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Annual Review of Immunology Apr 2018The complement system is an evolutionarily ancient key component of innate immunity required for the detection and removal of invading pathogens. It was discovered more... (Review)
Review
The complement system is an evolutionarily ancient key component of innate immunity required for the detection and removal of invading pathogens. It was discovered more than 100 years ago and was originally defined as a liver-derived, blood-circulating sentinel system that classically mediates the opsonization and lytic killing of dangerous microbes and the initiation of the general inflammatory reaction. More recently, complement has also emerged as a critical player in adaptive immunity via its ability to instruct both B and T cell responses. In particular, work on the impact of complement on T cell responses led to the surprising discoveries that the complement system also functions within cells and is involved in regulating basic cellular processes, predominantly those of metabolic nature. Here, we review current knowledge about complement's role in T cell biology, with a focus on the novel intracellular and noncanonical activities of this ancient system.
Topics: Adaptive Immunity; Animals; Autoimmunity; B-Lymphocytes; Complement Activation; Complement System Proteins; Energy Metabolism; Host-Pathogen Interactions; Humans; Immunity, Cellular; Immunomodulation; Membrane Cofactor Protein; T-Lymphocytes; Th1 Cells
PubMed: 29677470
DOI: 10.1146/annurev-immunol-042617-053245 -
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 -
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 -
Nature Reviews. Drug Discovery Sep 2019The complement system plays a key role in pathogen immunosurveillance and tissue homeostasis. However, subversion of its tight regulatory control can fuel a vicious... (Review)
Review
The complement system plays a key role in pathogen immunosurveillance and tissue homeostasis. However, subversion of its tight regulatory control can fuel a vicious cycle of inflammatory damage that exacerbates pathology. The clinical merit of targeting the complement system has been established for rare clinical disorders such as paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome. Evidence from preclinical studies and human genome-wide analyses, supported by new molecular and structural insights, has revealed new pathomechanisms and unmet clinical needs that have thrust a new generation of complement inhibitors into clinical development for a variety of indications. This review critically discusses recent clinical milestones in complement drug discovery, providing an updated translational perspective that may guide optimal target selection and disease-tailored complement intervention.
Topics: Chronic Disease; Complement Activation; Complement Inactivating Agents; Complement System Proteins; Drug Discovery; Humans; Inflammation; Models, Biological
PubMed: 31324874
DOI: 10.1038/s41573-019-0031-6 -
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 -
Blood Apr 2023
Topics: Humans; Hemoglobinuria, Paroxysmal; Complement Factor H; Complement System Proteins; Erythrocytes; Germ Cells
PubMed: 37052944
DOI: 10.1182/blood.2022019576 -
American Journal of Hematology May 2023COVID-19 is a complex disease manifesting in a broad severity spectrum and involving distinct organs and systems. Hyperinflammation, including complement... (Review)
Review
COVID-19 is a complex disease manifesting in a broad severity spectrum and involving distinct organs and systems. Hyperinflammation, including complement over-activation, has a pivotal role in severe COVID-19 pathobiology, stimulating the inflammatory response, causing microangiopathy, platelet-neutrophil activation, and hypercoagulability. SARS-CoV-2 can directly activate the complement system by the classic, alternative, and lectin pathways, and infected cells can produce intracellular complement (the complesome). COVID-19 severity appears to be associated with the degree of complement activation, and it has been hypothesized that patients with COVID-19 may benefit from therapeutic complement inhibition. Different complement cascade molecules may be targeted with potential advantages and disadvantages. Which target(s) is the most effective and when is the best timing for intervention remain open questions. Early phase I and phase II clinical trials have shown promising but conflicting results, warranting phase III controlled randomized trials. Upstream complement inhibition appears to better and more effectively block hyperinflammation with potential clinical significance. Understanding how SARS-CoV-2 exploits the complement system can add precious information about the pathogenesis of other infections, inflammatory, and autoimmune diseases beyond COVID-19.
Topics: Humans; COVID-19; SARS-CoV-2; Inflammation; Complement Activation; Neutrophils; Complement System Proteins
PubMed: 36999459
DOI: 10.1002/ajh.26746 -
British Journal of Pharmacology Jul 2021The complement system, well known for its central role in innate immunity, is currently emerging as an unexpected, cell-autonomous, orchestrator of normal cell... (Review)
Review
The complement system, well known for its central role in innate immunity, is currently emerging as an unexpected, cell-autonomous, orchestrator of normal cell physiology. Specifically, an intracellularly active complement system-the complosome-controls key pathways of normal cell metabolism during immune cell homeostasis and effector function. So far, we know little about the exact structure and localization of intracellular complement components within and among cells. A common scheme, however, is that they operate in crosstalk with other intracellular immune sensors, such as inflammasomes, and that they impact on the activity of key subcellular compartments. Among cell compartments, mitochondria appear to have built a particularly early and strong relationship with the complosome and extracellularly active complement-not surprising in view of the strong impact of the complosome on metabolism. In this review, we will hence summarize the current knowledge about the close complosome-mitochondria relationship and also discuss key questions surrounding this novel research area. LINKED ARTICLES: This article is part of a themed issue on Canonical and non-canonical functions of the complement system in health and disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.14/issuetoc.
Topics: Complement System Proteins; Homeostasis; Humans; Immunity, Innate; Immunologic Factors; Mitochondria
PubMed: 32840864
DOI: 10.1111/bph.15238 -
The AAPS Journal Sep 2021Targeted drug delivery and nanomedicine hold the potential promise of delivering drugs solely to target organs or cell types, thus decreasing off-target side effects and... (Review)
Review
Targeted drug delivery and nanomedicine hold the potential promise of delivering drugs solely to target organs or cell types, thus decreasing off-target side effects and improving efficacy. However, nano-scale drug carriers face several barriers to this goal, with one of the most formidable being the complement cascade. Complement proteins, especially C3, opsonize not just the microbes they evolved to contain, but also nanocarriers. This results in multiple problems, including marking the nanocarriers for clearance by leukocytes, likely fouling of the targeting moieties on nanocarriers, and release of toxins which produce deleterious local and systemic effects. Here, we review how complement achieves its blockade of nanomedicine, which nanocarrier materials properties best avoid complement, and current and future strategies to control complement to unleash nanomedicine's potential.
Topics: Animals; Complement System Proteins; Drug Carriers; Drug Delivery Systems; Humans; Nanomedicine; Nanoparticles; Pharmaceutical Preparations
PubMed: 34505951
DOI: 10.1208/s12248-021-00630-9 -
Nature Immunology Nov 2017Progress at the beginning of the 21st century transformed the perception of complement from that of a blood-based antimicrobial system to that of a global regulator of... (Review)
Review
Progress at the beginning of the 21st century transformed the perception of complement from that of a blood-based antimicrobial system to that of a global regulator of immunity and tissue homeostasis. More recent years have witnessed remarkable advances in structure-function insights and understanding of the mechanisms and locations of complement activation, which have added new layers of complexity to the biology of complement. This complexity is readily reflected by the multifaceted and contextual involvement of complement-driven networks in a wide range of inflammatory and neurodegenerative disorders and cancer. This Review provides an updated view of new and previously unanticipated functions of complement and how these affect immunity and disease pathogenesis.
Topics: CD4-Positive T-Lymphocytes; Complement Activation; Complement System Proteins; Homeostasis; Humans; Immunity, Innate; Inflammation; Neoplasms
PubMed: 29144501
DOI: 10.1038/ni.3858