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Dimerization of complement factor H-related (FHR) proteins: FHR-5 forms homodimers whereas FHR-1 and FHR-2 both homodimerize and heterodimerize with each other
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Abstracts / Immunobiology 221 (2016) 1131–1225
from the noncatalytic subunit (nCS; C4b/C3b) of the classical/lectin (C4b2a) and alternative (C3bBb) pathway C3-convertases. This activity is dubbed as “decay-acceleration activity (DAA)”. Initial study on the domain requirements of DAF identified that out of its four domains (D1-D4), D2-D3 are essential for its classical/lectin pathway (CP/LP)-DAA, while D2-D4 are required for the alternative pathway (AP)-DAA. Further insights into AP-DAA of DAF gained from a surface plasmon resonance study utilizing deletion mutants showed that D2 and D4 interact with Bb and C3b, respectively, while D3 does not interact with any of the subunits of AP C3-convertase and therefore serves as an essential spacer. Data obtained using site-directed mutagenesis and VCP-DAF chimeras, however clearly implicated the role of D3 in AP/CP-DAA. In the present study, we therefore, re-examined the functional contribution of individual domains of DAF, but in the context of a 4 domain structural framework using domain swap approach. Herein, we swapped one or more domains of membrane cofactor protein (MCP; M1-M3) which lacks DAA, with the homologous domains of DAF (D2-D4) and characterised these mutants for gain of function. Our data showed that: (i) replacement of M1 with D2 was sufficient to gain CP-DAA, but only when it was swapped with the contiguous D2-D3 linker indicating direct involvement of this domain and the linker in CP-DAA. This construct however did not show any AP-DAA; (ii) swapping of M1-M2 and the connecting linkers with D2-D3 and the linkers was sufficient to gain AP-DAA and the construct displayed CP- and AP-DAA comparable to that of DAF indicating critical involvement of D3 in addition to D2 and linkers in DAA; (iii) replacement of M1-M3 with D2-D4 also resulted in gain in CP- and AP-DAA, though the AP-DAA activity of the construct was ∼10-fold lower compared to DAF owing to its slow dissociation rate for C3b. Based on our results, earlier mutagenesis data, and the available structures of C3b,Bb and C3b-DAF, we propose that interaction of DAF with F-␣7 loop of CS, and nCS is enough to mediate CP-DAA, but not AP-DAA which also requires interaction with ␣5-E loop of CS. Besides this, AP-DAA also requires additional interaction of DAF with nCS, which can be provided by D4 or M3–M4. http://dx.doi.org/10.1016/j.imbio.2016.06.128 114 Activation of complement in crescentic IgA nephropathy Xinfang Xie ∗ , Jicheng Lv, Sufang Shi, Li Zhu, Lijun Liu, Min Chen, Yu Wang, Zhao Cui, Xin Wang, Li Liu, Xiaojuan Yu, Fude Zhou, Minghui Zhao, Hong Zhang Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China Background: Complement activation has a role in the pathogenesis of IgA nephropathy (IgAN), however its role in the development of diffuse crescents forming in this disease is still unknown. In this study we aim to assess the activation of complement and its association with the disease progression in patients with crescentic IgAN, one of the most common form of rapidly progressive glomerulonephritis. Methods: 36 patients with diffuse crescentic IgAN entered this study, and 37 patients with non-crescentic IgAN worked as control. Urine complement components levels (including Bb, C4d, MBL, C3a, C5a and soluble C5b-9 (sC5b-9)), representing the renal complement activation, were determined using ELISA. We also evaluate sequential plasma and urine levels of complement
activation products with the disease progression in 12 crescentic IgAN patients who received plasma exchange (PE) therapy. Results: Urine complement activation products were significant much higher in patients with crescentic IgAN as compared to those with non-crescentic IgAN: Bb 0.58 (0.15–4.08) vs. 0.02 (0.01–0.03) g/mg Creatinine (Cr); C4d 0.83 (0.02–2.68) vs. 0 (0–0.002) g/mg Cr; MBL 4.41 (0–16.22) vs. 0 (0–0.05) g/mg Cr; C3a 14.05 (3.57–66.65) vs. 0.02(0–0.17) ng/mg Cr; C5a 30.44 (7–95.09) vs. 0.20 (0.10–0.97) ng/mg Cr; Sc5b-9 311.39 (54.62–1446.05) vs. 1.34 (0.30–3.39) ng/mg Cr, all p < 0.01). Twelve patients who had reached dialysis or did not response to immunosuppressive therapy received a median of 7 PE courses (range: 5–10), 6 of them were free of dialysis during a mean follow-up of 15.6 months (6–51 months). PE therapy significantly reduced the plasma IgA–IgG complex level in that group of patients. Levels of plasma C3a, C5a and Sc5b-9 were also significantly decreased (C3a pre-PE: 308.7 (80.4–502.5) vs. post-PE: 69.5 (24.0–174.1) ng/ml; C5a pre-PE: 20.6 (9.5–30.7) vs. post-PE: 6.1 (2.6–12.1) ng/ml; sC5b-9 pre-PE: 874.3 (638.1–1017.0) vs. post-PE: 546.9(189.7–756.0) ng/ml, remaining persistent low level until the last follow-up. Similarly, urinary sequential levels of C3a, C5a, and Sc5b-9 significantly decreased in four patients of recovered from dialysis while not in one patients progressed to end-stage kidney disease. Conclusion: Patients with crescentic IgAN showed significant activation of complement through the alternative and lectin pathway. Plasma exchange therapy could reduce the levels of active complement products, which was possibly associated with ameliorating kidney injury. http://dx.doi.org/10.1016/j.imbio.2016.06.129 115 Dimerization of complement factor H-related (FHR) proteins: FHR-5 forms homodimers whereas FHR-1 and FHR-2 both homodimerize and heterodimerize with each other Anna E. van Beek 1,2,∗ , Richard B. Pouw 1,2 , Mieke C. Brouwer 1 , G. van Mierlo 1 , T. Rispens 1 , Taco W. Kuijpers 2,3 , Diana Wouters 1 1
Department of Immunopathology, Sanquin Research and Landsteiner laboratory of the Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands 2 Department of Pediatric Hematology, Immunology & Infectious Diseases, Emma children’s hospital, Academic Medical Centre, Amsterdam, The Netherlands 3 Department of Blood Cell Research, Sanquin Research and Landsteiner laboratory of the Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands Protection of human cells against unwanted complement activation is acquired by Factor H (FH), a regulator of the alternative pathway (AP). Genetic variations in the CFH region are associated with complement-mediated diseases, including AMD and aHUS. Next to variations in FH, also polymorphisms in the highly similar FH-related (FHR) proteins are linked to disease. FHRs are highly similar to FH in the C3b and heparin binding regions, but lack domains that correspond to the regulatory domains of FH. By competing with FH, FHRs are thought to fine tune the inhibitory role of FH in regulating the AP on cell surfaces. Furthermore, while there are no indications for FHR-3 or FHR-4 to form dimers, FHR-1, FHR-2 and FHR-5 would increase their binding avidity to cellular
Abstracts / Immunobiology 221 (2016) 1131–1225
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membranes by forming dimers, thus enhancing their function as competitors of FH. Plasma concentrations of FHR-1, FHR-2 and FHR-5 have not yet been established, as the dimer composition has prevented their detailed characterization to date. We immunized mice with recombinant (r) FHR-1, FHR-2 and FHR-5, produced in HEK293F cells and obtained monoclonal antibodies that were screened for binding specificity and crossreactivity against rFHRs and plasma-derived FH. FHR dimerization was investigated using pull-down assays, sucrose gradients and heparin chromatography. rFHR-2 and FHR-5 were fluorescently labeled to study monomer exchange via FRET assays. We demonstrate that FHR-1 and FHR-2 can exchange monomers and are equally able to form homo- and heterodimers, whereas FHR-5 can form only homodimers. The kinetics indicate that the dimerization and monomer exchange is a fast process and free monomers presumably do not exist. Sucrose gradients of serum from healthy donors confirmed that serum-derived proteins circulate as dimers in vivo as well. Also subsequent immunoprecipitations of FHR-1 or FHR-2 from human serum demonstrated that FHR-1 and FHR-2 are present as both homo- and heterodimers. These dimer species all have their own heparin binding capacity. FHR-1 homodimers bind heparin at a similar strength as FH, while FHR-2 homodimers and FHR-1/FHR-2 heterodimers have minimal and intermediate heparin binding capacity, respectively. This research advances our knowledge about the factor Hrelated proteins. The now elucidated dimer profile allows for accurate measurements of FHR plasma levels and provides new insights on the role of these dimers in complement regulation. Taco W. Kuijpers and Diana Wouters contributed equally to this work.
3 or 7 days. It was found that C5L2−/− mice were protected against IR injury, resulting in significant lower plasma creatinine and BUN levels, and reduced acute tubular necrosis. Next, an in vivo migration study, where WT, C5aR−/− and C5L2−/− mice were injected intraperitoneally with complement ligands, revealed that C5L2 is not involved in leukocyte migration. To investigate the contribution of renal-expressed C5L2 versus leukocyte-expressed C5L2 to renal IR injury, bone marrow chimeras were created. Our data show that renal-expressed C5L2 and leukocyte-expressed C5L2 mediate IR injury-induced renal dysfunction. Therefore, C5L2 is a functional receptor in renal IR injury rather than a simple decoy receptor. For that reason, next to C5aR, C5L2 is a potential target for intervention during renal IR injury.
http://dx.doi.org/10.1016/j.imbio.2016.06.130
Background: Hemodialysis (HD) is a lifesaving treatment for patients with end stage renal disease not suitable for renal transplantation or awaiting a donor kidney. However, patients receiving HD have much higher rates of cardiovascular morbidity and mortality compared to the general population. Mannose-binding lectin (MBL) has been shown to play an important role in the development of cardiovascular disease. However, this relationship is complex and studies suggest that MBL can be either detrimental or beneficial. In addition, it has been shown that MBL concentration and functionality are altered by HD. Therefore, this study aimed to determine the predictive value of MBL levels for cardiac and cardiovascular events and all-cause mortality in HD patients. Methods: We conducted a prospective study of 107 HD patients on maintenance dialysis. Plasma MBL was measured before and after HD using a sandwich ELISA. The prognostic effect of MBL levels after HD was evaluated using Cox regression models. The primary endpoint was the incidence of cardiac (C-event) and cardiovascular events (CV-event). The secondary endpoint was all-cause mortality. Results: During median follow-up of 27 months, 21 participants (20%) developed C-events, while 36 (34%) had CV-events. Furthermore, 37 patients (35%) died during the study and 21 (20%) received a kidney transplant. After the study period, 58% of patients with low MBL levels (<319 ng/mL) and 26% of patients with high MBL levels (≥319 ng/mL) had a CV-event. The incidence of both cardiac and cardiovascular events was significantly higher in patients with low MBL levels. Low MBL levels were associated with a hazard ratio of 2.64 (95% CI, 1.36–5.13; p = 0.004) for a CV-event and 2.60 (95% CI, 1.10–6.18; p = 0.03) for a C-event. After adjustment, the hazard ratio for future CV-event was 3.98 (95% CI, 1.88–8.24; p < 0.001) or 3.96 (95% CI, 1.49–10.54; p = 0.006) for C-event in HD patients with low MBL levels. No association was found between low MBL levels and all-cause mortality. Conclusion: Low MBL is associated with a higher risk of cardiac and cardiovascular events, but not all-cause mortality. Therefore,
116 A functional role for complement receptor C5L2 in the pathogenesis of renal ischemia-reperfusion injury Felix Poppelaars 1,∗ , Maaike van Werkhoven 1 , Juha Kotimaa 2 , Zwanida Veldhuis 3 , Albertina Ausema 4 , Stefan Broeren 1 , Jeffrey Damman 5 , Cordelia Hempel 1 , Henri Leuvenink 3 , Mohamed Daha 1,2 , Willem van Son 1 , Cees van Kooten 2 , Ronald van Os 4 , Jan-Luuk Hillebrands 6 , Marc Seelen 1 1 Department of Nephrology, University of Groningen, Groningen, The Netherlands 2 Department of Nephrology, University of Leiden, Leiden, The Netherlands 3 Department of Surgery, University of Groningen, Groningen, The Netherlands 4 Laboratory of Ageing Biology and Stem Cells, University of Groningen, Groningen, The Netherlands 5 Department of Pathology, University of Amsterdam, Amsterdam, The Netherlands 6 Department of Pathology, University of Groningen, Groningen, The Netherlands
The complement system, and specifically C5a, is involved in renal ischemia-reperfusion (IR) injury. The two receptors for C5a, C5aR and C5L2, are expressed on leukocytes as well as in the kidney. Extensive evidence shows that C5aR inhibition protects kidneys from IR injury, but the role of C5L2 in IR injury has not been studied so far. Therefore, WT, C5aR−/− and C5L2−/− mice were subjected to 40 min of bilateral renal ischemia, followed by reperfusion for 1,
http://dx.doi.org/10.1016/j.imbio.2016.06.131 117 Low mannose-binding lectin levels predict cardiovascular disease in hemodialysis patients Mariana Gaya da Costa 1,∗ , Felix Poppelaars 1 , Stefan Berger 1 , Solmaz Assa 2 , Anita Meter-Arkema 1 , Mohamed Daha 1,3 , Willem Van Son 1 , Casper Franssen 1 , Marc Seelen 1 1
Department of Nephrology, University of Groningen, Groningen, The Netherlands 2 Department of Cardiology, University of Groningen, Groningen, The Netherlands 3 Department of Nephrology, University of Leiden, Leiden, The Netherlands
Abstracts / Immunobiology 221 (2016) 1131–1225
from the noncatalytic subunit (nCS; C4b/C3b) of the classical/lectin (C4b2a) and alternative (C3bBb) pathway C3-convertases. This activity is dubbed as “decay-acceleration activity (DAA)”. Initial study on the domain requirements of DAF identified that out of its four domains (D1-D4), D2-D3 are essential for its classical/lectin pathway (CP/LP)-DAA, while D2-D4 are required for the alternative pathway (AP)-DAA. Further insights into AP-DAA of DAF gained from a surface plasmon resonance study utilizing deletion mutants showed that D2 and D4 interact with Bb and C3b, respectively, while D3 does not interact with any of the subunits of AP C3-convertase and therefore serves as an essential spacer. Data obtained using site-directed mutagenesis and VCP-DAF chimeras, however clearly implicated the role of D3 in AP/CP-DAA. In the present study, we therefore, re-examined the functional contribution of individual domains of DAF, but in the context of a 4 domain structural framework using domain swap approach. Herein, we swapped one or more domains of membrane cofactor protein (MCP; M1-M3) which lacks DAA, with the homologous domains of DAF (D2-D4) and characterised these mutants for gain of function. Our data showed that: (i) replacement of M1 with D2 was sufficient to gain CP-DAA, but only when it was swapped with the contiguous D2-D3 linker indicating direct involvement of this domain and the linker in CP-DAA. This construct however did not show any AP-DAA; (ii) swapping of M1-M2 and the connecting linkers with D2-D3 and the linkers was sufficient to gain AP-DAA and the construct displayed CP- and AP-DAA comparable to that of DAF indicating critical involvement of D3 in addition to D2 and linkers in DAA; (iii) replacement of M1-M3 with D2-D4 also resulted in gain in CP- and AP-DAA, though the AP-DAA activity of the construct was ∼10-fold lower compared to DAF owing to its slow dissociation rate for C3b. Based on our results, earlier mutagenesis data, and the available structures of C3b,Bb and C3b-DAF, we propose that interaction of DAF with F-␣7 loop of CS, and nCS is enough to mediate CP-DAA, but not AP-DAA which also requires interaction with ␣5-E loop of CS. Besides this, AP-DAA also requires additional interaction of DAF with nCS, which can be provided by D4 or M3–M4. http://dx.doi.org/10.1016/j.imbio.2016.06.128 114 Activation of complement in crescentic IgA nephropathy Xinfang Xie ∗ , Jicheng Lv, Sufang Shi, Li Zhu, Lijun Liu, Min Chen, Yu Wang, Zhao Cui, Xin Wang, Li Liu, Xiaojuan Yu, Fude Zhou, Minghui Zhao, Hong Zhang Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China Background: Complement activation has a role in the pathogenesis of IgA nephropathy (IgAN), however its role in the development of diffuse crescents forming in this disease is still unknown. In this study we aim to assess the activation of complement and its association with the disease progression in patients with crescentic IgAN, one of the most common form of rapidly progressive glomerulonephritis. Methods: 36 patients with diffuse crescentic IgAN entered this study, and 37 patients with non-crescentic IgAN worked as control. Urine complement components levels (including Bb, C4d, MBL, C3a, C5a and soluble C5b-9 (sC5b-9)), representing the renal complement activation, were determined using ELISA. We also evaluate sequential plasma and urine levels of complement
activation products with the disease progression in 12 crescentic IgAN patients who received plasma exchange (PE) therapy. Results: Urine complement activation products were significant much higher in patients with crescentic IgAN as compared to those with non-crescentic IgAN: Bb 0.58 (0.15–4.08) vs. 0.02 (0.01–0.03) g/mg Creatinine (Cr); C4d 0.83 (0.02–2.68) vs. 0 (0–0.002) g/mg Cr; MBL 4.41 (0–16.22) vs. 0 (0–0.05) g/mg Cr; C3a 14.05 (3.57–66.65) vs. 0.02(0–0.17) ng/mg Cr; C5a 30.44 (7–95.09) vs. 0.20 (0.10–0.97) ng/mg Cr; Sc5b-9 311.39 (54.62–1446.05) vs. 1.34 (0.30–3.39) ng/mg Cr, all p < 0.01). Twelve patients who had reached dialysis or did not response to immunosuppressive therapy received a median of 7 PE courses (range: 5–10), 6 of them were free of dialysis during a mean follow-up of 15.6 months (6–51 months). PE therapy significantly reduced the plasma IgA–IgG complex level in that group of patients. Levels of plasma C3a, C5a and Sc5b-9 were also significantly decreased (C3a pre-PE: 308.7 (80.4–502.5) vs. post-PE: 69.5 (24.0–174.1) ng/ml; C5a pre-PE: 20.6 (9.5–30.7) vs. post-PE: 6.1 (2.6–12.1) ng/ml; sC5b-9 pre-PE: 874.3 (638.1–1017.0) vs. post-PE: 546.9(189.7–756.0) ng/ml, remaining persistent low level until the last follow-up. Similarly, urinary sequential levels of C3a, C5a, and Sc5b-9 significantly decreased in four patients of recovered from dialysis while not in one patients progressed to end-stage kidney disease. Conclusion: Patients with crescentic IgAN showed significant activation of complement through the alternative and lectin pathway. Plasma exchange therapy could reduce the levels of active complement products, which was possibly associated with ameliorating kidney injury. http://dx.doi.org/10.1016/j.imbio.2016.06.129 115 Dimerization of complement factor H-related (FHR) proteins: FHR-5 forms homodimers whereas FHR-1 and FHR-2 both homodimerize and heterodimerize with each other Anna E. van Beek 1,2,∗ , Richard B. Pouw 1,2 , Mieke C. Brouwer 1 , G. van Mierlo 1 , T. Rispens 1 , Taco W. Kuijpers 2,3 , Diana Wouters 1 1
Department of Immunopathology, Sanquin Research and Landsteiner laboratory of the Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands 2 Department of Pediatric Hematology, Immunology & Infectious Diseases, Emma children’s hospital, Academic Medical Centre, Amsterdam, The Netherlands 3 Department of Blood Cell Research, Sanquin Research and Landsteiner laboratory of the Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands Protection of human cells against unwanted complement activation is acquired by Factor H (FH), a regulator of the alternative pathway (AP). Genetic variations in the CFH region are associated with complement-mediated diseases, including AMD and aHUS. Next to variations in FH, also polymorphisms in the highly similar FH-related (FHR) proteins are linked to disease. FHRs are highly similar to FH in the C3b and heparin binding regions, but lack domains that correspond to the regulatory domains of FH. By competing with FH, FHRs are thought to fine tune the inhibitory role of FH in regulating the AP on cell surfaces. Furthermore, while there are no indications for FHR-3 or FHR-4 to form dimers, FHR-1, FHR-2 and FHR-5 would increase their binding avidity to cellular
Abstracts / Immunobiology 221 (2016) 1131–1225
1183
membranes by forming dimers, thus enhancing their function as competitors of FH. Plasma concentrations of FHR-1, FHR-2 and FHR-5 have not yet been established, as the dimer composition has prevented their detailed characterization to date. We immunized mice with recombinant (r) FHR-1, FHR-2 and FHR-5, produced in HEK293F cells and obtained monoclonal antibodies that were screened for binding specificity and crossreactivity against rFHRs and plasma-derived FH. FHR dimerization was investigated using pull-down assays, sucrose gradients and heparin chromatography. rFHR-2 and FHR-5 were fluorescently labeled to study monomer exchange via FRET assays. We demonstrate that FHR-1 and FHR-2 can exchange monomers and are equally able to form homo- and heterodimers, whereas FHR-5 can form only homodimers. The kinetics indicate that the dimerization and monomer exchange is a fast process and free monomers presumably do not exist. Sucrose gradients of serum from healthy donors confirmed that serum-derived proteins circulate as dimers in vivo as well. Also subsequent immunoprecipitations of FHR-1 or FHR-2 from human serum demonstrated that FHR-1 and FHR-2 are present as both homo- and heterodimers. These dimer species all have their own heparin binding capacity. FHR-1 homodimers bind heparin at a similar strength as FH, while FHR-2 homodimers and FHR-1/FHR-2 heterodimers have minimal and intermediate heparin binding capacity, respectively. This research advances our knowledge about the factor Hrelated proteins. The now elucidated dimer profile allows for accurate measurements of FHR plasma levels and provides new insights on the role of these dimers in complement regulation. Taco W. Kuijpers and Diana Wouters contributed equally to this work.
3 or 7 days. It was found that C5L2−/− mice were protected against IR injury, resulting in significant lower plasma creatinine and BUN levels, and reduced acute tubular necrosis. Next, an in vivo migration study, where WT, C5aR−/− and C5L2−/− mice were injected intraperitoneally with complement ligands, revealed that C5L2 is not involved in leukocyte migration. To investigate the contribution of renal-expressed C5L2 versus leukocyte-expressed C5L2 to renal IR injury, bone marrow chimeras were created. Our data show that renal-expressed C5L2 and leukocyte-expressed C5L2 mediate IR injury-induced renal dysfunction. Therefore, C5L2 is a functional receptor in renal IR injury rather than a simple decoy receptor. For that reason, next to C5aR, C5L2 is a potential target for intervention during renal IR injury.
http://dx.doi.org/10.1016/j.imbio.2016.06.130
Background: Hemodialysis (HD) is a lifesaving treatment for patients with end stage renal disease not suitable for renal transplantation or awaiting a donor kidney. However, patients receiving HD have much higher rates of cardiovascular morbidity and mortality compared to the general population. Mannose-binding lectin (MBL) has been shown to play an important role in the development of cardiovascular disease. However, this relationship is complex and studies suggest that MBL can be either detrimental or beneficial. In addition, it has been shown that MBL concentration and functionality are altered by HD. Therefore, this study aimed to determine the predictive value of MBL levels for cardiac and cardiovascular events and all-cause mortality in HD patients. Methods: We conducted a prospective study of 107 HD patients on maintenance dialysis. Plasma MBL was measured before and after HD using a sandwich ELISA. The prognostic effect of MBL levels after HD was evaluated using Cox regression models. The primary endpoint was the incidence of cardiac (C-event) and cardiovascular events (CV-event). The secondary endpoint was all-cause mortality. Results: During median follow-up of 27 months, 21 participants (20%) developed C-events, while 36 (34%) had CV-events. Furthermore, 37 patients (35%) died during the study and 21 (20%) received a kidney transplant. After the study period, 58% of patients with low MBL levels (<319 ng/mL) and 26% of patients with high MBL levels (≥319 ng/mL) had a CV-event. The incidence of both cardiac and cardiovascular events was significantly higher in patients with low MBL levels. Low MBL levels were associated with a hazard ratio of 2.64 (95% CI, 1.36–5.13; p = 0.004) for a CV-event and 2.60 (95% CI, 1.10–6.18; p = 0.03) for a C-event. After adjustment, the hazard ratio for future CV-event was 3.98 (95% CI, 1.88–8.24; p < 0.001) or 3.96 (95% CI, 1.49–10.54; p = 0.006) for C-event in HD patients with low MBL levels. No association was found between low MBL levels and all-cause mortality. Conclusion: Low MBL is associated with a higher risk of cardiac and cardiovascular events, but not all-cause mortality. Therefore,
116 A functional role for complement receptor C5L2 in the pathogenesis of renal ischemia-reperfusion injury Felix Poppelaars 1,∗ , Maaike van Werkhoven 1 , Juha Kotimaa 2 , Zwanida Veldhuis 3 , Albertina Ausema 4 , Stefan Broeren 1 , Jeffrey Damman 5 , Cordelia Hempel 1 , Henri Leuvenink 3 , Mohamed Daha 1,2 , Willem van Son 1 , Cees van Kooten 2 , Ronald van Os 4 , Jan-Luuk Hillebrands 6 , Marc Seelen 1 1 Department of Nephrology, University of Groningen, Groningen, The Netherlands 2 Department of Nephrology, University of Leiden, Leiden, The Netherlands 3 Department of Surgery, University of Groningen, Groningen, The Netherlands 4 Laboratory of Ageing Biology and Stem Cells, University of Groningen, Groningen, The Netherlands 5 Department of Pathology, University of Amsterdam, Amsterdam, The Netherlands 6 Department of Pathology, University of Groningen, Groningen, The Netherlands
The complement system, and specifically C5a, is involved in renal ischemia-reperfusion (IR) injury. The two receptors for C5a, C5aR and C5L2, are expressed on leukocytes as well as in the kidney. Extensive evidence shows that C5aR inhibition protects kidneys from IR injury, but the role of C5L2 in IR injury has not been studied so far. Therefore, WT, C5aR−/− and C5L2−/− mice were subjected to 40 min of bilateral renal ischemia, followed by reperfusion for 1,
http://dx.doi.org/10.1016/j.imbio.2016.06.131 117 Low mannose-binding lectin levels predict cardiovascular disease in hemodialysis patients Mariana Gaya da Costa 1,∗ , Felix Poppelaars 1 , Stefan Berger 1 , Solmaz Assa 2 , Anita Meter-Arkema 1 , Mohamed Daha 1,3 , Willem Van Son 1 , Casper Franssen 1 , Marc Seelen 1 1
Department of Nephrology, University of Groningen, Groningen, The Netherlands 2 Department of Cardiology, University of Groningen, Groningen, The Netherlands 3 Department of Nephrology, University of Leiden, Leiden, The Netherlands