Summary
The complement system is an important part of the innate immune defence. It contributes not only to local inflammation, removal and killing of pathogens, but it also assists in shaping of the ...adaptive immune response. Besides a role in inflammation, complement is also involved in physiological processes such as waste disposal and developmental programmes. The complement system comprises several soluble and membrane‐bound proteins. The bulk of the soluble proteins is produced mainly by the liver. While several complement proteins are produced by a wide variety of cell types, other complement proteins are produced by only a few related cell types. As these data suggest that local production by specific cell types may have specific functions, more detailed studies have been employed recently analysing the local and even intracellular role of these complement proteins. Here we review the current knowledge about extrahepatic production and/or secretion of complement components. More specifically, we address what is known about complement synthesis by cells of the human immune system.
This review describes the production of complement proteins by cells of the human immune system. In addition the role of local and even intracellular complement activation is highlighted.
Sleep problems have a high prevalence and negative daytime consequences in adolescents. Current sleep measures for this age group have limitations. The Patient‐Reported Outcomes Measurement ...Information System (PROMIS®) developed sleep item banks for adults. In a previous validation study, these item banks were adapted to a shortened version for adolescents. The current study aimed to further explore the psychometric properties of the 11‐item Sleep‐Related Impairment and 23‐item Sleep Disturbance item banks in Dutch adolescents. We investigated structural validity by testing item response theory assumptions and model fit; measurement invariance by performing differential item functioning analyses; performance as a computerized adaptive test; reliability by marginal reliability estimates and test–retest reliability (intraclass correlation coefficients and limits of agreement); and construct validity by hypothesis testing. Additionally, we provide mean values for the item banks. The study sample consisted of 1,046 adolescents (mean age 14.3 ± 1.6), including 1,013 high‐school students and 33 sleep‐clinic patients. The Sleep Disturbance‐23 showed lack of unidimensionality, but had sufficient test–retest reliability, and could distinguish between adolescents with and without sleep or health issues. The Sleep‐Related Impairment‐11 showed sufficient unidimensionality and model fit and was thus tested as a computerized adaptive test, demonstrating an equal amount of reliable measures to the full item bank. Furthermore, the Sleep‐Related Impairment‐11 could distinguish between adolescents with and without sleep or health issues and test–retest reliability was moderate. The use of both item banks in the full form and the use of the Sleep‐related Impairment‐11 as a computer adaptive test is recommended.
Extending kidney donor criteria, including donation after circulatory death (DCD), has resulted in increased rates of delayed graft function (DGF) and primary nonfunction. Here, we used Nuclear ...Magnetic Resonance (NMR) spectroscopy to analyze the urinary metabolome of DCD transplant recipients at multiple time points (days 10, 42, 180, and 360 after transplantation). The aim was to identify markers that predict prolonged duration of functional DGF (fDGF). Forty‐seven metabolites were quantified and their levels were evaluated in relation to fDGF. Samples obtained at day 10 had a different profile than samples obtained at the other time points. Furthermore, at day 10 there was a statistically significant increase in eight metabolites and a decrease in six metabolites in the group with fDGF (N = 53) vis‐à‐vis the group without fDGF (N = 22). In those with prolonged fDGF (≥21 days) (N = 17) urine lactate was significantly higher and pyroglutamate lower than in those with limited fDGF (<21 days) (N = 36). In order to further distinguish prolonged fDGF from limited fDGF, the ratios of all metabolites were analyzed. In a logistic regression analysis, the sum of branched‐chain amino acids (BCAAs) over pyroglutamate and lactate over fumarate, predicted prolonged fDGF with an AUC of 0.85. In conclusion, kidney transplant recipients with fDGF can be identified based on their altered urinary metabolome. Furthermore, two ratios of urinary metabolites, lactate/fumarate and BCAAs/pyroglutamate, adequately predict prolonged duration of fDGF.
Day 10 urinary ratios of branch‐chain amino acids over pyroglutamate and lactate over fumarate, measured by routine high‐throughput nuclear magnetic resonance spectroscopy, correlate with prolonged duration of delayed graft function (beyond 21 days) in donation after circulatory death kidney transplant recipients.
Ischemia/reperfusion injury (IRI) remains a major problem in renal transplantation. Clinical studies have identified that high serum levels of Mannan‐binding lectin (MBL), the initiator of the lectin ...pathway of complement activation, are associated with inferior renal allograft survival. Using a rat model, we identified an entirely novel role for MBL in mediating renal IRI. Therapeutic inhibition of MBL was protective against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. Following reperfusion, exposure of tubular epithelial cells to circulation‐derived MBL resulted in internalization of MBL followed by the rapid induction of tubular epithelial cell death. Interestingly, this MBL‐mediated tubular injury was completely independent of complement activation since attenuation of complement activation was not protective against renal IRI. Our identification that MBL‐mediated cell death precedes complement activation strongly suggests that exposure of epithelial cells to MBL immediately following reperfusion is the primary culprit of tubular injury. In addition, also human tubular epithelial cells in vitro were shown to be susceptible to the cytotoxic effect of human MBL. Taken together, these data reveal a crucial role for MBL in the early pathophysiology of renal IRI and identify MBL as a novel therapeutic target in kidney transplantation.
The authors find that the therapeutic inhibition of mannan‐binding lectin protects against renal ischemia/reperfusion injury, and that following reperfusion, mannan‐binding lectin is cytotoxic to tubular cells independent of complement activation.
We investigated the time evolution of the density of giant spin polarons in a magnetic semiconductor. Spin polarons (SPs) were photoexcited and observed using time-resolved Faraday rotation. We find ...the existence of two types of SPs, a short-lived spin polaron with a lifetime of around τsl = 0.5 ns and a long-lived spin polaron with a lifetime of τll = 0.45 ± 0.03 µs, at T = 5 K. The stark difference of three order of magnitude between these lifetimes suggests that in the long lived SP the electron-hole pair is relaxed and its recombination is forbidden. The short-lived SP is probably associated with SP recombination before such relaxation has occured. An extraordinary finding is that the magnitude of τsl, as well as its decrease with increasing temperature, reproduces exactly the characteristic time for SP growth. This suggests that the thermal fluctuations, responsible for SP magnetic moment growth, are also responsible for increasing the recombination probability of SPs.
•Complement activation in IgA nephropathy is a major pathogenic process.•Lectin and alternative pathway activation are the main complement routes involved in IgA nephropathy.•In IgA nephropathy, ...variation in IgA consists of isoforms, glycoforms and presence of IgA containing immune complexes.•Variations in IgA might be responsible for complement activation in both systemic and kidney compartments.•Novel complement inhibitory strategies are currently tested in phase II or III trials in IgA nephropathy.
IgA Nephropathy (IgAN) is the main cause of primary glomerulonephritis, globally. This disease is associated with a wide range of clinical presentations, variable prognosis and a spectrum of histological findings. More than fifty years after its first description, this heterogeneity continues to complicate efforts to understand the pathogenesis. Nevertheless, involvement of the complement system in IgAN was identified early on. Dysfunction of the immunoglobulin A (IgA) system, the principal offender in this disease, including modification of isoforms and glycoforms of IgA1, the nature of immune complexes and autoantibodies to galactose deficient IgA1 might all be responsible for complement activation in IgAN. However, the specific mechanisms engaging complement are still under examination. Research in this domain should allow for identification of patients that may benefit from complement-targeted therapy, in the foreseeable future.
Acute rejection is a risk factor for inferior long‐term kidney transplant survival. Although T cell immunity is considered the main effector in clinical acute rejection, the role of myeloid cells is ...less clear. Expression of S100 calcium‐binding protein A8 (S100A8) and S100A9 was evaluated in 303 biopsies before and after transplantation from 190 patients. In two independent cohorts of patients with acute rejection (n = 98 and n = 11; mostly cellular rejections), high expression of S100 calcium‐binding protein A8 (S100A8) and A9 (S100A9) was related to improved graft outcome. Mechanisms of action of the S100 molecules were investigated. In the graft and peripheral blood cells, S100A8 and S100A9 expression correlated with myeloid‐derived suppressor markers. In line with this finding, recombinant S100A8 and S100A9 proteins inhibited maturation and the allogeneic T cell stimulatory capacity of dendritic cells. S100A9 enhanced the production of reactive oxygen species by macrophages, which suppressed T cell activity at low concentrations in the form of hydrogen peroxide. Intragraft S100A8 and S100A9 expression linked to reduced expression of T cell immunity and tissue injury markers and higher expression of immune regulatory molecules. This study sheds new light on the importance of myeloid cell subsets in directing the outcome of T cell–mediated acute rejection.
The authors find an association between levels of S100 calcium‐binding proteins A8 and A9 during acute kidney transplant rejection with graft outcome, and that these myeloid cell–expressed proteins have immunoregulatory effects toward T cells.
Dendritic cells (DCs) play critical roles in immune responses and can be distinguished in two major subsets, myeloid and plasmacytoid DCs. Although the presence of DC in all peripheral organs, ...including the kidney, has been well documented, no accurate estimates of DC subsets in human kidneys have been reported. This study shows a detailed analysis of DC subsets in cryosections of human renal tissue. The cortex of normal kidneys contains at least two different HLA-DR+ myeloid DC subtypes characterized by BDCA-1+DC-SIGN+ and BDCA-1+DC-SIGN−. The staining for DC-SIGN completely overlapped with CD68 in the renal interstitium. Unexpectedly, BDCA-2+DC-SIGN− plasmacytoid DCs are also abundantly present. Both subsets are located in the tubulo–interstitium often with a high frequency around, but rarely observed within glomeruli. Quantification of BDCA-1+, DC-SIGN+, and BDCA-2+ cells in normal human renal tissue (pretransplant biopsy living donors; n=21) revealed that BDCA-1 is about four times as frequently present as BDCA-2. A preliminary cross-sectional analysis of DC in diseased kidneys, including rejection and immunoglobulin A nephropathy, revealed that the number of DC as well as their anatomical distribution might change under pathophysiological conditions. In conclusion, we show that human kidneys contain a dense network of myeloid and plasmacytoid DCs and provide the tools for phenotyping and enumeration of these cells to better understand interindividual differences in immune responses.
CD40-CD40 ligand Kooten, Cees; Banchereau, Jacques
Journal of leukocyte biology,
01/2000, Letnik:
67, Številka:
1
Journal Article
Recenzirano
CD40 is a cell surface receptor that belongs to the tumor necrosis factor‐R (TNF‐R) family, and that was first identified and functionally characterized on B lymphocytes. Its critical role in T ...cell‐dependent humoral immune responses was demonstrated by patients with the hyper‐IgM syndrome, as well as by gene targeting in mice. However, in recent years it has become clear that CD40 is expressed much more broadly, including expression on monocytes, dendritic cells, endothelial cells, and epithelial cells. In addition, the CD40‐ligand (CD40‐L/CD154), a member of the TNF family, is also expressed more widely than activated CD4+ T cells only. Therefore it is now thought that CD40‐CD40‐L interactions play a more general role in immune regulation. Collectively these studies have culminated in pre‐clinical and clinical studies that are in progress. This article reviews recent developments in this field of research, with main emphasis on (1) structure and expression of CD40 and its ligand; (2) CD40 signal transduction; (3) in vitro function of CD40 on different cell types; and (4) in vivo functions of CD40/CD40‐L interactions. J. Leukoc. Biol. 67: 2–17; 2000.
Eryhropoiesis‐stimulating agents have demonstrated tissue‐protective effects in experimental models of ischemia‐reperfusion injury. PROTECT was a 12‐month, randomized, double‐blind, ...placebo‐controlled, single center study with high‐dose recombinant human erythropoietin‐β (Epoetin) in 92 donation after cardiac death (DCD) kidney transplant recipients. Patients were randomized to receive an intravenous bolus of Epoetin (3.3 × 104 international unit (IU); n = 45) or placebo (saline 0.9% solution; n = 47) on 3 consecutive days, starting 3–4 h before the transplantation and 24 h and 48 h after reperfusion. The immunosuppressive regimen included an anti‐CD25 antibody, steroids, mycophenolate mofetil and delayed introduction of cyclosporine. Primary end point was a composite of the incidence of primary nonfunction and delayed graft function, either defined by spontaneous functional recovery or need for dialysis in the first week. Secondary objectives included duration of delayed function, renal function and proteinuria up to 1 year and thrombotic adverse events. Results showed no differences in the incidence or duration of delayed graft function and/or primary nonfunction (Epoetin 77.8 vs. placebo 78.7%, p = 1.00). Epoetin treatment significantly increased the risk of thrombotic events at 1 month and 1 year (Epoetin 24.4% vs. placebo 6.4%, p = 0.02).
This randomized controlled trial with high‐dose epoetin in donation after cardiac death kidney transplant recipients shows no benefit on the incidence and duration of delayed graft function and/or primary nonfunction.
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