The cells that mediate innate immunity include neutrophils, macrophages (macrophages come from specific white blood cells called monocytes) , and NK cells.

 

The microbiome — The human microbiome is the collection of bacteria, fungi, and viruses that live in and on the human body, which may also be considered a component of the innate immune system, as it impacts mechanisms of host defense [10-17]. The body's microbial composition directly effects the maturation of the immune response and its continued effectiveness, protects against pathogen overgrowth, and modulates the balance between inflammation and immune homeostasis [15,18-20]. As examples, coagulase-negative staphylococci on the skin produce an antimicrobial peptide that can inhibit growth of Staphylococcus aureus. These protective strains are deficient in atopic dermatitis [21]. Alteration in the composition, diversity, or metabolites of the microbiome (ie, dysbiosis), such as that caused by antibiotic use, is associated with diseases affecting a variety of organ systems [15-17,22-26]. Dysbiosis is also believed to play a role in development of food allergy, asthma, and atopic dermatitis [16,20,27]. In plant systems, healthy soils have a microbiome that suppresses the invasion of plant root pathogens [28].

CRITICAL FUNCTIONSEssential functions of the innate immune system include the following:

●Detection of micro-organisms and first-line defense against invasion and infection. (See 'Microbial detection through pattern recognition' below.)

●Regulation of inflammation – The cardinal signs of inflammation (tumor, rubor, calor, and dolor [swelling, redness, heat, and pain]) are products of the protective action of innate immunity. To limit damage to the host, these responses must also be terminated when no longer needed. (See 'Homeostasis in the innate immune system' below.)

●Maintenance of "immunologic homeostasis" within the host. (See 'Homeostasis in the innate immune system' below.)

●Activation and instruction of adaptive immune responses.

MICROBIAL DETECTION THROUGH PATTERN RECOGNITIONInnate immune responses are largely mediated by a variety of proteins that recognize and interact with components that are specific to microbes. These proteins are grouped in their broad biologic context as "pattern recognition receptors" (PRRs) to emphasize their common function in host defense. The molecular components of micro-organisms recognized by PRRs are called pathogen-associated molecular patterns (PAMPs).

Pattern recognition receptors — Pattern recognition receptors (PRRs) can be divided into two broad groups: Secreted and circulating proteins and peptides and transmembrane and intracellular signal-transducing receptors (receptors in the more traditional sense). Some of the best studied molecules are discussed here.

Secreted and circulating pattern recognition receptors — Secreted and circulating pattern recognition molecules include antimicrobial peptides (AMPs), collectins, lectins, and pentraxins. These proteins and peptides mediate direct microbial killing, act as helper proteins for transmembrane receptors, and function as enhancers of phagocytosis (opsonins) by immune effector cells. The first component of complement, C1q, is a circulating and cell-associated pattern recognition receptor (PRR) that plays a broad role in host protection. It triggers the complement cascade upon binding to antibody that is fixed to a microbe. The resulting attachment of C3b promotes phagocytosis of (ie, opsonizes) the microbe. (See 'Collectins' below and "Complement pathways".)

Antimicrobial peptides — Antimicrobial peptides (AMPs) are a group of secreted pattern recognition receptors (PRRs) that are important in the protection of the skin and mucosal membranes and in the killing of phagocytosed organisms. AMPs secreted onto epithelial surfaces at a site of injury create a microbicidal shield that damages micro-organisms prior to attachment and invasion. They are microbicidal against a broad range of bacteria, fungi, chlamydiae, parasites, and enveloped viruses [29-42].

Petrolatum, commonly used in the management of atopic dermatitis, increases the concentration of AMPs in occluded skin [43]. A database of over 1200 AMPs published in 2009 links amino acid composition to activity against specific types of micro-organisms [40].

AMPs form pores through the outer membranes of a microbe that disrupt the membrane integrity and lead to death of the microbe. AMPs exist in many different forms and structures but all contain clusters of hydrophobic, cationic (positively-charged) amino acids that bind to negatively-charged phospholipids in the outer bilayer of bacterial membranes. The outer cell membranes of animals contain lipids (including cholesterol) that differ from those of microbes, and AMPs are not attracted to them.

Prototypic secreted and circulating PRRs include the following (table 1):

●Defensins, which are divided into alpha- and beta-defensins:

•Human alpha-defensins 1 to 4 (HDs 1 to 4) are contained in the azurophilic granules of neutrophils and are also synthesized by Paneth cells at the base of small intestinal crypts (alpha-defensins 5 and 6) [31,33,35]. Defensins are short peptides (30 to 45 amino acids) that have three disulfide bonds that protect the peptide from protease degradation. They comprise 2 to 4 percent of the neutrophil cellular protein and are released into the phagocytic vacuole with captured organisms. HD5 kills microbes directly. HD6 does not kill directly but forms microscopic net-like meshworks (nanonets) that entrap the microbial cells, as do the extracellular traps that are released from dying neutrophils [35,36].

•Human beta-defensins 1 to 6 (HBDs 1 to 6) are expressed on all epithelial surfaces, including those of the airways, urinary and gastrointestinal tracts, mouth, cornea and conjunctivae, and skin. Their production by epithelial cells can be constitutive (baseline, unstimulated) or inducible. Infectious or traumatic injury of epithelium elicits inflammatory cytokines that induce beta-defensin production [31,39,44]. Deficiency of HBD1 in sperm is associated with male infertility [45].

●Cathelicidins are a family of AMPs widely distributed in nature. The human cathelicidin LL-37, the most widely studied, is released from both neutrophils and epithelial cells. It exhibits a broad range of antimicrobial activities [32,34], neutralizes lipopolysaccharide (LPS), and plays a role in wound healing, angiogenesis, and clearance of dead cells. LL-37 is induced by vitamin D [46-48]. In both keratinocytes and macrophages, stimulation of toll-like receptor 2 (TLR2) results in the induction of the cytochrome P450 enzyme that converts vitamin D to its active form, which in turn induces the expression of LL-37. In this way, vitamin D can influence microbicidal defenses of both skin and circulating phagocytic cells [49]. This may explain, at least in part, why certain human infections (eg, tuberculosis) are more prevalent among populations with inadequate plasma levels of vitamin D, including those with more deeply pigmented skin [49]. (See "Vitamin D and extraskeletal health", section on 'Immune system'.)

●Bacterial permeability-increasing protein (BPI) is expressed in neutrophil azurophilic granules and in oral, pulmonary, and gastrointestinal mucosal surfaces [50]. It selectively damages membranes of gram-negative bacteria and can opsonize the bacteria for phagocytosis by neutrophils. It has a high affinity for the lipid A region of LPS, which gives it the capacity to downregulate the effects of LPS on inflammation.

●Epithelial and innate immune cells express multiple AMPs from several different structural classes across the body. These include:

•C-terminal fragments of keratin released from corneal epithelial cells, which protect the cornea from infection, as do lysozyme, lactoferrin, and lipocalin in tears [51,52]

•The bacteriostatic protein lipocalin 2 is secreted by alpha-intercalated cells in the collecting duct of the kidney, which also acidify the urine and defend against upper and lower urinary tract infection by binding uropathogenic Escherichia coli (E. coli) [53].

•Hepcidin, which has weak antimicrobial capacity but influences absorption and distribution of dietary iron. Hepcidin could affect the pathogenicity of malaria, human immunodeficiency virus-1 (HIV-1), and tuberculosis [54,55].

•Several chemokines, which are small chemotactic proteins that control migration of leukocytes into body tissues [56].

The existence of this broad repertoire of AMPs may in part explain the rarity of AMP resistance among pathogenic microbes. However, a second major function of these peptides is to govern the composition of the commensal micro-organisms that colonize our body surfaces. These species, which lack the attributes of major pathogens, can be relatively resistant to AMPs and thus may have had an evolutionary advantage over other microbes in adapting to this niche [29,32,57,58]. In fact, human gut microbes from all dominant species can resist even the high levels of AMPs secreted in response to inflammation [59].

Inherited variability in defensin gene expression has been reported to contribute to the risk of several diseases, including Crohn disease and psoriasis, and research suggests that AMPs play a part in the pathophysiology of other diseases, such as atopic dermatitis and necrotizing enterocolitis [31]. Neutrophils and saliva in children with Kostmann severe congenital neutropenia are deficient in defensins and LL-37. These children suffer life-threatening infections and severe periodontal disease. Granulocyte colony-stimulating factor administration corrects the neutropenia but not the periodontitis. Bone marrow transplantation restores salivary LL-37 and allows control of the periodontal disease [60]. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

Collectins — The collectins represent another type of secreted PRR (table 1). Collectins are collagen-like proteins that bind to carbohydrate or lipid moieties in microbial cell walls. They can have direct microbicidal activity or flag the microbial cell for recognition by the complement system and phagocytosis. They can promote uptake of cells that have undergone apoptosis (cell death without cell disintegration), particularly neutrophils, to avoid release of tissue-toxic constituents [61-66].

●The first component of complement, the collectin C1q, is a circulating and cell-associated PRR. It fixes to antibody-coated micro-organisms, some unopsonized organisms, immune complexes, apoptotic cells, and damage-associated molecular patterns (DAMPs) to initiate the complement cascade and clearance of the organism or particle. It plays a fundamental role in host defense and in preventing autoimmune disease, as demonstrated by the increased frequency of infections and systemic lupus erythematosus (SLE) in individuals who lack C1q [67]. (See "Complement pathways" and "Inherited disorders of the complement system".)

C1q is involved in a broad array of physiologic functions beyond its role in complement activity. These include dendritic cell development, apoptotic cell clearance, placental development, cell metabolism, and synapse pruning [68,69]. It is recognized that complement activation is not confined to the extracellular space but also occurs within cells to promote cell homeostasis. Proteolytic cleavage of intracellular C3 and C5 releases C3a and C5a, which can react with cell surface C3a and C5a "anaphylatoxin" receptors in autocrine fashion or these C3/C5 byproducts can bind to their receptors within the cell. This system stabilizes intracellular metabolism of immune cells in the basal state or during response to infection [70,71].

●Mannose-binding lectin (MBL) is an antimicrobial lectin, a well-characterized collectin, and an acute-phase reactant produced by the liver [66]. MBL recognizes terminal mannose residues of carbohydrates on gram-positive and gram-negative bacteria, fungi, and some viruses and parasites. MBL can opsonize microbes for phagocytosis via the C1q receptor and activate the complement pathway, leading to microbial cell lysis, chemoattraction of neutrophils, and phagocytosis. The relevance of MBL deficiency to host defense is unclear.

●Two of the four pulmonary surfactant proteins (SP-A and SP-D) are collectins that are found in a variety of tissues [72-74]. These proteins bind oligosaccharide PAMPs found on many gram-positive and gram-negative bacteria, viruses, and fungi [62-65,72]. SP-A is expressed in the placental amnion and amniotic fluid, where it may contribute to the amniotic anti-inflammatory response during pregnancy [65].

Lectins — Lectins are proteins that bind carbohydrates. In the context of host defense, they bind to microbial carbohydrates. MBL is the prototypic host defense lectin, but ficolins 1, 2, and 3, and galectins are other important host defense lectins [75-78]. MBL and ficolins can bind directly to microbes and trigger antibody-independent activation of the lectin pathway, the third of the core pathways of complement activation (with the classical and alternative pathways). There are at least 15 members of the mammalian galectin family. Some human galectins can bind directly to bacteria, disrupt their membranes, and kill them in the absence of complement. Galectins can inhibit replication of the influenza virus and induce apoptosis of certain cells [78-80]. The lectin RegIII-gamma can kill gram-positive bacteria in the small intestines. It also has the special property of maintaining a thin zone that physically separates gut microbiota from the small intestinal epithelial surface [81,82].

Pentraxins — Pentraxins are a large family of proteins, highly conserved through evolution and characterized by a C-terminal pentraxin domain with five subunits [83-85]. C-reactive protein (CRP) and serum amyloid P are the structurally short-arm family members. Pentraxin 3 (PTX3) is the prototypic "long pentraxin." All are acute-phase reactants secreted in response to toll-like receptor (TLR) activation or proinflammatory cytokines. CRP was the first PRR to be described. It is secreted by the liver and was named for its capacity to react with C-polysaccharide of pneumococci. It functions like an innate, rapidly responsive antibody in that it can fix C1q and activate the complement system, thereby promoting phagocytic clearance. CRP also promotes phagocytosis by directly binding immunoglobulin G (IgG) Fc-gamma receptors on phagocytes. PTX3 is secreted in a variety of tissues, particularly by macrophages and dendritic cells. It can bind to endothelial surface P-selectin at sites of inflammation, which blocks neutrophil attachment and recruitment, thereby acting to diminish inflammation as infection is controlled [85]. (See "Acute phase reactants", section on 'Roles of CRP'.)

Cell-associated pattern recognition receptors — Membrane-bound pattern recognition receptors (PRRs) are expressed constitutively on many types of innate immune cells and on the professional (most active) antigen-presenting cells (macrophages, dendritic cells, monocytes, and B lymphocytes). On all of these cells, transmembrane signaling PRRs act as sentinels. Upon activation, they induce rapid upregulation of other PRRs.

The principal transmembrane and intracellular signal-transducing PRRs include the following (table 2) [86-92]:

●Plasma membrane-bound and intracellular TLRs and their associated microbe detection-enhancing proteins (lipopolysaccharide [LPS]-binding protein, CD14, and MD-2).

●C-type lectin receptors (dectins 1 and 2) and macrophage-inducible C-type lectin (MINCLE) on macrophages and dendritic cells.

●Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), termed NOD1 and 2.

●RIG-1-like receptors (RLRs), termed RIG-1 (for retinoic acid-inducible gene 1), melanoma-associated differentiation protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2).

Toll-like receptors — Toll-like receptors (TLRs) are transmembrane PRRs that are found on and within cells of the innate immune system (particularly monocytes, macrophages, epithelial cells, and neutrophils), as well as dendritic cells and many other cell types [86-91]. TLRs recognize a variety of PAMPs, including microbial cell wall components, proteins, and nucleic acids (table 3). TLR signaling results in changes in the transcription factors that regulate a multitude of genes, including those encoding important proinflammatory cytokines. The Drosophila protein toll signals dorsoventral patterning and resistance to fungi in fruit flies and has a cytoplasmic signaling domain homologous with that of mammalian TLRs [93]. The sea urchin has 222 TLRs, illustrating the importance of these receptors to host defense throughout phylogeny [94]. (See "Toll-like receptors: Roles in disease and therapy".)

Ten human TLRs have been identified (table 3). The first identified was TLR4, which is constitutively expressed on many human cell types. TLR4 is specific for and exquisitely sensitive to the presence of bacterial endotoxin (LPS) [95,96]. Picogram amounts of LPS (estimated to equal approximately 10 molecules per cell) are sufficient to stimulate immune cells [97]. The relative protection of the Indiana Amish farming community from asthma is driven by a long-term, low-level proinflammatory innate immune response mediated through TLRs [98,99].

TLRs are homologous with the mammalian interleukin-1 (IL-1) receptor [100], and they share a MyD88-dependent signaling pathway that induces the transcription factors NF-kappa-B (nuclear factor for the kappa-light chain enhancer in B cells) and activating protein-1 (AP-1). These factors transcribe the secretion of potent proinflammatory cytokines, including tumor necrosis factor (TNF), interleukin-6 (IL-6), and pro-IL-1-beta.

The central role of TLRs in host defense is demonstrated by experiments of nature in which genetic polymorphisms or mutations are associated with disease. Predisposition to serious viral infections illustrates this point:

●Five of the 10 TLRs (TLRs 3, 4, 7, 8, and 9) can trigger production of the type-1 interferons (IFN-alpha, -beta, and -lambda), which are essential for antiviral immunity. Patients with deficiency of TLR3 [101], UNC93B (the TLR 3, 7, 8, 9 signaling molecule) [102], or STAT-1 (the signal transducer and activator of transcription-1) [103], have suffered severe viral infections, particularly herpes simplex virus-1 encephalitis [104]. (See "Toll-like receptors: Roles in disease and therapy", section on 'UNC93B1 deficiency, TLR3 mutations, TRIF deficiency, TRAF3 deficiency, and TBK1 deficiency'.)

●Hepatocytes express PRRs, including TLRs 2, 3, and 4, and when challenged by pathogens, can deliver innate immune responses in the liver or the acute-phase response systemically. Hepatocytes play a direct role in the innate defense against hepatitis C and hepatitis B viruses [105].

●Polymorphisms in TLRs have been associated with impaired resistance to respiratory syncytial virus [106] and increased risk of invasive fungal infections [107]. In contrast, a polymorphism in TLR3 confers protection against HIV-1 infection [108].

TLRs are found on cells of both innate and adaptive immune systems, and although they play a fundamental role in host defense, they have also been reported to contribute to a variety of inflammation-associated pathologic conditions, including cancer, rheumatoid arthritis, psoriasis, diabetes, coronary heart disease, cardiac ischemia, transplant rejection, and asthma [109,110]. (See "Toll-like receptors: Roles in disease and therapy".)

Pattern recognition receptors linked to phagocytosis — Phagocytes express membrane-bound pattern recognition receptors (PRRs) on their cell surface, which often function in concert with the secreted PRRs. When these cell surface PRRs bind PAMPs, they initiate phagocytosis, release of toxic oxidants, and delivery of pathogens to phagolysosomes filled with microbicidal products. In macrophages, pathogen-derived proteins are also processed into peptides and presented by cell surface major histocompatibility complex (MHC) molecules to engage and instruct antigen-specific T lymphocytes. (See "Antigen-presenting cells".)

The best studied PRRs found on macrophages include the following (table 2):

●The macrophage mannose receptor recognizes carbohydrates with terminal mannan that are characteristic of a variety of microbes, especially fungi [66,111].

●Certain members of the macrophage scavenger receptor family can bind bacterial cell walls and trigger phagocytic clearance of the bacteria [112-114].

●Dectin-1 is a transmembrane lectin receptor expressed on human macrophages, monocytes, neutrophils, eosinophils, dendritic cells, and lymphocytes [115-117]. It has binding specificity for beta-1,3-glucans, an important component of fungal cell walls. Mutations leading to deficient expression of dectin-1 have been reported in women with recurrent mucocutaneous fungal infections, particularly vulvovaginal candidiasis and onychomycosis [118]. Phagocytosis and killing of fungi by leukocytes from these individuals was normal, emphasizing the special role of dectin-1 in defense of skin and mucosa. An autosomal recessive mutation in caspase recruitment-containing domain 9 (CARD9), which is involved in signaling from dectin-1, has been associated with chronic mucocutaneous candidiasis [119]. (See "Chronic mucocutaneous candidiasis", section on 'Dectin-1 deficiency' and "Primary disorders of phagocyte number and/or function: An overview".)

●Another example of a membrane-bound PRR that promotes phagocytosis is the N-formylmethionine (N-fmet) receptor, which is expressed on neutrophils, monocytes, macrophages, and dendritic cells. The amino acid sequence N-fmet initiates all bacterial proteins but only mitochondrial proteins in mammalian cells [120]. Engagement of these bacterial structures by the N-fmet receptor on host immune cells chemoattracts these cells to the bacteria and activates them for phagocytosis and killing.

Intracellular pattern recognition receptors — Intracellular pattern recognition receptors (PRRs) include some of the TLRs, the NOD-like receptors, and the RIG-1-like receptor family (table 2).

●TLRs 3, 7, 8, 9, and 10 reside inside the cell in endolysosomes, membrane-bound compartments that can contain bacterial breakdown products or viruses and digestive enzymes from fused lysosomes. These TLRs recognize nucleic acids derived from viruses and bacteria and stimulate the production of IFN-alpha, IFN-beta, IFN-lambda, and proinflammatory cytokines. (See "Toll-like receptors: Roles in disease and therapy".)

●NOD-like receptors, NOD1 and NOD2, are PRRs that reside in the cytoplasm and recognize different structural core motifs of bacterial peptidoglycans [86,87,90-92,121]. NOD1 recognizes peptidoglycan of all gram-negative bacteria and certain gram-positive bacteria. NOD2 recognizes muramyl dipeptide, a peptidoglycan motif present in all gram-positive and gram-negative bacteria [86,90,121-123]. NOD2 expression is restricted to monocytes, macrophages, dendritic cells, epithelial and endothelial cells, and intestinal Paneth cells. TNF-alpha and IFN-gamma can upregulate the NOD2 gene in intestinal epithelial cells [124]. Engagement of either NOD1 or NOD2 activates NF-kappa-B, which results in upregulated transcription and production of proinflammatory mediators. NOD2 has been of particular interest in Crohn disease, because three polymorphisms in the NOD2 gene are associated with a 2- to 4-fold risk of this disorder in heterozygotes and an 11- to 27-fold risk in homozygotes [125-127]. (See "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease", section on 'Immune dysregulation and IBD'.)

●The RIG-1-like receptor family (RIG-1, MDA5, and LPG2) is a second family of cytoplasmic PRRs. These PRRs recognize the RNA of internalized viruses and mediate production of type-1 IFNs and antiviral immune responses [86,87,91,128].

●Genetic defects of PRRs are variable in severity, have a narrow specificity for particular classes of pathogens, and often decrease in severity with age [129].

Pathogen-associated molecular patterns — Pattern recognition receptors (PRRs) are capable of distinguishing between self-tissues and microbes by recognizing highly-conserved pathogen-associated molecular patterns (PAMPs). Each type of PAMP is characteristic of a specific group of microbes.

PAMP structures have certain features in common:

●PAMPs are produced only by microbes.

●PAMPs are typically invariant structures shared by entire classes of pathogens.

●PAMP structures are usually fundamental to the integrity, survival, and pathogenicity of the micro-organisms, such that a microbe cannot mutate its PAMPs to avoid the host's defense mechanisms and still survive.

A prototypical PAMP is bacterial endotoxin (LPS), a component of the outer membrane of all gram-negative bacteria. Endotoxin contains lipid A, a highly conserved structure of the lipid bilayer of the outer bacterial cell membrane that confers many of endotoxin's biologic activities [130]. Lipid A specifically interacts with TLR4 (see 'Toll-like receptors' above). Other examples of PAMPs include the following:

●Membrane components common to large categories of bacteria, such as peptidoglycan, lipoteichoic acids, and mannans.

●Unmethylated microbial DNA.

●Double-stranded RNA of viral origin.

●Glucans, polysaccharides, or proteins that are common to microbes but not to animals or humans.

 

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All these cells respond to molecular patterns produced by bacteria and to other substances characteristic of viruses, tumor, and transplant cells. Many cells that are not professional immunocytes may nevertheless also contribute to innate immune responses, such as endothelial and epithelial cells. The activated cells produce their effects via the release of cytokines, as well as, in some cases, complement and other systems.

Innate immunity in Drosophila centers around a receptor protein named toll, which binds fungal antigens and triggers activation of genes coding for antifungal proteins. An expanding list of toll-like receptors (TLRs) has now been identified in humans and other vertebrates. One of these, TLR4, binds bacterial lipopolysaccharide and a protein called CD14, and this initiates intracellular events that activate transcription of genes for a variety of proteins involved in innate immune responses. This is important because bacterial lipopolysaccharide produced by gram-negative organisms is the cause of septic shock. TLR2 mediates the response to microbial lipoproteins, TLR6 cooperates with TLR2 in recognizing certain peptidoglycans, TLR5 recognizes a molecule known as flagellin in bacterial flagellae, and TLR9 recognizes bacterial DNA. TLRs are referred to as pattern recognition receptors (PRRs)because they recognize and respond to the molecular patterns expressed by pathogens. Other PRRs may be intracellular, such as the so-called NOD proteins. One NOD protein, NOD2, has received attention as the product of a candidate gene leading to the intestinal inflammatory condition, Crohn disease (Clinical Box 3–2).

• Recruiting immune cells to sites of infection, through the production of chemical factors, including specialized chemical mediators, called cytokines
• Activation of the complement cascade to identify bacteria, activate cells, and promote clearance of antibody complexes or dead cells
• The identification and removal of foreign substances present in organs, tissues, the blood and lymph, by specialised white blood cells
• Activation of the adaptive immune system through a process known as antigen presentation. The sensory apparatus that allows detection of infectious microbes are toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I–like helicases (RLHs) permit recognition of specific molecules of microbial origin. [ these fully differentiated effector cells have membrane receptors for various chemoattractants and mediators, facilitating the activation or destruction of target cells.]
• Acting as a physical and chemical barrier to infectious agents.

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