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Kidney transplantation is a life-saving strategy for patients with end-stage renal diseases. Despite the advances in surgical techniques and immunosuppressive agents, the long-term graft survival remains a challenge. Growing evidence has shown that the complement system, part of the innate immune response, is involved in kidney transplantation. Nov...
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Context 1
... treatment was also beneficial for successful renal transplantation in patients with antiphospholipid antibody syndrome or C3 glomerulopathy (175)(176)(177). Eculizumab treatment has been suggested for the prevention or treatment of AMR in several clinical trials ( Table 2). A recent single-arm trial examining the safety and efficacy of eculizumab in preventing AMR in sensitized recipients (NCT01567085) has shown encouraging outcomes. ...Citations
... Complement proteins have been conventionally viewed as the effector arm for antibodies. However, recent investigations reveal that their functions are far beyond this initial understanding [57]. In transplantation, they promote IRI associated with organ procurement and cold storage during transportation and contribute to subsequent delayed graft function (DGF); they interact with coagulation pathways to promote thrombosis and exacerbate vascular inflammation; and most recently, they are found to directly activate B cells through B cell-surface complement receptors and promote B cell maturation and antibody-producing capacity, thereby contributing to AMR. ...
... The speculation of their direct role in kidney IRI was initially based on the unexpected discovery of complement gene expression by renal tubuloepithelial cells, particularly in association with inflammatory renal tubular diseases [57]. Such local complement production can be induced by a number of kidney injuries, with IRI being the most relevant to transplantation [58]. ...
Purpose of Review
Despite a significant decrease in the rate of acute rejection, long-term solid organ allotransplant success is limited by chronic rejection. Transplant research has historically focused on adaptive immune responses. However, there is a growing appreciation that the innate immune system is a potential contributor to short- and long-term graft injuries. We seek to provide an overview of the current literature on innate immunity in transplantation, discussing both innate naïve and memory immune responses, mechanisms by which innate cells recognize allogeneic signals, specific subsets of innate cells implicated in these responses, and soluble mediators that may aid in the graft inflammation.
Recent Findings
The mechanisms by which innate cells recognize allogeneic tissue are being uncovered, and prior exposure to allogeneic cells may impact the strength of that response, thereby giving the innate cells “memory” of the previously encountered alloantigens. The implicated and discussed ligands & receptors for the innate immune recognition include ischemia-reperfusion injury products & the DAMP receptors, class I MHC & PIRA, CD47 & SIRPα. Additionally, the roles of macrophages, NK cells, γδ T cells, and complement proteins are examined.
Summary
It is likely that innate immune cells and pathways contribute to significantly altering the longevity of transplanted allografts, therefore warrant future investigations. Innate immune cells and their respective molecular targets might represent new points of intervention.
... Given the kidney's unique susceptibility to complement attack, considerable research is being undertaken to elucidate the potential efficacy of complement inhibitors in the setting of various kidney pathologies, including renal transplant [145][146][147][148], lupus nephritis [149,150], IgA nephropathy [141,151], immune complex-mediated membranoproliferative glomerulonephritis [152,153], and C3 glomerulopathies [139,140,154,155]. The potential therapeutic benefit of targeting complement in chronic kidney pathologies, such as DKD, remains to be further explored. ...
Diabetic kidney disease (DKD) affects 30–40% of patients with diabetes and is currently the leading cause of end-stage renal disease (ESRD). The activation of the complement cascade, a highly conserved element of the innate immune system, has been implicated in the pathogenesis of diabetes and its complications. The potent anaphylatoxin C5a is a critical effector of complement-mediated inflammation. Excessive activation of the C5a-signalling axis promotes a potent inflammatory environment and is associated with mitochondrial dysfunction, inflammasome activation, and the production of reactive oxygen species. Conventional renoprotective agents used in the treatment of diabetes do not target the complement system. Mounting preclinical evidence indicates that inhibition of the complement system may prove protective in DKD by reducing inflammation and fibrosis. Targeting the C5a-receptor signaling axis is of particular interest, as inhibition at this level attenuates inflammation while preserving the critical immunological defense functions of the complement system. In this review, the important role of the C5a/C5a-receptor axis in the pathogenesis of diabetes and kidney injuries will be discussed, and an overview of the status and mechanisms of action of current complement therapeutics in development will be provided.
... Secondly, complement can be considered a bridge between innate and adaptive immunity [13]: for example, complement can increase antibody responses and strengthen the immunological memory because C3 receptors are expressed binding to their receptors on target cells. These essential components of the complement system could be classified into complement receptors (CR1, CR2, CR3, and CR4) and anaphylatoxin receptors (C3aR, C5aR1, and C5aR2) [30]. The CR1 molecule has multiple functions, depending on where it is expressed. ...
... Preformed or post-transplant de-novo donor-specific antibodies (DSAs) bind to donor MHC epitopes [30], thus initiating the CP through C1q engagement and then resulting in acute or hyperacute ABMR, with damage to the transplant and potential graft loss. Endothelial cells are the main target of DSAs. ...
... Indeed, linear C4d deposition in peritubular capillaries or medullary vasa recta is one of the criteria of the Banff classification score for defining active or chronic ABMR [128]. The cascade activated by complement-fixing antibodies culminates in MAC formation that can cause endothelial cell lysis and subsequent direct damage to the vasculature within the graft [30]. MAC also leads to the upregulation and exposure of P-selectin, tissue factor [129], and von Willebrand Factor on endothelial cells [130], promoting a thrombogenic response. ...
Kidney transplantation is the therapy of choice for patients who suffer from end-stage renal diseases. Despite improvements in surgical techniques and immunosuppressive treatments, long-term graft survival remains a challenge. A large body of evidence documented that the complement cascade, a part of the innate immune system, plays a crucial role in the deleterious inflammatory reactions that occur during the transplantation process, such as brain or cardiac death of the donor and ischaemia/reperfusion injury. In addition, the complement system also modulates the responses of T cells and B cells to alloantigens, thus playing a crucial role in cellular as well as humoral responses to the allograft, which lead to damage to the transplanted kidney. Since several drugs that are capable of inhibiting complement activation at various stages of the complement cascade are emerging and being developed, we will discuss how these novel therapies could have potential applications in ameliorating outcomes in kidney transplantations by preventing the deleterious effects of ischaemia/reperfusion injury, modulating the adaptive immune response, and treating antibody-mediated rejection.
The crosstalk among the complement system, immune cells, and mediators of inflammation provides an efficient mechanism to protect the organism against infections and support the repair of damaged tissues. Alterations in this complex machinery play a role in the pathogenesis of different diseases. Core complement proteins C3 and C5, their activation fragments, their receptors, and their regulators have been shown to be active intracellularly as the complosome. The kidney is particularly vulnerable to complement-induced damage, and emerging findings have revealed the role of complement system dysregulation in a wide range of kidney disorders, including glomeru-lopathies and ischemia-reperfusion injury during kidney transplantation. Different studies have shown that activation of the complement system is an important component of tumorigenesis and its elements have been proved to be present in the TME of various human malignancies. The role of the complement system in renal cell carcinoma (RCC) has been recently explored. Clear cell and papillary RCC upregulate most of the complement genes relative to normal kidney tissue. The aim of this narrative review is to provide novel insights into the role of complement in kidney disorders.
Objective:
This study aimed to establish a complement-tolerance test as a marker of protein fragility and discuss its clinical significance.
Methods:
Total complement activity (TCA) of serum was measured using a self-hemolysis colorimetric method. Human O-erythrocytes and rabbit anti-human O-erythrocyte antibodies were used to replace sheep erythrocytes and the corresponding hemolysin for the hemolysis test, respectively. The antigen-antibody specific binding activated the classical pathway of complement, generating a membrane attack complex (MAC), and the red blood cells rupture. A complement-tolerance test (CTT) was established to measure complement heat tolerance according to the sensitivity of complement proteins to temperature, which was calculated according to differences in TCA at different temperatures. The smaller the CTT, the stronger the complement resistance to heat. The method was applied to the detection of diabetic patients and healthy controls.
Results:
The mean value of CTT (Mean) = 0.063 ± 0.003 with a coefficient of variation of 4.8% for the same specimen tested for complementary thermal resistance on five consecutive days, which is a good stability of the assy. Application of CTT on samples from patients with different ages revealed significantly higher mean CTT values for elderly patients (≥60-years old) relative to those for younger patients (20-40-years old) (p < 0.05). Additionally, the mean CTT values for diabetic patients were significantly higher than those for healthy patients (p < 0.001).
Conclusion:
We successfully established a method that uses complement thermal resistance as a marker of protein fragility, with the results demonstrating the ability of the CTT identify age- and disease-related variations in patient samples and its potential efficacy for clinical application.
Tripartite motif 35 (TRIM35) is a member of the tripartite motif protein family and has been recognized to play a key role in immune-inflammatory diseases. However, the role of TRIM35 in renal ischemia-reperfusion injury (IRI) remains unclear. Our study proved that knockdown of TRIM35 alleviates kidney IRI by inhibiting oxidative stress and enhancing mitochondrial fusion. In addition, our experimental results found that TRIM35 interacts with TP53-induced glycolysis and apoptosis regulator (TIGAR) and promotes the polyubiquitination of TIGAR and induces its degradation in the proteasome pathway. Furthermore, TIGAR knockdown significantly inhibited mitochondrial fusion. These results indicate that TRIM35 is a potential therapeutic target for renal IRI.
