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Zambrano S, He L, Kano T, Sun Y, Charrin E, Lal M, Betsholtz C, Suzuki Y, Patrakka J. Molecular insights into the early stage of glomerular injury in IgA nephropathy using single-cell RNA sequencing. Kidney Int 2021; 101:752-765. [DOI: 10.1016/j.kint.2021.12.011] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 11/18/2021] [Accepted: 12/03/2021] [Indexed: 12/13/2022]
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Min XY, Liu CF, Cao B, Zhang T, Yang X, Ma N, Wang N, Li K. Human CD3 +CD56 +NKT-like cells express a range of complement receptors and C3 activation has negative effects on these cell activity and effector function. Hum Immunol 2021; 82:625-633. [PMID: 34134908 DOI: 10.1016/j.humimm.2021.06.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 05/20/2021] [Accepted: 06/02/2021] [Indexed: 11/22/2022]
Abstract
CD3+CD56+NKT-like cells are a rare population of lymphocytes that serve important roles in various types of immune-related diseases, and particularly in cancer. The complement system regulates inflammatory and immune responses by interacting with complement receptors expressed on a range of immune cells. However, whether CD3+CD56+NKT-like cells are regulated by the complement system has still not been definitively determined. In the present study, the expression of complement receptors and regulators in gated CD3+CD56+NKT-like cells isolated from human peripheral blood was assessed using PCR and flow cytometry. The results showed that human CD3+CD56+NKT-like cells expressed a range of complement receptors and regulators, such as CR3, C3aR, C5aR, C5L2, CD46 and CD55. Furthermore, the presence of complement component 3 (C3), a key component in complement activation in culture supernatant, mitigated the activity, IFN-γ production and killing function of CD3+CD56+NKT-like cells. The present study provides evidences supporting the relationship between complement activation and functional modulation of CD3+CD56+NKT-like cells, expanding our knowledge of the complement regulatory network, and also highlighting a potential target for treatment of numerous immune-related diseases, particularly NKT cell-based tumor adoptive immunotherapy.
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Affiliation(s)
- Xiao-Yun Min
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China.
| | - Cheng-Fei Liu
- Cancer Centre, The Second Hospital of Shandong University, Ji'nan, Shandong, PR China
| | - Bo Cao
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Ting Zhang
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Xiao Yang
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Ning Ma
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Na Wang
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China
| | - Ke Li
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi, PR China.
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The Influence of Donor and Recipient Complement C3 Polymorphisms on Liver Transplant Outcome. Int J Hepatol 2021; 2021:6636456. [PMID: 34123432 PMCID: PMC8168477 DOI: 10.1155/2021/6636456] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Accepted: 04/27/2021] [Indexed: 12/19/2022] Open
Abstract
Despite early reports of an impact of complement C3 polymorphism on liver transplant patient and graft survival, subsequent evidence has been conflicting. Our aim was to clarify the contributions of donor and recipient C3 genotype, separately and together, on patient and graft outcomes and acute rejection incidence in liver transplant recipients. Eight donor/recipient groups were analyzed according to their genotype and presence or absence of C3 F allele (FFFS, FFSS, FSFF, FSFS, FSSS, SSFF, SSFS, and SSSS) and correlated with clinical outcomes of patient survival, graft survival, and rejection. The further impact of brain death vs. circulatory death during liver donation was also considered. Over a median 5.3 y follow-up of 506 patients with clinical information and matching donor and recipient tissue, five-year patient and graft survival (95% confidence interval) were 90(81-91)% and 77(73-85)%, respectively, and 72(69-94)% were rejection-free. Early disadvantages to patient survival were associated with donor C3 F variant, especially in brain-death donors. Recipient C3 genotype was an independent determinant of graft survival by Cox proportional hazards analysis (hazard ratio 0.26, P = 0.04), and the C3 F donor variant was again associated with worse liver graft survival, particularly in brain-death donors. C3 genotype did not independently determine rejection incidence, but a greater proportion of recipient C3 F carriers were rejection-free in the circulatory death, but not the brain-death cohort. Cox proportional hazards analysis revealed significant effects of acute rejection on patient survival (hazard ratio 0.24, P = 0.018), of retransplantation on rejection risk (hazard ratio 6.3, P = 0.009), and of donor type (circulatory-death vs. brain-death) on rejection incidence (hazard ratio 4.9, P = 0.005). We conclude that both donor and recipient complement C3 genotype may influence patient and graft outcomes after liver transplantation but that the type of liver donor is additionally influential, possibly via the inflammatory environment of the transplant.
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Wang X, Wang D, Wang X, Wang X, Sha JC, Gao Q. Mechanisms underlying the production of chemokine CXCL11 in the reaction of renal tubular epithelial cells with CD4 + and CD8 + T cells. Transpl Immunol 2020; 65:101337. [PMID: 32971208 DOI: 10.1016/j.trim.2020.101337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 09/15/2020] [Accepted: 09/19/2020] [Indexed: 11/28/2022]
Abstract
AIM To study the release mechanism of C-X-C motif chemokine 11 (CXCL11) and other chemokines after the co-cultivation of CD4+ and CD8+ T cells with the renal tubular epithelial cells (RTEC) in the process of allograft renal transplantation rejection. METHODS The Human CD4+, CD8+ T cells were obtained from the blood of volunteers and kidney transplantation (Ktx) patients, and co-cultured with renal tubular epithelial cells (RTEC) in vitro. RT-PCR was run for detecting the mRNA transcription of CXCL11, IFN-induced protein of 10 (CXCL10), and IL-6 in cells after RTEC was stimulated with IFN-γ or co-cultured with CD4+ and CD8+ T cells. The concentration of CXCL11, CXCL10 and IL-6 in the culture medium was detected by Multiplex Assay after RTEC was stimulated with IFN-γ or co-cultured with CD4+ and CD8+ T cells. IFN-γ receptor antibody was used for interfering with the above reaction and the blocking effect was observed. Western blot was used for protein expression analysis. Finally, we applied renal biopsies from kidney transplantation patients with and without rejection to verify the results of the above experiments by using RT-PCR and Western blot. RESULTS The mRNA expression of CXCL11 and CXCL10 were significantly increased after RTEC was stimulated with IFN-γ or co-cultured with CD4+ and CD8+ T cells. Multiplex Assay showed that the concentration of CXCL11 and CXCL10 in the supernatant were significantly increased in a time-dependence fashion after stimulation RTEC by IFN-γ. Anti-IFN-γ receptor1 (anti-IFN-γR1) antibody could reduce the production of CXCL11 and CXCL10 in this situation. The concentration of CXCL11 and CXCL11 in the supernatant was significantly increased with a time-dependent effect after the co-culture of CD4+ and CD8+ T cells with RTEC. The anti-IFN-γR1 blocked this effect. Our study showed that the expression levels of CXCL11 and CXCL10 were upgraded in the biopsies of patients with renal transplant rejection comparatively to pre-transplant biopsies, both at mRNA and protein levels. CONCLUSIONS RTEC and T cells can stimulate each other during the acute rejection of allogeneic kidney transplantation and secret CXCL11，CXCL10 and other chemokines. IFN-γ plays a key role in this process.
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Affiliation(s)
- Xiaoping Wang
- Department of Nephrology, Shandong University & Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250000, China.
| | - Dan Wang
- Department of Nephrology, Shandong University & Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250000, China.
| | - Xiao Wang
- Department of Nephrology, Shandong University & Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250000, China.
| | - Xiaoqi Wang
- Department of Cardiology, Shandong University & Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250000, China.
| | - Ji-Chang Sha
- Department of Neurosurgery, Zhangqiu District People's Hospital, Jinan 250200, China.
| | - Qingzhen Gao
- Department of Nephrology, Shandong University & Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan 250000, China.
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Amann K, Daniel C, Büttner-Herold M. [The complement system-a "hot topic" not only for kidney diseases]. DER PATHOLOGE 2020; 41:238-247. [PMID: 32240352 DOI: 10.1007/s00292-020-00773-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Increasing interest in the role of the complement system in systemic and renal disease is based on new pathophysiological and therapeutic insights of the recent past and particularly in genetic analyses in children with atypical hemolytic uremic syndrome (aHUS). aHUS is the prototypical systemic disease associated with excessive activation of the alternative complement pathway and manifests in the kidney, but also in other organs as thrombotic microangiopathy (TMA). Pathomechanisms discovered to induce the overactivation of the alternative complement pathway in aHUS led to the first successful therapeutic application of a C5b9 inhibitor. This suppression of the terminal complement cascade succeeded in inhibiting local tissue damage. Thereafter, thanks to advanced modern technologies, further systemic and renal diseases associated with mutations or auto-antibodies targeting the complement pathway were identified. Hereby, disease onset is frequently associated with an additional trigger, e.g. infection or hormonal alterations/imbalances, against the background of a pre-existing predisposition of the patient.Due to the growing understanding of the regulation, and thus the possibility of therapeutic modulation of the different complement pathways, and due to the increasing availability of a variety of drugs inhibiting the complement system, interest in complement-mediated systemic and renal disease has been steadily increasing, making it a "hot-topic" in medicine in recent years.
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Affiliation(s)
- Kerstin Amann
- Abt. Nephropathologie, Pathologisches Institut, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054, Erlangen, Deutschland.
| | - Christoph Daniel
- Abt. Nephropathologie, Pathologisches Institut, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054, Erlangen, Deutschland
| | - Maike Büttner-Herold
- Abt. Nephropathologie, Pathologisches Institut, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054, Erlangen, Deutschland
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Howard MC, Nauser CL, Farrar CA, Wallis R, Sacks SH. l-Fucose prevention of renal ischaemia/reperfusion injury in Mice. FASEB J 2019; 34:822-834. [PMID: 31914693 PMCID: PMC6972607 DOI: 10.1096/fj.201901582r] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 10/04/2019] [Accepted: 10/08/2019] [Indexed: 01/16/2023]
Abstract
In a recent study, we identified a fucosylated damage‐associated ligand exposed by ischemia on renal tubule epithelial cells, which after recognition by collectin‐11 (CL‐11 or collectin kidney 1 (CL‐K1)), initiates complement activation and acute kidney injury. We exploited the ability to increase the local tissue concentration of free l‐fucose following systemic administration, in order to block ligand binding by local CL‐11 and prevent complement activation. We achieved a thirty‐five‐fold increase in the intrarenal concentration of l‐fucose following an IP bolus given before the ischemia induction procedure ‐ a concentration found to significantly block in vitro binding of CL‐11 on hypoxia‐stressed renal tubule cells. At this l‐fucose dose, complement activation and acute post‐ischemic kidney injury are prevented, with additional protection achieved by a second bolus after the induction procedure. CL‐11−/− mice gained no additional protection from l‐fucose administration, indicating that the mechanism of l‐fucose therapy was largely CL‐11‐dependent. The hypothesis is that a high dose of l‐fucose delivered to the kidney obstructs the carbohydrate recognition site on CL‐11 thereby reducing complement‐mediated damage following ischemic insult. Further work will examine the utility in preventing post‐ischemic injury during renal transplantation, where acute kidney injury is known to correlate with poor graft survival.
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Affiliation(s)
- Mark C Howard
- MRC Centre for Transplantation, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Christopher L Nauser
- MRC Centre for Transplantation, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Conrad A Farrar
- MRC Centre for Transplantation, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, London, UK
| | - Russell Wallis
- Department of Respiratory Science and Infection, University of Leicester, London, UK
| | - Steven H Sacks
- MRC Centre for Transplantation, Peter Gorer Department of Immunobiology, School of Immunology & Microbial Sciences, King's College London, London, UK
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Post-transplant Alternative Complement Pathway Activation Influences Kidney Allograft Function. Arch Immunol Ther Exp (Warsz) 2019; 67:171-177. [PMID: 31028405 PMCID: PMC6509066 DOI: 10.1007/s00005-019-00541-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Accepted: 03/29/2019] [Indexed: 12/31/2022]
Abstract
The complement system is one of the crucial pathophysiological mechanisms that directly influence the function of a transplanted kidney. Since the complement pathways’ activation potential can be easily determined via their functional activity measurement, we focused on fluctuation in the cascade activity in the early post-transplant period. The aim of the study was to relate the kidney transplantation-induced complement system response to allograft outcome. Forty-two kidney recipients (aged: 53.5 [37–52], 17 females/25 males) and 24 healthy controls (aged: 40.5 [34–51], 13 females/11 males) were enrolled in the study. The functional activities of alternative, classical, and lectin pathways were determined before and in the first week after transplantation using Wielisa®-kit. We observed that the baseline functional activity of the alternative pathway (AP) was higher in chronic kidney disease patients awaiting transplantation compared to healthy controls and that its level depended on the type of dialysis. AP-functional activity was decreased following transplantation procedure and its post-transplant level was related to allograft function. The baseline and transplantation-induced functional activities of the classical and lectin pathways were not influenced by dialysis type and were not associated with transplant outcome. Moreover, our study showed that intraoperative graft surface cooling had a protective effect on AP activation. Our study confirms the influence of dialysis modality on persistent AP complement activation and supports the role of AP in an early phase after kidney transplantation and allograft outcome.
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Michielsen LA, van Zuilen AD, Kardol-Hoefnagel T, Verhaar MC, Otten HG. Association Between Promoter Polymorphisms in CD46 and CD59 in Kidney Donors and Transplant Outcome. Front Immunol 2018; 9:972. [PMID: 29867953 PMCID: PMC5960667 DOI: 10.3389/fimmu.2018.00972] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 04/18/2018] [Indexed: 12/21/2022] Open
Abstract
Complement regulating proteins, including CD46, CD55, and CD59, protect cells against self-damage. Because of their expression on the donor endothelium, they are hypothesized to be involved in accommodation. Polymorphisms in their promoter regions may affect their expression. The aim of this study was to investigate if donor polymorphisms in complement regulating proteins influence kidney transplant outcomes. We included 306 kidney transplantations between 2005 and 2010. Five polymorphisms in the promoters of CD46, CD55, and CD59 were genotyped. A CD59 promoter polymorphism (rs147788946) in donors was associated with a lower 1-year rejection-free survival [adjusted hazard ratio (aHR) 2.18, 95% CI 1.12–4.24] and a trend toward impaired 5-year graft survival (p = 0.08). Patients receiving a kidney with at least one G allele for the CD46 promoter polymorphism rs2796267 (A/G) showed a lower rejection-free survival, though this became borderline significant after adjustment for potential confounders (aHR 1.87, 95% CI 0.96–3.65). A second CD46 promoter polymorphism (rs2796268, A/G), was also associated with a lower freedom from acute rejection in the presence of at least one G allele (aHR 1.95, 95% CI 1.03–3.68). Finally, the combined presence of both favorable genotypes of rs2796267 and rs147788946 had an additional protective effect both on acute rejection (p = 0.006) and graft survival (p = 0.03). These findings could help to identify patients who could benefit from intensified immunosuppressive therapy or novel complement inhibitory therapeutics.
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Affiliation(s)
- Laura A Michielsen
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Arjan D van Zuilen
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Tineke Kardol-Hoefnagel
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Marianne C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Henny G Otten
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
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Li K, Wu KY, Wu W, Wang N, Zhang T, Choudhry N, Song Y, Farrar CA, Ma L, Wei LL, Duan ZY, Dong X, Liu EQ, Li ZF, Sacks SH, Zhou W. C5aR1 promotes acute pyelonephritis induced by uropathogenic E. coli. JCI Insight 2017; 2:97626. [PMID: 29263309 PMCID: PMC5752266 DOI: 10.1172/jci.insight.97626] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Accepted: 11/21/2017] [Indexed: 02/01/2023] Open
Abstract
C5a receptor 1 (C5aR1) is a G protein-coupled receptor for C5a and also an N-linked glycosylated protein. In addition to myeloid cells, C5aR1 is expressed on epithelial cells. In this study, we examined the role of C5aR1 in bacterial adhesion/colonization of renal tubular epithelium and addressed the underlying mechanisms of this role. We show that acute kidney infection was significantly reduced in mice with genetic deletion or through pharmacologic inhibition of C5aR1 following bladder inoculation with uropathogenic E. coli (UPEC). This was associated with reduced expression of terminal α-mannosyl residues (Man; a ligand for type 1 fimbriae of E. coli) on the luminal surface of renal tubular epithelium and reduction of early UPEC colonization in these mice. Confocal microscopy demonstrated that UPEC bind to Man on the luminal surface of renal tubular epithelium. In vitro analyses showed that C5a stimulation enhances Man expression in renal tubular epithelial cells and subsequent bacterial adhesion, which, at least in part, is dependent on TNF-α driven by C5aR1-mediated intracellular signaling. Our findings demonstrate a previously unknown pathogenic role for C5aR1 in acute pyelonephritis, proposing a potentially novel mechanism by which C5a/C5aR1 signaling mediates upregulation of carbohydrate ligands on renal tubules to facilitate UPEC adhesion.
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Affiliation(s)
- Ke Li
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Kun-Yi Wu
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Weiju Wu
- Medical Research Council (MRC) Centre for Transplantation, King's College London, Guy's Hospital, United Kingdom (UK)
| | - Na Wang
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Ting Zhang
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Naheed Choudhry
- Medical Research Council (MRC) Centre for Transplantation, King's College London, Guy's Hospital, United Kingdom (UK)
| | - Yun Song
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Conrad A Farrar
- Medical Research Council (MRC) Centre for Transplantation, King's College London, Guy's Hospital, United Kingdom (UK)
| | - Liang Ma
- Medical Research Council (MRC) Centre for Transplantation, King's College London, Guy's Hospital, United Kingdom (UK)
| | - Lin-Lin Wei
- Core Research Laboratory, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Zhao-Yang Duan
- Department of Nephrology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Xia Dong
- Medical Research Council (MRC) Centre for Transplantation, King's College London, Guy's Hospital, United Kingdom (UK)
| | - En-Qi Liu
- Research Institute of Atherosclerotic Disease, School of Medicine, Xi'an Jiaotong University, Xi'an, China
| | - Zong-Fang Li
- National Local Joint Engineering Research Centre of Biodiagnostics and Biotherapy, The Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Steven H Sacks
- Medical Research Council (MRC) Centre for Transplantation, King's College London, Guy's Hospital, United Kingdom (UK)
| | - Wuding Zhou
- Medical Research Council (MRC) Centre for Transplantation, King's College London, Guy's Hospital, United Kingdom (UK)
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Zhang K, Li GQ, He QH, Li Y, Tang M, Zheng QY, Xu GL, Zhang KQ. C5a/C5aR pathway accelerates renal ischemia-reperfusion injury by downregulating PGRN expression. Int Immunopharmacol 2017; 53:17-23. [PMID: 29031143 DOI: 10.1016/j.intimp.2017.10.006] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Revised: 09/22/2017] [Accepted: 10/05/2017] [Indexed: 12/26/2022]
Abstract
Recent reports indicate that the complement C5a/C5aR pathway and progranulin (PGRN) deficiency both contribute to ischemia-reperfusion (IR)-induced acute kidney injury. However, the underlying relationship between the C5a/C5aR signaling pathway and PGRN expression during acute kidney injury is poorly understood. In this study, we showed that C5aR expression was significantly upregulated after renal IR, and that C5aR deficiency led to a marked increase in PGRN expression and a significant reduction in tubular damage and production of inflammatory cytokines. In accordance with these results, recombinant C5a caused downregulation of PGRN protein and mRNA levels in renal tubular epithelial cells (HK-2 cells), which could be negated by disruption of C5a/C5aR signaling by the C5aR antagonist, as confirmed by immunofluorescence, western blotting, and quantitative real-time PCR. Moreover, C5aR deficiency resulted in attenuated NF-κB expression 24h after IR, and recombinant C5a potentiated TNFα-induced NF-κB activation in HK-2 cells. Inhibition of NF-κB activation reversed C5a-induced downregulation of PGRN expression. Our results show for the first time that the complement C5a/C5aR pathway aggravates IR-induced acute kidney injury by suppressing PGRN expression and confirm that suppression of PGRN expression is associated with increased NF-κB activation induced by C5a.
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Affiliation(s)
- Kun Zhang
- Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Gui-Qing Li
- Department of Immunology, Third Military Medical University, Chongqing 400038, China
| | - Qian-Hui He
- Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - You Li
- Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Ming Tang
- Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Quan-You Zheng
- Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Gui-Lian Xu
- Department of Immunology, Third Military Medical University, Chongqing 400038, China
| | - Ke-Qin Zhang
- Department of Nephrology, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
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11
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González-Molina M, Ruiz-Esteban P, Caballero A, Burgos D, Cabello M, Leon M, Fuentes L, Hernandez D. Immune response and histology of humoral rejection in kidney transplantation. Nefrologia 2016; 36:354-67. [PMID: 27267916 DOI: 10.1016/j.nefro.2016.03.023] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Revised: 02/22/2016] [Accepted: 03/26/2016] [Indexed: 11/15/2022] Open
Abstract
The adaptive immune response forms the basis of allograft rejection. Its weapons are direct cellular cytotoxicity, identified from the beginning of organ transplantation, and/or antibodies, limited to hyperacute rejection by preformed antibodies and not as an allogenic response. This resulted in allogenic response being thought for decades to have just a cellular origin. But the experimental studies by Gorer demonstrating tissue damage in allografts due to antibodies secreted by B lymphocytes activated against polymorphic molecules were disregarded. The special coexistence of binding and unbinding between antibodies and antigens of the endothelial cell membranes has been the cause of the delay in demonstrating the humoral allogenic response. The endothelium, the target tissue of antibodies, has a high turnover, and antigen-antibody binding is non-covalent. If endothelial cells are attacked by the humoral response, immunoglobulins are rapidly removed from their surface by shedding and/or internalization, as well as degrading the components of the complement system by the action of MCP, DAF and CD59. Thus, the presence of complement proteins in the membrane of endothelial cells is transient. In fact, the acute form of antibody-mediated rejection was not demonstrated until C4d complement fragment deposition was identified, which is the only component that binds covalently to endothelial cells. This review examines the relationship between humoral immune response and the types of acute and chronic histological lesion shown on biopsy of the transplanted organ.
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Affiliation(s)
- Miguel González-Molina
- Nephrology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain.
| | - Pedro Ruiz-Esteban
- Nephrology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain
| | - Abelardo Caballero
- Immunology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain
| | - Dolores Burgos
- Nephrology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain
| | - Mercedes Cabello
- Nephrology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain
| | - Miriam Leon
- Pathology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain
| | - Laura Fuentes
- Nephrology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain
| | - Domingo Hernandez
- Nephrology Department, Regional University Hospital of Malaga, Malaga University, IBIMA, REDINREN RD12/0021/0015, Malaga, Spain
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Montero RM, Sacks SH, Smith RA. Complement-here, there and everywhere, but what about the transplanted organ? Semin Immunol 2016; 28:250-9. [PMID: 27179705 DOI: 10.1016/j.smim.2016.04.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 04/20/2016] [Accepted: 04/26/2016] [Indexed: 12/15/2022]
Abstract
The part of the innate immune system that communicates and effectively primes the adaptive immune system was termed "complement" by Ehrlich to reflect its complementarity to antibodies having previously been described as "alexine" (i.e protective component of serum) by Buchner and Bordet. It has been established that complement is not solely produced systemically but may have origin in different tissues where it can influence organ specific functions that may affect the outcome of transplanted organs. This review looks at the role of complement in particular to kidney transplantation. We look at current literature to determine whether blockade of the peripheral or central compartments of complement production may prevent ischaemic reperfusion injury or rejection in the transplanted organ. We also review new therapeutics that have been developed to inhibit components of the complement cascade with varying degrees of success leading to an increase in our understanding of the multiple triggers of this complex system. In addition, we consider whether biomarkers in this field are effective markers of disease or treatment.
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Affiliation(s)
- R M Montero
- MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, NIHR Comprehensive Biomedical Research Centre, King's College London, Guy's & St Thomas' NHS Foundation Trust, United Kingdom
| | - S H Sacks
- MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, NIHR Comprehensive Biomedical Research Centre, King's College London, Guy's & St Thomas' NHS Foundation Trust, United Kingdom.
| | - R A Smith
- MRC Centre for Transplantation, Division of Transplant Immunology and Mucosal Biology, NIHR Comprehensive Biomedical Research Centre, King's College London, Guy's & St Thomas' NHS Foundation Trust, United Kingdom
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Farrar CA, Tran D, Li K, Wu W, Peng Q, Schwaeble W, Zhou W, Sacks SH. Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury. J Clin Invest 2016; 126:1911-25. [PMID: 27088797 DOI: 10.1172/jci83000] [Citation(s) in RCA: 114] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Accepted: 02/24/2016] [Indexed: 12/20/2022] Open
Abstract
Physiochemical stress induces tissue injury as a result of the detection of abnormal molecular patterns by sensory molecules of the innate immune system. Here, we have described how the recently discovered C-type lectin collectin-11 (CL-11, also known as CL-K1 and encoded by COLEC11) recognizes an abnormal pattern of L-fucose on postischemic renal tubule cells and activates a destructive inflammatory response. We found that intrarenal expression of CL-11 rapidly increases in the postischemic period and colocalizes with complement deposited along the basolateral surface of the proximal renal tubule in association with L-fucose, the potential binding ligand for CL-11. Mice with either generalized or kidney-specific deficiency of CL-11 were strongly protected against loss of renal function and tubule injury due to reduced complement deposition. Ex vivo renal tubule cells showed a marked capacity for CL-11 binding that was induced by cell stress under hypoxic or hypothermic conditions and prevented by specific removal of L-fucose. Further analysis revealed that cell-bound CL-11 required the lectin complement pathway-associated protease MASP-2 to trigger complement deposition. Given these results, we conclude that lectin complement pathway activation triggered by ligand-CL-11 interaction in postischemic tissue is a potent source of acute kidney injury and is amenable to sugar-specific blockade.
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Salvadori M, Rosso G, Bertoni E. Update on ischemia-reperfusion injury in kidney transplantation: Pathogenesis and treatment. World J Transplant 2015; 5:52-67. [PMID: 26131407 PMCID: PMC4478600 DOI: 10.5500/wjt.v5.i2.52] [Citation(s) in RCA: 267] [Impact Index Per Article: 26.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2014] [Revised: 01/16/2015] [Accepted: 04/27/2015] [Indexed: 02/05/2023] Open
Abstract
Ischemia/reperfusion injury is an unavoidable relevant consequence after kidney transplantation and influences short term as well as long-term graft outcome. Clinically ischemia/reperfusion injury is associated with delayed graft function, graft rejection, chronic rejection and chronic graft dysfunction. Ischemia/reperfusion affects many regulatory systems at the cellular level as well as in the renal tissue that result in a distinct inflammatory reaction of the kidney graft. Underlying factors of ischemia reperfusion include energy metabolism, cellular changes of the mitochondria and cellular membranes, initiation of different forms of cell death-like apoptosis and necrosis together with a recently discovered mixed form termed necroptosis. Chemokines and cytokines together with other factors promote the inflammatory response leading to activation of the innate immune system as well as the adaptive immune system. If the inflammatory reaction continues within the graft tissue, a progressive interstitial fibrosis develops that impacts long-term graft outcome. It is of particular importance in kidney transplantation to understand the underlying mechanisms and effects of ischemia/reperfusion on the graft as this knowledge also opens strategies to prevent or treat ischemia/reperfusion injury after transplantation in order to improve graft outcome.
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Salvadori M, Rosso G, Bertoni E. Complement involvement in kidney diseases: From physiopathology to therapeutical targeting. World J Nephrol 2015; 4:169-184. [PMID: 25949931 PMCID: PMC4419127 DOI: 10.5527/wjn.v4.i2.169] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 12/22/2014] [Accepted: 01/15/2015] [Indexed: 02/06/2023] Open
Abstract
Complement cascade is involved in several renal diseases and in renal transplantation. The different components of the complement cascade might represent an optimal target for innovative therapies. In the first section of the paper the authors review the physiopathology of complement involvement in renal diseases and transplantation. In some cases this led to a reclassification of renal diseases moving from a histopathological to a physiopathological classification. The principal issues afforded are: renal diseases with complement over activation, renal diseases with complement dysregulation, progression of renal diseases and renal transplantation. In the second section the authors discuss the several complement components that could represent a therapeutic target. Even if only the anti C5 monoclonal antibody is on the market, many targets as C1, C3, C5a and C5aR are the object of national or international trials. In addition, many molecules proved to be effective in vitro or in preclinical trials and are waiting to move to human trials in the future.
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Fearn A, Sheerin NS. Complement activation in progressive renal disease. World J Nephrol 2015; 4:31-40. [PMID: 25664245 PMCID: PMC4317626 DOI: 10.5527/wjn.v4.i1.31] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 11/14/2014] [Accepted: 12/10/2014] [Indexed: 02/06/2023] Open
Abstract
Chronic kidney disease (CKD) is common and the cause of significant morbidity and mortality. The replacement of functioning nephrons by fibrosis is characteristic of progressive disease. The pathways that lead to fibrosis are not fully understood, although chronic non-resolving inflammation in the kidney is likely to drive the fibrotic response that occurs. In patients with progressive CKD there is histological evidence of inflammation in the interstitium and strategies that reduce inflammation reduce renal injury in pre-clinical models of CKD. The complement system is an integral part of the innate immune system but also augments adaptive immune responses. Complement activation is known to occur in many diverse renal diseases, including glomerulonephritis, thrombotic microangiopathies and transplant rejection. In this review we discuss current evidence that complement activation contributes to progression of CKD, how complement could cause renal inflammation and whether complement inhibition would slow progression of renal disease.
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Activation of endogenous anti-inflammatory mediator cyclic AMP attenuates acute pyelonephritis in mice induced by uropathogenic Escherichia coli. THE AMERICAN JOURNAL OF PATHOLOGY 2015; 185:472-84. [PMID: 25478807 PMCID: PMC4305187 DOI: 10.1016/j.ajpath.2014.10.007] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2014] [Revised: 09/30/2014] [Accepted: 10/21/2014] [Indexed: 12/19/2022]
Abstract
The pathogenesis of pyelonephritis caused by uropathogenic Escherichia coli (UPEC) is not well understood. Here, we show that besides UPEC virulence, the severity of the host innate immune response and invasion of renal epithelial cells are important pathogenic factors. Activation of endogenous anti-inflammatory mediator cAMP significantly attenuated acute pyelonephritis in mice induced by UPEC. Administration of forskolin (a potent elevator of intracellular cAMP) reduced kidney infection (ie, bacterial load, tissue destruction); this was associated with attenuated local inflammation, as evidenced by the reduction of renal production of proinflammatory mediators, renal infiltration of inflammatory cells, and renal myeloperoxidase activity. In primary cell culture systems, forskolin not only down-regulated UPEC-stimulated production of proinflammatory mediators by renal tubular epithelial cells and inflammatory cells (eg, monocyte/macrophages) but also reduced bacterial internalization by renal tubular epithelial cells. Our findings clearly indicate that activation of endogenous anti-inflammatory mediator cAMP is beneficial for controlling UPEC-mediated acute pyelonephritis in mice. The beneficial effect can be explained at least in part by limiting excessive inflammatory responses through acting on both renal tubular epithelial cells and inflammatory cells and by inhibiting bacteria invasion of renal tubular epithelial cells.
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Zhou M, Ma H, Lin H, Qin J. Induction of epithelial-to-mesenchymal transition in proximal tubular epithelial cells on microfluidic devices. Biomaterials 2013; 35:1390-401. [PMID: 24239111 DOI: 10.1016/j.biomaterials.2013.10.070] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2013] [Accepted: 10/27/2013] [Indexed: 01/09/2023]
Abstract
In proteinuric nephropathy, epithelial-to-mesenchymal transition (EMT) is an important mechanism that causes renal interstitial fibrosis. The precise role of EMT in the pathogenesis of fibrosis remains controversial, partly due to the absence of suitable in vitro or in vivo models. We developed two microfluidic and compartmental chips that reproduced the fluidic and three-dimensional microenvironment of proximal tubular epithelial cells in vivo. Using one microfluidic device, we stimulated epithelial cells with a flow of healthy human serum, heat-inactivated serum and complement C3a, which mimicked the flow of urine within the proximal tubule. We observed that epithelial cells exposed to serum proteins became apoptotic or developed a mesenchymal phenotype. Incubating cells with C3a induced similar features. However, cells exposed to heat-inactivated serum did not adopt the mesenchymal phenotype. Furthermore, we successfully recorded the cellular morphological changes and the process of transmigration into basement membrane extract during EMT in real-time using another three-dimensional microdevice. In conclusion, we have established a cell-culture system that mimics the native microenvironment of the proximal tubule to a certain extent. Our data indicates that EMT did occur in epithelial cells that were exposed to serum proteins, and C3a plays an essential role in this pathological process.
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Affiliation(s)
- Mengying Zhou
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Rd, Dalian 116011, China
| | - Huipeng Ma
- Department of Biotechnology, Dalian Institute of Chemical Physics, CAS, No. 457 Zhongshan Rd, Dalian 116023, China; College of Medical Laboratory, Dalian Medical University, 9 Western Section, Lvshun South Street, Lvshunkou District, Dalian 116044, China
| | - Hongli Lin
- Department of Nephrology, The First Affiliated Hospital of Dalian Medical University, No. 222 Zhongshan Rd, Dalian 116011, China.
| | - Jianhua Qin
- Department of Biotechnology, Dalian Institute of Chemical Physics, CAS, No. 457 Zhongshan Rd, Dalian 116023, China.
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Abstract
The sensitive and broadly reactive character of the innate immune system makes it liable to activation by stress factors other than infection. Thermal and metabolic stresses experienced during the transplantation procedure are sufficient to trigger the innate immune response and also augment adaptive immunity in the presence of foreign antigen on the donor organ. The resulting inflammatory and immune reactions combine to form a potent effector response that can lead to graft rejection. Here we examine the evidence that the complement and toll-like receptor systems are central to these pathways of injury and present a formidable barrier to transplantation. We review extensive information about the effector mechanisms that are mediated by these pathways, and bring together what is known about the damage-associated molecular patterns that initiate this sequence of events. Finally, we refer to two ongoing therapeutic trials that are evaluating the validity of these concepts in man.
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Affiliation(s)
- Conrad A Farrar
- MRC Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King's College London School of Medicine at Guy's, King's College and St. Thomas' Hospitals, London SE1 9RT, United Kingdom
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21
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The complement cascade and renal disease. Arch Immunol Ther Exp (Warsz) 2013; 62:47-57. [PMID: 24030732 PMCID: PMC3898353 DOI: 10.1007/s00005-013-0254-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 08/21/2013] [Indexed: 01/27/2023]
Abstract
Serum complement cascade, a part of innate immunity required for host protection against invading pathogens, is also a mediator of various forms of disease and injury. It is activated by classical, lectin, and alternative pathways that lead to activation of C3 component by C3 convertases, release of C3b opsonin, C5 conversion and eventually membrane attack complex formation. The tightly regulated activation process yields also C3a and C5a anaphylatoxins, which target a broad spectrum of immune and non-immune cells. The review discusses the involvement of the complement cascade in kidney disease pathogenesis and injury. The role of the complement pathways in autoantibody-mediated forms of glomerulonephritis (lupus nephritis, anti-glomerular basement membrane disease, anti-neutrophil cytoplasmic autoantibody-induced or membranoproliferative glomerulonephritis, membranous nephropathy), C3 glomerulopathy, atypical forms of hemolytic uremic syndrome, ischemic-reperfusion injury of transplanted kidney, and antibody-mediated renal allograft rejection are discussed. The disturbances in complement activation and regulation with underlying genetics are presented and related to observed pathology. Also promising strategies targeting the complement system in complement-related disorders are mentioned.
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Lin Y, Li Y, Wang X, Gong T, Zhang L, Sun X. Targeted drug delivery to renal proximal tubule epithelial cells mediated by 2-glucosamine. J Control Release 2013; 167:148-56. [PMID: 23415893 DOI: 10.1016/j.jconrel.2013.02.001] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Revised: 01/23/2013] [Accepted: 02/02/2013] [Indexed: 10/27/2022]
Abstract
In order to develop a novel kidney-targeted drug delivery system, we synthesized prednisolone carbamate-glucosamine conjugate (PCG) using 2-glucosamine as a ligand, and investigated its potential targeting efficacy. In vitro studies demonstrated that PCG could remarkably improve the uptake of drug by kidney cells. And the specific uptake of PCG could be largely reduced by the inhibitors of megalin receptor. More importantly, PCG showed an excellent kidney targeting property in vivo, and the concentration of the conjugate in the kidney was 8.1-fold higher than that of prednisolone group at 60 min after intravenous injection. Besides, PCG could significantly reverse the disease progression in renal ischemia-reperfusion (I/R) injury animal models. Furthermore, PCG presented no adverse effect on bone density while prednisolone resulted in severe osteoporosis. Thus, it indicated that 2-glucosamine could be a potential ligand for kidney-targeted delivery of prednisolone.
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Affiliation(s)
- Yan Lin
- Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, Sichuan University, Sichuan, People's Republic of China
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Błogowski W, Dołęgowska B, Sałata D, Budkowska M, Domański L, Starzyńska T. Clinical analysis of perioperative complement activity during ischemia/reperfusion injury following renal transplantation. Clin J Am Soc Nephrol 2012; 7:1843-51. [PMID: 22904122 DOI: 10.2215/cjn.02200312] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES The complement cascade seems to be an important mediator modulating renal ischemia/reperfusion injury. This study analyzed whether significant changes occur in the levels of a terminal panel of complement molecules (C3a, C5a, and C5b-9/membrane attack complex) during the early phase of human kidney allograft reperfusion and evaluated the potential association of these changes with clinical post-transplant graft function in kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Seventy-five renal transplant recipients undergoing transplantation between 2004 and 2006 were enrolled in the study and divided into early, slow, and delayed graft function groups. Blood samples were collected perioperatively during consecutive minutes of allograft reperfusion from the renal vein. Levels of complement molecules were measured using ELISA. RESULTS Analysis revealed no significant changes in C3a and C5a levels throughout reperfusion. The main complement molecule that was significantly associated with post-transplant graft function was C5b-9/membrane attack complex; throughout the reperfusion period, perioperative levels of C5b-9/membrane attack complex were around two to three times higher in delayed graft function patients than early and slow graft function individuals (P<0.005). In addition, C5b-9/membrane attack complex levels had a relatively high clinical sensitivity and specificity (70%-87.5%) for the prediction of early and long-term (1 year) post-transplant allograft function. CONCLUSIONS This clinical study supports a role for the complement cascade in delayed graft function development. However, additional studies are needed to elucidate the exact mechanisms responsible for this phenomenon. In addition, perioperative measurements of C5b-9/membrane attack complex are highlighted as promising potential clinical markers of post-transplant renal allograft function.
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Affiliation(s)
- Wojciech Błogowski
- Department of Gastroenterology, Pomeranian Medical University, Szczecin, Poland.
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Peng Q, Li K, Smyth LA, Xing G, Wang N, Meader L, Lu B, Sacks SH, Zhou W. C3a and C5a promote renal ischemia-reperfusion injury. J Am Soc Nephrol 2012; 23:1474-85. [PMID: 22797180 DOI: 10.1681/asn.2011111072] [Citation(s) in RCA: 167] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Renal ischemia reperfusion injury triggers complement activation, but whether and how the small proinflammatory fragments C3a and C5a contribute to the pathogenesis of this injury remains to be elucidated. Using C3aR-, C5aR-, or C3aR/C5aR-deficient mice and models of renal ischemia-reperfusion injury, we found that deficiency of either or both of these receptors protected mice from injury, but the C3aR/C5aR- and C5aR-deficient mice were most protected. Protection from injury was associated with less cellular infiltration and lower mRNA levels of kidney injury molecule-1, proinflammatory mediators, and adhesion molecules in postischemic kidneys. Furthermore, chimera studies showed that the absence of C3aR and C5aR on renal tubular epithelial cells or circulating leukocytes attenuated renal ischemia-reperfusion injury. In vitro, C3a and C5a stimulation induced inflammatory mediators from both renal tubular epithelial cells and macrophages after hypoxia/reoxygenation. In conclusion, although both C3a and C5a contribute to renal ischemia-reperfusion injury, the pathogenic role of C5a in this injury predominates. These data also suggest that expression of C3aR and C5aR on both renal and circulating leukocytes contributes to the pathogenesis of renal ischemia-reperfusion injury.
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Affiliation(s)
- Qi Peng
- MRC Centre for Transplantation, King's College London, London SE1 9RT, United Kingdom
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Abstract
The complement system is a key element of the innate immune system, and the production of complement components can be divided into central (hepatic) and peripheral compartments. Essential complement components such as C3 are produced in both of these compartments, but until recently the functional relevance of the peripheral synthesis of complement was unclear. Here, we review recent findings showing that local peripheral synthesis of complement in a transplanted organ is required for the immediate response of the donor organ to tissue stress and for priming alloreactive T cells that can mediate transplant rejection. We also discuss recent insights into the role of complement in antibody-mediated rejection, and we examine how new treatment strategies that take into account the separation of central and peripheral production of complement are expected to make a difference to transplant outcome.
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Spivey TL, Uccellini L, Ascierto ML, Zoppoli G, De Giorgi V, Delogu LG, Engle AM, Thomas JM, Wang E, Marincola FM, Bedognetti D. Gene expression profiling in acute allograft rejection: challenging the immunologic constant of rejection hypothesis. J Transl Med 2011; 9:174. [PMID: 21992116 PMCID: PMC3213224 DOI: 10.1186/1479-5876-9-174] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2011] [Accepted: 10/12/2011] [Indexed: 02/06/2023] Open
Abstract
In humans, the role and relationship between molecular pathways that lead to tissue destruction during acute allograft rejection are not fully understood. Based on studies conducted in humans, we recently hypothesized that different immune-mediated tissue destruction processes (i.e. cancer, infection, autoimmunity) share common convergent final mechanisms. We called this phenomenon the "Immunologic Constant of Rejection (ICR)." The elements of the ICR include molecular pathways that are consistently described through different immune-mediated tissue destruction processes and demonstrate the activation of interferon-stimulated genes (ISGs), the recruitment of cytotoxic immune cells (primarily through CXCR3/CCR5 ligand pathways), and the activation of immune effector function genes (IEF genes; granzymes A/B, perforin, etc.). Here, we challenge the ICR hypothesis by using a meta-analytical approach and systematically reviewing microarray studies evaluating gene expression on tissue biopsies during acute allograft rejection. We found the pillars of the ICR consistently present among the studies reviewed, despite implicit heterogeneity. Additionally, we provide a descriptive mechanistic overview of acute allograft rejection by describing those molecular pathways most frequently encountered and thereby thought to be most significant. The biological role of the following molecular pathways is described: IFN-γ, CXCR3/CCR5 ligand, IEF genes, TNF-α, IL-10, IRF-1/STAT-1, and complement pathways. The role of NK cell, B cell and T-regulatory cell signatures are also addressed.
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Affiliation(s)
- Tara L Spivey
- Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland 20892, USA
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Abstract
Antibody-mediated rejection has become critical clinically because this form of rejection is usually unresponsive to conventional anti-rejection therapy, and therefore, it has been recognized as a major cause of allograft loss. Our group developed experimental animal models of vascularized organ transplantation to study pathogenesis of antibody- and complement-mediated endothelial cell injury leading to graft rejection. In this review, we discuss mechanisms of antibody-mediated graft rejection resulting from activation of complement by C1q- and MBL (mannose-binding lectin)-dependent pathways and interactions with a variety of effector cells, including macrophages and monocytes through Fcgamma receptors and complement receptors.
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Abstract
PURPOSE OF REVIEW Despite the introduction of advanced immunosuppressive drug therapies, clinical and subclinical rejections still occur in many graft recipients with a negative impact on the long-term transplant outcome. The immunological status of the patients awaiting the transplantation is a key factor for these processes. Here we summarize the recent efforts to identify and develop biomarkers and functional assays that allow an individual pretransplant risk assessment. RECENT FINDINGS New sensitive techniques assessing T-cell memory and B-cell activation have been developed. Furthermore, the expression level of soluble and molecular markers reflecting the activation state of the immune system and donor graft intrinsic factors have been shown to influence graft outcome. SUMMARY A variety of parameters and assays that determine the pretransplant immune activation status has been developed. Some of these assays have already been used prospectively to define high-risk patients receiving advanced immunosuppressive induction therapy.However, the conflicting results obtained in different studies show that biomarker analysis and functional assays performance need to be further standardized and validated in large prospective trials before they can be routinely implemented into a pretransplant risk assessment. Subsequently, a combined effort to design pretransplant risk stratification algorithms should lead to personalized immunosuppressive treatment regimes and improved graft survival and long-term graft function.
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Tang Z, Sheerin N. Complement Activation and Progression of Chronic Kidney Disease. Int J Organ Transplant Med 2009. [DOI: 10.1016/s1561-5413(09)60241-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022] Open
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Renal tubular epithelial cells as immunoregulatory cells in renal allograft rejection. Transplant Rev (Orlando) 2009; 23:129-38. [DOI: 10.1016/j.trre.2009.02.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Naesens M, Li L, Ying L, Sansanwal P, Sigdel TK, Hsieh SC, Kambham N, Lerut E, Salvatierra O, Butte AJ, Sarwal MM. Expression of complement components differs between kidney allografts from living and deceased donors. J Am Soc Nephrol 2009; 20:1839-51. [PMID: 19443638 DOI: 10.1681/asn.2008111145] [Citation(s) in RCA: 102] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
A disparity remains between graft survival of renal allografts from deceased donors and from living donors. A better understanding of the molecular mechanisms that underlie this disparity may allow the development of targeted therapies to enhance graft survival. Here, we used microarrays to examine whole genome expression profiles using tissue from 53 human renal allograft protocol biopsies obtained both at implantation and after transplantation. The gene expression profiles of living-donor kidneys and pristine deceased-donor kidneys (normal histology, young age) were significantly different before reperfusion at implantation. Deceased-donor kidneys exhibited a significant increase in renal expression of complement genes; posttransplantation biopsies from well-functioning, nonrejecting kidneys, regardless of donor source, also demonstrated a significant increase in complement expression. Peritransplantation phenomena, such as donor death and possibly cold ischemia time, contributed to differences in complement pathway gene expression. In addition, complement gene expression at the time of implantation was associated with both early and late graft function. These data suggest that complement-modulating therapy may improve graft outcomes in renal transplantation.
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Affiliation(s)
- Maarten Naesens
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA
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Zhang Z, Zheng Q, Han J, Gao G, Liu J, Gong T, Gu Z, Huang Y, Sun X, He Q. The targeting of 14-succinate triptolide-lysozyme conjugate to proximal renal tubular epithelial cells. Biomaterials 2009; 30:1372-81. [DOI: 10.1016/j.biomaterials.2008.11.035] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2008] [Accepted: 11/27/2008] [Indexed: 11/29/2022]
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Abstract
PURPOSE OF REVIEW This review emphasizes new information concerning the role of anaphylatoxins in the regulation of the immune response to allografts. Its timeliness relates the growing concept of the innate immune response as a regulator of the adaptive immune system and to how this concept lends itself to therapeutic advance. RECENT FINDINGS Recent work has extended our understanding of the role of local complement synthesis and how this facilitates the interaction between antigen-presenting cells and alloreactive T cells, resulting in a potent effector response. In particular, this work has identified new roles for anaphylatoxins as regulators of antigen presentation, T-cell proliferation and T-cell longevity. SUMMARY Strategies for comprehensive blockade of complement at the site of action, or for more selective blockade of specific complement components, are not only possible but merit further exploration based on these results.
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Affiliation(s)
- Steven Sacks
- MRC Centre for Transplantation, King's College London, Guy's Hospital, London, UK.
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Welch TR, Blystone LW. Immune complex glomerulonephritis following bone marrow transplantation in C3 deficient mice. PLoS One 2008; 3:e3334. [PMID: 18836527 PMCID: PMC2553262 DOI: 10.1371/journal.pone.0003334] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2008] [Accepted: 09/11/2008] [Indexed: 11/21/2022] Open
Abstract
Background The role of circulating complement in host defense and immune disease is well established. Although a number of cells and tissues are capable of synthesizing complement components locally, the importance of such local synthesis in immune disease has been difficult to establish. Methodology/Principal Findings We used bone marrow transplantation (BMT) between C3 knockout (C3KO) and wild type (WT) mice to construct animals that were discordant for systemic (hepatic) and local (monocytic) C3 synthetic capacity. An immune complex glomerulonephritis (GN) was then induced using intraperitoneal injections of horse spleen apoferritin (HSA) with a lipopolysaccharide (LPS) adjuvant. All HSA/LPS animals developed a proliferative GN with glomerular infiltration by monocytes. By sensitive ELISA, monocyte C3 synthesis could be detected in C3KO animals transplanted with WT bone marrow cells. Despite this, there were no significant differences among groups of mice in measures of clinical (proteinuria, renal function) or histologic (glomerular cellularity, crescents) disease severity. Conclusions/Significance In this model of GN, local synthesis of C3 by infiltrating cells does not appear to be of pathologic importance.
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Affiliation(s)
- Thomas R Welch
- Department of Pediatrics, SUNY Upstate Medical University, Syracuse, New York, United States of America.
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Abstract
Long-term kidney graft survival is affected by different variables including donor condition, ischemia-reperfusion injury, and graft rejection during the transplantation process. The complement system is an important mediator of renal ischemia-reperfusion injury and in rejecting allografts. However, donor complement C3 seems to be crucial in renal transplantation-related injury as renal injury is attenuated in C3 deficient kidney grafts. Interestingly, before ischemia-reperfusion induced C3 expression, C3 is already induced in donors suffering from brain death. Therefore, strategies targeting complement activation in the brain-dead donor may increase graft viability and transplant outcome.
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Li K, Sacks SH, Zhou W. The relative importance of local and systemic complement production in ischaemia, transplantation and other pathologies. Mol Immunol 2007; 44:3866-74. [PMID: 17768105 DOI: 10.1016/j.molimm.2007.06.006] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2007] [Indexed: 10/22/2022]
Abstract
Besides a critical role in innate host defence, complement activation contributes to inflammatory and immunological responses in a number of pathological conditions. Many tissues outside the liver (the primary source of complement) synthesise a variety of complement proteins, either constitutively or response to noxious stimuli. The significance of this local synthesis of complement has become clearer as a result of functional studies. It revealed that local production not only contributes to the systemic pool of complement but also influences local tissue injury and provides a link with the antigen-specific immune response. Extravascular production of complement seems particularly important at locations with poor access to circulating components and at sites of tissue stress responses, notably portals of entry of invasive microbes, such as interstitial spaces and renal tubular epithelial surfaces. Understanding the relative importance of local and systemic complement production at such locations could help to explain the differential involvement of complement in organ-specific pathology and inform the design of complement-based therapy. Here, we will describe the lessons we have learned over the last decade about the local synthesis of complement and its association with inflammatory and immunological diseases, placing emphasis on the role of local synthesis of complement in organ transplantation.
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Affiliation(s)
- Ke Li
- MRC Centre for Transplantation and Department of Nephrology and Transplantation, King's College London School of Medicine at Guy's Hospital, London, UK
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Abstract
The innate immune system not only participates in host defence but also contributes to the control of adaptive immune responses. Complement and Toll-like receptors (TLR) are key components of innate immunity. Emerging evidence suggests their activation is involved in all major aspects of transplantation. This paper reviews the current understanding of how the complement and TLR on impact transplant injury.
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Affiliation(s)
- Tao Lin
- Department of Nephrology and Transplantation, King's College London School of Medicine at Guy's, King's College and St Thomas' Hospitals, London, UK
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Abstract
The complement system is an important component of the innate immune system and a modulator of adaptive immunity. The entire complement system is focused on C3 and C5. Thus, there are proteins that activate C3 and C5, those that regulate this activation, and those that transduce the effects of C3 and C5 activation products; each can affect the kidney in renal injury. The normal kidney has the inherent capacity to protect itself from complement activation through cellular expression of decay-accelerating factor, membrane cofactor protein (in human beings), and Crry (in rodents). In addition, plasma factor H protects vascular spaces in the kidney. Although the main function of these proteins is to limit complement activation, there is now considerable evidence that they can transduce signals on engagement in immune cells. The G-protein-coupled 7-span transmembrane receptors for C3a and C5a, and the integral membrane complement receptors (CR) for C3b, iC3b, and C3dg, are expressed outside the kidney, particularly in cells of hematopoietic and immune lineage. These are important in renal injury through their infiltration of the kidney and/or by affecting kidney-directed immune responses. There is mounting evidence that intrinsic glomerular and tubular cell C3aR and C5aR expression and activation also can affect renal injury. CR1 on podocytes and the beta2 integrins CR3 and CR4 in kidney dendritic cells have functions that remain poorly defined. Cells of the kidney also have the capacity to produce and activate their own complement proteins. Thus, intrinsic renal cells express decay-accelerating factor, membrane cofactor protein, Crry, C3aR, C5aR, CR1, CR3, and CR4. These can be engaged by C3 and C5 activation products derived from systemic and local pools in renal injury. Given their capacity to provide signals that influence kidney cellular behavior, their activation can have substantial effects in renal injury. Defining these in a cell- and disease-specific fashion is an exciting challenge for future research.
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Affiliation(s)
- Tipu S Puri
- Section of Nephrology, University of Chicago, Chicago, IL 60637, USA
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Zhou W, Peng Q, Li K, Sacks SH. Role of dendritic cell synthesis of complement in the allospecific T cell response. Mol Immunol 2007; 44:57-63. [PMID: 16870256 DOI: 10.1016/j.molimm.2006.06.012] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2006] [Revised: 06/27/2006] [Accepted: 06/27/2006] [Indexed: 11/26/2022]
Abstract
Although extrahepatic synthesis of complement and particularly C3 has been widely studied in most cells and tissues, new information is emerging on dendritic cells (DCs). This research has shown that mouse bone marrow (BM) derived DCs are able to synthesise C3 and this synthesis has a substantial impact on DC activation, affecting the diverse range of DC functions relevant to the allospecific T cell response. Thus, local production of C3 appears to regulate the capacity of DCs to trigger the primary T cell response against donor alloantigen. Understanding of the key mechanisms by which complement activation modulates DC maturation could lead to the development of therapeutic strategies to down regulate DC activation thus reduce allograft rejection.
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Affiliation(s)
- Wuding Zhou
- King's College London School of Medicine at Guy's, King's College and St. Thomas' Hospitals, Department of Nephrology and Transplantation, London, SE1 9RT, UK.
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Braun MC, Li L, Ke B, Dubinsky WP, Pickering MC, Chang JY. Proteomic profiling of urinary protein excretion in the factor H-deficient mouse. Am J Nephrol 2006; 26:127-35. [PMID: 16549904 DOI: 10.1159/000092211] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2005] [Accepted: 02/21/2006] [Indexed: 12/25/2022]
Abstract
BACKGROUND Since the 1970s a variety of experimental techniques have been employed in an attempt to identify urinary biomarkers of renal injury. While these approaches have met with some success, modern proteomic tools now permit broad based high-throughput analysis of the urinary proteome. METHODS Using the ICAT isotopic labeling based LC/MS/MS approach, comparative urinary protein profiling was performed in a murine model of membranoproliferative glomerulonephritis. Paired samples were analyzed mice with a targeted deletion of the complement regulatory protein factor H (FH-/-) and control mice. RESULTS 25 distinct urinary proteins were identified of which 7 were differentially expressed in the FH-/- mice. Two proteins were markedly altered in the urine of FH-/- mice compared to controls: uromodulin (5.5-fold lower) and the MHC class II molecule H2e (8.6-fold higher). Differential expression was confirmed by Western blot and RT-PCR. Immunofluorescent staining demonstrated a marked increased expression of H2e and a reduction of uromodulin expression in the tubular epithelium of FH-/- mice. CONCLUSIONS These findings provide insight into early complement-dependent alterations in tubular protein expression which may play critical roles in the development of tubulointerstitial disease, and provide experimental support for the use of urinary proteomic profiling in murine models of renal injury.
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Affiliation(s)
- Michael C Braun
- The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas 77030, USA.
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Brown KM, Kondeatis E, Vaughan RW, Kon SP, Farmer CKT, Taylor JD, He X, Johnston A, Horsfield C, Janssen BJC, Gros P, Zhou W, Sacks SH, Sheerin NS. Influence of donor C3 allotype on late renal-transplantation outcome. N Engl J Med 2006; 354:2014-23. [PMID: 16687714 DOI: 10.1056/nejmoa052825] [Citation(s) in RCA: 145] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND The complement system has a critical role in both the innate and the adaptive immune responses. In humans, C3 exists as two main allotypes, F (fast) and S (slow), which are known to affect the incidence of inflammatory disease. We conducted a study to address the influence of these alleles on late renal-graft outcome. METHODS We determined the C3 allotypes of 662 pairs of adult kidney donors and recipients from 1993 through 2002 and then related C3F/S polymorphism status to demographic and clinical outcome data. The median length of follow-up was 3.3 years. RESULTS Analysis of 513 pairs of white donors and recipients identified 113 C3S/S recipients of a C3S/F or a C3F/F kidney and 179 C3S/S recipients of a C3S/S kidney. Graft survival was significantly better with a C3F/F or C3F/S donor allotype than a C3S/S allotype (P=0.05). The hazard ratio for graft loss of C3S/S kidneys, as compared with C3F/F or C3F/S kidneys, was 2.21 (95 percent confidence interval, 1.04 to 4.72; P=0.04). The graft function of C3F/F or C3F/S donor kidneys was significantly better than that of C3S/S donor kidneys (P<0.001). The effect of the C3F allele was specific to recipients who did not themselves possess this allele. Multivariate analysis excluded effects of other factors known to influence graft outcome. CONCLUSIONS Expression of C3 alleles by donor renal cells appears to have a differential effect on late graft outcome. Among white C3S/S recipients, receipt of a C3F/F or C3F/S donor kidney, rather than a C3S/S donor kidney, is associated with a significantly better long-term outcome. These findings suggest that the two alleles have functional differences.
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Affiliation(s)
- Katherine M Brown
- Department of Nephrology and Transplantation, King's College London, Guy's Hospital, London, United Kingdom
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Sacks SH, Zhou W. Allograft rejection: effect of local synthesis of complement. SPRINGER SEMINARS IN IMMUNOPATHOLOGY 2005; 27:332-44. [PMID: 16189650 DOI: 10.1007/s00281-005-0005-0] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/15/2005] [Accepted: 03/18/2005] [Indexed: 12/12/2022]
Abstract
The complement system is known for its ability to participate in non-specific inflammation and membrane injury as well as contributing to antigen-specific immune stimulation. In renal transplantation, the complement cascade behaves true to form in that both non-immune- and immune-mediated destruction of the renal tubules are complement dependent. What is remarkable, however, is the extent of involvement of local synthesis of complement in both of these injuries, suggesting that the extravascular tissue compartment is the domain of local synthesis, whereas the effect of circulating complement is much less. This creates a new paradigm for studying the influence of local synthesis of complement in other organ-based diseases and underlines the need for tissue-targeting strategies in successful therapeutic development.
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Affiliation(s)
- Steven H Sacks
- Department of Nephrology and Transplantation, King's College London School of Medicine at Guy's, St Thomas Hospitals, 5th Floor Thomas Guy House, Guy's Hospital, London SE1 9RT, UK.
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Serinsöz E, Bock O, Gwinner W, Schwarz A, Haller H, Kreipe H, Mengel M. Local complement C3 expression is upregulated in humoral and cellular rejection of renal allografts. Am J Transplant 2005; 5:1490-4. [PMID: 15888059 DOI: 10.1111/j.1600-6143.2005.00873.x] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Evidence on the role of the complement system in transplantation pathology has been accelerated by the discovery of C4d as an in situ marker of antibody-mediated rejection. However, a local or systemic source of complement expression during acute rejection is under discussion. Thus, we quantitatively analyzed local RNA expression of complement component C3 as a pivotal molecule in active humoral and cellular rejection of renal allografts. After laser microdissection, real-time RT-PCR was performed for C3 using RNA extracted from tubuli and glomeruli of 68 paraffin-embedded renal allograft biopsies. Protocol and indication biopsies with signs of humoral and/or cellular rejection were investigated. Quantitative expression analysis of cytokines (IFN gamma, MCP-1, IL2, IL8) potentially influencing local C3 expression was performed. We observed a significant increase in median expression level of C3 mRNA in tubuli of C4d-positive indication biopsies, and in tubuli from indication biopsies with signs of T-cell-mediated cellular rejection. Highest expression levels were found in C4d-positive indication biopsies with signs of cellular rejection. Biopsies with upregulated C3 showed increased IFN gamma expression, suggesting allograft-infiltrating T-cells as potential stimulus for local C3 expression. Therefore, locally synthesized complement component C3 contributes to both humoral and cellular rejection, with tubular epithelial cells being a major source.
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Affiliation(s)
- Ebru Serinsöz
- Department of Pathology, Medizinische Hochschule Hannover, Germany
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