105 results found
IgA nephropathy (IgAN) is common and often progresses to end stage renal disease. IgAN encompasses a wide range of histology and clinical features. IgAN pathogenesis is incompletely understood; the current multi-hit hypothesis of IgAN pathogenesis does not explain the range of glomerular inflammation and renal injury associated with mesangial IgA deposition. Although associations between IgAN and glomerular and circulating markers of complement activation are established, the mechanism of complement activation and contribution to glomerular inflammation and injury are not defined. Recent identification of specific complement pathways and proteins in severe IgAN cases had advanced our understanding of complement in IgAN pathogenesis. In particular, a growing body of evidence implicates the complement factor H related proteins 1 and 5 and lectin pathway as pathogenic in a subset of patients with severe disease. These data suggest complement deregulation and activity may be dominant drivers of renal injury in IgAN. Thereby, markers of complement activation may identify IgAN patients likely to progress to significant renal impairment and complement inhibition may emerge as an effective method of preventing and reducing glomerular injury in IgAN.
Kiss MG, Ozsvar-Kozma M, Porsch F, et al., 2019, Complement Factor H Modulates Splenic B Cell Development and Limits Autoantibody Production, FRONTIERS IN IMMUNOLOGY, Vol: 10, ISSN: 1664-3224
Foschi V, Bortolotti D, Doyle AF, et al., 2019, Analysis of HLA-G expression in renal tissue in lupus nephritis: a pilot study, Lupus, ISSN: 1477-0962
BACKGROUND: The study aimed to investigate whether HLA-G antigen is expressed in the kidneys of patients affected by lupus nephritis (LN) and whether its detection in renal biopsies could be adopted as a marker of treatment response and prognosis. METHODS: Thirty renal biopsies from patients with LN were selected and analyzed through immunohistochemistry. Laboratory and clinical data were retrospectively collected at baseline, 6 and 12 months and at the latest clinical appointment. A number of patients (63.3%) were treated with rituximab (RTX) +/- methylprednisolone in the induction phase. The expression of HLA-G in glomeruli, tubules and infiltrating cells was examined and compared between lupus patients who achieved either complete or partial renal response and those who did not respond to treatment. RESULTS: HLA-G staining was observed in the glomeruli of 20 of 30 samples from patients with LN. The expression of the antigen was detected in podocytes, along glomerular capillary walls, on parietal glomerular epithelial cells and within the juxtaglomerular apparatus. Seventy per cent of patients whose glomeruli expressed HLA-G achieved partial or complete response at 6 months and 75% at the latest available follow up compared with 30% and 40%, respectively, of those who did not show any expression. The pattern of staining in tubules and infiltrating cells was highly variable precluding any clinical correlation. CONCLUSION: This study demonstrates that HLA-G is expressed in renal tissue in LN. Our retrospective data suggest that its expression could correlate with response to treatment.
Smith RJH, Appel GB, Blom AM, et al., 2019, C3 glomerulopathy - understanding a rare complement-driven renal disease, NATURE REVIEWS NEPHROLOGY, Vol: 15, Pages: 129-143, ISSN: 1759-5061
Smith-Jackson K, Yang Y, Denton H, et al., 2019, Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice, Journal of Clinical Investigation, ISSN: 0021-9738
Atypical hemolytic uremic syndrome (aHUS) is frequently associated in humans with loss-of-function mutations in complement-regulating proteins or gain-of-function mutations in complement-activating proteins. Thus, aHUS provides an archetypal complement-mediated disease with which to model new therapeutic strategies and treatments. Herein, we show that, when transferred to mice, an aHUS-associated gain-of-function change (D1115N) to the complement-activation protein C3 results in aHUS. Homozygous C3 p.D1115N (C3KI) mice developed spontaneous chronic thrombotic microangiopathy together with hematuria, thrombocytopenia, elevated creatinine, and evidence of hemolysis. Mice with active disease had reduced plasma C3 with C3 fragment and C9 deposition within the kidney. Therapeutic blockade or genetic deletion of C5, a protein downstream of C3 in the complement cascade, protected homozygous C3KI mice from thrombotic microangiopathy and aHUS. Thus, our data provide in vivo modeling evidence that gain-of-function changes in complement C3 drive aHUS. They also show that long-term C5 deficiency is not accompanied by development of other renal complications (such as C3 glomerulopathy) despite sustained dysregulation of C3. Our results suggest that this preclinical model will allow testing of novel complement inhibitors with the aim of developing precisely targeted therapeutics that could have application in many complement-mediated diseases.
Wilson HR, Medjeral-Thomas NR, Gilmore AC, et al., 2019, Glomerular membrane attack complex is not a reliable marker of ongoing C5 activation in lupus nephritis, Kidney International, Vol: 95, Pages: 655-665, ISSN: 0085-2538
Complement plays an important role in the pathogenesis of lupus nephritis (LN). With the emergence of therapeutic complement inhibition, there is a need to identify patients in whom complement-driven inflammation is a major cause of kidney injury in LN. Clinical and histopathological data were obtained retrospectively from 57 biopsies with class III, IV, and V LN. Biopsies were stained for complement components C9, C5b-9, C3c, and C3d and for the macrophage marker CD68. C9 and C5b-9 staining were highly correlated (r = 0.92 in the capillary wall). C5b-9 staining was detected in the mesangium and/or capillary wall of both active and chronic proliferative LN in all but one biopsy and in the capillary wall of class V LN in all biopsies. C5b-9 staining intensity in the tubular basement membrane correlated with markers of tubulointerstitial damage, and more intense capillary wall C5b-9 staining was significantly associated with nonresponse to conventional treatment. Glomerular C5b-9 staining intensity did not differ between active and chronic disease; in contrast, C3c and CD68 staining were associated with active disease. Evaluation of serial biopsies and comparison of staining in active and chronic LN demonstrated that C5b-9 staining persisted for months to years. These results suggest that C5b-9 staining is almost always present in LN, resolves slowly, and is not a reliable marker of ongoing glomerular C5 activation. This limits the utility of C5b-9 staining to identify patients who are most likely to benefit from C5 inhibition.
Zhu L, Guo W-Y, Shi S-F, et al., 2018, Circulating complement factor H-related protein 5 levels contribute to development and progression of IgA nephropathy, KIDNEY INTERNATIONAL, Vol: 94, Pages: 150-158, ISSN: 0085-2538
Koskinen AR, Cheng Z-Z, Pickering MC, et al., 2018, Distribution of exogenous complement factor H in mice invivo, Scandinavian Journal of Immunology, Vol: 88, ISSN: 0300-9475
Factor H is an important regulator of complement activation in plasma and on cell surfaces in both humans and mice. If FH function is compromised, inappropriate complement activation on self‐surfaces can have disastrous effects as seen in the kidney diseases atypical haemolytic uremic syndrome (aHUS) and C3 glomerulopathy. As FH constructs have been proposed to be used in treatment for these diseases, we studied the distribution of exogenous FH fragments in mice. Full‐length mFH, mFH1‐5 and mFH18‐20 fragments were radiolabelled, and their distribution was examined in WT, FH−/− and FH−/−C3−/− mice in vivo. Whole body scintigraphy revealed accumulation of radioactivity in the abdominal part of the mice, but also to the thyroid gland and urinary bladder. At organ level in WT mice, some full‐length FH accumulated in internal organs, but most of it remained in the circulation. Both of the mFH fragments accumulated in the kidneys and were excreted in urine. For mFH1‐5, urinary secretion is the likely cause for the accumulation. Concentration of mFH18‐20 to kidneys was slower, and at tissue level, mFH18‐20 was localized at the proximal tubuli in WT and FH−/−C3−/− mice. No C3‐independent binding to glomeruli was detected. In conclusion, these results show that glomerular glycosaminoglycans and sialic acids alone do not collect FH in kidneys. Deposition of C3 fragments is also needed, which implies that in aHUS, the problem is in simultaneous recognition of C3 fragments and glycosaminoglycans or sialic acids by FH, not just the inability of FH to recognize glomerular endothelium as such.
Yang Y, Denton H, Davies OR, et al., 2018, An Engineered Complement Factor H Construct for Treatment of C3 Glomerulopathy, JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 29, Pages: 1649-1661, ISSN: 1046-6673
Saja M, Cook HT, Ruseva M, et al., 2018, A triglyceride-rich lipoprotein environment exacerbates renal injury in the accelerated nephrotoxic nephritis model, Clinical and Experimental Immunology, Vol: 192, Pages: 337-347, ISSN: 1365-2249
Hyperlipidaemia accompanies chronic renal disease either as a consequence of the renal dysfunction or as part of generalized metabolic derangements. Under both situations, the lipid profile is characterized by accumulation of triglyceride‐rich lipoproteins (TGRLs). This lipid profile is recognized as a risk factor for cardiovascular complications. Whether it may pose a risk for renal injury as well remains unclear. A hyper‐TGRL state was generated in C57BL/6 mice using poloxamer‐407 (P‐407) and immune complex‐mediated renal injury was triggered using the accelerated nephrotoxic nephritis (ANTN) model. The hyper‐TGRL animals were hypersensitive to ANTN demonstrated by greater haematuria and glomerular cellularity. These changes were accompanied by increased glomerular accumulation of CD68+ macrophages. The hypersensitive response to ANTN was not seen in low‐density lipoprotein receptor knock‐out mice fed with a high fat diet, where triglyceride levels were lower but cholesterol levels comparable to those obtained using P‐407. These data indicate that a hyper‐TGRL state might be more detrimental to the kidneys than low‐density lipoprotein‐driven hypercholesterolaemia during immune complex‐mediated nephritis. We speculate that the hyper‐TGRL environment primes the kidney to exacerbated renal damage following an inflammatory insult with increased accumulation of macrophages that may play a key role in mediating the injurious effects.
Medjeral-Thomas NR, Troldborg A, Constantinou N, et al., 2018, Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin-Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H-Related Protein-5 (FHR5) Deposition, KIDNEY INTERNATIONAL REPORTS, Vol: 3, Pages: 426-438, ISSN: 2468-0249
IntroductionIgA nephropathy (IgAN) is characterized by glomerular deposition of galactose-deficient IgA1 and complement proteins and leads to renal impairment. Complement deposition through the alternative and lectin activation pathways is associated with renal injury.MethodsTo elucidate the contribution of the lectin pathway to IgAN, we measured the 11 plasma lectin pathway components in a well-characterized cohort of patients with IgAN.ResultsM-ficolin, L-ficolin, mannan-binding lectin (MBL)–associated serine protease (MASP)-1 and MBL-associated protein (MAp) 19 were increased, whereas plasma MASP-3 levels were decreased in patients with IgAN compared with healthy controls. Progressive disease was associated with low plasma MASP-3 levels and increased glomerular staining for C3b/iC3b/C3c, C3d, C4d, C5b-9, and factor H–related protein 5 (FHR5). Glomerular FHR5 deposition positively correlated with glomerular C3b/iC3b/C3c, C3d, and C5b-9 deposition, but not with glomerular C4d. These observations, together with the finding that glomerular factor H (fH) deposition was reduced in progressive disease, are consistent with a role for fH deregulation by FHR5 in renal injury in IgAN.ConclusionOur data indicate that circulating MASP-3 levels could be used as a biomarker of disease severity in IgAN and that glomerular staining for FHR5 could both indicate alternative complement pathway activation and be a tissue marker of disease severity.
Cook HT, Pickering MC, 2017, Clusters not classifications: making sense of complement-mediated kidney injury, Journal of the American Society of Nephrology, Vol: 29, Pages: 9-12, ISSN: 1046-6673
Kane SJ, Farley TK, Gordon EO, et al., 2017, Complement regulatory protein factor H is a soluble prion receptor that potentiates peripheral prion pathogenesis, Journal of Immunology, Vol: 199, Pages: 3821-3827, ISSN: 1550-6606
Several complement proteins exacerbate prion disease, including C3, C1q, and CD21/35. These proteins of the complement cascade likely increase uptake, trafficking, and retention of prions in the lymphoreticular system, hallmark sites of early prion propagation. Complement regulatory protein factor H (fH) binds modified host proteins and lipids to prevent C3b deposition and, thus, autoimmune cell lysis. Previous reports show that fH binds various conformations of the cellular prion protein, leading us to question the role of fH in prion disease. In this article, we report that transgenic mice lacking Cfh alleles exhibit delayed peripheral prion accumulation, replication, and pathogenesis and onset of terminal disease in a gene-dose manner. We also report a biophysical interaction between purified fH and prion rods enriched from prion-diseased brain. fH also influences prion deposition in brains of infected mice. We conclude from these data and previous findings that the interplay between complement and prions likely involves a complex balance of prion sequestration and destruction via local tissue macrophages, prion trafficking by B and dendritic cells within the lymphoreticular system, intranodal prion replication by B and follicular dendritic cells, and potential prion strain selection by CD21/35 and fH. These findings reveal a novel role for complement-regulatory proteins in prion disease.
Medjeral-Thomas NR, Lomax-Browne HJ, Beckwith H, et al., 2017, Circulating complement factor H-related proteins 1 and 5 correlate with disease activity in IgA nephropathy, Kidney International, Vol: 92, Pages: 942-952, ISSN: 0085-2538
IgA nephropathy (IgAN) is a common cause of chronic kidney disease and end-stage renal failure, especially in young people. Due to a wide range of clinical outcomes and difficulty in predicting response to immunosuppression, we need to understand why and identify which patients with IgAN will develop progressive renal impairment. A deletion polymorphism affecting the genes encoding the complement factor H-related protein (FHR)-1 and FHR-3 is robustly associated with protection against IgAN. Some FHR proteins, including FHR-1 and FHR-5, antagonize the ability of complement factor H (fH), the major negative regulator of the complement alternative pathway, to inhibit complement activation on surfaces, a process termed fH deregulation. From a large cohort of patients, we demonstrated that plasma FHR-1 and the FHR-1/fH ratio were elevated in IgAN and associated with progressive disease. Plasma FHR-1 negatively correlated with eGFR but remained elevated in patients with IgAN with normal eGFR. Serum FHR5 was slightly elevated in IgAN but did not correlate with eGFR. Neither FHR5 levels nor the FHR-5/fH ratio was associated with progressive disease. However, higher serum FHR-5 levels were associated with a lack of response to immunosuppression, the presence of endocapillary hypercellularity, and histology scores of disease severity (the Oxford Classification MEST score). Thus, FHR-1 and FHR-5 have a role in IgAN disease progression.
Stratigou V, Doyle, Carlucci F, et al., 2017, Altered expression of signalling lymphocyte activation molecule (SLAM) receptors in T cells from lupus nephritis patients - a potential biomarker of disease activity., Rheumatology, Vol: 56, Pages: 1206-1216, ISSN: 1462-0332
Objectives. The aim was to investigate whether the signalling lymphocyte activation molecule (SLAM) signalling pathways contribute to LN and whether SLAM receptors could be valuable biomarkers of disease activity.Methods. Peripheral blood mononuclear cells from 30National Research Ethics Service SLE patients with biopsy-proven LN were analysed by flow cytometry. Clinical measures of disease activity were assessed. The expression of the SLAM family receptors on T-cell subpopulations [CD4, CD8 and double negative (DN) T cells] was measured and compared between lupus patients with active renal disease and those in remission.Results. The frequency of CD8 T cells expressing SLAMF3, SLAMF5 and SLAMF7 was significantly lower in LN patients who were in remission. In contrast, these subsets were similar in patients with active renal disease and in healthy individuals. Patients with active nephritis had an increased percentage of circulating monocytes, consistent with a potential role played by these cells in glomerular inflammation. Changes in the frequency of DN T cells positive for SLAMF2, SLAMF4 and SLAMF7 were observed in lupus patients irrespective of the disease activity. We detected alterations in the cellular expression of the SLAM family receptors, but these changes were less obvious and did not reveal any specific pattern. The percentage of DN T cells expressing SLAMF6 could predict the clinical response to B-cell depletion in patients with LN.Conclusion. Our study demonstrates altered expression of the SLAM family receptors in SLE T lymphocytes. This is consistent with the importance of the SLAM-associated pathways in lupus pathogenesis.
Calippe B, Augustin S, Beguier F, et al., 2017, Complement factor H inhibits CD47-mediated resolution of inflammation, IMMUNITY, Vol: 46, Pages: 261-272, ISSN: 1074-7613
Variants of the CFH gene, encoding complement factor H (CFH), show strong association with age-related macular degeneration (AMD), a major cause of blindness. Here, we used murine models of AMD to examine the contribution of CFH to disease etiology. Cfh deletion protected the mice from the pathogenic subretinal accumulation of mononuclear phagocytes (MP) that characterize AMD and showed accelerated resolution of inflammation. MP persistence arose secondary to binding of CFH to CD11b, which obstructed the homeostatic elimination of MPs from the subretinal space mediated by thrombospsondin-1 (TSP-1) activation of CD47. The AMD-associated CFH(H402) variant markedly increased this inhibitory effect on microglial cells, supporting a causal link to disease etiology. This mechanism is not restricted to the eye, as similar results were observed in a model of acute sterile peritonitis. Pharmacological activation of CD47 accelerated resolution of both subretinal and peritoneal inflammation, with implications for the treatment of chronic inflammatory disease.
Goodship THJ, Cook HT, Fakhouri F, et al., 2016, Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference, Kidney International, Vol: 91, Pages: 539-551, ISSN: 0085-2538
In both atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) complement plays a primary role in disease pathogenesis. Herein we report the outcome of a 2015 Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference where key issues in the management of these 2 diseases were considered by a global panel of experts. Areas addressed included renal pathology, clinical phenotype and assessment, genetic drivers of disease, acquired drivers of disease, and treatment strategies. In order to help guide clinicians who are caring for such patients, recommendations for best treatment strategies were discussed at length, providing the evidence base underpinning current treatment options. Knowledge gaps were identified and a prioritized research agenda was proposed to resolve outstanding controversial issues.
IgA Nephropathy (IgAN) is the most common form of primary glomerulonephritis and an important cause of kidney failure. Characteristically, IgAN patients have increased serum levels of under-galactosylated IgA1 (gd-IgA1). We assessed the degree to which serum gd-IgA1 levels are genetically determined in healthy individuals. Serum IgA and gd-IgA1 level were determined by ELISA in a sample of 148 healthy female twins including 27 monozygotic and 47 dizygotic pairs. Using the classical twin model, the heritability of serum gd-IgA1 and IgA levels were 80% (95% CI: 66-89%) and 46% (95% CI: 15-69%) respectively. These data indicate that serum gd-IgA1 levels are highly heritable. Elucidating the genetic basis of this heritability will be important in understanding the pathogenesis of IgAN.
Mulloy B, Wu N, Gyapon-Quast F, et al., 2016, Abnormally high content of free glucosamine residues identified in a preparation of commercially available porcine intestinal heparan sulfate, Analytical Chemistry, Vol: 88, Pages: 6648-6652, ISSN: 1520-6882
Heparan sulfate (HS) polysaccharides are ubiquitous in animal tissues as components of proteoglycans, and they participate in many important biological processes. HS carbohydrate chains are complex and can contain rare structural components such as N-unsubstituted glucosamine (GlcN). Commercially available HS preparations have been invaluable in many types of research activities. In the course of preparing microarrays to include probes derived from HS oligosaccharides, we found an unusually high content of GlcN residue in a recently purchased batch of porcine intestinal mucosal HS. Composition and sequence analysis by mass spectrometry of the oligosaccharides obtained after heparin lyase III digestion of the polysaccharide indicated two and three GlcN in the tetrasaccharide and hexasaccharide fractions, respectively. 1H NMR of the intact polysaccharide showed that this unusual batch differed strikingly from other HS preparations obtained from bovine kidney and porcine intestine. The very high content of GlcN (30%) and low content of GlcNAc (4.2%) determined by disaccharide composition analysis indicated that N-deacetylation and/or N-desulfation may have taken place. HS is widely used by the scientific community to investigate HS structures and activities. Great care has to be taken in drawing conclusions from investigations of structural features of HS and specificities of HS interaction with proteins when commercial HS is used without further analysis. Pending the availability of a validated commercial HS reference preparation, our data may be useful to members of the scientific community who have used the present preparation in their studies.
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.
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.
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(low) Monocytes, CELL REPORTS, Vol: 12, Pages: 1802-1815, ISSN: 2211-1247
Vernon KA, Ruseva MM, Cook HT, et al., 2015, 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.
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.
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