Introduction
The innate immune response is the first mechanism for host defense found in all multicellular organisms. The innate immune system is more ancient than the acquired or adaptive immune response, and it has developed and evolved to protect the host from the surrounding environment in which a variety of toxins and infectious agents including bacteria, fungi, viruses and parasites are found (1).
The immune system is complex and is divided in two categories: i) the innate or nonspecific immunity, which consists of the activation and participation of preexistent mechanisms including the natural barriers (skin and mucosa) and secretions; and ii) the adaptive or specific immunity, which is targeted against a previously recognized specific microorganism or antigen. Thus, when a given pathogen is new to the host, it is initially recognized by the innate immune system and then the adaptive immune response is activated (2). Innate immunity is the host’s first line of defense and is intended to prevent infection and attack the invading pathogens.This nonspecific mechanism is fast (minutes to hours) while the adaptive response takes longer (days to weeks).
Innate immunity is comprised of different components including physical barriers (tight junctions in the skin, epithelial and mucous membrane surfaces, mucus itself); anatomical barriers; epithelial and phagocytic cell enzymes (i.e., lysozyme), phagocytes (i.e., neutrophils, monocytes, macrophages), inflammation-related serum proteins (e.g., complement, C-reactive protein, lectins such as mannose-binding lectin, and ficolins); surface and phagocyte granule antimicrobial peptides (e.g., defensins, cathelicidin, etc.); cell receptors that sense microorganisms and signal a defensive response (e.g., Toll-like receptors); and cells that release cytokines and inflammatory mediators (i.e., macrophages, mast cells, natural-killer cells). Once the interaction host-invader pathogen enters, a signaling cascade is initiated which enhances the immune response and activates specific mechanisms (3-5). This natural immune response is designed to: a) prevent infection, b) eliminate invader pathogens, and c) stimulate the acquired immune response.
Components of the innate immune system
The innate immune system includes physical and anatomical barriers as well as effector cells, antimicrobial peptides, soluble mediators, and cell receptors (Table 1). Skin and mucosa provide an effective immune barrier between the internal and external environment. Skin acts as not only a physical barrier but also a chemical shield. The most external layer of epidermis mainly consists of keratinocytes, which are tightly linked by desmosomes and embedded in a layer of extracellular matrix proteins. Keratinocytes not only act as a physical barrier but also express pattern recognition receptors (PRRs) and are capable of producing cytokines and antimicrobial peptides that, in turn, induce an inflammatory cascade and microbial destruction respectively (6,7). Furthermore, sebaceous glands associated with hair follicles produce large amounts of fatty acids which create an acidic environment that is hostile to microorganisms. Mucous membranes in the digestive, respiratory, and genitourinary tracts have a continuous epithelium that prevents microorganisms from entering the host. In addition, these epithelial cells produce antimicrobial peptides such as defensins. The production of defensins is also enhanced by the action of inflammatory cytokines including interleukin (IL)-1 and tumor necrosis factor alpha (TNF-α) which are produced by macrophages and other immune cells in response to invading pathogens (2,8-11).
Table 1
Components of the innate immune system.
A malfunction in the epidermis can lead to an inadequate host response to a pathogen or a persistent inflammatory state. Atopic dermatitis is the most common inflammatory skin disorder. It is characterized by abnormalities in the skin barrier structures (i.e., stratum corneum and tight junctions), a robust TH2 response to environmental antigens, defects in innate immunity, and an altered microbiome. Many of these abnormalities may occur as a consequence of epidermal dysfunction through pattern recognition receptors.
Epithelial cells in the gastrointestinal and respiratory mucosa have cilia, an extension of the cell surface which has the ability to move back and forth and thus keep the mucosa clear of mucus, dust, and possible invading microorganisms. In addition, intraepithelial lymphocytes are located in the skin and mucosal epithelium. These lymphocytes are predominantly gamma/delta T lymphocytes (LT-γδ), which are involved in host defense through cytokine production, phagocyte activation and, destruction of infected and tumoral cells. There is a subpopulation of B lymphocytes (LB-1) in this compartment that secretes immunoglobulin M (IgM), which are also known as natural antibodies. These natural antibodies protect against microbial pathogens through recognition of highly conserved epitopes and also exert homeostatic functions (2,10,11).
Structure of and immunological threat to the airways
The human respiratory apparatus consists of nose, oropharynx, larynx, conducting airways, and the respiratory surface. Despite containing a volume of approximately 5 L, the total respiratory surface of the lung exceeds 120 m2 (12), which is more than 60 times the body surface. This is due to the presence of millions of small alveoli, spheroid sacs at the terminal end of the conducting airways that provide an extremely thin epithelium. This is optimized for the diffusion of respiratory gases. A recent re-estimation of the total number of alveoli in the human lung represent 480 million units with a remarkably narrow size distribution that is around 4.2*106 /ml. This is equal to an alveolar radius of approximately 100 ml (13). There is continuous intense confrontation between the extensive surface of the respiratory tract and noxious airborne threats and potentially pathogenic microorganisms. As a result, the mucosal tissue in the nasal passages and oropharynx is always colonized by a multitude of bacteria.
An effective system of surveillance and cleaning has evolved in order to constantly monitor and maintain the sterility of the lung. This system is characterized by a unique design for the conducting airways and alveoli. Starting in the nose, a coarse filter consisting of hair and mucus will obstruct the entry of material exceeding a certain size limit. Combined with a rapid sneezing reflex, potentially hazardous or allergenic material will immediately be removed from the airways or trapped in the mucus. Despite being very sticky and viscous, the mucus also contains many antibiotic factors such as antimicrobial peptides or oxidizing enzymes (14). Thus, mucus not only constitutes a physical trap but also has considerable antibiotic properties. Specialized epithelial cells containing a ciliated surface line the airways. The design of an alveolus directly reflects its main function in the respiratory surface. It is covered by two types of alveolar epithelial cells (AECs), type I and type II. Type I AECs provide the thin respiratory surface of an alveolus. Type II AECs are almost round in appearance and contain the so-called lamellar bodies. They are storage sites for surfactant, a thin liquid film that is constantly produced by type II AECs (15). This film covers the entire surface of the alveolus and has important functions for the biology of the lung. AECs II are considered precursors for type I AECs and can replace them at sites of alveolar damage (16). Individual alveoli are separated from each other by thin septae, within which the capillaries of the pulmonary blood vessels flow. Alveoli are connected to each other by multiple holes within the septae, the so-called pores of Kohn. Immune cells recruited to the surface of alveoli can migrate through these pores (17).
Immunological control of alveolar integrity: Surfactant
Surfactant is a compound mixture of phospholipids (90%) and proteins (10%). An important physical effect of the thin surfactant layer is that it compresses cells lying under its surface very flat. In the conducting airways, surfactant surface forces transport particulate matter from the rigid surface (gel phase) of the surfactant layer into the more liquid underlying sol phase, which is in direct contact with the mucocilliary border of the epithelium. The presence of particles in the sol phase facilitates their mucocilliary transportation (18).
Surfactant contains four types of proteins (SP-A to SP-D) of which three have important immunological functions. Among them are the binding of bacterial lipopolysaccharide to or the direct absorption of surfactant proteins into the surface of pathogens. Surface binding of surfactant proteins can lead to pathogen aggregation and direct killing or the increase of the phagocytosis and killing activity of attached immune cells. In addition, surfactant proteins can also interfere with dendritic cell (DC) maturation or inhibit T cell proliferation and thus have an immunoregulatory function. Absence of surfactant proteins leads to the deviation of a protective T-helper 1 (Th2) towards a non-protective Th2 response during pulmonary hypersensitive reactions against Aspergillus antigens (19).
Effector molecules and microbicidal mechanisms of innate immunity
There are several chemical and enzymatic compounds capable of inhibiting and destroying microbial pathogens. These include: lysozyme, which is present in the saliva, tears, and nasal secretions and is able to affect microbial growth; hydrochloric acid and digestive proteins such as pancreatin and peptidase in the gastrointestinal tract, which destroy microbial pathogens; and fatty and bile acids, transferrin, lactoferrin and fibronectin that can control the growth of the host’s normal microbiota as well as the entrance of microbial pathogens through the mucosa (4,20).
Plasma proteins include the secreted PRRs: MBL and CRP. These molecules recognize carbohydrates which are acting as opsonins. In addition, these PRRs may bind and activate complement factors such as C1q thus enhancing the inflammatory response (21,22).
The coagulation system, in addition to its role in controlling bleeding and clotting formation during a tissue injury, is also involved in the innate immune response by preventing microbial dissemination. Fibrinogen, one of the coagulation system components, can sense microorganisms and act as an opsonin (21).
Complement is considered one of the most important enzymatic systems involved in the innate immune response (See chapter 4). This enzymatic system is activated three different ways. Some of the components of this system act as opsonins or anaphylatoxins that enhance the immune response (23).
Activation of the innate immune system is initiated by soluble pattern recognition molecules, which may be expressed on innate immune cells, bound to the extracellular matrix, or circulate in the blood as soluble molecules. One such soluble pattern recognition molecule is MBL, which is primarily synthesized in the liver and secreted to circulation (24,25). Small amounts of MBL are also synthesized in the kidney, thymus, tonsils, small intestine, and vagina, where mRNA has been detected (25-27).
MBL protein has also been found in other organs such as the skin, brain, and lung although its mRNA has not been detected in those areas (24-29). In the lung, MBL is found in the bronchial alveolar lavage of healthy individuals and also on the smooth muscle in airways following infection (28,30). In the skin and the brain, MBL is observed only following burn and trauma injury respectively (28,29,31).
MBL functions as an opsonin and activates the complement through the lectin complement pathway. The lectin pathway is also activated by ficolins, which are structurally similar to MBL and circulate in the blood. The lectin pathway requires activation of MBL-associated serine proteases (MASPs) (24,28,31-34).
There are two genes and five MASP gene products. MASP-1, MASP-3, and MAp44 (or MAP-1) are the alternative splice products of the MASP-1/3 gene while MASP-2 and MAp19 (or sMAP) are the alternative splice products of the MASP-2 gene (35). MASPs form complexes with MBL (35, 36), and MBL binding to carbohydrate ligands is thought to induce conformational changes that enhance proteolytic activities in the associated MASP. MASP-1 and MASP-2 have been shown to activate the alternative pathway and the lectin complement pathway (37–40).
MBL deficiency increases susceptibility to infection by reduced opsono-phagocytic activity and a reduced activation of the lectin complement pathway. The MBL deficiency may manifest as disseminated intravascular coagulation and organ failure with infection.
Successful innate immune protection is achieved through two steps. First, identifying targets, such as pathogens and abnormal tissues and cells. Second, by orchestrating humoral and cell effectors to neutralize and eliminate the identified targets. In this sense, MBL contributes to both immunity from pathogens and maintenance of tissue integrity and homeostasis.
MBL deficiency
MBL deficiency can be caused by inherited gene defects, which have been identified in 5%–30% of the population. MBL deficiency is a common primary immunodeficiency (41-43). There are three coding region single nucleotide polymorphisms (SNPs) at codons 52, 54 and 57, termed the C, B, and D alleles respectively (44). All of these SNPs are located in the collagen-like domain (all are located close to the N-terminus side of the kink and produce aberrant proteins) [44]. The frequency of these alleles varies depending on ethnicities. While all three alleles are observed in Caucasians, alleles C and D are very rare in Asians (45,46).
Most MBL deficiency is due to the heterozygosity of these SNPs and results in a wide range of MBL blood concentrations from undetectable to as high as 10 μg/ml (45, 47). Some aberrant MBLs were found to be dysfunctional in activating the lectin complement pathway. Mechanisms for this lack of complement pathway activation are related to reduced ligand binding due to decreased oligomerization and decreased activation of MASPs due to impaired association with mutant MBL (48,49).
MBL-deficient hosts may present with systemic infection involving multiple organs, including blood (bacteremia), and uncontrolled inflammation due to cytokine storm. Such infection and subsequent cytokine release may establish an autocrine loop with further escalating complications.
Other effector microbicidal mechanisms
Oxygen-dependent mechanisms: Reactive oxygen species (ROS)
Reactive oxygen species (ROS) and reactive oxygen intermediates (ROI) are produced by mammalian cells, particularly phagocytes, as a reaction against several microbial pathogens (50). These molecules are generated by activation of the enzymatic complex nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) and include superoxide anion (O2-), hydrogen peroxide (H2O2), hydroxyl radical (·OH), peroxynitrite (ONOO-),hypochlorous acid (-OCl), etc. (50). Both ROS and ROI are known to play diverse roles in inflammation, host defense, and homeostasis. Chronic granulomatous disease (CGD) is an inherited condition in which a deficiency of NOX2 results in the inability of phagocytes to generate microbicidal superoxide anion and its metabolites. Thus, patients with CGD have recurrent, life-threatening bacterial and fungal infections as well as chronic inflammatory diseases due to dysregulated inflammatory pathways (51).
Oxygen-independent mechanisms
Innate cells, mainly phagocytes, are equipped with an enzymatic arsenal capable of destroying several microorganisms. These enzymes include proteases, cationic proteins, lysozyme, elastases, capthesin G, defensins, etc., all of which exhibit microbicidal activities (52-55). In addition, antimicrobial peptides and other mechanisms involving reactive nitrogen intermediates (RNI) and DNA extracellular traps have been described and will be discussed below.
Antimicrobial peptides (AMPs)
AMPs are host defense peptides secreted mainly by innate and epithelial cells including keratinocytes. Their antimicrobial activity is broadly based especially against fungi, bacteria, and viruses (20). About 1700 AMPs have been described so far. They are found constitutively or can be induced after activation of the host cells through several PRRs during an infection or injury (6). Additionally, these AMPs are involved in other cell processes including cell migration, proliferation, differentiation, cytokine production, angiogenesis, and wound healing, along with other functions (6). Several families of AMPs have been described.
Cathelicidin or LL-37 is released by neutrophils and epithelial cells. This AMP has the ability to kill Gram-negative and Gram-positive bacteria, fungi, and viruses. It induces an immune response which triggers inflammatory cell recruitment and cytokine release by host cells (6). Of note, LL-37 is induced by vitamin D3, and the absence of this vitamin is associated with the development of certain infectious diseases (20,56-59).
Defensins include α- and β-defensins. α-defensins (hαD-1, -2, -3, -4) are stored in the azurophil granules of neutrophils, and HαD-5 and -6 are synthesized by the Paneth cells in the gastrointestinal tract (60). β-defensins (hβD-1, -2, -3) are produced mainly by keratinocytes. Defensins also exhibit antimicrobial activity, and like cethelicidins, they are chemotactic and induce cytokine and chemokine synthesis (6,61,62).
Other AMPs include dermicidin and psoriasin, which also show antimicrobial activities. Alterations in the AMP expression are related to atopic dermatitis and psoriasis (6).
Nitric oxide (NO)
Nitric oxide (NO) is considered to be one of the most important RNI and is produced by an oxidative mechanism involving the catabolism of L-arginine (63). NO production by the enzymatic action of inducible nitric oxide synthase (iNOS) represents one of the major microbicidal mechanisms that phagocytic cells use against several pathogens (64). In turn, iNOS can be induced by several stimuli, including IFN-γ, TNF-α, and LPS, and is expressed by immune cells such as macrophages, neutrophils, dendritic cells, and NK cells (63). Like ROS, NO may be involved in inflammation and its regulation process.
Extracellular traps
Extracellular DNA traps are part of innate immunity and are associated with infectious processes and allergic and autoimmune diseases. These structures are generated by different leukocytes including neutrophils, eosinophils, monocytes, and mast cells. They are called NETs, EETs, METs, and MCETs respectively. Extracellular traps are composed of DNA, histones, and the content of the intracellular granules such as elastase, myeloperoxidase (MPO), cathelicidins, tryptase, cationic proteins, and major basic protein, etc. These traps are induced by the action of the granulocyte/macrophage-colony stimulating factor (GM-CSF), interferons, IL-8, C5a, and LPS. Once formed, extracellular traps are capable of binding to and killing microbial pathogens. As was mentioned, these DNA traps may be involved in the development of autoimmune and chronic inflammatory diseases (65) (See chapter 13).
Effector cells of innate immunity
Cell components encompass phagocytic cells, epithelial and endothelial cells, natural killer cells, innate lymphoid cells, and platelets (Figure 1). Phagocytic cells consist of granulocytes (i.e., neutrophils, eosinophils, basophils, and mast cells), monocytes/macrophages, and dendritic cells. These cells participate in not only the phagocytosis but also the inflammatory process. “The majority of cell components expresses PRRs on the cell surface, and they are able to secrete cytokines: thus exhibiting microbicidal mechanisms”. These cells with effector mechanisms of innate immunity are modulated by both the innate and acquired immune systems (66,67).
Figure 1
Effector mechanisms of the innate immune response: The innate immune response involves a set of cells that produce cytokines/chemokines that participate in phagocytosis, inflammation, and the synthesis of acute phase proteins.
Granulocytes
Granulocytes are effector cells that predominate during the early or acute phase of the innate immune response. The main function of these cells is to identify, ingest, and destroy microbial pathogens through receptors, oxidative mechanisms, and enzymes including lysozyme, collagenase, and elastase, etc. This group of cells is composed of neutrophils, eosinophils, basophils and mast cells (53,68).
Neutrophils
These cells are most abundant and effective during the inflammation and phagocytosis processes. Neutrophils (PMN) are characterized as being the first cell line that is recruited at the inflammation site after chemotactic stimuli. These stimuli include the complement factors such as the C5a factor, chemokines such as IL-8, and leukotrienes (L) including the L-B4, which exerts a paracrine and autocrine function on other neutrophils. All these substances that allow migration to the injury site are recognized by specific receptors or PRRs. These phagocytes possess Fc or complement receptors (RFc or CR) that recognize the immunoglobulin Fc fractions or complement factors respectively. This allows the phagocytosis of tagged (opsonized) microorganisms by antibodies (mainly IgG) or complement (mainly C3b or iC3b). Moreover, neutrophils have stored an enzymatic arsenal capable of exerting a lytic effect on microbial pathogens or inducing microbicidal systems through oxygen-dependent and -independent mechanisms (53,55,68,69) in their granules. In addition to proinflammatory cytokines, the hematopoietic growth factors, granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) are critical for recruitment and activation of PMNs (70). Three different PMN subsets have been described in mice based on their cytokine and chemokine production as well as on the toll-like receptor (TLR) and surface antigen expression and macrophage activation. Normal PMNs (PMN-N) which are CD49d- and CD11b- express TLR2, TLR4, TLR9, and have no cytokine/chemokine production or effect on macrophage activation. PMN-I subsets which are CD49+ and CD11b− and express TLR2, TLR4, TLR5, TLR8, produce IL-12 and CCL3 and activate type-1 macrophages or classically activated macrophages. PMN-II subsets, which are CD49- and CD11b+, express TLR2, TLR4, TLR7, and TLR9, produce IL-10 and CCL2 and activate macrophages alternatively (71). Two additional populations have been described based on the expression of the surface marker Gr-1 (Gr-1 high and Gr-1 medium) (72). More recently, a subset of mature neutrophils which express the surface markers CD11c brigth, CD62L dim, CD11b bright, and CD16 bright have been identified in humans. Apparently, this circulating population of myeloid cells is capable of suppressing T cell proliferation (73). Once PMNs have completed their tasks, they die by apoptosis, netosis or necrosis (see Chapter 13). The latter process can cause tissue damage through the release of their granule contents, thus prolonging the inflammatory reactions (72).
Eosinophils
These granulocytes are present in the respiratory, gastrointestinal, and urinary tract, and they are less abundant than neutrophils. Their effector function is mediated by degranulation and release of histamine, cationic proteins, major basic protein, sulfatases, and chemotactic factors such as leukotrienes and prostaglandins. The degranulation process is mediated by the IgE or other chemotactic factors, including the IL-5. The main function of these cells is to destroy microbial pathogens, mainly parasites, but they also play an important role in the allergic processes together with mast cells (74).
Basophils and mast cells
These cells are not phagocytic in nature and have several receptors including IgE receptors. The proportion of basophils in circulation is lower than the proportion of other granulocytes. Mast cells are located in tissues, mainly in mucosa, and their granules contain heparin, serotonin, and histamine. They may also release a variety of cytokines that enhance the inflammatory process, especially during the early events. These cells are involved in allergic and viral processes. Mast cells are present mainly in the connective tissue. They expressTLR-1, -2, -4, and -6, complement receptors (CR), mannose receptor (MR) in their cell membrane and release TNF-α, IL-8, platelet activator factor, proteases, antimicrobial peptides (catelicidin LL-37 and defensins), and other inflammatory mediators (75-79).
Monocytes/macrophages
Monocyte/macrophages together with DC are considered important actors in both innate and adaptive immunity. Monocytes circulate in peripheral blood and have the ability to not only migrate to the inflammatory site but also exhibit the plasticity to transform themselves into tissue macrophages (80). Once in the tissue, these cells are named macrophages and have different functions: i) they are phagocytic and exhibit a microbicidal mechanism through oxygen -dependent and-independent mechanism; ii) they are able to present antigens and activate lymphocytes; iii) once activated, they release and stimulate cytokine secretion; iv) they modulate the immune response; v) they participate in tissue reorganization after the inflammation process has ceased through production of extracellular matrix proteins (i.e., collagen and elastase) and matrix metalloproteinases; and vi) they produce cytotoxic factors involved in the immunity against tumors (80). Based on the biological function, there are three populations of macrophages: i) classically activated macrophages or type 1-activated macrophages; ii) alternatively activated macrophages; and iii) type 2-activated macrophages (81). Type 1-activated macrophages are usually stimulated by IFN-γ or TNF-α in combination with microbial products such as LPS and are considered effector cells in the Th2 immune response. Once activated, type 1 macrophages up-regulate expression and production of pro-inflammatory cytokines and chemokines [TNF-α, IL-23/IL-12, IL-6, IL-1, IP-10, macrophage inflammatory protein 1 alpha (MIP-1α), and monocyte chemoattractant protein 1 (MCP-1)], major histocompatibility complex (MHC) class II, and co-stimulatory molecules and enhance their ability to kill microbial pathogens through NO and ROS production (81,82). The alternatively activated macrophages are stimulated mainly by IL-4 and glucocorticoids, and once activated, they synthetize IL-10, IL-8, MIP1β, MCP-1, and RANTES. They also produce high levels of fibronectin and other extracellular matrix, as well as arginase. These are involved in polyamine and proline synthesis which, in turn, induces cell growth and collagen formation and thus participates in tissue repair. These alternative macrophages do not produce NO and subsequently fail to kill intracellular microorganisms (81,82). The type 2-activated macrophages are stimulated after recognition of IgG complex and TLR ligands. Once FcγRs recognize their ligands IgG complex), macrophages become activated and produce IL-10, TNF-α, and IL-6. These cells do not produce arginase but induce T cells to produce IL-4 (81,82).
Dendritic cells (DCs)
DCs are considered to be professional antigen-presenting cells (APC). They reside in and patrol the skin and mucosal surfaces, thus playing an important role in the innate immune system with subsequent activation of T cell responses to provide a cell-mediated immunity against microbial pathogens. Antigen uptake occurs through different mechanisms including phagocytosis, endocytosis, picnocystosis, and macropicnocytosis. DCs have the ability to transport and carry the antigens from peripheral to primary lymphatic nodes where the antigen presentation takes place. These APC lead to the processing and presentation of antigens via major histocompatibility complex (MHC) class II molecules, thus bridging the innate and acquired immune response (83). Additionally, DCs participate in the induction of peripheral immunological tolerance, regulate the types of T cell immune responses, and function as effector cells in innate immunity against several microbial pathogens. These diverse functions depend on the diversity of DC subsets (83). In fact, there are various subsets of DCs including immature DCs (imDCs) and precursors (pre-DCs).
imDCs display different phenotypes and functions and are produced from hematopoietic stem cells (HSC) within the bone marrow. Thus, CD34+ HSC differentiate into common lymphoid progenitors (CLP) and common myeloid progenitors (CMP). CD34+ CMP differentiate into CD34+CLA+ and CD34+CLA−, which, in turn, differentiate into CD11c+CD1a+ and CD11c+CD1a-imDCs respectively (84). CD11c+CD1a+imDCs migrate to the skin epidermis and become Langerhans cells while CD11c+CD1a-imDCs migrate to the skin dermis and other tissues and become interstitial imDCs (85).
There are two types of pre-DCs: monocytes (pre-DC1) and plasmacytoid cells (pre-DC2). Pre-DC1 expresses the myeloid antigens (CD11b, CD11c, CD13, CD14, and CD33), CD1a-d, and mannose receptor. it also produces IL-12 and induces a Th2 pattern and cytotoxic T lymphocyte responses. Pre-DC2 expresses specific markers for lymphocyte lineage. It also produces IL-10 and induces a Th2 profile and CD8+T suppressor cells (83). Functionally, imDCs are involved in the antigen presentation while pre-DCs participate directly as effector cells in innate immunity to microbial pathogens.
Innate lymphoid cells (ILC)
ILCs have been identified as new members of the lymphoid linage that are involved in regulating tissue homeostasis and inflammation. These cells do not express a T cell receptor and, consequently, do not respond antigen-specifically. Moreover, these cells do not express cell-surface markers associated with other immune cell lineages (86). These cells are divided in three subsets: i) Group I, ILCs, which is made up of ILC1 and NK cells. Both of these produce proinflammatory and type 1 cytokines and induce cytotoxicity through the expression of perforin and granzymes. ii) Group II, which consists of ILCs2, is characterized by the production of type-2 cytokines and is present in the mesenteric fat-associated lymph clusters, mesenteric lymph nodes, spleen, liver, intestines, and Peyers’ patches. Group II plays a role in the antihelminthic response and allergic lung inflammation. iii) Group III, is composed of ILCs3 and lymphoid tissue-inducer (LTi) cells. ILCs3 express the NK cell activating receptor NKp46 but lack cytotoxic effects and do not produce type-1 cytokines. These ILC3 cells reside in mucosal tissue and appear to play a crucial role in mediating the delicate balance between symbiotic microbiota and the intestinal immune system. LTI cells produce IL-17 and IL-22 and express molecules required for the development of lymphoid tissue. Subsequently they appear to be involved in the generation of lymph nodes and Peyers’ patches (86). Note that disruption of the intestinal homeostasis maintained by these ILC cells is associated with the development of inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis (86).
Natural killer (NK) cells
NK cells exhibit an immunomodulatory role in the cell-mediated immune responses due their cytotoxic activity. They are also involved in antimicrobial defense and in the immunological surveillance by controlling tumoral growth and maintaining the immunological homeostasis (Figure 2). These cells employ a strategy known as “negative recognition.” While a T or B cell is activated after recognition of an antigen via MHC, NK cells are activated when the antigen cannot be recognized the same way (87,88). NK cell receptors are “inhibitory receptors” in nature due to the fact that they keep the lytic activity of these cells suppressed since they detect the presence of MHC antigens. These cells detect infected cells (mainly infected by viruses) or malignant cells in which expression of MHC molecules has decreased, is altered or abolished. NK cells have the ability to distinguish the normal host cells through the killer cell immunoglobulin-like receptor (KIR) and CD94-NKG2A inhibitory receptors which recognize the MHC class I expressed on the surface of these normal cells (88,87). The binding of these receptors inhibits lysis and cytokine secretion by NK cells (89). In addition, NK cells have granules with perforins and granzymes that act on target cells inducing lysis or apoptosis and also express PRRs including TLR-2, -3, -4, -5, -7, and -8 (90,91). Once activated, NK cells secrete IFN-γ, TNF-α growth factors, IL-5, IL-10, IL-13, and chemokines (92-94).
Figure 2
Recognition mechanisms and cellular innate immune response: functional characteristics of NK cells. NK cells trigger their activation once virus-infected or tumor cells suppress the expression of MHC molecules through the interaction of inhibitor or activator (more...)
Epithelial and endothelial cells
In addition to acting as a physical barrier, epithelial and endothelial cells express PRRs on their surface that recognize pathogen-associated molecular patterns (PAMPs) from microorganisms; secrete proinflammatory cytokines including IL-1, IL-6, and IL-8; and release antimicrobial peptides (8). Epithelial cells, mainly alveolar epithelial cells, are the most studied innate immunity component so far. In addition to providing an anatomic barrier that separates the organism from the external environment, alveolar epithelium serves as a defense mechanism against potential inhaled pathogens (58). This alveolar epithelium consists of two cell types: alveolar type I and alveolar type II cells. The former is ~95% of the alveolar epithelium and expresses TLR-4, a receptor for lipopolysaccharides (LPS). It produces pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1β in response to LPS stimulation (57). Type II alveolar cells are~5% of the alveolar epithelium and produce cytokines and chemokines including TNF-α, IL-6, IL-1β, MCP-1, growth related oncogene alpha (GRO-α), and GM-CSF, etc.,in response to various stimuli such as bacteria and viruses. Moreover, these cells also produce surfactant proteins which enhance chemotaxis and phagocystosis (58). Both type I and type II alveolar epithelial cells are important players in the innate immune response.
Platelets
Platelets are recognized by their participation in the coagulation process, control of bleeding, and defense against infectious agents (95,96). These cells express PRRs on their surface and produce cytokines and chemotactic molecules to recruit leukocytes at the inflammatory site. Platelets interact with leukocytes and endothelial cells through the expression of the adhesion molecule, P-selectin, which mediates proinflammatory events (95).
Characteristics of the innate immune system and its recognition mechanisms
Innate immune response is characterized by its ability to distinguish structural components from microbial pathogens, which are present only in these microorganisms and are absent in the normal host cells. This recognition process is mediated by a variety of proteins present in the host cells such as the PRRs, which have already been mentioned (3,96). PRRs are germ-line encoded and do not show variability in comparison to the receptors involved in adaptive immunity. This characteristic indicates that innate immunity may identify clusters of microorganisms while adaptive immunity may distinguish between different antigens from one microorganism, which indicates that innate immunity is not specific. Another characteristic is that the innate immune response does not generate immunological memory after the recognition of the pathogen while adaptive immunity does (3). PRRs are evolutionarily conserved receptors that detect relatively invariant molecular patterns found in most microbial agents, the PAMPs. PRRs not only recognize PAMPs from invading pathogens but also have the ability to sense inflammatory components, also called damage-associated molecular patterns (DAMPs), released from damaged cells. PRRs include TLRs, NOD-like receptors (NLRs), C-type lectin receptors (CLRs), and RIG-I-like receptors (RLRs) (97). Nonetheless, in spite of the microbial recognition by innate cells, several microorganisms have developed evasion mechanisms to avoid recognition by these receptors.
Pattern recognition receptors
PRRs have been divided into 4 subclasses: TLRs, NOD-like receptors (NLRs), retinoic acid–inducible gene (RIG)–like receptors (RLRs), and C-type lectin receptors (CLRs) (98). Although peptidoglycan recognition proteins (PGLYRPs) are not included in this classification, they are also recognized as PRRs and are thought to be important for bacterial infections.
PRRs and the epidermal chemical barrier
In addition to establishing a formidable physical barrier, keratinocytes are the major producers of antimicrobial peptides (AMPs). AMPs serve as a chemical defense against cutaneous pathogens and are increasingly recognized for their effects on wound repair. The classical human AMPs are LL-37 (a cathelicidin) and the β-defensin family. A number of other proteins produced by keratinocytes–including ribonucleases (RNases), S100 family proteins (e.g., S100A7, S100A8, and S100A9), dermcidin, and regenerating islet-derived protein 3a (REG3a)– are also recognized for their antimicrobial properties (99,100). Human keratinocytes constitutively express human β-defensin (HBD) 1, whereas HBD2, HBD3, and LL-37 are produced in response to inflammatory cytokines or PRR signaling (18,101,102). RNase7 has extensive antimicrobial properties and is constitutively expressed by human keratinocytes, but this is further enhanced by inflammation or bacterial exposure (103). Psoriasin (S100A7) is produced by differentiated keratinocytes and is most highly expressed around hair follicles and sebaceous units. Its expression is enhanced by IL-1, TNF-α, IL-17A, and IL-22 and repressed by IL-4 and histamine (104,105). Keratinocytes also express S100A8 and S100A9, which can exist as monomers or heterodimers (calpro- tectin) (106). Dermcidin is constitutively produced by eccrine sweat glands with extensive antimicrobial activity (107). Its proinflammatory actions induce the epidermal production of cytokines and chemokines (62). REG3a is produced in response to wounding or IL-17A exposure and, not surprisingly, is highly expressed in psoriatic skin lesions (100). Lastly, filaggrin is proteolytically cleaved into the hygroscopic amino acids, urocanic acid, and pyrrolidone carboxylic acid, which are referred to as natural moisturizing factors. This is an example of an alteration in the physical barrier that directly affects the chemical barrier.
In addition to their antimicrobial activities, AMPs have been found to play a role in physical barrier repair. The novel AMP REG3a enhances wound repair, at least in part, by inducing keratinocyte proliferation and differentiation (100). Not surprisingly, a number of PRRs are induced in response to wounding. For example, the expression of CD14 and TLR2 rise along the edge of the wound after an injury to the skin (108). This expression is dependent on the CYP27B1 enzyme, which converts 25-hydroxyvitamin D to the active 1.25 dihydroxy vitamin D form. This highlights a role for vitamin D in innate immune responses observed at sites of wounding and suggests that therapeutic approaches that increase vitamin D levels might enhance the host’s innate immune response and help repair wounds.
PRRs are located on the surface and/or in the cytoplasm of virtually all nucleated cells. Nonetheless, there is a small group of PRR molecules that can be secreted and act as a bridge between the microbial or cell target and host cells. PRRs include the TLRs, CLRs, NLRs, and RLRs (Table 2).
Table 2
Pattern recognition receptors, their ligands and functions.
Toll-like receptors
To date, 10 TLRs have been identified in humans (TLR1-10) and 12 in mice (TLR1-9 and TLR11-13) (109,110) (see Chapter 3). TLRs 1, 2, 4, 5, and 6 are expressed on the cell surface, while TLRs 3, 7, 8, 9, and 10 are found at the cytoplasm level. The main interactions of TLRs and their ligands are the following: TLR1/TLR2 recognize triacylated lipopetides, TLR3 binds double-strand (dsRNA), TLR4 recognizes LPS, TLR5 binds flagellin, TLR2/TLR6 bind diacylated lipopetides and lipoteichoic acid (LTA), TLR4/TLR6 recognize oxidized lipids (OxLDL) and β-amyloid, TLR7 and TLR8 sense single-strand (ssRNA), and TLR9 recognizes unmethylated CpG DNA and hemozoin (110) (Table 2).
TLRs are composed of 1) a leucin-rich repeat (LRR) domain that is usually involved in ligand binding and microbial sensing and 2) a cytoplasmic domain known as the Toll/interleukin-1 receptor (TIR). Thus, after a TLR binds to its ligand, an activation process is initiated through a signaling pathway via TIR domain-containing adaptor proteins. Several adaptor proteins that participate in TLR-mediated mechanisms have been described. These molecules include the myeloid differentiation primary-response protein 88 (MyD88), Toll/interleukin-1 receptor (TIR) domain-containing adaptor protein (TIRAP), MyD88-adaptor-like protein (Mal), TIR domain-containing adaptor-including interferon-β (TRIF), and TRIF-related adaptor molecule (TRAM). These adaptors mediate the activation of transcription factors such as the nuclear factor- κB (NF- κB) and the interferon regulatory factor (IRF), which, in turn, induce the expression of inflammatory and anti-inflammatory cytokine and chemokine genes (111,112). Note that TLR polymorphisms have been said to be associated with an increased risk of developing viral and fungal infections (113,114).
C-type lectin receptors (CLRs)
CLRs are considered the other major PRR family. These PRRs recognize not only sugar moieties from bacteria and fungi but also molecules associated with dead or dying cells (97). This family consists of two groups, those present on the cell membrane and the soluble forms, which are secreted mainly by immune cells. Membrane CLRs include Dectin-1, which recognizes β-glucans present in the fungal cells; Dectin-2, which recognizes both high-mannose structures and α-mannan; mannose receptors (MR) that recognize N-linked mannan; DC-SIGN (a receptor on the dendritic cells), which also recognizes mannan; and galectin-3, which recognizes β-mannosides (115). It is noteworthy that several of these membrane CLRs, including Dectin-1, DC-SIGN and galectin-3, have been identified as TLR2 co-receptors (115).
The soluble CLRs are divided into two groups as follows:
Collectins. These PRRs are proteins that are structurally similar to collagen. They bind carbohydrates present on the microbial cell wall. These soluble molecules act as opsonins, and in addition, they induce lysis of target cells and act as chemoattracting molecules for leukocytes through complement activation. Collectins include MBL, which recognizes mannan, surfactant proteins (SP) that sense oligosaccharides, and ficollins 1, 2 and 3 that bind microbial carbohydrates (3).
Pentraxins. These proteins are highly conserved through evolution and are characterized as having a domain with five subunits of 200 aminoacids searching the C-terminal region. This group of CLRs includes C-reactive protein (CRP), serum amyloid P component, and pentraxin 3 (PTX3). These soluble molecules are secreted by macrophages and DC after activation via TLRs and proinflammatory cytokines (116).
NOD-like receptors (NLRs)
The nucleotide-binding oligomerization domain (NOD) receptors (NLRs) are intracellular PRRs that sense bacterial components including peptidoglycans, which are directly introduced into the cytoplasm (3,4,96). NLRs include several family members such as NODs (NOD 1–4), NLRPs (NLRP 1–14), and IPAF. These molecules are regulators of immunity in response to a variety of pathogens (117). NLRs in concur with the AIM2 protein, the adaptor protein ASC, and caspase-1 constitute the inflammasome (97). NOD expression is regulated by IFN-γ and TNF-α, and polymorphisms in NOD2 gene influence the risk of acquiring Crohn’s disease (79).
RIG-like receptors (RLRs)
Retinoic acid inducible gen-I (RIG)-like receptor (RLRs) is an intracellular protein able to sense viral dsRNA during viral replication. RIG-I consists of two N-terminal caspase recruitment domains (CARD) and a RNA helicase domain. After interaction with its ligand, this receptor induces the production of antiviral cytokines such as IFNs and thus modulates the anti-viral immune response (3,4,117,96).
Pathogen–associated molecular patterns (PAMPs)
PAMPs are polysaccharides and polynucleotides in nature and they are shared by several groups of pathogens. These molecules are conserved at the molecular level within a class of pathogens. PAMPs include a variety of molecules recognized mainly by PRRs. The most characteristic PAMP molecules are: LPS, an endotoxin found in the Gram negative bacterial membranes, lipoteichoic acid from Gram positive bacteria, bacterial flagellin, peptidoglycan, ssRNA and dsRNA from viruses, unmethylated DNA (CpG motifs), mannose present on yeast surfaces, and β-glucans present on the fungal cell wall, etc. (3) (Table 2).
Damage-associated molecular patterns (DAMPs)
Besides recognition of microbial PAMPs, the immune system has the ability to sense other signals associated with infection or tissue damage, including host components released from infected, damaged, or necrotic cells, which, in turn, are able to activate and amplify the immune response. These components are called damage-associated molecular patterns (DAMPS) or alarmins. These inflammatory components liberated from damaged cells include nucleic acids, intracellular proteins, extracellular matrix components, oxidized lipids, crystals such as uric acids, silica, β-amyloid, and cholesterol (97,117). One of the differences between PMAPs and DAMPs is that the former stimulate the synthesis of pro-IL-1β, but not its secretion while the latter stimulates the assembly of inflammasome with subsequent activation of caspase-1. This, in turn, cleaves pro-IL-1β into IL-1β thus allowing its secretion (117). Sensing these endogenous ligands by the corresponding PRRs induce persistent inflammation, a phenomenon associated with the development of chronic inflammatory and autoimmune diseases (97).
Inflammation and inflammasome
Inflammation
Inflammation is a nonspecific mechanism generated by the host in response to an infectious, physical, or chemical injury with recruitment of peripheral blood leukocytes and plasma proteins to the site of injury or tissue damage. In this process, there is an increase in both blood flow and vascular permeability, mainly in the vascular endothelial at the local level. Vascular permeability is a consequence of the endothelial cell retraction to allow the transmigration of leukocytes and the ingress of plasmatic proteins such as complement, coagulation factors, and antibodies, etc. (118).
After an injury, there is tissue damage with the release of components by epithelial or endothelial cells as well as by cells present in that tissue such as mast cells or ILCs. These substances include histamine, leukotrienes, extracellular matrix components, and pro-inflammatory cytokines and chemokines, all of which have the ability to induce chemotaxis and cell adhesion molecule (CAM) expression in both endothelium and leucocytes. These CAMs include selectins, integrins, immunoglobuline-like superfamily molecules and cadherins. Expression of these CAMs allows interaction between leukocytes and endothelium and the subsequent leukocyte transmigration at the site of the injury. In the latter process, cells are guided by chemoattractant stimuli (Figure 3). The cell migration process is complex and depends on cell type as well as on the differentiation and activation state of the cells (118). As was mentioned, the first cells recruited at the site of the injury are neutrophils. They are also the most abundant during the first hours or days of the inflammation process followed by mononuclear cells. If the inflammatory reaction cannot be resolved, this process may become chronic with other implications for the host.
Figure 3
Recruiting phagocytes into the inflammation site and phagocytosis. Phagocyte recruitment involves several phases including: i) marginalization, which decrease leukocyte traffic with a subsequent endothelium approach; ii)adhesion, a process that depends (more...)
During the inflammation process, there is another important event known as phagocytosis. Phagocytosis is considered one of the most important processes during the innate immune response. Once phagocytes arrive at the infectious site, they ingest microbial pathogens in vacuoles called phagosomes. Here, after activation, these microorganisms are destroyed and then presented to lymphocytes via MHC. The microbicidal mechanisms included are, therefore, oxygen-dependent and -independent as described previously (5,119).
The phagocytic process is mediated by the cytoskeleton of the phagocytic cells as well as by endocytic and signaling receptors (96). These receptors, mainly PRRs present on cell surfaces, bind microbial PAMPs, and this interaction usually generates an intracellular signal which, in turn, allows the synthesis and release of proinflammatory cytokines and other effector molecules (3).
Proinflammatory cytokines play an important role during the inflammation process, and they participate in the interactions of the cells involved in not only the innate immune response but also the establishment of acquired immunity. Proinflammatory cytokines participate during the activation and effector phases of the innate immune response. These cytokines include TNF-α, IL-1, and type I IFNs. Nonetheless, other cytokines are also important during the establishment of the innate immune response (Table 3). Functions and characteristics of these cytokines are extensively described in Chapter 9.
Table 3
Cytokines of innate immunity.
Inflammasome
Inflammasome is a complex of proteins consisting of caspase-1, ASC (a CARD-containing adaptor), and NLRs. Once these are activated, they cleave the pro-IL-1β and pro-IL-18 with subsequent maturation and secretion of these cytokines. Inflammasome activation is required for many inflammatory processes. In addition to the initial recognition of PAMPs or DAMPS by TLRs or CLRs, recognition by intracytoplasmic NLRs is necessary. Inflammasome may be also activated by ROS, lysosomal damage, and cytosolic K+ efflux at the intracellular level (110,117). Several members of the NLR family are involved in the assembly of inflammasome. These molecules include NLRP3, NLRP1, NLRP6, and IPAF (NLRC4). Moreover, the AIM2 protein, a non-NLR that is identified as a PYHIN (pyrin and HIN domain-containing protein) family member, is also involved in the inflammasome activation (117).
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