Complement-mediated kidney diseases Poppelaars, Felix; Thurman, Joshua M.
Molecular immunology,
December 2020, 2020-12-00, 20201201, Letnik:
128
Journal Article
Recenzirano
Odprti dostop
•Immune-complexes activate the classical pathway of complement in many forms of glomerulonephritis.•The alternative and lectin pathways are also activated in several forms of kidney ...disease.•Complement activation in the kidney can be detected by immunostaining of biopsy tissue and by examining complement levels in plasma.•Therapeutic complement inhibitors are to be protective in several forms of kidney disease, and there are many ongoing clinical trials.
It has long been known that the complement cascade is activated in various forms of glomerulonephritis. In many of these diseases, immune-complexes deposit in the glomeruli and activate the classical pathway. Researchers have also identified additional mechanisms by which complement is activated in the kidney, including diseases in which the alternative and lectin pathways are activated. The kidney appears to be particularly susceptible to activation of the alternative pathway, and this pathway has been implicated as a primary driver of atypical hemolytic uremic syndrome, C3 glomerulopathy, anti-neutrophil cytoplasmic antibody-associated vasculitis, as well as some forms of immune-complex glomerulonephritis. In this paper we review the shared and distinct mechanisms by which complement is activated in these different diseases. We also review the opportunities for using therapeutic complement inhibitors to treat kidney diseases.
The current immunosuppressive protocols used in transplant recipients have improved short-term outcomes, but long-term allograft failure remains an important clinical problem. Greater understanding ...of the immunologic mechanisms that cause allograft failure are needed, as well as new treatment strategies for protecting transplanted organs. The complement cascade is an important part of the innate immune system. Studies have shown that complement activation contributes to allograft injury in several clinical settings, including ischemia/reperfusion injury and antibody mediated rejection. Furthermore, the complement system plays critical roles in modulating the responses of T cells and B cells to antigens. Therapeutic complement inhibitors, therefore, may be effective for protecting transplanted organs from several causes of inflammatory injury. Although several anti-complement drugs have shown promise in selected patients, the role of these drugs in transplantation medicine requires further study.
Rhabdomyolysis is frequently associated with kidney injury. Unfortunately, there are no specific treatments for this condition, and patient care primarily consists of supportive measures. In this ...edition of Kidney International, Boudhabhay et al. demonstrate that myoglobin released from injured skeletal muscle cells triggers tubulointerstitial complement activation. In a mouse model of the disease, interventions that scavenged free heme or that prevented complement activation ameliorated kidney injury, raising the possibility that these strategies may be effective treatments for the condition.
Cellular-state information between generations of developing cells may be propagated via regulatory regions. We report consistent patterns of gain and loss of DNase I-hypersensitive sites (DHSs) as ...cells progress from embryonic stem cells (ESCs) to terminal fates. DHS patterns alone convey rich information about cell fate and lineage relationships distinct from information conveyed by gene expression. Developing cells share a proportion of their DHS landscapes with ESCs; that proportion decreases continuously in each cell type as differentiation progresses, providing a quantitative benchmark of developmental maturity. Developmentally stable DHSs densely encode binding sites for transcription factors involved in autoregulatory feedback circuits. In contrast to normal cells, cancer cells extensively reactivate silenced ESC DHSs and those from developmental programs external to the cell lineage from which the malignancy derives. Our results point to changes in regulatory DNA landscapes as quantitative indicators of cell-fate transitions, lineage relationships, and dysfunction.
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•Cell fate and lineage relationships can be derived from DHS patterns•The proportion of a cell’s DHSs shared with ESCs is a benchmark of maturity•Developmentally stable DHSs encode binding sites for self-regulating TFs•Cancer cells reactivate both ESC DHSs and those from noncognate lineages
Gains and losses of DNase I-hypersensitive sites (DHSs) during cellular differentiation provide a measure of developmental maturity and lineage relationships between cell types. Whereas developing cells exhibit a steady pruning of DHSs shared with ESCs, cancer cells show a disordered acquisition of multiple unrelated DHSs.
Many autoimmune diseases are characterized by generation of autoantibodies that bind to host proteins or deposit within tissues as a component of immune complexes. The autoantibodies can activate the ...complement system, which can mediate tissue damage and trigger systemic inflammation. Complement inhibitory drugs may, therefore, be beneficial across a large number of different autoimmune diseases. Many new anti-complement drugs that target specific activation mechanisms or downstream activation fragments are in development. Based on the shared pathophysiology of autoimmune diseases, some of these complement inhibitory drugs may provide benefit across multiple different diseases. In some antibody-mediated autoimmune diseases, however, unique features of the autoantibodies, the target antigens, or the affected tissues may make it advantageous to block individual components or pathways of the complement system. This paper reviews the evidence that complement is involved in various autoimmune diseases, as well as the studies that have examined whether or not complement inhibitors are effective for treating these diseases.
Idiopathic nephrotic syndrome often responds to immunosuppressive treatment. Nevertheless, this syndrome-and the drugs used to treat it-remain important causes of patient morbidity. Idiopathic ...nephrotic syndrome is usually caused by minimal change disease or FSGS, diseases that primarily affect the podocytes. In spite of decades of research, the underlying causes of both diseases remain incompletely understood. There is, however, a large body of observational and experimental data linking the immune system with both minimal change disease and FSGS, including associations with systemic infections and hematologic malignancies. Perhaps most compellingly, many different immunomodulatory drugs are effective for treating idiopathic nephrotic syndrome, including biologic agents that have well-defined immune targets. In fact, the unexpected efficacy of targeted therapeutic agents has provided important new insights into the pathogenesis of these diseases. Given the large number of drugs that are available to deplete or block specific cells and molecules within the immune system, a better understanding of the immunologic causes of idiopathic nephrotic syndrome may lead to better diagnostic and therapeutic approaches.
Complement activation is an important cause of tissue injury in patients with Ab-mediated rejection (AMR) of transplanted organs. Complement activation triggers a strong inflammatory response, and it ...also generates tissue-bound and soluble fragments that are clinically useful markers of inflammation. The detection of complement proteins deposited within transplanted tissues has become an indispensible biomarker of AMR, and several assays have recently been developed to measure complement activation by Abs reactive to specific donor HLA expressed within the transplant. Complement inhibitors have entered clinical use and have shown efficacy for the treatment of AMR. New methods of detecting complement activation within transplanted organs will improve our ability to diagnose and monitor AMR, and they will also help guide the use of complement inhibitory drugs.
BLISS in the Treatment of Lupus Nephritis Thurman, Joshua M
Clinical journal of the American Society of Nephrology,
06/2021, Letnik:
16, Številka:
6
Journal Article
All Things Complement Thurman, Joshua M; Nester, Carla M
Clinical journal of the American Society of Nephrology,
10/2016, Letnik:
11, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The complement (C) cascade is an ancient system of proteins whose primary role is to initiate and modulate immune responses. During C activation, circulating proteins are cleaved and nascent cleavage ...fragments participate in a broad range of downstream innate and adaptive immune functions. Although the majority of these functions are either homeostatic or protective, a large body of experimental and clinical evidence also highlights a central role for the C system in the pathogenesis of many types of glomerular disease. From classic pathway activation in lupus nephritis to alternative pathway dysregulation in C3 glomerulopathy, our understanding of the spectrum of C involvement in kidney disease has expanded greatly in recent years. However, the characteristics that make the glomerulus so uniquely susceptible to C-mediated injury are not fully understood, and this remains an area of ongoing investigation. Several C inhibitors have been approved for clinical use, and additional C inhibitory drugs are in development. The use of these drugs in patients with kidney disease will expand our understanding of the benefits and limitations of C inhibition.