement: comparison to homologs in vaccinia and variola and evidence for dimer formation. Herpes simplex virus type 1 glycoprotein gC mediates immune evasion in vivo. J Virol 72 — Bacterial complement evasion. Mol Immunol 44 — Immune evasion by pathogenic Leptospira strains: the secretion of proteases that directly cleave complement proteins. J Infect Dis — Anti-opsonic properties of staphylokinase.
Microbes Infect 7 — Staphylococcal proteases aid in evasion of the human complement system. Staphylococcus aureus metalloprotease aureolysin cleaves complement C3 to mediate immune evasion. Neisseria meningitidis NalP cleaves human complement C3, facilitating degradation of C3b and survival in human serum.
Inhibition of the classical pathway of complement by meningococcal capsular polysaccharides. A novel factor I activity in Nipah virus inhibits human complement pathways through cleavage of C3b. J Virol 89 — A structural basis for complement inhibition by Staphylococcus aureus. Nat Immunol 8 —7. Electrostatic contributions drive the interaction between Staphylococcus aureus protein Efb-C and its complement target C3d. Protein Sci 17 — Staphylococcus aureus proteins Sbi and Efb recruit human plasmin to degrade complement C3 and C3b.
Identification and characterization of the C3 binding domain of the Staphylococcus aureus extracellular fibrinogen-binding protein Efb. J Biol Chem —6. Inhibition of complement activation by a secreted Staphylococcus aureus protein. J Infect Dis —9. Characterization of Ehp, a secreted complement inhibitory protein from Staphylococcus aureus.
The Staphylococcus aureus protein Sbi acts as a complement inhibitor and forms a tripartite complex with host complement factor H and C3b. PLoS Pathog 4 :e Structure-function analysis of the C3 binding region of Staphylococcus aureus immune subversion protein Sbi. Staphylococcal complement evasion by various convertase-blocking molecules. Molecular basis for complement recognition and inhibition determined by crystallographic studies of the staphylococcal complement inhibitor SCIN bound to C3c and C3b.
Advances in understanding the structure, function, and mechanism of the SCIN and Efb families of staphylococcal immune evasion proteins. Adv Exp Med Biol — A molecular insight into complement evasion by the staphylococcal complement inhibitor protein family.
Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor. Nat Immunol 10 —7. Staphylococcal complement inhibitor modulates phagocyte responses by dimerization of convertases. J Immunol —5. Ricklin D, Lambris JD. Compstatin: a complement inhibitor on its way to clinical application.
Molecular mechanisms of complement evasion: learning from staphylococci and meningococci. Nat Rev Microbiol 8 —9. The complement system in systemic lupus erythematosus: an update. Ann Rheum Dis 73 —6. Molecular basis of hereditary C1q deficiency — revisited: identification of several novel disease-causing mutations. Genes Immun 12 — Diagnostic value of serum anti-C1q antibodies in patients with lupus nephritis: a meta-analysis.
Lupus 21 — Identification of a major linear C1q epitope allows detection of systemic lupus erythematosus anti-C1q antibodies by a specific peptide-based enzyme-linked immunosorbent assay. Arthritis Rheum 64 — Anti-C1q autoantibodies, novel tests, and clinical consequences. Front Immunol 4 Anti-C1q autoantibodies deposit in glomeruli but are only pathogenic in combination with glomerular C1q-containing immune complexes.
J Clin Invest — Autoantibodies against complement C1q specifically target C1q bound on early apoptotic cells. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med — Alternative complement pathway assessment in patients with atypical HUS. J Immunol Methods :8— C3 glomerulopathy: a new classification.
Nat Rev Nephrol 6 —9. Sethi S, Fervenza FC. Membranoproliferative glomerulonephritis — a new look at an old entity. Genetics of hemolytic uremic syndromes.
The binding of factor H to a complex of physiological polyanions and C3b on cells is impaired in atypical hemolytic uremic syndrome. Mutations of factor H impair regulation of surface-bound C3b by three mechanisms in atypical hemolytic uremic syndrome. J Biol Chem —8. Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome.
Mutations in components of complement influence the outcome of factor I-associated atypical hemolytic uremic syndrome. Kidney Int 77 — Mutations in complement factor I as found in atypical hemolytic uremic syndrome lead to either altered secretion or altered function of factor I.
Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome.
0コメント