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Associations of the alternative pathway and classical pathway of complement activation with incident metabolic syndrome: The CODAM study
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Abstracts / Molecular Immunology 89 (2017) 188–193
147
148
Associations of the alternative pathway and classical pathway of complement activation with incident metabolic syndrome: The CODAM study
Cell-type specific complement expression in aging, albino mice
Ying Xin ∗ , Elisabeth Hertle, Carla J.H. van der Kallen, Casper G. Schalkwijk, Coen D.A. Stehouwer, Marleen M.J. van Greevenbroek Dept of Internal Medicine, Maastricht University Medical Centre and CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands Background: Plasma concentrations of various complement components are higher in obese individuals and may contribute to adipose tissue dysfunction and development of the metabolic syndrome. We investigated the associations of components of the alternative [C3, C3a, Bb, factor D (FD), factor H (FH), properdin], and the classical complement pathway (C4, C1q, C1-inhibitor) with prevalent and incident metabolic syndrome (MetS) in a human cohort. Materials and methods: The study cohort was n = 574 (61% men, age 59.6 ± 7.0 years) at baseline and n = 489 after 7 years follow-up. Multiple logistic regression was used to investigate associations of complement at baseline (standardized values) with (1) prevalence of MetS in all, and (2) incident MetS in those without MetS at baseline (n = 189). In this latter group, linear regression models were then used to evaluate the associations between baseline complement and worsening of MetS components (i.e. fasting triglycerides, HDL-cholesterol, glucose, systolic and diastolic blood pressure, waist circumference) during follow-up. All analyses were adjusted for age, sex, smoking, alcohol consumption, physical activity, energy intake and medication use, and in linear regression also for baseline value of the MetS component. Results and conclusions: C3 concentrations were higher in those with MetS compared to those without (odds ratio (OR): 3.60 [95% confidence interval: 2.73; 4.75]). Similar associations were observed for C3a (OR: 1.25 [1.03; 1.52]), FH (OR: 2.93 [2.24; 3.83]), properdin (OR: 1.88 [1.50; 2.34]), and C4 (OR: 1.39 [1.13; 1.69]), but not for Bb, C1q or C1-iinhibitor. Notably, C3 (OR: 1.63 [1.03; 2.58] and C4 (OR: 2.03 [1.34; 3.06]), but none of the other complement factors, were positively associated with incident MetS (n = 40 cases). Baseline C3 was weakly but positively associated with plasma glucose (in mmol/L, log2 -transformed) at follow up (ˇ = 0.03 [0.01; 0.06]), while C4 showed a borderline significant association with triglycerides (in mmol/L, log2 -transformed) at follow-up (ˇ = 0.08 [−0.00; 0.15]). Taken together, these findings suggest a role for C3 and C4 in the development of MetS, but with different underlying mechanisms. For C3 these associations may, at least partly, be driven by effects on glucose metabolism, while for C4 this may be via lipid metabolism. http://dx.doi.org/10.1016/j.molimm.2017.06.188
Diana Pauly 1,∗ , Nicole Schäfer 1 , Antje Grosche 2 1 Department of Ophthalmology, University Hospital Regensburg, Regensburg, Germany 2 Institute of Human Genetics, University Regensburg, Regensburg, Germany
Background: Age-related retinal degeneration is associated with a local chronic parainflammation. The role of the complement system, a pathway of the innate immunity, is still not completely understood. Retinal complement activity has been related so far to microglia/macrophages or to the influence of the systemic, liverderived complement system. We describe the liver-independent retinal complement system in the aging mouse retina by cell-type specific complement analysis. Methods: Microglia/macrophages, endothelial cells, Müller cells and neurons were separated by MACS cell separation technology from 8, 16 and 24 week old mouse retinae. Samples from retinal pigmented epithelium (RPE)/choroidal cells were collected from the same eye. Gene expression of specific cell-marker and complement factor 3 (c3), c1s, factor B (cfb), properdin (cfp), factor I (cfi) and factor H (cfi) were performed by qPCR. Results: All isolated cell populations, characterized by specific cell marker, showed complement expression. The RPE/choroidal cells expressed the majority of the tested complement transcripts. Cfb and c3 were the dominant complement transcripts in the retina. However, c3 was preferentially expressed in Müller cells, cfp in endothelial cells and cfi in neurons. The cell-type specific ratio of complement expression revealed a complement inhibitory function for RPE/choroidal cells and microglia/macrophages with a majority of cfh transcripts. Whereas, 89% of the Müller cell complement transcripts were activating factors c3, cfb, cfp and c1s. Complement expression changed in aging mice. Cfp and cfi expression was enhanced in neurons, RPE/choroidal and endothelial cells in 24 week old mice. Microglia/macrophages, RPE/choroidal and endothelial cells increased c3 and cfb expression in older retinae. Cfh and cfi were downregulated in Müller cells and neurons, respectively. Conclusion: Retinal cells produce and regulate complement factors independently from the liver-derived complement system. The very individual signatures of complement factor expression in the various retinal cell types implies their well-orchestrated interplay in the regulation of the local complement homeostasis in the aging mouse retina. http://dx.doi.org/10.1016/j.molimm.2017.06.189 149 Characterization of collectin LK, CL-LK Soren W.K. Hansen ∗ , Maiken L. Henriksen Institute of Molecular Medicine, Odense, University of Southern Denmark, Denmark The complement system is an important part of the innate immune system. By binding of complement associated pattern recognitions molecules (PRRs) to microbial PAMPs, the complement cascade activates. These PRRs comprise mannan-binding lectin, ficolins, and the recently described heteromeric complex of collectin liver 1 (CL-L1) and kidney 1 (CL-K1), referred to as CL-LK. Their ligands include preferential microbial patterns of high-mannose glycoconjugates or acetylated structures.
Abstracts / Molecular Immunology 89 (2017) 188–193
147
148
Associations of the alternative pathway and classical pathway of complement activation with incident metabolic syndrome: The CODAM study
Cell-type specific complement expression in aging, albino mice
Ying Xin ∗ , Elisabeth Hertle, Carla J.H. van der Kallen, Casper G. Schalkwijk, Coen D.A. Stehouwer, Marleen M.J. van Greevenbroek Dept of Internal Medicine, Maastricht University Medical Centre and CARIM School for Cardiovascular Diseases, Maastricht University, The Netherlands Background: Plasma concentrations of various complement components are higher in obese individuals and may contribute to adipose tissue dysfunction and development of the metabolic syndrome. We investigated the associations of components of the alternative [C3, C3a, Bb, factor D (FD), factor H (FH), properdin], and the classical complement pathway (C4, C1q, C1-inhibitor) with prevalent and incident metabolic syndrome (MetS) in a human cohort. Materials and methods: The study cohort was n = 574 (61% men, age 59.6 ± 7.0 years) at baseline and n = 489 after 7 years follow-up. Multiple logistic regression was used to investigate associations of complement at baseline (standardized values) with (1) prevalence of MetS in all, and (2) incident MetS in those without MetS at baseline (n = 189). In this latter group, linear regression models were then used to evaluate the associations between baseline complement and worsening of MetS components (i.e. fasting triglycerides, HDL-cholesterol, glucose, systolic and diastolic blood pressure, waist circumference) during follow-up. All analyses were adjusted for age, sex, smoking, alcohol consumption, physical activity, energy intake and medication use, and in linear regression also for baseline value of the MetS component. Results and conclusions: C3 concentrations were higher in those with MetS compared to those without (odds ratio (OR): 3.60 [95% confidence interval: 2.73; 4.75]). Similar associations were observed for C3a (OR: 1.25 [1.03; 1.52]), FH (OR: 2.93 [2.24; 3.83]), properdin (OR: 1.88 [1.50; 2.34]), and C4 (OR: 1.39 [1.13; 1.69]), but not for Bb, C1q or C1-iinhibitor. Notably, C3 (OR: 1.63 [1.03; 2.58] and C4 (OR: 2.03 [1.34; 3.06]), but none of the other complement factors, were positively associated with incident MetS (n = 40 cases). Baseline C3 was weakly but positively associated with plasma glucose (in mmol/L, log2 -transformed) at follow up (ˇ = 0.03 [0.01; 0.06]), while C4 showed a borderline significant association with triglycerides (in mmol/L, log2 -transformed) at follow-up (ˇ = 0.08 [−0.00; 0.15]). Taken together, these findings suggest a role for C3 and C4 in the development of MetS, but with different underlying mechanisms. For C3 these associations may, at least partly, be driven by effects on glucose metabolism, while for C4 this may be via lipid metabolism. http://dx.doi.org/10.1016/j.molimm.2017.06.188
Diana Pauly 1,∗ , Nicole Schäfer 1 , Antje Grosche 2 1 Department of Ophthalmology, University Hospital Regensburg, Regensburg, Germany 2 Institute of Human Genetics, University Regensburg, Regensburg, Germany
Background: Age-related retinal degeneration is associated with a local chronic parainflammation. The role of the complement system, a pathway of the innate immunity, is still not completely understood. Retinal complement activity has been related so far to microglia/macrophages or to the influence of the systemic, liverderived complement system. We describe the liver-independent retinal complement system in the aging mouse retina by cell-type specific complement analysis. Methods: Microglia/macrophages, endothelial cells, Müller cells and neurons were separated by MACS cell separation technology from 8, 16 and 24 week old mouse retinae. Samples from retinal pigmented epithelium (RPE)/choroidal cells were collected from the same eye. Gene expression of specific cell-marker and complement factor 3 (c3), c1s, factor B (cfb), properdin (cfp), factor I (cfi) and factor H (cfi) were performed by qPCR. Results: All isolated cell populations, characterized by specific cell marker, showed complement expression. The RPE/choroidal cells expressed the majority of the tested complement transcripts. Cfb and c3 were the dominant complement transcripts in the retina. However, c3 was preferentially expressed in Müller cells, cfp in endothelial cells and cfi in neurons. The cell-type specific ratio of complement expression revealed a complement inhibitory function for RPE/choroidal cells and microglia/macrophages with a majority of cfh transcripts. Whereas, 89% of the Müller cell complement transcripts were activating factors c3, cfb, cfp and c1s. Complement expression changed in aging mice. Cfp and cfi expression was enhanced in neurons, RPE/choroidal and endothelial cells in 24 week old mice. Microglia/macrophages, RPE/choroidal and endothelial cells increased c3 and cfb expression in older retinae. Cfh and cfi were downregulated in Müller cells and neurons, respectively. Conclusion: Retinal cells produce and regulate complement factors independently from the liver-derived complement system. The very individual signatures of complement factor expression in the various retinal cell types implies their well-orchestrated interplay in the regulation of the local complement homeostasis in the aging mouse retina. http://dx.doi.org/10.1016/j.molimm.2017.06.189 149 Characterization of collectin LK, CL-LK Soren W.K. Hansen ∗ , Maiken L. Henriksen Institute of Molecular Medicine, Odense, University of Southern Denmark, Denmark The complement system is an important part of the innate immune system. By binding of complement associated pattern recognitions molecules (PRRs) to microbial PAMPs, the complement cascade activates. These PRRs comprise mannan-binding lectin, ficolins, and the recently described heteromeric complex of collectin liver 1 (CL-L1) and kidney 1 (CL-K1), referred to as CL-LK. Their ligands include preferential microbial patterns of high-mannose glycoconjugates or acetylated structures.