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Although these mechanisms have been known for many years, they have generally been considered to have only minor roles in the immune system, and evidence has been lacking as to their specific, non-redundant functions in host defence.
Consequently, they have not received much attention in front-line immunology research. Here we discuss the constitutive innate immune responses in comparison with the better-described inducible innate responses triggered by PRRs. In addition, we present evidence suggesting that efficient action of constitutive innate immune mechanisms leads to both antimicrobial activity and mitigation of PRR-driven activities Fig.
a Constitutive innate immune mechanisms eliminate pathogens during the initial stages of an infection, which prevents the accumulation of pathogen-associated molecular patterns PAMPs that would otherwise activate an inducible immune response through pattern recognition receptors PRRs.
In addition, many of the constitutive mechanisms are known to directly downregulate PAMP signalling through PRRs. Both of these effects limit PRR-induced expression of type I interferon and IL-1β.
b The relationship between the different proposed layers of the immune response. A first layer of defence is exerted by physical and chemical barriers. Constitutive innate immune mechanisms function as soon as a danger signal is detected and eliminate harmful microorganisms and host molecules by specific non-inflammatory mechanisms that operate independently of PRRs.
This prevents establishment of the infection and accumulation of PAMPs, thus limiting the activation of PRR-based inducible innate immune responses. If PRR-based immunity is activated, owing to the level of PAMPs exceeding a certain threshold, this leads to inflammation and promotes activation of the adaptive immune response mediated by T cells and antibodies.
IRF, interferon regulatory factor. PRRs detect pathogen-associated molecular patterns PAMPsmicroorganism-associated molecular patterns 14host-derived danger-associated molecular patterns 15 and molecular signatures associated with homeostasis-altering molecular processes These molecular patterns activate PRR signalling, which ultimately leads to the transcription of antimicrobial and proinflammatory genes.
Downstream activities of PRR signalling include the production of type I interferon interferon-α IFNα and IFNβIL-1β and tumour necrosis factor TNF.
These cytokines, in turn, activate antimicrobial and proinflammatory activities, as well as the maturation of antigen-specific adaptive immune responses 17 PRR-based immune responses can be highly potent, and numerous inflammatory diseases are driven by excessive PRR signalling pathways 21920 Box 1.
However, the nature of PRR-based immunity is influenced by many factors, and it is worth mentioning that the gut microbiota and chronic viral infections can induce PRR-based, host-beneficial responses that tend towards tolerance rather than inflammation 21 Nevertheless, given the potency of PRR-based immunity, full activation of PRR-driven immune responses each time a microorganism is encountered may not be beneficial for an organism in the longer term.
Moreover, it is essential to control the activation and duration of PRR signalling-induced activities. This is achieved through multiple mechanisms, including two-step procedures for full PRR activation 2324the requirement for a threshold PAMP concentration to achieve PRR activation 25262728amplification loops from initial low responses 29 and numerous negative-feedback mechanisms One way in which the activation of PRR signalling in response to very low levels of PAMPs is avoided at the molecular level is through supramolecular organizing centres.
These are higher-order signalling complexes at specific subcellular locations that rely on amplification mechanisms to achieve full activation, thus preventing signalling by subthreshold levels of PAMPs but amplifying signalling by superthreshold levels of PAMPs The double-edged sword-like nature of PRR-induced immune responses in terms of their roles in both protection and disease is also supported by evolutionary evidence.
OAS1 is an interferon-inducible protein that is associated with both antiviral and pathological activities 32 Excessive or prolonged activation of pattern recognition receptor PRR signalling is associated with a range of human diseases.
Several cytokines are involved in PRR-driven diseases, including tumour necrosis factor TNFIL-1β, IL-6 and type I interferon Among these, IL-1β and type I interferon are induced exclusively by PRR signalling. Thus, the existence of human diseases that are mediated by these two classes of cytokines provides strong evidence for the pathological potential of PRR-based immune responses.
Here we describe some examples of sterile inflammation involving IL-1β and type I interferon. We now know that diseases such as familial Mediterranean fever, TNF receptor-associated periodic syndrome, hyper-IgD syndrome and cryopyrin-associated periodic syndrome are characterized by increased expression of IL-1β; furthermore, blocking ILinduced signalling in these disease can relieve clinical symptoms and improve disease outcome For several of these diseases, inhibition of Janus kinase 1 JAK1 and JAK3, which are involved in interferon-induced signalling, significantly reduces disease activity There are marked differences in the pathogenesis of ILdriven diseases and interferon-driven diseases.
Diseases that depend on IL-1 are generally neutrophilic and associated with fever and increased levels of acute phase reactants, whereas interferon-driven diseases are characterized mainly by lymphopenia, vasculitis, central nervous system manifestations in some diseases, skin manifestations and varying levels of autoantibodies Constitutive innate immune mechanisms respond to microbial activities, cellular stress and metabolic alterations by inducing antimicrobial effector functions.
As there is most evidence for constitutive innate immune mechanisms that exert antiviral and antibacterial activities, these are the focus of this Review Fig.
A large range of constitutive mechanisms of innate immunity have been identified, including restriction factors, antimicrobial peptides, basal autophagy and proteasomal degradation Box 2 ; Table 1. Here we divide these mechanisms into two classes: those that target specific steps in microbial replication cycles, such as restriction factors 3435and those that lead to degenerative processes, such as autophagy 9 The constitutive mechanisms that target specific steps in microbial replication function by blocking molecularly defined events that are essential for the replication of specific microorganisms but are dispensable for cellular fitness.
By contrast, those mechanisms that operate through degenerative programmes target microbial or altered host molecules for recycling or degradation.
The modes of action of representative examples from each of these mechanistic classes are described in the following sections. a Constitutive innate immune mechanisms and viral infection. The accumulation of specific viral molecular structures such as double-stranded RNA dsRNA or capsids and cellular stress responses such as autophagy activate constitutive—latent mechanisms with direct antiviral activity, independently of pattern recognition receptors.
Some of the antiviral effector functions target microbial replication by blocking specific steps in the replication cycles of viruses; these effectors include soluble lectins, antimicrobial peptides, restriction factors, RNA interference RNAi and metabolites. Other antiviral effectors of the constitutive response function through the degradation of virus particles; these include nucleases such as TREX1, which degrades viral DNA in the cytoplasm, and RNase L, which degrades viral RNA, as well as autophagy and proteasomal degradation.
Viruses can be targeted for proteasomal degradation by the ubiquitin E3 ligase TRIM21, which binds to antibody-attached viral capsids.
b Constitutive innate immune mechanisms and bacterial infection. The presence of bacteria changes the local microenvironment, for example through the accumulation of hydrophobic and charged bacterial surfaces or alteration of cellular metabolism.
This activates antibacterial activities independently of pattern recognition receptors, including inactivation by soluble lectins and antimicrobial peptides, nutritional depletion by natural resistance-associated macrophage protein 1 NRAMP1 and lactoferrin, and bacterial degradation by phagocytosis and basal autophagy.
dsDNA, double-stranded DNA; RISC, RNA-induced silencing complex; ROS, reactive oxygen species; viRNA, virus-derived small interfering RNA. Given the ability of constitutive immune mechanisms to exert antimicrobial activity, one consequence of their successful action is decreased levels of PAMPs Fig.
This, in turn, limits PRR activation and the downstream inflammatory response Fig. Thus, constitutive immune mechanisms equip cells and tissues with a layer of defence that can fight infections immediately and hence potentially limit the requirement for inducible immune responses, such as type I interferon, IL-1β and other proinflammatory cytokines.
In most respects, constitutive and inducible immune responses operate through different principles; however, in certain cases, their downstream effector activities may overlap. For example, autophagy can be activated during infection and upon sterile danger 9 Similarly, phagocytosis can be activated by both Toll-like receptor TLR -dependent and TLR-independent mechanisms, Moreover, many restriction factors are expressed at basal levels to exert immediate antiviral activity, but are also induced transcriptionally in response to stimulation with type I interferon 3540 Nevertheless, despite these minor areas of overlap between constitutive immune mechanisms and the pattern recognition receptor PRR -induced immune responses, the differences are more pronounced.
The key difference between constitutive immune mechanisms and PRR-induced immunity is that the former mechanisms are all activated through pre-existing molecules to directly eliminate danger, whereas the latter system functions mainly through inducible transcription-dependent proinflammatory programmes.
In addition, inducible innate responses can amplify adaptive responses, whereas constitutive innate responses do not amplify inducible innate responses. Direct inhibition of microbial replication is executed by molecules that interfere with specific steps in the replication cycle of a given microorganism.
: Immune system defense mechanisms| Definition | Given the ability of constitutive immune mechanisms to exert antimicrobial activity, one consequence of their successful action is decreased levels of PAMPs Fig. Nguyen GT, Green ER, Mecsas J. Archived 21 October at the Wayback Machine World Health Organization. The majority of neutrophil-derived granule contents promote tumor progression, such as elastase, cathepsin D, cathepsin B, and proteinase 3. In addition to the constitutive immune mechanisms described in this Review, several pathways are activated in response to infections and sterile challenge that function independently of pattern recognition receptors PRRs and antigen-specific receptors to control infection. et al. Yan G, Zhao H, Zhang Q, Zhou Y, Wu L, Lei J, et al. |
| How the immune system protects against infection - Inivos | Binding of PAMPs to toll-like receptors in tissues is the alarm signal that triggers an inflammatory response, and PAMPs can also activate the complement system which will be described later in this module. In humans they are called the human leukocyte antigen system HLA. Eliminate danger through specific effector functions that target defined host or microbial structures and activities. Mogensen Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Søren R. Army Walter Reed Army Medical Center. CAS PubMed PubMed Central Google Scholar Holze, C. Control of the Complement System. |
| Top bar navigation | This allows killer T cells to recognize the tumor cell as abnormal. Some tumors evade the immune system and go on to become cancers. Paradoxically, macrophages can promote tumor growth [] when tumor cells send out cytokines that attract macrophages, which then generate cytokines and growth factors such as tumor-necrosis factor alpha that nurture tumor development or promote stem-cell-like plasticity. The hypoxia reduces the cytokine production for the anti-tumor response and progressively macrophages acquire pro-tumor M2 functions driven by the tumor microenvironment, including IL-4 and IL Some drugs can cause a neutralizing immune response, meaning that the immune system produces neutralizing antibodies that counteract the action of the drugs, particularly if the drugs are administered repeatedly, or in larger doses. This limits the effectiveness of drugs based on larger peptides and proteins which are typically larger than Da. Computational methods have been developed to predict the immunogenicity of peptides and proteins, which are particularly useful in designing therapeutic antibodies, assessing likely virulence of mutations in viral coat particles, and validation of proposed peptide-based drug treatments. Early techniques relied mainly on the observation that hydrophilic amino acids are overrepresented in epitope regions than hydrophobic amino acids; [] however, more recent developments rely on machine learning techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a training set. It is likely that a multicomponent, adaptive immune system arose with the first vertebrates , as invertebrates do not generate lymphocytes or an antibody-based humoral response. Echinoderms , hemichordates , cephalochordates , urochordates. Many species, however, use mechanisms that appear to be precursors of these aspects of vertebrate immunity. Immune systems appear even in the structurally simplest forms of life, with bacteria using a unique defense mechanism, called the restriction modification system to protect themselves from viral pathogens, called bacteriophages. Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with pathogens. Antimicrobial peptides called defensins are an evolutionarily conserved component of the innate immune response found in all animals and plants, and represent the main form of invertebrate systemic immunity. Ribonucleases and the RNA interference pathway are conserved across all eukaryotes , and are thought to play a role in the immune response to viruses. Unlike animals, plants lack phagocytic cells, but many plant immune responses involve systemic chemical signals that are sent through a plant. Systemic acquired resistance is a type of defensive response used by plants that renders the entire plant resistant to a particular infectious agent. Evolution of the adaptive immune system occurred in an ancestor of the jawed vertebrates. Many of the classical molecules of the adaptive immune system for example, immunoglobulins and T-cell receptors exist only in jawed vertebrates. A distinct lymphocyte -derived molecule has been discovered in primitive jawless vertebrates , such as the lamprey and hagfish. These animals possess a large array of molecules called Variable lymphocyte receptors VLRs that, like the antigen receptors of jawed vertebrates, are produced from only a small number one or two of genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies , and with the same degree of specificity. The success of any pathogen depends on its ability to elude host immune responses. Therefore, pathogens evolved several methods that allow them to successfully infect a host, while evading detection or destruction by the immune system. These proteins are often used to shut down host defenses. An evasion strategy used by several pathogens to avoid the innate immune system is to hide within the cells of their host also called intracellular pathogenesis. Here, a pathogen spends most of its life-cycle inside host cells, where it is shielded from direct contact with immune cells, antibodies and complement. Some examples of intracellular pathogens include viruses, the food poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria Plasmodium spp. and leishmaniasis Leishmania spp. Other bacteria, such as Mycobacterium tuberculosis , live inside a protective capsule that prevents lysis by complement. Such biofilms are present in many successful infections, such as the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis. The mechanisms used to evade the adaptive immune system are more complicated. This is called antigenic variation. An example is HIV, which mutates rapidly, so the proteins on its viral envelope that are essential for entry into its host target cell are constantly changing. These frequent changes in antigens may explain the failures of vaccines directed at this virus. In HIV, the envelope that covers the virion is formed from the outermost membrane of the host cell; such "self-cloaked" viruses make it difficult for the immune system to identify them as "non-self" structures. Immunology is a science that examines the structure and function of the immune system. It originates from medicine and early studies on the causes of immunity to disease. The earliest known reference to immunity was during the plague of Athens in BC. Thucydides noted that people who had recovered from a previous bout of the disease could nurse the sick without contracting the illness a second time. Although he explained the immunity in terms of "excess moisture" being expelled from the blood—therefore preventing a second occurrence of the disease—this theory explained many observations about smallpox known during this time. These and other observations of acquired immunity were later exploited by Louis Pasteur in his development of vaccination and his proposed germ theory of disease. It was not until Robert Koch 's proofs , for which he was awarded a Nobel Prize in , that microorganisms were confirmed as the cause of infectious disease. Immunology made a great advance towards the end of the 19th century, through rapid developments in the study of humoral immunity and cellular immunity. Köhler and César Milstein for theories related to the immune system. Contents move to sidebar hide. Article Talk. Read Edit View history. Tools Tools. What links here Related changes Upload file Special pages Permanent link Page information Cite this page Get shortened URL Download QR code Wikidata item. Download as PDF Printable version. In other projects. Wikimedia Commons Wikiquote Wikiversity. Biological system protecting an organism against disease. Further information: Innate immune system. Further information: Inflammation. Further information: Adaptive immune system. Further information: Cell-mediated immunity. Further information: Humoral immunity. Further information: Immunity medical. Main article: Immune system contribution to regeneration. Further information: Immunodeficiency. Further information: Autoimmunity. Further information: Hypersensitivity. Further information: Immune-mediated inflammatory diseases. Main articles: Immunostimulant , Immunotherapy , and Vaccination. Further information: Vaccination. Further information: Cancer immunology. Further information: Innate immune system § Beyond vertebrates. Further information: History of immunology. Nature Reviews. doi : PMC PMID Current Opinion in Immunology. S2CID British Medical Bulletin. Current Topics in Microbiology and Immunology. ISBN Clinica Chimica Acta; International Journal of Clinical Chemistry. Identity and significance". The Biochemical Journal. J Food Prot. Annals of Medicine. Bibcode : Natur. Bibcode : Sci International Reviews of Immunology. Annual Review of Immunology. Int Immunopharmacol. Comparative Immunology, Microbiology and Infectious Diseases. Journal of Immunological Methods. Journal of Cell Science. Archived from the original on 31 March Retrieved 6 November Current Pharmaceutical Design. Archived from the original PDF on 31 March Current Opinion in Cell Biology. Journal of Leukocyte Biology. 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Symptoms include rash at the site of larval entry and sometimes abdominal pain or other Many mucous membranes are bathed in secretions that have antimicrobial properties. For example, cervical mucus, prostatic fluid, and tears contain lysozyme, which splits the muramic acid linkage in bacterial cell walls, especially in gram-positive organisms; gram-negative bacteria are protected by lipopolysaccharides in their outer membrane. Local secretions also contain immunoglobulins, principally IgG and secretory IgA, which prevent microorganisms from attaching to host cells, and proteins that bind iron, which is essential for many microorganisms. The respiratory tract has upper airway filters. If invading organisms reach the tracheobronchial tree, the mucociliary epithelium transports them away from the lung. Coughing also helps remove organisms. If the organisms reach the alveoli, alveolar macrophages and tissue histiocytes engulf them. However, these defenses can be overcome by large numbers of organisms, by compromised effectiveness resulting from air pollutants eg, cigarette smoke , interference with protective mechanisms eg, endotracheal intubation, tracheostomy , or by inborn defects eg, cystic fibrosis Cystic Fibrosis Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency Gastrointestinal tract barriers include the acid pH of the stomach and the antibacterial activity of pancreatic enzymes, bile, and intestinal secretions. Peristalsis and the normal loss of intestinal epithelial cells remove microorganisms. If peristalsis is slowed eg, because of drugs such as belladonna or opium alkaloids , this removal is delayed and prolongs some infections, such as symptomatic shigellosis Shigellosis Shigellosis is an acute infection of the intestine caused by the gram-negative Shigella species. Symptoms include fever, nausea, vomiting, tenesmus, and diarrhea that is usually bloody read more and Clostridioides difficile—induced colitis Clostridioides formerly Clostridium difficile —Induced Diarrhea Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. Symptoms are diarrhea, sometimes bloody Compromised gastrointestinal defense mechanisms may predispose patients to particular infections eg, achlorhydria predisposes to Salmonella Overview of Salmonella Infections The genus Salmonella is divided into 2 species, S. enterica and S. Some of these serotypes are named. In such cases, common read more , Campylobacter Campylobacter and Related Infections Campylobacter infections typically cause self-limited diarrhea but occasionally cause bacteremia, with consequent endocarditis, osteomyelitis, or septic arthritis. Diagnosis is by culture read more , and C. difficile Clostridioides formerly Clostridium difficile —Induced Diarrhea Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. read more infections. Normal bowel flora can inhibit pathogens; alteration of this flora with antibiotics can allow overgrowth of inherently pathogenic microorganisms eg, Salmonella Typhimurium , overgrowth and toxin formation of C. difficile , or superinfection with ordinarily commensal organisms eg, Candida albicans. Martin, Klaus Resch. Institute of Pharmacology, Hannover Medical School, Hannover, Germany. Synonyms Immunity. |
| REVIEW article | Branch-like cells found in the skin, known as macrophages and lymphocytes, play a key role in activating the immune response. Neutrophil extracellular trap cell death requires both autophagy and superoxide generation. Zhang Y, Choksi S, Chen K, Pobezinskaya Y, Linnoila I, Liu ZG. Immune defense is the ability of higher organisms to identify and combat potentially harmful microorganisms such as viruses, bacteria, fungi, protozoa and helminths by highly sophisticated mechanisms involving soluble factors Humoral Immunity and immune competent cells Cellular Immunity. The role IL-1 in tumor-mediated angiogenesis. |
| Host Defense Mechanisms Against Infection | The skin usually bars invading microorganisms unless it is physically disrupted eg, by arthropod vectors, injury, IV catheters, surgical incision. Exceptions include the following:. Human papillomavirus Human Papillomavirus HPV Infection Human papillomavirus HPV infects epithelial cells. read more , which can invade normal skin, causing warts. Some parasites eg, Schistosomiasis Schistosomiasis is infection with blood flukes of the genus Schistosoma , which are acquired transcutaneously by swimming or wading in contaminated freshwater. The organisms infect the read more , Strongyloides stercoralis Strongyloidiasis Strongyloidiasis is infection with Strongyloides stercoralis. Findings include abdominal pain and diarrhea, rash, pulmonary symptoms including cough and wheezing , and eosinophilia read more , those that cause hookworm infection Hookworm Infection Ancylostomiasis is infection with the hookworm Ancylostoma duodenale or Necator americanus. Symptoms include rash at the site of larval entry and sometimes abdominal pain or other Many mucous membranes are bathed in secretions that have antimicrobial properties. For example, cervical mucus, prostatic fluid, and tears contain lysozyme, which splits the muramic acid linkage in bacterial cell walls, especially in gram-positive organisms; gram-negative bacteria are protected by lipopolysaccharides in their outer membrane. Local secretions also contain immunoglobulins, principally IgG and secretory IgA, which prevent microorganisms from attaching to host cells, and proteins that bind iron, which is essential for many microorganisms. The respiratory tract has upper airway filters. If invading organisms reach the tracheobronchial tree, the mucociliary epithelium transports them away from the lung. Coughing also helps remove organisms. If the organisms reach the alveoli, alveolar macrophages and tissue histiocytes engulf them. However, these defenses can be overcome by large numbers of organisms, by compromised effectiveness resulting from air pollutants eg, cigarette smoke , interference with protective mechanisms eg, endotracheal intubation, tracheostomy , or by inborn defects eg, cystic fibrosis Cystic Fibrosis Cystic fibrosis is an inherited disease of the exocrine glands affecting primarily the gastrointestinal and respiratory systems. It leads to chronic lung disease, exocrine pancreatic insufficiency Gastrointestinal tract barriers include the acid pH of the stomach and the antibacterial activity of pancreatic enzymes, bile, and intestinal secretions. Peristalsis and the normal loss of intestinal epithelial cells remove microorganisms. If peristalsis is slowed eg, because of drugs such as belladonna or opium alkaloids , this removal is delayed and prolongs some infections, such as symptomatic shigellosis Shigellosis Shigellosis is an acute infection of the intestine caused by the gram-negative Shigella species. Symptoms include fever, nausea, vomiting, tenesmus, and diarrhea that is usually bloody read more and Clostridioides difficile—induced colitis Clostridioides formerly Clostridium difficile —Induced Diarrhea Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. Symptoms are diarrhea, sometimes bloody Compromised gastrointestinal defense mechanisms may predispose patients to particular infections eg, achlorhydria predisposes to Salmonella Overview of Salmonella Infections The genus Salmonella is divided into 2 species, S. enterica and S. Some of these serotypes are named. In such cases, common read more , Campylobacter Campylobacter and Related Infections Campylobacter infections typically cause self-limited diarrhea but occasionally cause bacteremia, with consequent endocarditis, osteomyelitis, or septic arthritis. Diagnosis is by culture read more , and C. difficile Clostridioides formerly Clostridium difficile —Induced Diarrhea Toxins produced by Clostridioides difficile strains in the gastrointestinal tract cause pseudomembranous colitis, typically after antibiotic use. read more infections. Normal bowel flora can inhibit pathogens; alteration of this flora with antibiotics can allow overgrowth of inherently pathogenic microorganisms eg, Salmonella Typhimurium , overgrowth and toxin formation of C. difficile , or superinfection with ordinarily commensal organisms eg, Candida albicans. Genitourinary tract barriers include the length of the urethra 20 cm in men, the acid pH of the vagina in women, the hypertonic state of the kidney medulla, and the urine urea concentration. The kidneys also produce and excrete large amounts of Tamm-Horsfall mucoprotein, which binds certain bacteria, facilitating their harmless removal. Cytokines Cytokines The immune system consists of cellular components and molecular components that work together to destroy antigens Ags. See also Overview of the Immune System. Acute phase reactants are plasma read more including interleukins 1 and 6, tumor necrosis factor-alpha, and interferon-gamma are produced principally by macrophages and activated lymphocytes and mediate an acute-phase response that develops regardless of the inciting microorganism. The response involves fever and increased production of neutrophils by the bone marrow. Endothelial cells also produce large amounts of interleukin-8, which attracts neutrophils. Myeloid cells express complement receptors that bind C3-derivatives, leading to phagocytosis, cell-cell adhesion and adhesion to the extracellular matrix Complement can also steer the adaptive immunity by activating B and T cells through combined engagement of complement receptors and the B-cell receptor or TCR, respectively Overall, the resulting effector mechanisms of complement activation are 1 cell-mediated phagocytosis complement-dependent cellular phagocytosis or CDCP and 2 cytotoxicity complement-dependent cellular cytotoxicity or CDCC , initiated by the interaction between opsonized target cells or microbes and CR-expressing myeloid cells, as well as 3 complement-dependent cytotoxicity CDC through the formation of the MAC in the membrane of target cells or microorganisms, and 4 the recognition and clearance of dying cells Figure 3. However, distinguishing the different effector mechanisms that contribute to cancer-cell eradication as a result of complement activation remains challenging up to now. Furthermore, complement-induced cytolytic effector mechanisms on the surface of host cells is prevented through the expression of complement regulatory proteins CRPs , such as CD46, CD55, CD59 and factor H. Several cancer types overexpress CRPs and make use of this defense mechanism against complement-induced cytolysis — , whereas downregulation or blockade of CRPs sensitizes cancer cells to complement- and antibody-mediated cytotoxicity , Figure 3. Cell-dependent and -independent effector mechanisms of complement activation and FcR-mediated killing. Complement factor- and antibody-opsonized cancer cells can be eliminated through cell-dependent and cell-independent effector mechanisms. The classical pathway of complement activation mediates a cell-independent form of lytic cell death by introducing a MAC in the membrane of antibody opsonized target cells that are recognized by complement C1 complex. ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cell-mediated phagocytosis; CDC, complement-dependent cytotoxicity; CDCC, complement-dependent cell-mediated cytotoxicity; CDCP, complement-dependent cell-mediated phagocytosis; CRs, complement receptors; IFNγ, interferon gamma; TNFα, tumor necrosis factor alpha; C5a, complement factor 5a; C3a, complement factor C3a; FcγR, crystallizable fragment receptor gamma; C1, complement factor. Complement activation has been reported to promote tumor progression through the recruitment of immune suppressive macrophages, MDSCs and neutrophils, while on the other hand, there are also reports of its capacity to stimulate antitumoral T-cell responses and the recruitment of NK cells — Recruitment of MDSCs in response to anaphylatoxins has been demonstrated in several studies — Markiewski et al. revealed that aside from increased recruitment of MDSCs to the tumor in response to C5a, the latter also enhances the production of ROS and RNS in MDSCs via C5aR signaling As mentioned earlier, ROS and RNS release by MDSCs in the TME abrogates antigen recognition by CTLs and instead induces tolerance 67 , Moreover, C5a is also implicated in the formation of new blood vessels. Corrales et al. demonstrated that human umbilical vein endothelial cells treated with C5a form vessel-like structures. They further elaborated on the vessel-like structures in a murine 3LL lung cancer model, where they showed that the number of newly formed microvessels in the tumor is reduced upon C5aR antagonism While the role of C5a in cancer progression has been extensively studied, less is known about the implication of C3a in cancer. Tumor-infiltrating macrophages and neutrophils also carry the potential to suppress the detrimental effects of complement activation through IL-1ß-induced expression of pentraxin 3 PTX3 Surface-expressed PTX3 recruits complement factor H that inhibits the C3 cleavage upstream of the complement cascade and prevents complement-induced inflammation and recruitment of immunosuppressive myeloid cells to the TME. However, Ptx3 is epigenetically silenced at the gene level in murine and human colorectal cancer through hypermethylation Despite the intrinsic protumoral functions of complement in cancer, it should not be forgotten that complement can be useful in the context of antibody-mediated cancer immunotherapy. Indeed, the classical pathway of complement activation, initiated by antibody-opsonized target cells, is one of the effector mechanisms of therapeutic monoclonal antibodies mAb , This was demonstrated in a study by Lee et al. However, the release of proinflammatory mediators IL-6, TNFα and degranulation by granulocytes in response to complement anaphylatoxins contribute to the toxic side effects of anti-CD20 therapy, such as fever, dyspnea, chills and flushes Similarly, the in vivo effector functions of Cetuximab, an anti-EGFR mAb, have been attributed to complement activation in several murine models of non-small cell lung carcinoma Moreover, the efficacy of antibody-based therapy, that relies on the cytotoxic effector mechanisms of complement and FcR-mediated cytotoxicity, is restricted by the limited availability of suitable antigens for therapeutic targeting. In addition, the dual role of complement in cancer must be taken into account when using complement as an effector mechanism of antibody-based therapy. It appears that complement can promote tumor growth through high C5a concentrations, sublytic MACs levels and high CRP levels on the surface of cancer cells, while intermediate concentrations of C5a, increased MAC formation in the membrane of cancer cells and low surface expression of CRPs could eliminate cancer cells , Future therapeutic strategies should take this delicate balance between tumor promotion and tumor eradication into account. When the Fc part of an antibody interacts with cognate surface-expressed FcRs, this may result in ADCC, ADCP, antigen presentation, degranulation and an altered cytokine production profile Figure 3 NK cells are thought to be the main effector cells of ADCC, yet studies have shown that antibody-based cellular destruction mechanisms can also take place in the absence of NK cells The relevance for therapeutic mAbs is shown by mice deficient in the common gamma chain of the FcγR. These mice do not engage ADCC or ADCP in the presence of Trastuzumab and Rituximab , Members of the mononuclear phagocyte system, including monocytes and macrophages, are responsible for the working mechanism of Rituximab Indeed, CDtargeted B-cell depletion seems to be dependent on FcγRI and FcγRIII expressed by monocytes and macrophages and is absent in colony stimulating factor 1-deficient mice, which lack tissue macrophage subsets Biburger et al. discovered a murine subset of Ly6C low non-classical monocytes capable of autoantibody-mediated platelet depletion and antibody-dependent B-cell depletion via ADCC and ADCP mediated by FcγRIV, a low affinity FcγR that is not expressed by NK cells or tissue-resident macrophages The number of murine B16 melanoma metastases in the lung of FcγRIIb-deficient mice significantly decreased when treated with a mAb targeting melanoma differentiation antigen gp75 FcγRIIb is an inhibitory Fc receptor which is not expressed by NK cells. Moreover, a synergistic effect was observed when combining FcγRIIb deficiency and a therapeutic mAb against mouse and human HER2 4D5, Trastuzumab However, not all FcR-mediated effects are beneficial in the context of mAb-mediated therapy. For example, phagocytosis of antibody-opsonized cancer cells by TAMs was shown to activate the inflammasome AIM2, which results in the subsequent release of IL-1ß, hence increasing PD-L1 surface expression and cytosolic IDO production in TAMs As a result, TAMs that underwent ADCP display an immunosuppressive phenotype, which is relieved upon PD-L1 and IDO blockade Furthermore, in vivo imaging by Arlauckas et al. Hence, TAMs could serve as a sink for anti-PD-1 antibodies and possibly also other mAbs, strongly diminishing the efficacy of mAb-dependent therapies such as immune checkpoint blockade Innate immune responses are often regarded as the default first-line defense responses, that become less significant once a more complex, adaptive and antigen-directed response is initiated. With this review, we provide evidence for the detrimental effects of innate effector mechanisms performed by myeloid cells during cancer development and progression. Noteworthy, effector mechanisms that are initially deployed by innate myeloid cells, such as ROS production, release of inflammatory mediators and response to PRR signaling, can be adopted by cancer cells. However, contradicting literature studies are available on the role of several innate defense mechanisms in cancer, and this duality between tumor-promoting and -eradicating roles seems to be linked to the presence of persisting, tumor-associated inflammation. Inflammation is required to mount anti-tumor immune responses, while chronic tumor-associated inflammation promotes tumor progression. Cold tumors, however, are still infiltrated by myeloid cells, that create an immune suppressive environment, which impedes T-cell infiltration and tumor eradication. Therefore, innate defense strategies might play a more important role in cancers with an inflammatory nature or origin, for example in organs like the liver, stomach, lungs and skin due to alcohol abuse, H. pylori infection, tobacco and asbestos, UV irradiation and even obesity. In any case, due to the abundance of tumor-infiltrating myeloid cells in multiple solid tumor types, their effector mechanisms should be investigated in depth and exploited in cancer therapy, perhaps alongside T-cell stimulatory immunotherapy to improve therapy outcome. EL has conceptualized, written, reviewed, and edited the content of this review, with contributions from SA, PB, and MK. JV and GR contributed to the conceptualization and reviewing of this review. All authors contributed to the article and approved the submitted version. This work was supported by grants of the Research Foundation Flanders FWO-Vlaanderen , Kom op tegen Kanker Stand up to Cancer , and Stichting tegen Kanker Foundation against Cancer granted to GR and JV. EL, SA, PB, and MK received a doctoral grant from FWO-Vlaanderen. MK was also supported by a doctoral finishing grant from Kom op Tegen Kanker. 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