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Clinical Infection & Immunity

Review

Volume 1, Number 2, December 2016, pages 31-40

Immune Recognition in Lung Diseases: Basic Research and Clinical Application

The respiratory system constitutes a large surface of the human body in contact with the outside environment. While the pharyngeal mucosa is colonized by microbes that do not necessarily cause strong inflammatory reactions, the lower respiratory tract is considered to be sterile [1]. Invasion, however, of pathogenic microbes into the lower respiratory tract represents a serious threat that requires immune responses. Since 2004, the WHO estimated at 429 million the number of cases of acute lower respiratory tract infection, the third leading death cause worldwide [2]. In 2008, childhood pneumonia was reported as the first leading cause of death in children under 5 years, with 1.8 million deaths per year, mostly in developing countries [3]. But chronic respiratory tract infection is a global health problem. Tuberculosis, a scourge since prehistoric times, affects more than 9 million people and kills 1.5 million people each year [4]. In addition, non-infectious and chronic diseases contribute substantially to morbidity and mortality in the world population. Chronic obstructive pulmonary disease (COPD), for example, is the fourth leading cause of death in the world today, will rise to third place in 2020, and affects the lives of approximately 200 million people [5-7]. Bronchial asthma is the most common chronic inflammatory disease in children and adults and affects the lives of about 300 million people worldwide [8].

Inflammation is a term credited to Celsus. It was used as a metaphor because the dermal response to injury was reminiscent of a fire, characterized by redness (rubor), heat (calor), swelling (tumor), and pain (dolor), and some of these Latin terms are used today in medical schools. Virchow described a fifth change, loss of function (functio laesa). A sixth change, repair, could also be added, because a new growth occurs after tissue injury, just like after the fire occurs in the forests, prairies and even cities in an attempt to preserve the function and life [9]. When injury and inflammatory responses are abrogated, resorption of extracellular matrix proteins occurs, promoting organ repair. When chronic injury persists, the unremitting activation of effector cells results in the continuous deposition of extracellular matrix, progressive scarring and organ damage [10].

While it is true metaphor of Celsus remains suitable for academic purposes, semantics has over-simplified biological phenomena. The “inflammatory process” is incredibly complex, diverse and involves the participation of many cell and molecular products, interacting in complex combinations, activation of immune responses and pattern recognition receptors (PRRs). Briefly, the innate immune system is comprised of various anatomical barriers to infection, including physical barriers (bronchial epithelium and cilia), chemical barriers (alkalinity of bronchial mucus), and biological barriers (oropharyngeal flora) [11]. Added to these barriers are soluble factors and phagocytic cells that form the first line of defense against pathogens. Soluble factors include the complement system, the reactants acute phase proteins and chemical messenger proteins called cytokines [12]. The complement system (a biochemical network of more than 30 proteins in plasma or cell surfaces) is a key component of innate immunity. The system develops responses that kill invading pathogens by direct lysis (cell disruption) or promoting phagocytosis. These proteins also produce inflammatory responses, which are an important part of innate immunity. The acute phase reactant proteins are a class of plasma proteins that are important in inflammation. Cytokines secreted by immune cells in the early stages of inflammation stimulate the synthesis of acute phase reactant proteins by the liver [13]. The cytokines have an important role in regulating the immune response; some cytokines directly interfere with pathogens. Interferons (IFNs) have antiviral activity [14]. Soluble factors are important to recruit phagocytic cells to local areas of infection, such as monocytes, macrophages and neutrophils that engulf and digest invading microorganisms through a process called phagocytosis. In addition, neutrophils also form extracellular traps, which are chromatin networks containing antibacterial proteins that can trap and kill extracellular bacteria. These cells express the PRRs identifying the pathogen-associated molecular patterns (PAMPs) (diverse biochemical signatures) that are unique to pathogenic microorganisms but preserved through several families of pathogens. Immediate immune response is non-specific and does not have “immunological memory”, which means that the same response (same time and same intensity) must be orchestrated each time the system re-encounters the antigen.

Adaptive immunity (also called acquired immunity), a second line of defense against pathogens, takes several days, even weeks to develop to the fullest. However, adaptive immunity is much more complex because it involves an antigen specificity and “immunological memory”. Exposure to a specific antigen stimulates production of immune cells that target the pathogen for destruction [12]. Immunological “memory” means that the immune response to a second exposure of the same pathogen is faster and stronger because the antigens are “remembered”. The primary mediators of this response are B and T lymphocytes. B lymphocytes produce antibodies which are specialized proteins that recognize and bind to foreign proteins or pathogens in order to neutralize or facilitate destruction by macrophages. The response mediated by antibodies is called humoral immunity. In contrast, cellular immunity is mediated by T lymphocytes, which develop in the thymus. Different subsets of T cells have different roles in immunity adaptive. For example, cytotoxic T (natural killer) cells directly attack and kill infected cells, while helper T cells increase the response and help the function of other cells [11]. Regulatory T cells (also called suppressor T) suppress the immune response [12]. In addition to its vital role in innate immunity, the complement system modulates the adaptive immune response and is an example of interaction between the two immune systems [13]. Obviously, both response systems work together to protect the body from infection and disease.

The PRRs are expressed in alveolar macrophages, epithelial lung cells, dendritic cells (DCs), endothelial cells and stromal cells as well as immune cells. PRRs not only recognize PAMPs, danger-associated molecular patterns (DAMPs), and tumor-associated molecular patterns (TAMPs), but also large particles such as asbestos fibers, aluminum and silica crystals being critically involved in the pathogenesis of pneumoconiosis [15-18]. Therefore, the PRRs sense these molecules and produce inflammatory cytokines, IFNs and chemokines, which activate more cells around them (paracrine activity), macrophages and neutrophils (innate immune response) that in turn, amplify the production and activity of more cytokines. The PRRs activate in antigen presenting cells, such as macrophages and DCs, and with the participation of the major histocompatibility complex II (HLA-II), provide a mandatory signal to induce and activate T lymphocytes (Th1, Th2, and Th17) and production antibody (adaptive immune response) [19-22]. Therefore, both immune responses depend directly or indirectly on the PRRs recognizing the molecules, and explain why these receptors play a key role in acute respiratory infections such as pneumonia, infectious exacerbation of COPD, inflammatory response to a sterile tissue damage, such as acute lung injury or disease from exposure to inorganic dusts.

The aim of this paper was therefore to define the immunological characteristics of these receptors, its expression and immunopathology activity in various lung diseases and which therapeutic tools are being implemented that, impacting them as target molecules, can alter the natural history of these diseases.

TLRs are a family of protein receptors that play a key role in recognizing molecules in the immune system. They are non-catalytic receptors distributed mainly in the membrane of sentinel cells (macrophages and DCs), structural airway cells, parenchymal, inflammatory and immune cells. These type I transmembrane proteins are characterized by a leucine-rich extracellular domain and a stalk in the cytoplasm [23]. TLRs along with the receptors of interleukin-1 (IL-1) form a superfamily of receptors known as “IL-1 receptor/Toll-like superfamily receptor”, which has a domain common called TIR (Toll/IL-1 receptor) [24]. TLRs are located predominantly on the cell surface or in the membrane of lysosomal/endosomal. To date, 10 TLRs in humans have been identified along with several TLR ligands and adapter molecules. These receptors were the first PRRs to be identified and are the best characterized [25].

They received their name from the similarity to the protein encoded by the toll gene identified in fruit fly Drosophila melanogaster in 1985 by Christiane Nusslein-Volhard. The researchers were so surprised and spontaneously said in German “Das ist ja toll!” which translates as “That’s great!” [26]. Jules Hoffmann, Bruce Beutler and Ralph Steinman (discoverer of DCs) won the Nobel Prize in 2011 for the discovery of TLRs in humans [27].

Ligand binding to the TLRs marks key molecular events that lead to an innate immune response and the development of acquired immunity specific for antigens. This is really its function [28]. Exogenous ligands (PAMPs) include a wide range such as lipoproteins and peptidoglycans, lipopolysaccharides (LPS), lipoteichoic acid, bacterial flagellin, viral CpGDNA, ssRNA and dsRNA viral, Toxoplasma gondii propfiling, and Mycobacterium TDM (trehalose dimycolate) [29, 30]. Many of these PAMPs have sugar, so they are known as sugar complexed PAMPs (SCPs). Endogenous ligands (DAMPs) are host molecules produced by tissue damage and non-physiological death, such as fibrinogen, heat shock proteins (HSPs), high-mobility group box 1 (HMGB1), extracellular matrix components of cell death, own DNA, uric acid and calgranulins [31].

TLRs act as dimers (homodimers or heterodimers), and sometimes require co-receptors to maximize sensitivity to ligand. Signaling is mediated by protein kinases and adapter. TLRSs recruit these adapter molecules into the cytoplasm of cells to propagate the signal. Four proteins are involved as adapter molecules, which contain the domain TIR: myeloid differentiation primary response gene 88 (MyD88), MyD88-adapter-like (Mal), TIR domain-containing adapter inducing IFN-β (TRIF), and TRIF-related adapter molecule (TRAM) [32, 33]. Thus, TLRs signaling is divided into two routes: the MyD88-dependent and TRIF-dependent. The MyD88-dependent leads, by a series of complex biochemical processes, degradation Ikβ (inhibitor of NF-kβ) allowing NF-kβ diffuse the cytoplasm to the nucleus and initiate transcription and consequent induction of inflammatory proteins. The TRIF-dependent activates type I IFNs and mature DCs [34]. The TLR signals activate thousands of genes, constituting one of the most pleiotropic genetic pathways for modulation.

The NLR family consists of 22 members in humans, and only some of them have been functionally characterized. Many of them, unlike TLRs, are fundamentally membranous, found in the cytosol. They all consist of a central NOD and leucine-rich repeats (LRRs) C-terminal which are those that mediate ligand binding possibly. They also have an N-terminal effector domain that allows subdividing the family on five subfamilies based on the type of effector domains that is either a caspase recruitment domain (CARD), to pyrin domain (PYD), or baculovirus inhibitor of apoptosis protein repeat (BIR) domain [35].

Among the NLRs best studied are the NOD1 and NOD2 containing CARD molecules. While NOD1 is ubiquitously expressed, NOD2 is expressed primarily in leukocytes and lung epithelial cells [36]. NOD1 detects peptidoglycan of bacterial cell walls, containing meso-diaminopimelic acid, found mainly in gram-negative bacteria. So, NOD1 recognizes bacteria such as Chlamydophila pneumoniae, Legionella pneumophila, Klebsiella pneumoniae, Haemophilus influenza and Pseudomona aeruginosa [37-40]. NOD2 recognizes the muramyl dipeptide (MDP) which is conserved in peptidoglycans of positive and gram-negative bacteria. NOD2 senses S. pneumoniae, S. aureus, Escherichia coli, C. pneumoniae and M. tuberculosis [41-43]. NOD1 and NOD2 both activated downstream signaling through Rip2 kinase, leading to the expression, NF-kB dependent, of pro- inflammatory mediators and the production of reactive oxygen species (ROS) [44].

The proteins NLRP is a subgroup of NLRs which is composed of 14 proteins of which the NLRP1, NLRP3, NLRP6, NLRP7 and NLRP12 form multiprotein complexed called inflammasomes, which consist of one or two NLR proteins, adapter molecule ASC (apoptosis-associated protein speck-like containing a CARD) (PYCARD) ) and procaspase-1 [45]. The inflammasomes serve as platform for autocatalytic activation of caspase-1, which critically regulates production of IL-1β and IL-18 processing pro-IL-1β and pro-IL-18 zymogens and induce a form of cell death called pyroptosis [46].

NLRP1 was the first NLR protein to be described as forming an inflammasome [47]. While the NLRP1 is abundantly expressed in myeloid cells, lymphocytes and respiratory epithelial cells in human, its role in pulmonary disease is not clear in humans [48]. The NLRP3 inflammasome responds to a wide range of microbial and non-microbial agents. Among the pulmonary pathogens are K. pneumoniae, S. pneumoniae, S. aureus, C. pneumoniae, M. tuberculosis, L. pneumophila, influenza virus, RSV, rhinovirus and Aspergillus fumigatus. The interaction is not direct and the signals remain elusive. Gram-negative bacteria can also activate them. They sense dangerous microbial and non-microbial signals [46]. The net effect of NLRP3 during pneumonia will depend on the load of pathogen, virulence, inflammasome expression and susceptibility of the patient to lung damage. The DAMPs that stimulate them are products of dying cells such as ATP, uric acid metabolites, biglycan and hyaluronan. They also respond to inhaled particles (silica, asbestos and aluminum). Its role in lung disease is much clearer. The NLRP4, NLRP6, NLRP7 and NLRP12 offer or less the inflammatory process in lung or there are not enough studies in humans, demonstrating a significant contribution to lung pathology. In any case they can cooperate with other innate sensors to process hazardous signals. Therapeutically manipulate is not in the very distant future.

RLRs are a family of RNA helicases that function as cytoplasmic sensors of PAMPs within viral RNA initiating and modulating antiviral immunity. To date, three RLRs members have been identified: RIG-I, which is the founding member and therefore best characterized of this family, melanoma differentiation associated factor 5 (MAD5) and laboratory of genetics and physiology 2 and a homolog of mouse D11IGp2 (LGP2) [49]. These receptors have three distinct domains. Basically, 14 virus families can be detected by RLRs [50].

Based on recent studies, we know that the RIG-I ligand RNA motifs that serve as PAMPs for recognition (e.g. ssRNA and dsRNA). These receptors also used adapter molecules. An example is IPS1, which consists of a CARD homolog, a proline-rich region, and a transmembrane domain. It is activated by RIG-1 and MAD5 to signal the production of antiviral INFs [51]. The signal is initiated by detection of viral PAMPs by receptors, which induces activation and association with IPS-1. This molecular association builds up to form an IPS signalosome that drives the production of IFNs. Signal transduction ultimately activates transcription of a program leading to the production of IFNs and induction of an antiviral state.

The RLRs also cooperate in crosstalk signaling networks with TLRs and other factors to impart innate immunity and modulate adaptive immune response [49]. Therefore, the essential and basic function is virus detection, signal IFNs production and induced an antiviral response including modulate genes that control viral replication, spread and serve to regulate the adaptive immune response. Dysregulation of expression or aberrant RLRs signals have been associated with autoimmune diseases such as diabetes mellitus, Crohn’s disease (not in ulcerative colitis), and lupus erythematosus, but its pathogenic role in autoimmune respiratory diseases is not clear. Understanding these signaling processes and response of the RLRs could generate knowledge for use as antiviral therapeutic targets and modification of immunity.

CLRs are composed of more than 1,000 proteins that recognize a diverse range of pathogens (parasites, fungi, bacteria and viruses), and are characterized by the presence of at least one C-type lectin-like domain (CTLD) [52]. Of particular interest are the single CTLD-containing extracellular receptors of dectin-1 and dectin-2 clusters which associate with signaling adaptor or possess integral intracellular signaling domains. The number of extracellular carbohydrate recognition domain (CRD) and their cellular localization classifies CRLs to type-I transmembrane, type-II transmembrane, and soluble CRLs [53]. CRLs recognize carbohydrate ligands, lipids and proteins by mechanisms not well understood. SCPs sensed by CLRs activate various signaling cascades through their own immunoreceptor tyrosine-based activation motifs (ITAMs) and that lead to the activation of NF-kβ through pathways tyrosine spleen kinase (Syk) and CARD9 resulting multiple cytokines such as TNF-α and ILs.

CRLs are traditionally associated with the recognition of fungi. For example, the polymorphism in dectin-1 and mutations in signaling molecule CARD9 have been associated with susceptibility to fungal infections in humans [54, 55]. Candida, Aspergillus, Pneumocystis, Coocidioides and C. glabrata have been involved. However, the role of these receptors during infection in humans is unclear. Recent studies have involved them in the new partnerships such as homeostasis, autoimmunity and allergy and recognition of dead and tumor cells but not clearly in specific respiratory diseases.

In addition to viruses, the production of IFN-α/β can be induced by bacteria that replicate in the cytosol of infected cells, or are capable of injecting microbial molecules into host cells (L. pneumophila and M. tuberculosis), or expressing toxins which form pores that destroy the membrane phagolysosome after bacterial phagocytosis (streptococci) [24]. There are multiple sensors for cytosolic bacterial DNA that sense, for example, dsDNA and RNA SCPs, and are responsible for the type I IFN and IFN-β responses and this process is much more complex than originally thought [23]. An important role of these receptors in bacterial infections of the respiratory tract can be envisioned [56, 57].

Another group of cytosolic DNA sensors are the cGAS that bind directly to the foreign DNA in the cytoplasm, triggering a series of events that culminate with the expression of antiviral cytokines [58]. Cyclic GMP-AMP synthase (cGAS) is a nucleotidyltransferase that catalyzes the production of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) from ATP. CGAMP acts as a second messenger by binding to the endoplasmic reticulum transmembrane adapter protein, stimulator of interferon genes (STING), activating the protein kinase TBK-1 and interferon regulatory factor 3 (IRF3). Subsequently, IRF3 is translocated to the nucleus where it orchestrates the expression of immune and inflammatory genes such as IFNs [59]. Human cGAs has a crystalloid structure and together with the 2'-5'-oligo-adenylate synthase (OAS) constitute a family of innate immunity sensors, which by their different structures, respond to different foreign nucleic acids such as dsRNA and dsDNA by OAS1 and cGAS [60].

CGAS has been shown to be required to activate the immune response during infection with various DNA viruses and bacterial pathogens [61]. But also, viruses have developed their evasion systems for these sensors. The protein gammaherpes-virus ORF52 binds to cGAS and directly inhibits enzymatic activation and antagonizes host cGAS-dependent DNA sensing [62].

Different PRRs are involved in the recognition of gram-positive and gram-negative bacteria extracellular and intracellular and viruses that cause pneumonia. TLRs cell surface (for example, TLR2, 4 and 5) is particularly important for immune response to extracellular bacteria and intracellular bacteria. TLRs 7-9 that sense nucleic acids and are key to viral infection appear to contribute to host defense against bacterial infections [24]. The inflammasomes as NLRP3 regulate key cytokines of the immune system (IL-1β and IL-18) and response to necrotic cells. Children with autosomal recessive deficiencies in MyD88 suffer from life-threatening infections caused by S. pneumoniae [63, 64]. Heterozygous patients S180L nucleotide polymorphism Mal adapter TLR2/4, which alters its function, are protected against invasive pneumococcal disease [65]. TLRs dysfunctional mutations in humans have been associated with increased susceptibility to Legionnaires’ disease [66]. TLRs play a key role in detecting invasive flagellated bacteria of the respiratory tract. Exogenous administration of flagellin may have a potential therapeutic role in lung infections [67]. Two common polymorphisms TLR4 (D299G and T399I) are associated with susceptibility to gram-negative sepsis, but both confer resistance to L. pneumophila pneumonia implying opposite effects depending on the environment [68]. A large case-control study conducted in Thai population suggests that single nucleotide polymorphism (SNP) TLR5 1174C>T is associated with reduced organ failure and improved survival in patients infected with B. pseudomallei, suggesting a protective effect among carriers of this variant mediated by reduced production of IL-10 [69].

Another important aspect is the fact that bacteria have acquired evasive strategies to prevent TLRs responses and establish lower respiratory tract infection. This occurs through regulators that can be extrinsic (bacterial) or host (induced by bacteria), which help pathogens to survive in a hostile environment. Bacteria use a plethora of mediators to modulate signals TLRS. The signals can be used to upregulate or downregulate the immune system [67]. For upregulation, there are direct paths (supra-activation of molecular signals or transcription factors by bacterial effectors) or use a positive regulator of the host as the triggering receptor expressed on myeloid cell-1 (TREM-1) that is an amplifier of inflammation TLR-mediated. Direct commitment from secretion system Dot/Tcm type IV of L. pneumophila in activating NF-kβ and mitogen-activated protein kinases (MAPKs) host has been shown. Prolonging the activation window of MAPKs and NF-kβ, apoptosis, a host defense mechanism critical for the control of this pathogen, is inhibited [70]. There is a correlation between TREM-1 upregulation and poor outcomes in patients with pneumonia caused by S. pneumoniae, S. aureus, P. aeuroginosa, H. influenza and B. pseudomallei [71]. They can also induce in the host the production of anti-inflammatory cytokines such as IL-10.

In the system cylindromatosis (CYLD), an enzyme produced deubiquitination degradation guest molecules increased survival of S. pneumoniae. In fact, it is believed that early lethality of pneumonia by this germ is because its pneumolysin toxin induces CYLD [72]. This system is also used by H. influenza. Some bacteria such as L. pneumonphila, B. pseudomallei and K. pneumoniae possess a “to lipid A moieties” in their LPS or express a “tetra-acylated” in the LPS (Francisella tularensis and Yersinia pestis) structure to evade recognition by TLR4. Finally, bacteria can reduce phenomena such as autophagy host, neutrophil recruitment and expression of inducible nitric oxide synthase [72].

Actually, reports of varied effects of polymorphisms of PRRs are conflicting and possibly related to susceptibility to various pathogens, defense mechanisms of bacteria, populations studied, small caseloads without statistical adjustments for multiple comparisons and validations. Polymorphisms also interact with other genetic predispositions and environmental factors in complex ways to protect or predispose to disease. Therefore, further research of these discrepancies in responses to human PRRs is required.

Long-term exposure to particles of silica, asbestos or coal results in occupational lung disease (pneumoconiosis) characterized by an inflammatory process and fibrosis, with increased susceptibility to tuberculosis and the risk of developing lung cancer. The silica or asbestos crystals engulfed by resident macrophages activated the NLRP3 inflammasome, leading to IL-1β production [73]. NLRP3 polymorphism appears to confer increased risk of pneumoconiosis in coal workers in Chinese population [74]. In contrast, NLRP3 is not critical in the development of asbestos-induced mesothelioma [75]. Sulfonylurea glyburide is the most used in USA for the treatment of type 2 diabetes mellitus. This drug prevents activation of inflammasome NLRP3 to join potassium channels that are ATP-sensitive (K_ATP) and is the first identified compound that prevents the secretion of IL-1β induced by crystals [76].

Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS), may originate from multiple insults such as sepsis, aspiration of gastric acid and infection with, for example, H5N1 influenza virus. ALI/ARDS are characterized by diffuse pulmonary inflammation resulting in non-cardiogenic pulmonary edema, altered gas exchange and possibly fibrosis, organ failure, and death. Possibly viral agents trigger the machinery of oxidative stress, resulting in the generation of ROS, local production of oxidized phospholipids, which activate TLR4 and TRIF adapter molecule. Both stimulate lung inflammation, edema formation and hyaline membranes, and thickening of the alveolar wall [24].

The inflammasome pathway and its downstream cytokines play critical roles in ARDS in humans [77]. Genetic studies have revealed that pathway like mitotic cell cycle has been closed related with development of ARDS. Genes including CCNB1, CCNB2, and TOP2A, as well as transcription factors like FOXM1 might be used as the novel gene therapy targets for sepsis-related ARDS [78]. In fact, inflammatory response after lung injury is critically dependent on the release of DAMPs by dying lung cells that activate PRRs.

COPD is a chronic inflammatory disease that leads to irreversible airway obstruction and lung parenchymal destruction (emphysema). Cigarette smoking is the primary risk factor in developed countries, as well as exposure to pollutants/biomass fuels in developing countries [79]. Respiratory infections also play a role in the development and progression of the disease, and are the major cause of acute exacerbations [8, 80]. Cigarette smoke, infection and autoimmunity lead to differential activation of multiple PRRs lung cells which trigger inflammation and contribute to mucus hypersecretion by epithelial cells, release of proteases by neutrophils recruited, and fibroblast proliferation [81].

Exposure to cigarette smoke activates TLR4 in humans, which may be dependent on the direct recognition of components of cigarette smoke, or DAMPs released by epithelial injury, by PRRs [82]. Inhaled toxic agents, ROS, infection, dead necrotic cells, hypoxia, hypercapnia, local hypoperfusion and tissue acidification, can lead to activation of DAMPs which activate the inflammasome NLRP3 [83]. COPD patients have significantly reduced concentrations of IL-1β antagonists regarding control subjects and the IL-1β levels correlate with clinical aspects of the severity of the disease. Recent studies suggest that the expression of TLR3 in sputum could be a candidate marker of exacerbations [84].

An essential feature of COPD patients is that the inflammatory process continues after stopping exposure to irritants [85]. It is likely that infection and autoimmunity are responsible for this behavior. In COPD, there are different types of stress such as inflammatory stress, endoplasmic reticulum stress, the nitrative stress, and the oxidative stress, which is particularly interesting and is produced by ROS exogenous and endogenous (mitochondrial respiration and inflammatory response to viruses and bacteria). ROS oxidizes proteins, lipids, carbohydrates and DNA, and produces reactive carbonyls, which in turn reacts with proteins [86]. Carbonyls modified proteins are highly immunogenic, producing autoantibodies which are elevated in the serum of patients with COPD. These auto-antibodies are IgG1 isotype (potentially destructive) and fix the complement component C3 [87]. Carbonylated proteins (carbonyl stress) are recognized by the innate immune system through the PRRs. Later, the acquired immunity is orchestrated, activating and attracting Th1 cells in the lung parenchyma and DCs in the small airways [88, 89]. These autoantibodies, when fixing the complement, contribute to the pathogenesis of emphysema.

COPD patients have an increased colonization by H. influenza, S. pneumoniae, P. aeruginosa and M. catarrhalis, which contribute to chronic inflammation and airway dysfunction. Infection with these and other pathogens (including viruses) is a major cause of acute exacerbations of COPD [80]. This increased susceptibility to these infections appears to be related to an aberrant, activated chronically and dysfunctional innate immune system and altered mucociliary clearance [24]. It is important to emphasize the role of PRRS in COPD, since they mediate the response to infection and autoimmunity, the two events that are involved in the persistence of the inflammatory process. Process becomes autonomous and does not disappear, even after exposure to irritants ceases.

The knowledge of this important role of PRRs and inflammasomes could help the development of new therapeutic approaches using, for example, substances that reduce the formation of DAMPs. Inhibitors of xanthine oxidase such as allopurinol, febuxostat and celestrol or AZ1 (an MPO 2-thioxanthine inhibitor) have potential use in pulmonary inflammatory diseases [90-92]. Inhibitors of the inflammasome-IL-1β pathway (IL-1Ra/anakinra, IL-1 Trap/rilanocept) or using neutralizing antibodies against IL-18 could limit the destruction and remodeling in COPD [93, 94].

Allergic asthma is characterized by airway hyperresponsiveness as well as chronic recurrent airflow obstruction and allergen-triggered airway inflammation. The hygiene hypothesis, raised by David Strachan in 1989, suggests that a decreased early exposure to infections, which are sensed by PRRs, skews the balance between Th1 and Th2 immunity toward Th2 responses, promoting the development of type I allergy [95]. Data obtained from epidemiological studies suggest that growth in farm environments, associated with abundant exposure to microbial products, may protect from asthma [96]. Moreover, TLR agonists, including CpG-DNA, have shown to impair the development of allergic airway disease Th2-dependent in some studies [97]. The very recent and elegant study of Stein et al shows the impact that lifestyle can have on the incidence of asthma. Amish and Hutterites are reproductively isolated farming communities ancestrally united, having originated in alpine regions of German-speaking Europe. There is a difference in the prevalence of asthma and allergic sensitization and this is due to different farming practices [98]. Traditional farming practices in the Amish communities protect against asthma by inducing a long-term, low-level, proinflammatory innate immune response. This protection involves activation by microbial signals (LPS), acting through MyD88 and TRIF and the production of tumor necrosis factor (TNF) and IL-1. The Hutterites, who practice mechanized farming and are not exposed to the same microbial influences, are not protected [99]. A deeper understanding of the relevant stimuli and the innate immunity pathways they engage may ultimately pave the way for the development of effective strategies for the prevention of asthma.

Polymorphism NOD1, allergic asthma, high levels of IgE, dermatitis and allergic rhinitis have been found associated. NOD1-primed human DCs polarize naive T cells toward a Th2 profile, favoring allergic exacerbations, and this is due to the induction of CCL17 (chemokine pro-Th2). Vaccine formulations that engage NOD1 could contribute to increasing allergic asthma [100]

Sarcoidosis is an inflammatory disease that usually affects the lungs. An analysis of Japanese patients with sarcoidosis found an association between increased susceptibility to disease and genetic variation in NOD1 [101]. Another study found that NOD2 polymorphism was associated with severe pulmonary sarcoidosis in white patients [102]. Human HSPs (DAMPS) and microbial HSPs (PAMPs) recognized by PRRs can induce sarcoid granulomas in genetically predisposed host [103].

Genetic variations in human TLR2, TLR4, or TLR5 have been associated with altered susceptibility to M. tuberculosis [104]. TLR4 are not critical for the control of mycobacteria in high or low doses in the acute phase, but it is in the control of bacterial load, dissemination and host response in chronic phase. Additionally, polymorphisms in molecules key signaling as MyD88, inhibitor kβ kinase 4 (IRAK-4), NF-kβ essential modulator (NEMO) and inhibitor kβα (I-kβα), all of which regulate NF-kB activation downstream of the TLRs, and other receptors, affect responses to different mycobacterial infections including human disease [63, 64]. The TLR2 SNP (Arg753GLn) increases the risk of developing tuberculosis in Turkish population [105], also, in white and African populations [106].

NOD2 polymorphisms have been associated with resistance or susceptibility to tuberculosis in African Americans [107]. The inflamasome pathway is associated with the coordinated release of cytokines such as IL-1β and IL-18 which also play a role in the pathogenesis of tuberculosis. Abnormalities in PRRs signaling pathways regulated by tuberculosis will affect the disease pathogenesis and need to be elucidated. Understanding the cross-talk between these signaling pathways will impact on the design of novel therapeutic strategies and in the development of vaccines and immunotherapy regimes [108].

Infectious and non-infectious respiratory diseases have high prevalence worldwide. Different PRRs are capable of detecting microbial and non-microbial molecules associated with lung injury and also mediate some reactions to large inhaled particles. This generates immune responses that may be beneficial or dangerous depending on the intensity, the magnitude, duration and the host involved. The PRRs and downstream signaling play a key role in the regulation of tissue homeostasis, and host protection in the pathology of pulmonary diseases. It is necessary to define the mechanisms underlying these phenomena. Determination of key nodes within these pathways could provide new therapeutic targets to generate better protective strategies to prevent the persistence of these diseases.

Source of Economic Support

None.

Conflicts of Interest

None.

Author Contributions

This work was carried out in collaboration between both authors. Authors AA and IA contributed equally in the planning, data collection, data analysis, writing and critical review. Both authors read and approved the final manuscript.

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