Publications
146 results found
Laskowski J, Renner B, Le Quintrec M, et al., 2016, Distinct roles for the complement regulators factor H and Crry in protection of the kidney from injury, Kidney International, Vol: 90, Pages: 109-122, ISSN: 1523-1755
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.
Vernon KA, Ruseva MM, Cook HT, et al., 2016, Partial complement factor H deficiency associates with C3 glomerulopathy and thrombotic microangiopathy, Journal of the American Society of Nephrology, Vol: 27, Pages: 1334-1342, ISSN: 1046-6673
The complement–mediated renal diseases C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) strongly associate with inherited and acquired abnormalities in the regulation of the complement alternative pathway (AP). The major negative regulator of the AP is the plasma protein complement factor H (FH). Abnormalities in FH result in uncontrolled activation of C3 through the AP and associate with susceptibility to both C3G and aHUS. Although previously developed FH–deficient animal models have provided important insights into the mechanisms underlying susceptibility to these unique phenotypes, these models do not entirely reproduce the clinical observations. FH is predominantly synthesized in the liver. We generated mice with hepatocyte–specific FH deficiency and showed that these animals have reduced plasma FH levels with secondary reduction in plasma C3. Unlike mice with complete FH deficiency, hepatocyte–specific FH–deficient animals developed neither plasma C5 depletion nor accumulation of C3 along the glomerular basement membrane. In contrast, subtotal FH deficiency associated with mesangial C3 accumulation consistent with C3G. Although there was no evidence of spontaneous thrombotic microangiopathy, the hepatocyte–specific FH–deficient animals developed severe C5–dependent thrombotic microangiopathy after induction of complement activation within the kidney by accelerated serum nephrotoxic nephritis. Taken together, our data indicate that subtotal FH deficiency can give rise to either spontaneous C3G or aHUS after a complement-activating trigger within the kidney and that the latter is C5 dependent.
Kirresh A, Everitt A, Kon OM, et al., 2016, Trapped without a diagnosis: Tumour necrosis factor receptor-associated periodic syndrome (TRAPS)., Practical Neurology, Vol: 16, Pages: 304-307, ISSN: 1474-7766
Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant condition caused by mutations in the TNFRSF1A gene. It is characterised by recurrent episodes of myalgia, followed by prolonged fever, migratory rashes, headache, serositis, arthralgia, abdominal pain and periorbital oedema. We describe a 49-year-old man with a self-limiting episode of paraparesis who reported recurrent bouts of abdominal symptoms and headaches since childhood. He had a persistent inflammatory response with night sweats and weight loss. We diagnosed TRAPS 2 years after having identified a TNFRSF1A gene mutation. His symptoms and inflammatory response resolved dramatically with the interleukin-1 receptor antagonist anakinra.
Barbour TD, Ling GS, Ruseva MM, et al., 2016, Complement receptor 3 mediates renal protection in experimental C3 glomerulopathy, Kidney International, Vol: 89, Pages: 823-832, ISSN: 1523-1755
C3 glomerulopathy is a complement-mediated renal disease that is frequently associated with abnormalities in regulation of the complement alternative pathway. Mice with deficiency of factor H (Cfh–/–), a negative alternative pathway regulator, are an established experimental model of C3 glomerulopathy in which complement C3 fragments including iC3b accumulate along the glomerular basement membrane. Here we show that deficiency of complement receptor 3 (CR3), the main receptor for iC3b, enhances the severity of spontaneous renal disease in Cfh–/– mice. This effect was found to be dependent on CR3 expression on bone marrow–derived cells. CR3 also mediated renal protection outside the setting of factor H deficiency, as shown by the development of enhanced renal injury in CR3-deficient mice during accelerated nephrotoxic nephritis. The iC3b–CR3 interaction downregulated the proinflammatory cytokine response of both murine and human macrophages to lipopolysaccharide stimulation in vitro, suggesting that the protective effect of CR3 on glomerular injury was mediated via modulation of macrophage-derived proinflammatory cytokines. Thus, CR3 has a protective role in glomerulonephritis and suggests that pharmacologic potentiation of the macrophage CR3 interaction with iC3b could be therapeutically beneficial.
Ruseva MM, Peng T, Lasaro MA, et al., 2016, Efficacy of targeted complement inhibition in experimental C3 glomerulopathy, Journal of the American Society of Nephrology, Vol: 27, Pages: 405-416, ISSN: 1533-3450
C3 glomerulopathy refers to renal disorders characterised by abnormal accumulation of C3 within the kidney, commonly along the glomerular basement membrane (GBM). C3 glomerulopathy is associated with complement alternative pathway dysregulation, which include functional defects in complement regulator factor H (FH). There is no effective treatment for C3 glomerulopathy. We investigated the efficacy of CR2-FH, a recombinant mouse protein comprised of domains from complement receptor 2 (CR2) and FH, in two models of C3 glomerulopathy, where there is either pre-existing or triggered C3 deposition along the GBM. FH-deficient mice spontaneously develop renal pathology associated with abnormal C3 accumulation along the GBM and secondary plasma C3 deficiency. CR2-FH partially restored plasma C3 levels in FH-deficient mice two hours after intravenous injection. CR2-FH specifically targeted glomerular C3 deposits, reduced the linear C3 reactivity assessed with anti-C3 and anti-C3b/iC3b/C3c antibodies and prevented further spontaneous accumulation of C3 fragments along the GBM. Reduction in glomerular C3d and C9/C5b-9 reactivity was seen after daily administration of CR2-FH for one week. In a second mouse model, utilising animals with combined deficiency of FH and complement factor I, CR2-FH prevented de novo C3 deposition along the GBM. These data showed that CR2-FH protected the GBM from both spontaneous and triggered C3 deposition in vivo and indicate that this approach should be tested in C3 glomerulopathy.
Renner B, Tong HH, Laskowski J, et al., 2016, Annexin A2 enhances complement activation by inhibiting factor H, Journal of Immunology, Vol: 196, Pages: 1355-1365, ISSN: 1550-6606
Factor H is a circulating protein that regulates activation of the alternative pathway (AP) of complement. Mutations and genetic variations of factor H are associated with several AP-mediated diseases, highlighting the critical role of factor H in AP regulation. AP-mediated inflammation is typically triggered by illness or tissue injury, however, and tissue injury can trigger AP activation in individuals with fully functional factor H. This suggests that factor H function is affected by local conditions within tissues. We hypothesized that inducible proteins impair the ability of factor H to locally control the AP, thereby increasing AP activation. We used purified murine factor H to immunoprecipitate binding partners from mouse kidneys. Using immunoaffinity liquid chromatography–mass spectrometry, we identified annexin A2 as a factor H binding partner. Further experiments showed that annexin A2 reduces the binding of factor H to cell surfaces. Recombinant annexin A2 impaired complement regulation by factor H and increased complement activation on renal cell surfaces in vitro and in vivo. In a murine model of acute pneumococcal otitis media, the administration of annexin A2 increased AP-mediated bacterial opsonization and clearance. In conclusion, the local production of annexin A2 within tissues suppresses regulation of the AP by factor H. Annexin A2 can contribute to AP-mediated tissue inflammation by locally impairing factor H function, but it can also improve complement-mediated bacterial clearance.
van der Maten E, Westra D, van Selm S, et al., 2016, Complement factor H serum levels determine resistance to pneumococcal invasive disease, Journal of Infectious Diseases, Vol: 213, Pages: 1820-1827, ISSN: 1537-6613
Streptococcus pneumoniae is a major cause of life-threatening infections. Complement activation plays a vital role in opsonophagocytic killing of pneumococci in blood. Initial complement activation via the classical and lectin pathways is amplified through the alternative pathway amplification loop. Alternative pathway activity is inhibited by complement factor H (FH). Our study demonstrates the functional consequences of the variability in human serum FH levels on host defense. Using an in vivo mouse model combined with human in vitro assays, we show that the level of serum FH correlates with the efficacy of opsonophagocytic killing of pneumococci. In summary, we found that FH levels determine a delicate balance of alternative pathway activity, thus affecting the resistance to invasive pneumococcal disease. Our results suggest that variation in FH expression levels, naturally occurring in the human population, plays a thus far unrecognized role in the resistance to invasive pneumococcal disease.
Østergaard JA, Ruseva MM, Malik TH, et al., 2016, Increased autoreactivity of the complement-activating molecule mannan-binding lectin in a type 1 diabetes model, Journal of Diabetes Research, Vol: 2016, ISSN: 2314-6753
Background. Diabetic kidney disease is the leading cause of end-stage renal failure despite intensive treatment of modifiable risk factors. Identification of new drug targets is therefore of paramount importance. The complement system is emerging as a potential new target. The lectin pathway of the complement system, initiated by the carbohydrate-recognition molecule mannan-binding lectin (MBL), is linked to poor kidney prognosis in diabetes. We hypothesized that MBL activates complement upon binding within the diabetic glomerulus. Methods. We investigated this by comparing complement deposition and activation in kidneys from streptozotocin-induced diabetic mice and healthy control mice. Results. After 20 weeks of diabetes, glomerular deposition of MBL was significantly increased. Diabetic animals had 2.0-fold higher (95% CI 1.6-2.5) immunofluorescence intensity from anti-MBL antibodies compared with controls (P < 0.001). Diabetes and control groups did not differ in glomerular immunofluorescence intensity obtained by antibodies against complement factors C4, C3, and C9. However, the circulating complement activation product C3a was increased in diabetes as compared to control mice (P = 0.04). Conclusion. 20 weeks of diabetes increased MBL autoreactivity in the kidney and circulating C3a concentration. Together with previous findings, these results indicate direct effects of MBL within the kidney in diabetes.
Panzer SE, Laskowski J, Renner B, et al., 2015, IgM exacerbates glomerular disease progression in complement-induced glomerulopathy, Kidney International, Vol: 88, Pages: 528-537, ISSN: 1523-1755
Although glomerular immunoglobulin M (IgM) deposition occurs in a variety of glomerular diseases, the mechanism of deposition and its clinical significance remain controversial. Some have theorized IgM becomes passively trapped in areas of glomerulosclerosis. However, recent studies found that IgM specifically binds damaged glomeruli. Therefore, we tested whether natural IgM binds to neo-epitopes exposed after insults to the glomerulus and exacerbates disease in mice deficient in the complement regulatory protein factor H; a model of non-sclerotic and nonimmune-complex glomerular disease. Immunofluorescence microscopy demonstrated mesangial and capillary loop deposition of IgM, whereas ultrastructural analysis found IgM deposition on endothelial cells and subendothelial areas. Factor H-deficient mice lacking B cells were protected from renal damage, as evidenced by milder histologic lesions on light and electron microscopy. IgM, but not IgG, from wild-type mice bound to cultured murine mesangial cells. Furthermore, injection of purified IgM into mice lacking B cells bound within the glomeruli and induced proteinuria. A monoclonal natural IgM-recognizing phospholipids also bound to glomeruli in vivo and induced albuminuria. Thus, our results indicate specific IgM antibodies bind to glomerular epitopes and that IgM contributes to the progression of glomerular damage in this mouse model of non-sclerotic glomerular disease.
Saja MF, Baudino L, Jackson WD, et al., 2015, Triglyceride-Rich Lipoproteins Modulate the Distribution and Extravasation of Ly6C/Gr1<SUP>low</SUP> Monocytes, CELL REPORTS, Vol: 12, Pages: 1802-1815, ISSN: 2211-1247
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- Citations: 29
Pickering MC, Ismajli M, Condon MB, et al., 2015, Eculizumab as rescue therapy in severe resistant lupus nephritis., Rheumatology, Vol: 54, Pages: 2286-2288, ISSN: 1462-0332
Nichols EM, Barbour TD, Pappworth IY, et al., 2015, An extended mini-complement factor H molecule ameliorates experimental C3 glomerulopathy., Kidney International, Vol: 88, Pages: 1314-1322, ISSN: 1523-1755
Abnormal regulation of the complement alternative pathway is associated with C3 glomerulopathy. Complement factor H is the main plasma regulator of the alternative pathway and consists of 20 short consensus repeat (SCR) domains. Although recombinant full-length factor H represents a logical treatment for C3 glomerulopathy, its production has proved challenging. We and others have designed recombinant mini-factor H proteins in which 'non-essential' SCR domains have been removed. Here, we report the in vitro and in vivo effects of a mini-complement factor H protein, FH(1-5^18-20), using the unique factor H-deficient (Cfh-/-) mouse model of C3 glomerulopathy. FH(1-5^18-20) is comprised of the key complement regulatory domains (SCRs 1-5) linked to the surface recognition domains (SCRs 18-20). Intraperitoneal injection of FH(1-5^18-20) in Cfh-/- mice reduced abnormal glomerular C3 deposition, similar to full-length factor H. Systemic effects on plasma alternative pathway control were comparatively modest, in association with a short half-life. Thus, FH(1-5^18-20) is a potential therapeutic agent for C3 glomerulopathy and other renal conditions with alternative pathway-mediated tissue injury.Kidney International advance online publication, 29 July 2015; doi:10.1038/ki.2015.233.
Barbour T, 2015, The role of complement iC3b in dense deposit disease
Dense deposit disease (DDD) is a rare, progressive and incurable kidney disease characterized by complement C3 accumulation along the glomerular basement membrane (GBM). It is the prototypical form of C3 glomerulopathy, which comprises renal disorders due to excessive C3 activation via the alternative pathway (AP). Human and murine studies indicate that renal inflammation in DDD is initiated by the specific C3 activation product iC3b. I have assessed the role of iC3b in DDD using the uniquely informative experimental model of C3 glomerulopathy in factor H (FH)-deficient mice. I demonstrate that coexisting deficiency of CD11b, the specific leukocyte receptor for iC3b, exacerbates the spontaneous renal phenotype in FH-deficient mice. This suggests that the iC3b-CD11b interaction may mediate partial renal protection in DDD. I also show that CD11b deficiency produces hypersensitivity to experimentally triggered glomerular injury in both FH-deficient and FH-sufficient mice. My second experimental approach in vivo and in vitro was to assess whether C3 activation in the circulation or on the GBM surface is the predominant cause of iC3b accumulation in DDD. This included experiments in which administration of a novel engineered human FH protein fragment reduced glomerular C3 staining in FH-deficient mice.
Csincsi AI, Kopp A, Zoeldi M, et al., 2015, Factor H-Related Protein 5 Interacts with Pentraxin 3 and the Extracellular Matrix and Modulates Complement Activation, Journal of Immunology, Vol: 194, Pages: 4963-4973, ISSN: 1550-6606
The physiological roles of the factor H (FH)-related proteins are controversial and poorly understood. Based on genetic studies, FHrelatedprotein 5 (CFHR5) is implicated in glomerular diseases, such as atypical hemolytic uremic syndrome, dense deposit disease,and CFHR5 nephropathy. CFHR5 was also identified in glomerular immune deposits at the protein level. For CFHR5, weak complementregulatory activity and competition for C3b binding with the plasma complement inhibitor FH have been reported, but itsfunction remains elusive. In this study, we identify pentraxin 3 (PTX3) as a novel ligand of CFHR5. Binding of native CFHR5 toPTX3 was detected in human plasma and the interaction was characterized using recombinant proteins. The binding of PTX3 toCFHR5 is of ∼2-fold higher affinity compared with that of FH. CFHR5 dose-dependently inhibited FH binding to PTX3 and alsoto the monomeric, denatured form of the short pentraxin C–reactive protein. Binding of PTX3 to CFHR5 resulted in increasedC1q binding. Additionally, CFHR5 bound to extracellular matrix in vitro in a dose-dependent manner and competed with FH forbinding. Altogether, CFHR5 reduced FH binding and its cofactor activity on pentraxins and the extracellular matrix, while at thesame time allowed for enhanced C1q binding. Furthermore, CFHR5 allowed formation of the alternative pathway C3 convertaseand supported complement activation. Thus, CFHR5 may locally enhance complement activation via interference with thecomplement-inhibiting function of FH, by enhancement of C1q binding, and by activating complement, thereby contributingto glomerular disease
Kerr H, Herbert AH, Malik T, et al., 2015, EVALUATION OF RECOMBINANT COMPLEMENT FACTOR H IN A MODEL OF DENSE DEPOSIT DISEASE, 52nd Congress of the European-Renal-Association-European-Dialysis-and-Transplant-Assocation, Publisher: OXFORD UNIV PRESS, ISSN: 0931-0509
Cook HT, Pickering MC, 2015, Histopathology of MPGN and C3 glomerulopathies, NATURE REVIEWS NEPHROLOGY, Vol: 11, Pages: 14-22, ISSN: 1759-5061
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- Citations: 65
Caesar JJE, Lavender H, Ward PN, et al., 2014, Competition between antagonistic complement factors for a single protein on N-meningitidis rules disease susceptibility, eLife, Vol: 3, ISSN: 2050-084X
Barbour TD, Ruseva MM, Pickering MC, 2014, Update on C3 glomerulopathy, Nephrology Dialysis Transplantation, Vol: 31, Pages: 717-725, ISSN: 1460-2385
C3 glomerulopathy refers to a disease process in which abnormal control of complement activation, degradation or deposition results in predominant C3 fragment deposition within the glomerulus and glomerular damage. Recent studies have improved our understanding of its pathogenesis. The key abnormality is uncontrolled C3b amplification in the circulation and/or along the glomerular basement membrane. Family studies in which disease segregates with structurally abnormal complement factor H-related (CFHR) proteins demonstrate that abnormal CFHR proteins are important in some types of C3 glomerulopathy. This is currently thought to be due to the ability of these proteins to antagonize the major negative regulator of C3 activation, complement factor H (CFH), a process termed 'CFH de-regulation'. Recent clinicopathological cohort studies have led to further refinements in case definition, culminating in a 2013 consensus report, which provides recommendations regarding investigation and treatment. Early clinical experience with complement-targeted therapeutics, notably C5 inhibitors, has also now been published. Here, we summarize the latest developments in C3 glomerulopathy.
Xiao X, Pickering MC, Smith RJH, 2014, C3 Glomerulopathy: The Genetic and Clinical Findings in Dense Deposit Disease and C3 Glomerulonephritis, SEMINARS IN THROMBOSIS AND HEMOSTASIS, Vol: 40, Pages: 465-471, ISSN: 0094-6176
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- Citations: 36
Ruseva MM, Takahashi M, Fujita T, et al., 2014, C3 dysregulation due to factor H deficiency is mannan-binding lectin-associated serine proteases (MASP)-1 and MASP-3 independent in vivo, Clinical and Experimental Immunology, Vol: 176, Pages: 84-92, ISSN: 0009-9104
Uncontrolled activation of the complement alternative pathway is associated with complement‐mediated renal disease. Factor B and factor D are essential components of this pathway, while factor H (FH) is its major regulator. In complete FH deficiency, uncontrolled C3 activation through the alternative pathway results in plasma C3 depletion and complement‐mediated renal disease. These are dependent on factor B. Mannan‐binding lectin‐associated serine proteases 1 and 3 (MASP‐1, MASP‐3) have been shown recently to contribute to alternative pathway activation by cleaving pro‐factor D to its active form, factor D. We studied the contribution of MASP‐1 and MASP‐3 to uncontrolled alternative pathway activation in experimental complete FH deficiency. Co‐deficiency of FH and MASP‐1/MASP‐3 did not ameliorate either the plasma C3 activation or glomerular C3 accumulation in FH‐deficient mice. Our data indicate that MASP‐1 and MASP‐3 are not essential for alternative pathway activation in complete FH deficiency.
Medjeral-Thomas N, Malik TH, Patel MP, et al., 2014, A novel CFHR5 fusion protein causes C3 glomerulopathy in a family without Cypriot ancestry, Kidney International, Vol: 85, Pages: 933-937, ISSN: 0085-2538
C3 glomerulopathy describes glomerular pathology associated with predominant deposition of complement C3 including dense deposit disease and C3 glomerulonephritis. Familial C3 glomerulonephritis has been associated with rearrangements affecting the complement factor H–related (CFHR) genes. These include a hybrid CFHR3-1 gene and an internal duplication within the CFHR5 gene. CFHR5 nephropathy, to date, occurred exclusively in patients with Cypriot ancestry, and is associated with a heterozygous internal duplication of the CFHR5 gene resulting in duplication of the exons encoding the first two domains of the CFHR5 protein. Affected individuals possess both the wild-type nine-domain CFHR5 protein (CFHR512-9) and an abnormally large mutant CFHR5 protein in which the initial two protein domains are duplicated (CFHR51212-9). We found CFHR51212-9 in association with familial C3 glomerulonephritis in a family without Cypriot ancestry. The genomic rearrangement was distinct from that seen in Cypriot CFHR5 nephropathy. Our findings strengthen the association between CFHR51212-9 and familial C3 glomerulonephritis and recommend screening for CFHR51212-9 in patients with C3 glomerulopathy irrespective of ethnicity. Since CFHR51212-9 can result from at least two genomic rearrangements, screening is most readily achieved through analysis of CFHR5 protein.
van der Veen S, Johnson S, Jongerius I, et al., 2014, Nonfunctional Variant 3 Factor H Binding Proteins as Meningococcal Vaccine Candidates, INFECTION AND IMMUNITY, Vol: 82, Pages: 1157-1163, ISSN: 0019-9567
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Medjeral-Thomas NR, O'Shaughnessy MM, O'Regan JA, et al., 2014, C3 Glomerulopathy: Clinicopathologic Features and Predictors of Outcome, CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 9, Pages: 46-53, ISSN: 1555-9041
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- Citations: 144
Liszewski MK, Kolev M, Le Friec G, et al., 2013, Intracellular Complement Activation Sustains T Cell Homeostasis and Mediates Effector Differentiation, IMMUNITY, Vol: 39, Pages: 1143-1157, ISSN: 1074-7613
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- Citations: 348
Pickering MC, D'Agati VD, Nester CM, et al., 2013, C3 glomerulopathy: consensus report, Kidney International, Vol: 84, Pages: 1079-1089, ISSN: 0085-2538
C3 glomerulopathy is a recently introduced pathological entity whose original definition was glomerular pathology characterized by C3 accumulation with absent or scanty immunoglobulin deposition. In August 2012, an invited group of experts (comprising the authors of this document) in renal pathology, nephrology, complement biology, and complement therapeutics met to discuss C3 glomerulopathy in the first C3 Glomerulopathy Meeting. The objectives were to reach a consensus on: the definition of C3 glomerulopathy, appropriate complement investigations that should be performed in these patients, and how complement therapeutics should be explored in the condition. This meeting report represents the current consensus view of the group.
Kraivong R, Vasanawathana S, Limpitikul W, et al., 2013, Complement alternative pathway genetic variation and Dengue infection in the Thai population, Clinical and Experimental Immunology, Vol: 174, Pages: 326-334, ISSN: 1365-2249
Dengue disease is a mosquito-borne infection caused by Dengue virus. Infection may be asymptomatic or variably manifest as mild Dengue fever (DF) to the most severe form, Dengue haemorrhagic fever (DHF). Mechanisms that influence disease severity are not understood. Complement, an integral component of the immune system, is activated during Dengue infection and the degree of activation increases with disease severity. Activation of the complement alternative pathway is influenced by polymorphisms within activation (factor B rs12614/rs641153, C3 rs2230199) and regulatory [complement factor H (CFH) rs800292] proteins, collectively termed a complotype. Here, we tested the hypothesis that the complotype influences disease severity during secondary Dengue infection. In addition to the complotype, we also assessed two other disease-associated CFH polymorphisms (rs1061170, rs3753394) and a structural polymorphism within the CFH protein family. We did not detect any significant association between the examined polymorphisms and Dengue infection severity in the Thai population. However, the minor allele frequencies of the factor B and C3 polymorphisms were less than 10%, so our study was not sufficiently powered to detect an association at these loci. We were also unable to detect a direct interaction between CFH and Dengue NS1 using both recombinant NS1 and DV2-infected culture supernatants. We conclude that the complotype does not influence secondary Dengue infection severity in the Thai population.
Barbour TD, Pickering MC, Cook HT, 2013, Dense Deposit Disease and C3 Glomerulopathy, SEMINARS IN NEPHROLOGY, Vol: 33, Pages: 493-507, ISSN: 0270-9295
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- Citations: 42
Kam JH, Lenassi E, Malik TH, et al., 2013, Complement Component C3 Plays a Critical Role in Protecting the Aging Retina in a Murine Model of Age-Related Macular Degeneration, AMERICAN JOURNAL OF PATHOLOGY, Vol: 183, Pages: 480-492, ISSN: 0002-9440
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Barbour TD, Pickering MC, Cook HT, 2013, Recent insights into C3 glomerulopathy, Nephrology Dialysis Transplantation, Vol: 28, Pages: 1685-1693, ISSN: 1460-2385
‘C3 glomerulopathy’ is a recent disease classification comprising several rare types of glomerulonephritis (GN), including dense deposit disease (DDD), C3 glomerulonephritis (C3GN) and CFHR5 nephropathy. These disorders share the key histological feature of isolated complement C3 deposits in the glomerulus. A common aetiology involving dysregulation of the alternative pathway (AP) of complement has been elucidated in the past decade, with genetic defects and/or autoantibodies able to be identified in a proportion of patients. We review the clinical and histological features of C3 glomerulopathy, relating these to underlying molecular mechanisms. The role of uncontrolled C3 activation in pathogenesis is emphasized, with important lessons from animal models. Methods, advantages and limitations of gene testing in the assessment of individuals or families with C3 glomerulopathy are discussed. While no therapy has yet been shown consistently effective, clinical evaluation of agents targeting specific components of the complement system is ongoing. However, limits to current knowledge regarding the natural history and the appropriate timing and duration of proposed therapies need to be addressed.
Tortajada A, Yebenes H, Abarrategui-Garrido C, et al., 2013, C3 glomerulopathy-associated <i>CFHR1</i> mutation alters FHR oligomerization and complement regulation, JOURNAL OF CLINICAL INVESTIGATION, Vol: 123, Pages: 2434-2446, ISSN: 0021-9738
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- Citations: 147
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