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Seminars in Nephrology Nov 2013Complement is an important component of the innate immune system that is crucial for defense from microbial infections and for clearance of immune complexes and injured... (Review)
Review
Complement is an important component of the innate immune system that is crucial for defense from microbial infections and for clearance of immune complexes and injured cells. In normal conditions complement is tightly controlled by a number of fluid-phase and cell surface proteins to avoid injury to autologous tissues. When complement is hyperactivated, as occurs in autoimmune diseases or in subjects with dysfunctional regulatory proteins, it drives a severe inflammatory response in numerous organs. The kidney appears to be particularly vulnerable to complement-mediated inflammatory injury. Injury may derive from deposition of circulating active complement fragments in glomeruli, but complement locally produced and activated in the kidney also may have a role. Many kidney disorders have been linked to abnormal complement activation, including immune-complex-mediated glomerulonephritis and rare genetic kidney diseases, but also tubulointerstitial injury associated with progressive proteinuric diseases or ischemia-reperfusion.
Topics: Adaptive Immunity; Complement Activating Enzymes; Complement Activation; Complement System Proteins; Humans; Immunity, Innate; Kidney Diseases
PubMed: 24161035
DOI: 10.1016/j.semnephrol.2013.08.001 -
Cell and Tissue Research Jan 2011The complement system consists of a tightly regulated network of proteins that play an important role in host defense and inflammation. Complement activation results in... (Review)
Review
The complement system consists of a tightly regulated network of proteins that play an important role in host defense and inflammation. Complement activation results in opsonization of pathogens and their removal by phagocytes, as well as cell lysis. Inappropriate complement activation and complement deficiencies are the underlying cause of the pathophysiology of many diseases such as systemic lupus erythematosus and asthma. This review represents an overview of the complement system in an effort to understand the beneficial as well as harmful roles it plays during inflammatory responses.
Topics: Adaptive Immunity; Anaphylatoxins; Animals; Complement Activation; Complement System Proteins; Humans; Immune Evasion
PubMed: 20838815
DOI: 10.1007/s00441-010-1034-0 -
Journal of Immunology (Baltimore, Md. :... Jan 2023The complement field has recently experienced a strong resurgence of interest because of the unexpected discovery of new complement functions extending complement's role... (Review)
Review
The complement field has recently experienced a strong resurgence of interest because of the unexpected discovery of new complement functions extending complement's role beyond immunity and pathogen clearance, a growing list of diseases in which complement plays a role, and the proliferation of complement therapeutics. Importantly, although the majority of complement components in the circulation are generated by the liver and activated extracellularly, complement activation unexpectedly also occurs intracellularly across a broad range of cells. Such cell-autonomous complement activation can engage intracellular complement receptors, which then drive noncanonical cell-specific effector functions. Thus, much remains to be discovered about complement biology. In this brief review, we focus on novel noncanonical activities of complement in its "classic areas of operation" (kidney and brain biology, infection, and autoimmunity), with an outlook on the next generation of complement-targeted therapeutics.
Topics: Complement System Proteins; Complement Activation
PubMed: 36596217
DOI: 10.4049/jimmunol.2200540 -
The Journal of Clinical Investigation Mar 2017In addition to being a component of innate immunity and an ancient defense mechanism against invading pathogens, complement activation also participates in the adaptive... (Review)
Review
In addition to being a component of innate immunity and an ancient defense mechanism against invading pathogens, complement activation also participates in the adaptive immune response, inflammation, hemostasis, embryogenesis, and organ repair and development. Activation of the complement system via classical, lectin, or alternative pathways generates anaphylatoxins (C3a and C5a) and membrane attack complex (C5b-9) and opsonizes targeted cells. Complement activation end products and their receptors mediate cell-cell interactions that regulate several biological functions in the extravascular tissue. Signaling of anaphylatoxin receptors or assembly of membrane attack complex promotes cell dedifferentiation, proliferation, and migration in addition to reducing apoptosis. As a result, complement activation in the tumor microenvironment enhances tumor growth and increases metastasis. In this Review, I discuss immune and nonimmune functions of complement proteins and the tumor-promoting effect of complement activation.
Topics: Animals; Apoptosis; Cell Communication; Cell Proliferation; Complement Pathway, Alternative; Complement Pathway, Classical; Complement System Proteins; Humans; Neoplasms; Signal Transduction
PubMed: 28248200
DOI: 10.1172/JCI90962 -
Molecular Immunology Oct 2019IgA nephropathy (IgAN) is common and often progresses to end stage renal disease. IgAN encompasses a wide range of histology and clinical features. IgAN pathogenesis is... (Review)
Review
IgA nephropathy (IgAN) is common and often progresses to end stage renal disease. IgAN encompasses a wide range of histology and clinical features. IgAN pathogenesis is incompletely understood; the current multi-hit hypothesis of IgAN pathogenesis does not explain the range of glomerular inflammation and renal injury associated with mesangial IgA deposition. Although associations between IgAN and glomerular and circulating markers of complement activation are established, the mechanism of complement activation and contribution to glomerular inflammation and injury are not defined. Recent identification of specific complement pathways and proteins in severe IgAN cases had advanced our understanding of complement in IgAN pathogenesis. In particular, a growing body of evidence implicates the complement factor H related proteins 1 and 5 and lectin pathway as pathogenic in a subset of patients with severe disease. These data suggest complement deregulation and activity may be dominant drivers of renal injury in IgAN. Thereby, markers of complement activation may identify IgAN patients likely to progress to significant renal impairment and complement inhibition may emerge as an effective method of preventing and reducing glomerular injury in IgAN.
Topics: Animals; Complement Activation; Complement System Proteins; Glomerulonephritis, IGA; Humans; Immunoglobulin A
PubMed: 31351413
DOI: 10.1016/j.molimm.2019.07.017 -
Frontiers in Immunology 2021
Topics: Animals; Complement Activation; Complement System Proteins; Drug Development; Humans; Immunomodulation; Molecular Targeted Therapy
PubMed: 33717205
DOI: 10.3389/fimmu.2021.663459 -
Seminars in Immunopathology Dec 2021The ability of the complement system to rapidly and broadly react to microbial intruders, apoptotic cells and other threats by inducing forceful elimination responses is... (Review)
Review
The ability of the complement system to rapidly and broadly react to microbial intruders, apoptotic cells and other threats by inducing forceful elimination responses is indispensable for its role as host defense and surveillance system. However, the danger sensing versatility of complement may come at a steep price for patients suffering from various immune, inflammatory, age-related, or biomaterial-induced conditions. Misguided recognition of cell debris or transplants, excessive activation by microbial or damaged host cells, autoimmune events, and dysregulation of the complement response may all induce effector functions that damage rather than protect host tissue. Although complement has long been associated with disease, the prevalence, impact and complexity of complement's involvement in pathological processes is only now becoming fully recognized. While complement rarely constitutes the sole driver of disease, it acts as initiator, contributor, and/or exacerbator in numerous disorders. Identifying the factors that tip complement's balance from protective to damaging effects in a particular disease continues to prove challenging. Fortunately, however, molecular insight into complement functions, improved disease models, and growing clinical experience has led to a greatly improved understanding of complement's pathological side. The identification of novel complement-mediated indications and the clinical availability of the first therapeutic complement inhibitors has also sparked a renewed interest in developing complement-targeted drugs, which meanwhile led to new approvals and promising candidates in late-stage evaluation. More than a century after its description, complement now has truly reached the clinic and the recent developments hold great promise for diagnosis and therapy alike.
Topics: Complement Activation; Complement System Proteins; Humans
PubMed: 34698894
DOI: 10.1007/s00281-021-00892-7 -
The New England Journal of Medicine Jul 2017Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies.
BACKGROUND
Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies.
METHODS
We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients' cells, which we confirmed by means of exogenous induction of expression of CD55.
RESULTS
We identified homozygous loss-of-function mutations in the gene encoding CD55 (decay-accelerating factor), which lead to loss of protein expression. Patients' T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation.
CONCLUSIONS
CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.).
Topics: CD55 Antigens; Child; Child, Preschool; Complement Activation; Complement Inactivating Agents; Complement System Proteins; Female; Homozygote; Humans; Immunoglobulin A; Infant; Intestine, Small; Male; Mutation; Pedigree; Protein-Losing Enteropathies; Statistics, Nonparametric; Syndrome; T-Lymphocytes; Thrombosis
PubMed: 28657829
DOI: 10.1056/NEJMoa1615887 -
Immunological Reviews Jan 2023Uncontrolled alternative pathway activation is the primary driver of several diseases, and it contributes to the pathogenesis of many others. Consequently, diagnostic... (Review)
Review
Uncontrolled alternative pathway activation is the primary driver of several diseases, and it contributes to the pathogenesis of many others. Consequently, diagnostic tests to monitor this arm of the complement system are increasingly important. Defects in alternative pathway regulation are strong risk factors for disease, and drugs that specifically block the alternative pathway are entering clinical use. A range of diagnostic tests have been developed to evaluate and monitor the alternative pathway, including assays to measure its function, expression of alternative pathway constituents, and activation fragments. Genetic studies have also revealed many disease-associated variants in alternative pathway genes that predict the risk of disease and prognosis. Newer imaging modalities offer the promise of non-invasively detecting and localizing pathologic complement activation. Together, these various tests help in the diagnosis of disease, provide important prognostic information, and can help guide therapy with complement inhibitory drugs.
Topics: Humans; Complement System Proteins; Complement Activation; Prognosis; Complement Pathway, Alternative
PubMed: 36305168
DOI: 10.1111/imr.13156 -
Advances in Chronic Kidney Disease Mar 2020The complement cascade was first recognized as a downstream effector system of antibody-mediated cytotoxicity. Consistent with this view, it was discovered in the 1960s... (Review)
Review
The complement cascade was first recognized as a downstream effector system of antibody-mediated cytotoxicity. Consistent with this view, it was discovered in the 1960s that complement is activated in the glomeruli of patients with immune complex glomerulonephritis. More recently, research has shown that complement system has many additional functions relating to regulation of the immune response, homeostasis, and metabolism. It has also become clear that the complement system is important to the pathogenesis of many non-immune complex mediated kidney diseases. In fact, in atypical hemolytic uremic syndrome and C3 glomerulopathy, uncontrolled complement activation is the primary driver of disease. Complement activation generates multiple pro-inflammatory fragments, and if not properly controlled it can cause fulminant tissue injury. Furthermore, the mechanisms of complement activation and complement-mediated injury vary from disease to disease. Many new drugs that target the complement cascade are in clinical development, so it is important to fully understand the biology of the complement system and its role in disease.
Topics: Complement Activation; Complement Inactivating Agents; Humans; Kidney; Kidney Diseases
PubMed: 32553250
DOI: 10.1053/j.ackd.2019.10.003