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Immunology and Microbiology » "Physiology and Pathology of Immunology", book edited by Nima Rezaei, ISBN 978-953-51-3692-7, Print ISBN 978-953-51-3691-0, Published: December 20, 2017 under CC BY 3.0 license. © The Author(s).

Chapter 6

Physiology and Pathology of Innate Immune Response Against Pathogens

By José Luis Muñoz Carrillo, Flor Pamela Castro García, Oscar Gutiérrez Coronado, María Alejandra Moreno García and Juan Francisco Contreras Cordero
DOI: 10.5772/intechopen.70556

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Overview

Immune response against bacteria. Mechanisms of the innate immune response to eradicate bacteria are (A) phagocytosis, (B) inflammatory response, and (C) participation of the complement system. Description in the text.
Figure 1. Immune response against bacteria. Mechanisms of the innate immune response to eradicate bacteria are (A) phagocytosis, (B) inflammatory response, and (C) participation of the complement system. Description in the text.
Immune response against fungi. PRRs, such as TLR2, 4, 6, NLRs, dectins-1 and 2, and RM, are involved in the recognition of some structures of the fungi. The activation of these receptors includes the binding to fungi and their phagocytosis. Description in the text.
Figure 2. Immune response against fungi. PRRs, such as TLR2, 4, 6, NLRs, dectins-1 and 2, and RM, are involved in the recognition of some structures of the fungi. The activation of these receptors includes the binding to fungi and their phagocytosis. Description in the text.
Immune response against viruses. (A) Innate immune response: NK cells recognize cells infected by viruses in an antigen-independent manner, exert cytotoxic activities and rapidly produce large amounts of IFN-γ to eliminate infected cells. (B) Antibody production directed against viral antigens. T CD8+ cells eliminate virus-infected cells and secrete cytokines such as TNF-α and IFN-γ. Description in the text.
Figure 3. Immune response against viruses. (A) Innate immune response: NK cells recognize cells infected by viruses in an antigen-independent manner, exert cytotoxic activities and rapidly produce large amounts of IFN-γ to eliminate infected cells. (B) Antibody production directed against viral antigens. T CD8+ cells eliminate virus-infected cells and secrete cytokines such as TNF-α and IFN-γ. Description in the text.
Immune response against parasites. (A) Th1 immune response: helminth parasites antigens induce maturation of DCs by polarizing a Th1 immune response, which is mainly characterized by the release of IL-12, INF-γ, GM-SCF, NO, PGE2, IL-1β, and TNF-α, which together with eosinophilia (derived from the Th2 immune response) enhance intestinal inflammatory response, resulting in the development of intestinal pathology, creating a favorable environment for the helminth parasites survival. (B) Th2 immune response: helminth parasites antigens activate T cells that together with IL-10 induce a Th2 immune response characterized by the release of IL-4, IL-5, IL-10, and IL-13 favoring helminth parasites antigens expulsion.
Figure 4. Immune response against parasites. (A) Th1 immune response: helminth parasites antigens induce maturation of DCs by polarizing a Th1 immune response, which is mainly characterized by the release of IL-12, INF-γ, GM-SCF, NO, PGE2, IL-1β, and TNF-α, which together with eosinophilia (derived from the Th2 immune response) enhance intestinal inflammatory response, resulting in the development of intestinal pathology, creating a favorable environment for the helminth parasites survival. (B) Th2 immune response: helminth parasites antigens activate T cells that together with IL-10 induce a Th2 immune response characterized by the release of IL-4, IL-5, IL-10, and IL-13 favoring helminth parasites antigens expulsion.

Physiology and Pathology of Innate Immune Response Against Pathogens

José Luis Muñoz Carrillo1, 5, Flor Pamela Castro García2, Oscar Gutiérrez Coronado3, María Alejandra Moreno García4 and Juan Francisco Contreras Cordero5
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Abstract

Pathogen infections are recognized by the immune system, which consists of two types of responses: an innate immune response and an antigen-specific adaptive immune response. The innate response is characterized by being the first line of defense that occurs rapidly in which leukocytes such as neutrophils, monocytes, macrophages, eosinophils, mast cells, dendritic cells, etc., are involved. These cells recognize the pathogen-associated molecular patterns (PAMPs), which have been evolutionarily conserved by the diversity of microorganisms that infect humans. Recognition of these pathogen-associated molecular patterns occurs through pattern recognition receptors such as Toll-like receptors and some other intracellular receptors such as nucleotide oligomerization domain (NOD), with the aim of amplifying the inflammation and activating the adaptive cellular immune response, through the antigenic presentation. In the present chapter, we will review the importance of the main components involved in the innate immune response, such as different cell types, inflammatory response, soluble immune mediators and effector mechanisms exerted by the immune response against bacteria, viruses, fungi, and parasites; all with the purpose of eliminating them and eradicating the infection of the host.

Keywords: innate immune response, eosinophils, mast cells, cytokines, inflammatory response, bacteria, fungi, viruses, parasites

1. Introduction

The immune system consists of a series of effector mechanisms capable of destroying pathogenic organisms such as bacteria, fungi, viruses, and parasites [1]. The immune system consists of two types of responses: an antigen-specific adaptive immune response and an innate immune response, also called natural, which recognizes pathogen-associated molecular patterns (PAMPs) [2]. These PAMPs are recognized by pattern recognition receptors (PRRs), mainly expressed in the innate immunity cells. PRRs can also recognize host molecules containing damage-associated molecular patterns (DAMPs), molecules that are often released from necrotic cells damaged by invading pathogens [3].

The innate immune system is composed mainly of physical barriers, such as skin and mucous membranes, chemical barriers, through the action of antimicrobial peptides and reactive oxygen species [4], innate immune cells, and soluble mediators such as the complement system, innate antibodies, and associated cytokines [2].

The main purpose of the innate immune system is: (1) to prevent the entry of pathogens into the body through physical and chemical barriers [4]; (2) to avoid the spread of infections through the complement system and other humoral factors; (3) to remove pathogens through phagocytosis and cytotoxicity mechanisms [5]; and (4) to activate the adaptive immune system through the synthesis of several cytokines and antigen presentation to T and B cells [6].

2. Innate immune system cells

The cells of the innate immune system have several functions that are essential for defense against pathogens. Some cells form physical barriers that impede infections. Several cell types express the various PRRs that recognize PAMPs and DAMPs, which respond by producing inflammatory cytokines to kill microbes or infected cells. These cells include nonmyeloid cells, myeloid cells, and some lymphoid cells.

2.1. Nonmyeloid cells

Nonmyeloid cells include epithelial cells, fibroblasts, etc., that basically form a barrier between the internal and external environment. These cells produce antimicrobial substances that hinder the entry of pathogens [1, 2]. These antimicrobial substances are called antimicrobial peptides (AMPs), and they are essential components of the innate immune response, which contribute to the first line of defense against infections [7]. In humans, AMPs are classified into three main families: defensins (α and β), cathelicidin, and statins. AMPs have a wide spectrum of antimicrobial activity, exerting their functions through electrostatic interactions between their positive charge and the negative charge that certain pathogens have on their cell wall. AMPs mediate the inflammatory response allowing cytokine release, cell proliferation, angiogenesis, wound healing, and chemotaxis [8]. Currently, their synergistic activity with antibiotics used in the clinic has been demonstrated. Therefore, their study on potent adjuvants in the eradication of bacterial infections continues to be studied [9].

2.2. Myeloid cells

Myeloid cells include monocytes, macrophages, dendritic cells (DCs), neutrophils, eosinophils, basophils, mast cells, and platelets. All these cells have specialized functions for defense against invading pathogens [2, 10].

2.2.1. Monocytes

Monocytes are cells that develop in the bone marrow, and they are released into the bloodstream to circulate for approximately 72 hours and then emigrate to different tissues where they differentiate into macrophages or DCs. They represent the major type of mononuclear phagocytes found in blood and are members of the myeloid cell family [11]. In humans, monocytes are classified into classical and nonclassical depending on their surface expression of cluster of differentiation (CD)-14 and CD16. Classical monocytes with phenotype CD14+CD16 are considered inflammatory cells representing more than 92% of total monocytes. In contrast, nonclassical monocytes with CD14+CD16+ phenotype can eliminate debris from the vascular system and produce low levels of proinflammatory cytokines, as well as high levels of anti-inflammatory factors. Several studies have shown both subpopulations under inflammatory conditions; the inflammatory response is a gradual process which starts with the main appearance of classical monocytes, and a few days later, nonclassical monocytes appear [12]. Among the main monocyte functions, is their involvement in the innate immune response against pathogens and during inflammatory processes, in which blood monocytes migrate to the infection site, where the process occurs, and they mature into macrophages or DCs to participate as phagocytes as either by digesting pathogens or cellular debris [13]. In addition, monocytes are antigen-presenting cells (APCs) known for their participation in the antigenic presentation through major histocompatibility complex (MHC) to T cells, also cooperating in the activation of the adaptive immune response [14].

2.2.2. Macrophages

Monocytes are precursor cells that are produced in the bone marrow, which are mobilized into the bloodstream and then differentiate into macrophages at the site of inflammation [15]. Macrophages are a very heterogeneous cell population, such as effector cells of the innate immune system, which play an important role in a host’s defense and inflammation. In general, macrophages can be divided into two populations: resident and inflammatory macrophages [16]. Resident macrophages are found in almost all tissues and contribute to their development, as well as immunological surveillance, homeostasis, and tissue repair [17, 18]. On the other hand, inflammatory macrophages are derived from circulatory monocytes and rapidly infiltrate tissues compromised by injury or infection. In response to several signals from the microenvironment, macrophages can be activated and adopt different functions: M1 macrophages (classically activated macrophages) and M2 macrophages (alternatively activated macrophages) [19, 20]. M1 macrophages have proinflammatory functions and participate in a host’s defense against pathogens and tumoral cells [21], and it is considered that they promote the Th1 immune response. When M1 macrophages are activated by interferon (IFN)-γ, granulocyte macrophage colony-stimulating factor (GM-CSF), or other ligands of Toll-like receptor, these macrophages produce proinflammatory cytokines such as interleukin (IL)-1β, IL-12, and tumor necrosis factor (TNF)-α, chemokine (C–C motif) ligand (CCL)-15, CCL20, C-X-C motif chemokine (CXC)-8-11 and CXCL13 and reactivate species of nitrogen and oxygen [22], increase the complement-mediated phagocytosis as their main purpose is to kill intracellular pathogens. In contrast, M2 macrophages are associated with tissue remodeling and tumor progression and have an immunoregulatory effect. M2 macrophages express IL-10, IL-1 receptor antagonist, chemokines (e.g., CCL22 and CCL17), transforming growth factor (TGF)-β, mannose, and galactose receptors and possess efficient phagocytic activity. M2 macrophages are considered to promote the Th2 immune response and antagonize the inflammatory response and its mediators [23, 24].

Macrophages possess a wide range of surface receptors, which gives them an ability to recognize a wide range of endogenous/exogenous ligands to respond adequately, which is critical in these cells. These receptors include Toll-like receptors (TLRs), NOD-like receptors, retinoic acid-inducible gene (RIG)-I family, lectins, and scavenger receptors, which recognize PAMPs, DAMPs, foreign substances, and dead or damaged cells [2527]. During the inflammatory response by pathogens, macrophages activated with an inflammatory phenotype produce several inflammatory mediators, such as TNF-α, IL-1, IL-6, and INF-γ, which are involved in the activation of microbicidal mechanisms contributing to the pathogen elimination. The inflammatory response of macrophages comprises mainly four stages: (1) recognition of the infectious agent through the macrophages PRRs; (2) in situ recruitment and proliferation of macrophages into infected tissue; (3) elimination of the infectious agent; and (4) the conversion to M2 macrophages to restore damaged tissue [28].

2.2.3. Dendritic cells

Monocytes circulate in the blood, bone marrow, and spleen [29, 30] and represent immune effector cells equipped with chemokine and adhesion receptors that mediate cell migration from blood to tissues during infection. Monocytes produce inflammatory cytokines and phagocyte, both cells and toxic molecules. Monocytes can differentiate into inflammatory DCs during inflammation. Migration to tissues and differentiation to inflammatory DCs depend on the inflammatory environment and PRRs [31]. These PRRs, including the TLR family, are capable to recognize PAMPs, on the surface of bacteria, viruses, fungi, and parasites [29].

DCs represent an important link between innate and adaptive immunity [2]. DCs are heterogeneous population of antigen-presenting cells that are crucial to initiate and polarize the immune response. Although, all DCs are capable of capturing, processing, and presenting antigens to T cells, DCs subtypes differ in origin, location, migration patterns, and specialized immunological roles [32]. There are mainly two subtypes of DCs: classical DCs and plasmacytoid DCs. The classical DCs are cells specialized in the processing and presentation of antigens, with high phagocytic activity as immature cells and high cytokine-producing capacity as mature cells [26]. Classical CDs are highly migratory cells that can move from tissues to the T cell and B cell zones of lymphoid organs. Classical DCs regulate T cell responses both at steady state and during infection. They are usually short-lived and replaced by blood-borne precursors [33, 34]. On the other hand, plasmacytoid DCs differ from classical DCs in that they are relatively long-lived [35]. Plasmacytoid DCs are present in the bone marrow and in all peripheral organs, and they are specialized to respond to viral infection with massive production of type I interferons (IFNs). However, they can also act as antigen presenting cells and control T cell responses [36].

2.2.4. Neutrophils

In humans, about 100 billion neutrophils enter the bloodstream each day [37]. Neutrophils originate from hematopoietic stem cells in response to both extracellular stimuli and intracellular regulators. They come from the myeloid cell line in the formation of granulocytes. The granulopoyesis that occurs in the bone marrow is initiated when the neutrophils myeloblasts (MB) develop in promyelocytes (PM), characterized by a round nucleus and presence of azurophil granules. Subsequently, they mature into myelocytes with specific granules, maturing to metamyelocytes (MM), cells composed by a nucleus with kidney form. Metamielocitos mature to band cells (CB) and in segmented cells (CS) also known as polymorphonuclear cells (PMNs). The PMNs are then called from their segmented nucleus, which are finally released into the bloodstream [38, 39]. Neutrophils play a major role in the resolution of microbial infections. After pathogens break into epithelial barriers, neutrophils are the first cell line of defense for the innate immune response, which are recruited from the bloodstream to the site of infection. Neutrophils cross the blood vessels and migrate to the infection site with the help of chemotactic factors and cytokines, which are produced as inflammatory signals during the tissue damage caused by the invading pathogens. Neutrophils reach the infection site and initiate the phagocytosis process through recognition of PAMPs by their receptors such as TLRs. Neutrophils exert their antimicrobial actions through the release of reactive oxygen species and cytotoxic components contained in their granules such as AMPs [40]. Likewise, neutrophils using a mechanism called extracellular traps (NETs) composed of DNA fibers, which are formed and released into the extracellular space, are used by the innate immune system to destroy and eliminate pathogens [41]. However, studies have shown that neutrophils NETs are involved in the development of several pathologies [4244]. Finally, neutrophils can also regulate the adaptive immune response, as they mediate suppression of T cells proliferation as well as their activity. Neutrophils can also stimulate and activate splenic B lymphocytes [45].

2.2.5. Eosinophils

Eosinophils are produced in the bone marrow from pluripotent stem cells, which first differentiate into a precursor for basophils and eosinophils and then differentiate into an eosinophilic lineage [46]. IL-3, IL-5, and GM-CSF are particularly important in regulating the eosinophils development [4750]. Of these three cytokines, IL-5 is the most specific for the eosinophilic lineage and is responsible for the selective differentiation [51] and release of eosinophils from the bone marrow into the peripheral circulation [52]. IL-5 plays a critical role in the eosinophils production, as the overproduction [53, 54] and neutralization [5557] of this cytokine are associated with a significant increase or decrease in eosinophilia, respectively.

Eosinophils are multifunctional leukocytes involved in the pathogenesis of numerous inflammatory processes [58], including parasitic helminths infections and allergic diseases [5961]. Under basal conditions, most eosinophils traffic into the gastrointestinal tract where they normally reside within the lamina propria, whose production is independent of lymphocyte production [62]. Recruitment of gastrointestinal eosinophils is regulated by the constitutive expression of eotaxin-1 [63], a chemokine involved in allergen-induced eosinophil responses [64].

In response to several stimuli, such as immunoglobulins, cytokines, and complement system, eosinophils are activated and recruited from the circulation to the site of inflammation [65]. The trafficking of eosinophils into inflammatory sites involves various cytokines derived from a Th2 immune response such as IL-4, IL-5, and IL-13 [66, 67], adhesion molecules (e.g., β1, β2, and β7 integrins) [68] and chemokines (e.g., eotaxins) [69]. Once at the site of inflammation, eosinophils can modulate the immune response through the secretion of several proinflammatory mediators such as IL-2, IL-6. IL-8, TGF-α/β, GM-CSF, TNF-α, INF-γ, as well as chemokines and lipid mediators, such as platelet-activating factor (PAF) and leukotriene (LT)-C4 [70], which exert proinflammatory effects as positive regulation of adhesion systems, modulation of cellular trafficking, activation and regulation of vascular permeability, mucus secretion, and smooth muscle constriction. In addition, eosinophils can serve as effector cells, which can induce tissue damage by releasing a diverse of cationic proteins from their cytotoxic granules, major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO), and neurotoxin derived from eosinophils (EDN) [59]. These proteins are very important, because they are directly related to the effector functions of eosinophils. For example, ECP is involved in the suppression of T cell proliferative responses, and the synthesis of immunoglobulins by B cells induces mast cell degranulation and stimulation of mucus secretion in the airways, as well as the production of glycosaminoglycans by human fibroblasts [71], while EPO is associated in the formation of reactive oxygen species and reactive nitrogen metabolites. These molecules promote oxidative stress and subsequent cell death by apoptosis and necrosis [7274].

In addition to the multiple effector actions of eosinophils, these cells can initiate antigen-specific immune responses by acting as APCs [75, 76], as they can process and present a variety of bacterial [77], viral [78], and parasitic [79] antigens. Although investigations demonstrated a direct association of eosinophils with parasitic helminths infections, establishing the hypothesis that eosinophils are the classic effector cells in a host’s defense [80]. Several studies have also shown that the eosinophils absence during parasitic helminths infections protects the host [81], so that eosinophils may influence the immune response in a manner that supports chronic infection and ensures survival of the parasite in the host [8284].

2.2.6. Basophils

Basophils are cells derived from the myeloid hematopoietic progenitors in the bone marrow, and they are phenotypically and functionally distinct from other leukocytes, including mast cells, since mast cells reside in tissues while basophils reside in the circulation and can be recruited to the tissues [8589]. Basophils have the ability to bridge innate and adaptive immunity, including the capacity to induce and propagate Th2 immune responses [90]. Basophils are important in all allergic diseases, including anaphylaxis, allergic rhinitis, asthma, urticaria, and food allergies. Basophils rapidly release histamine and synthesize LTC4 after that immunoglobulin (Ig)-E binds to their receptor FcεRI and subsequently produces Th2 cytokines such as IL-4 and IL-13 [9195], causing the clinical symptoms of immediate hypersensitivity, also promoting delayed hypersensitivity reactions [9699]. The role of basophils in protective immunity against helminths is well known [96, 100]. However, recently, basophils have also been implicated in the initiation of immune responses against bacterial respiratory infection [101].

2.2.7. Mast cells

Mast cells are granulated tissue-resident cells from CD34+ hematopoietic progenitor cells [102, 103]. Mast cells circulate as immature cells and migrate to vascularized tissues, where they complete their differentiation. Mast cells represent, together with dendritic cells, the first immune cells that interact with environmental antigens, pathogens, and toxins. Therefore, they can be considered “sentinels” of the innate immune system [104]. Mast cells are activated by danger stimuli, which they react by rapidly releasing a wide range of mediators, both preformed and newly produced. Some of these mediators (e.g., histamine, TNF-α, vascular endothelial growth factor, VEGF) contribute to local vascular permeability and edema at the site of inflammation [105], while chemokines (e.g., IL-8/CXCL8, eotaxin) induce the recruitment of other immune cells [106], such as neutrophils, natural killer (NK) cells, and eosinophils. It is important to note that mast cells may also be involved in the defense against pathogens by different mechanisms, such as phagocytosis, antimicrobial peptide release, or the production of extracellular traps similar to those described in neutrophils [107, 108]. Mast cells detect these invading pathogens through PRRs, such as TLRs [109]. Investigations have shown that bacterial and viral proteins can activate mast cells through specific receptors [110, 111].

Mast cells express the high affinity receptor for IgE (FcεRI) [90, 112]. Cross-linking of the FcεRI by IgE-antigens and/or allergens complexes induces mast cell activation and rapid release of proinflammatory mediators via degranulation. Due to this property, together with circulating basophils, mast cells are known primarily as effector cells for IgE-mediated (Th2-like) responses [113], an arm of the adaptive immune system against helminths infection [114], and as primary effector cells in hypersensitivity reactions [115]. In addition to their functions as effector cells, recent evidence suggests that mast cells are capable to modulate both the innate and adaptive immune response, acting as immunomodulatory cells [116, 117].

2.2.8. Platelets

Platelets are cytoplasmic fragments (1 to 4 μm in diameter) produced as a result of fragmentation from megakaryocytes that are cells from bone marrow. Platelets are non-nucleated organelles that have functional characteristics like complete cell, since they possess cytoskeleton, mitochondria, Golgi residues, and endoplasmic reticulum involved in the synthesis of enzymes, storage of calcium ions, as well as storage granules [118, 119]. These storage granules are δ-granules [120], α-granules, and lysosomal granules [121], which play an important role in homeostasis, inflammation, wound healing, and cell-matrix interactions. During the inflammatory response, platelets can be activated through their receptors, which act as adhesion molecules that interact with damaged endothelium, other platelets and leukocytes, playing an important role in the coagulation process for repairing the damaged blood vessel and restoring its integrity [122124].

2.3. Lymphoid cells

Lymphoid cells include the NK cells, natural killer T (NKT) cells, and innate lymphoid cells (ILCs). ILCs are a novel family of hematopoietic effectors that serve protective roles in innate immune responses to infectious microorganisms, in lymphoid tissue formation, in tissue remodeling after damage inflicted by injury or infection and in the homeostasis of tissue stromal cells [125].

2.3.1. Innate lymphoid cells (ILCs)

ILCs represent the innate version of helper and cytotoxic T cells as part of the innate immune system, which play essential roles in the early immune response [126, 127]. All members of the ILCs family are characterized by a classical lymphoid cell morphology and the expression of IL-7Ra (CD127) and CD161, but they lack the expression of cell surface molecules that characterize other types of immune cells such as T cells (CD3, TCRαβ, and TCRδ), B cells (CD19), NK cells (CD16 and CD94), myeloid cells (CD1a, CD14 and CD123), granulocytes (FcεR1α and CD123), stem cell hematopoietic (CD34), and plasmacytoid dendritic cells (BDCA2 and CD123), so they are defined as cells that do not express lineage markers (Lin-) [128]. ILCs can be classified based on their phenotypic and functional characteristics in three groups: Group 1 (ILC1) comprises cells that have the ability to produce IFN-γ as their major effector cytokine and express the T-bet transcription factor. The prototype cell of this group is the NK cell. Group 2 (ILC2) are cells that require IL-17 for their development. These cells are characterized by cytokine production associated with the Th2 immune response, in response to stimulation with IL-25, IL-33 and thymic stromal lymphopoietin (TSLP) and shows a GATA3 and RORα phenotype for their development and function. Group 3 (ILC3), includes cell subtypes that produce IL-17 and/or IL-22 and IFN-γ, and these cells depend on the RORγt transcription factor for their development and function [129]. Recent studies have identified various functions of ILCs cells: (1) ILCs promote a host’s defense against infections and regulate interactions with the microbiota; (2) as well as orchestrate wound healing and tissue repair and (3) in other circumstances, ILCs may promote inflammation and tumor progression [130]. ILCs are poorly represented in lymphoid tissues, but they are found to be important in parenchymal tissues, especially mucosal surfaces. Therefore, the subtypes of ILCs play an important role in the innate immune response to viruses, bacteria, fungi, and intracellular and extracellular parasites in this type of tissue, and they have a rapid activation through cytokines and growth factors [125, 131].

2.3.2. Natural killer cells

NK cells are derived from cellular lymphoid progenitors. However, they do not mediate the conventional adaptive immune response because they lack antigen-specific receptors such as T and B lymphocytes [132]. Previously, it was believed that the development of NK cells in humans occurred exclusively in the bone marrow. However, recent studies have shown that NK cells also develop in secondary lymphoid organs [133]. The dominant population of the NK cells in blood circulation has a CD56dimCD16+ phenotype corresponding to its final maturation stage, whereas the NK cells with phenotype CD56bright are considered as relatively immature cells [134]. NK cells are important effector lymphoid cells of the innate immune system, since they represent a key element in the rapid recognition and death of both infected or tumorigenic cells, which can cause damage to the integrity of host tissues. NK cells identify target cells (cells that have some damage) through complex combinations of signals from the activation or inhibition of receptors, which interact with ligands that are expressed on the surface of stressed or normal cells, respectively [135]. The decision to eliminate or not eliminate these cells depends on the result of the balance between positive (activation) and negative (inhibition) signals. Also, the activation of NK cells is regulated through cooperation with other immune cells, including DCs [136], which allows that NK cells to acquire potent cytotoxic activity, the ability to produce cytokines such as IFN-γ and contribute to the adaptive immune response by triggering the T cell–mediated response [137].

2.3.3. Natural killer T cells

NKT cells constitute a small subpopulation of lymphocytes that are characterized by the markers expression of the NK cell lineage, as well as receptors of the αβ T lineage. NKT cells develop in the thymus and have the same common lymphoid precursor of conventional T cells, but they have phenotypic and functional characteristics different of T cells [138]. Four subpopulations of NKT cells CD4+, CD8αβ+, CD8αα+, and double negatives (CD4CD8) were identified in human peripheral blood [139], which differ in the cytokine secretion profile and the expression of chemokines receptors, integrins, and NK receptors [140]. In addition, NKT cells recognize glycolipid antigens that are presented through CD1d molecules, MHC-like molecules that are constitutively expressed by antigen presenting cells such as DCs, B cells, and macrophages. NKT cells also have the ability to respond to cells participating in innate immunity with minimal involvement of the T cell receptor (TCR), and memory cells through a portion of the TCR, which makes them capable to be a bridge between the innate and adaptive immune response [141].

3. Pattern recognition receptors in innate immunity

Pathogens that invade a human host are controlled by the immune system, both innate and adaptive. The adaptive immune system, which is mediated by T and B cells, recognizes pathogens with high affinity through the rearrangement of certain receptors. However, the establishment of this adaptive immune response is often not fast enough to eradicate pathogens, and it also involves cell proliferation, genetic activation, and protein synthesis [142]. Thus, the fastest defense of a host mechanism is provided by the innate immune system, which has developed the ability to recognize invading pathogens and thus effectively eliminate them so that they do not cause damage to host cells.

The recognition of pathogens occurs through cells involved in the innate immunity response by nonspecific molecules that are commonly shared by most pathogens called PAMPs. PAMPs are highly conserved products and are produced by numerous microorganisms. These PAMPs do not show specific structures with antigenic variability, and host cells do not share the same molecular patterns with pathogens, resulting in recognition of the immune system, capable to discriminate between self and nonself [143]. Among the PAMPs that present the pathogens are lipopolysaccharide (LPS), peptidoglycan (PGN), lipoteichoic acid, unmethylated cytosine phosphor-guanine (CpG) motifs, double-stranded RNA virus, and the cell wall component of yeast called manan. LPS represents the major component of Gram-negative bacteria, as PGN represents the major component of Gram-positive bacteria [144]. Recognition of these PAMPs is mediated through PRRs, primarily attributed to the family TLRs [142].

However, pathogens are not the only cause of cell and tissue damage. A trauma, a vascular event, even in physiological states as well as in disease states, are other causes of damage, and when this occurs, intracellular proteins called “alarminas” are released, which are considered in a subgroup of a large quantity of DAMPs [145]. This occurs by identifying changes in the host’s own structures that show signs of damage and then repairing and removing damaged tissue. DAMPs include any endogenous molecule that experiences a change of state in association with a tissue injury, which allows the immune system to be informed that any damage has occurred [146].

When these DAMPs are released from damaged or necrotic cells, together with PAMPs, are recognized by certain PRRs for their subsequent activation and induction of a potent acute inflammatory response [147]. These PRRs include Toll-like receptors (TLRs), nucleotide-binding domain and leucine-rich repeat containing receptors (NLRs), and retinoic acid-inducible gene-I (RIG-)-like receptors (RLRs).

TLRs are evolutionarily conserved proteins that detect PAMPs. They were originally identified in the Drosophila fly as an important gene for its ontogenesis and its immunological resistance against fungal infections. In addition, it was found that during microbial infections of flies, Toll receptors induce the production of antimicrobial peptides [148]. In humans, the first protein structurally related to the Drosophila Toll receptor was identified and called the Toll-1 receptor (TLR-1). These proteins are characterized by the presence of an extracellular domain formed by leucine-rich repeats, in which the recognition of the PAMPs is given; and an intracellular region called intracellular Toll/IL-1R (TIR), which is responsible for the signals transmission that culminates in the activation of nuclear factor (NF)-κB, which induces the synthesis of proinflammatory cytokines [149]. Currently, 10 TLRs have been identified (TLR-1 to TLR-10), the TLR-1, TLR-2, TLR-4, TLR-5, and TLR-6 expressed on the cell surface; while TL-3, TLR-7, TLR-8, and TLR-9 are found intracellularly in endosomes [150].

Different TLRs specifically recognize distinct PAMPs and DAMPs [151]. TLR-2 forms heterodimers with TLR-1 or TLR-6. The TLR-1/TLR-2 complex mainly interacts with lipopeptide triacyl ligands in contrast to the TLR-2/TLR-6 complex, which binds only to diacyl lipopeptides. TLR-3 recognizes double-stranded RNA ligands, which are produced by most viruses in replication stages. TLR-4 requires binding with the MD-2 co-receptor and is specific for interacting with LPS ligands, which comes from Gram-negative bacteria. TLR-5 responds to bacterial flagellin ligands. Both TLR-7 and TLR-8 recognize single-stranded ARN. TLR-9 binds to ligands containing CpG motifs [152]. TLRs are a family of transmembrane receptors that are key in the response and regulation of both innate and adaptive immunity [151], since they recognize diverse pathogens and help to eliminate them.

There are other receptors such as NLRs, which are a family of 23 members that have been identified in humans. They are intracellular receptors that are structurally composed of caspase recruitment domains (CARDs), as in the case of members called NODs, a pryin domain, as in the case of NLRP members. Among the most important members of these receptors are NOD1 and NOD2, which recognize specific ligands from various pathogens. This family is involved in increasing the proinflammatory events caused by cell death, pyroptosis and pyronecrosis, and several more proinflammatory processes [153].

Another family of receptors is the RIGs. They are intracellular recognition receptors for patterns involved in the recognition of viruses by the action of the innate immune system. There are three members: RIG-1, MDA-5, and LGP2. They act as sensors for viral replication within human host cells necessary to mediate antiviral responses [154].

4. Soluble mediators of the innate immune system

In innate immunity, a large number of soluble mediators such as cytokines, chemokines, and the complement system participate. All these mediators provide protection in the initial phase of contact with pathogens and are responsible for preventing potentially harmful infections.

4.1. The complement system

The complement system has been considered as an effector response of the innate immune system capable of eliminating a great diversity of pathogens including bacteria, viruses, and parasites [155]. The complement system is composed of plasma proteins, which are present as inactive proteins [156]. After activation, the products that are generated from the complement system facilitate the recruitment of cells from the immune system to the site of damage to eliminate the pathogen through opsonization or direct destruction [157]. Activation of the complement system occurs through three pathways: (1) the classical pathway for the antigen–antibody complex; (2) the alternating pathway through the spontaneous hydrolysis of C3; and (3) the lectin pathway where certain sugars are recognized on the surface of the pathogens through mannose-binding lectin (MLB). Once activated, the pathway of the complement system generates a multimolecular enzyme complex that cuts to C3 and forms C3a and C3b. The C3b fragment that is generated binds to C3 convertase to form the C5 convertase, and once formed, this complex cuts to C5 to form C5a and C5b [155]. Then, C5b begins to recruit complement components C6, C7, C8, and C9 to form the membrane attack complex which is a lytic pore inserted into the membrane of the pathogen [158]. Since the complement system uses multiple activation pathways, it has the ability to maximize the number of pathogens that it can recognize and thus eliminating a great diversity of these. In addition, it is responsible for eliminating apoptotic cells, this occurs through depositing a low amount of C3b molecules which facilitates the removal of these cells by macrophages [159].

4.2. Cytokines

Cytokines form a molecular network that is synthesized and released by different cell types. These molecules act in a paracrine and endocrine way through their receptors that express the target cell. These molecules are synthesized and released in response to some damage or recognition of specific structures of the pathogens through their receptors (e.g., PAMPs and TLRs) [160]. Initially, the cytokines were defined based on the activity they performed, among these activities are regulating the immune system but also exerting an effector function on the cells, these effects not only occur at local level but also occur through the tissues or systems. Cytokines are involved in regulating the homeostasis of the organism but when its production or its signaling pathway in the cell is not regulated, this homeostasis is altered, which can trigger in a pathology [161, 162]. Cytokines can be classified into five groups: type I cytokines (include cytokines from IL-2 to IL-7), type II cytokines (interferons and cytokines of the IL-10 family), type III cytokines (the TNF family), type IV cytokines (IL-1 family, such as IL-1, IL-18, IL-36, IL-37, and IL-38), and type V cytokines (the IL-17 family that includes IL-17E) [162]. Cytokines may increase systemic level during some pathological condition, either acute or chronic, these molecules exert their effect by binding to their receptors, where the signal translation is given, which leads to the gene expression and finally can regulate the function of the target cell. The cytokine pattern that is released from the cell depends primarily on the nature of the antigenic stimulus and the type of cell being stimulated. Cytokines compromise leukocytes to respond to a microbial stimulus, through regulating positively the expression of adhesion molecules on endothelial cells and amplifying the release of molecules such as reactive oxygen species and nitrogen, histamine, serotonin, as well as arachidonic acid derivatives, which regulate the release of the cytokines. On the other hand, cytokines can promote apoptosis by binding to receptors that contain death domains, for example TNF receptor 1(R1) [163].

4.3. Chemokines

Chemokines or chemotactic cytokines are small molecules which constitute a large family of peptides (60–100 amino acids) structurally related to cytokines. Their main function is to stimulate leukocyte migration. They are secreted in response to some signals such as proinflammatory cytokines, where they play an important role in selectively recruiting monocytes, neutrophils, and lymphocytes [164, 165]. These molecules are defined by the presence of four conserved cysteine residues that form two disulfide bonds (Cys1-Cys3 and Cys2-Cys4) and are classified into four families based on the number of amino acids between the first two cysteines: CXC-(α), CC-(β), CX3C-(δ), and C-(γ) according to the systematic nomenclature [166]. The chemokines CXC and CC are distinguished according to the position of the first two cysteines, which are adjacent (CC) or separated by an amino acid (CXC) [167]. The CC chemokine family is the largest and can be subdivided into several subfamilies. One is monocyte chemotactic protein (MCP), this subfamily is characterized by recruiting monocytes to damaged tissue after ischemia, which is conformed for five members: CCL2 (MCP-1), CCL8 (MCP-2), CCL7 (MCP-3), CCL13 (MCP-4), and CCL12 (MCP-5). Another chemokine in this group is the macrophage inflammatory protein (MIP)-1α (CCL3), MIP-1β (CCL4), and RANTES (CCL5) [168]. The second family consists of CXC chemokines; the prototype of these chemokines is IL-8 (CXCL8); mainly this chemokine attracts polymorphonuclear cells to the site of acute inflammation. Also, CXCL8 activates monocytes and can recruit these cells to vascular injury. The third family, consisting of a single member is Fraktalkine (CX3CL1) which is one of the two transmembrane chemokines and has two isoforms, one binds to the membrane and the other is a soluble form. According to its isoform, it may have different functions, the form that is anchored to the membrane serves as adhesion molecule for cells expressing CX3CR1, while the soluble form possesses a potent chemotactic activity [169]. The fourth family has only one member lymphotoxin (XCL1); this chemokine is similar to members of the CC and CXC families, but the lack of two of the four cysteine residues are characteristic of this chemokine. Its chemotactic function is for lymphocytes and not for monocytes and neutrophils as do other chemotactic chemokines [170].

5. Immune response against pathogens

Inflammation is a protective response to extreme challenges to homeostasis, such as infection, tissue stress, and injury [171], which is characterized by its cardinal signs: redness, swelling, heat, pain, and disrupted function [172]. A typical inflammatory response consists of four components: (1) inflammatory inducers: depending on the type of infection (bacterial, viral, fungi or parasitic) [173]; (2) sensors that detect the inflammatory inducers: these sensors are receptors of the innate immune system such as TLRs, NLRs and RLRs [153, 174]; (3) inflammatory mediators induced by the sensors, such as cytokines, chemokines and the complement system [175]; (4) target tissues that are affected by the inflammatory mediator. Each component comes in multiple forms and their combinations function in distinct inflammatory pathways.

The inflammatory reaction is characterized by successive phases: (1) silent phase, where cells reside in the damaged tissue releases in the first inflammatory mediators, (2) a vascular phase, where vasodilation and increased vascular permeability occur, (3) cellular phase, which is characterized by the infiltration of leukocytes to the site of injury [176], and (4) resolution of inflammation, which is the process to return tissues to homeostasis [177, 178].

5.1. Immune response against bacteria

In an infection by extracellular bacteria, the host triggers a series of responses to combat the pathogen and prevent its spread. The main mechanism of the innate immune response to eradicate bacteria is activation of the complement system, phagocytosis, and inflammatory response (Figure 1). Both the alternative and the lectin pathways of the complement system participate in the bacteria opsonization and potentiate their phagocytosis. To perform the correct phagocytosis, activation of several surface receptors in phagocytes, including scavenger receptors, mannose, Fc, and mainly TLRs is required. Activation of these receptors results in inflammation, by recruiting leukocytes to the site of infection [152]. On the other hand, the humoral adaptive immune response is the main protective against extracellular bacteria. Its primary function is to block infection, through the release of antibodies that are directed against the antigens of the bacterial cell wall, as well as of the toxins secreted by certain extracellular bacteria. The effector mechanisms used by the antibodies include neutralization, opsonization, and classical complement pathway activation, which allow bacteria phagocytosis. In the case of neutralization, IgG, IgM, and IgA participate; while in the opsonization, the IgG participates; and in complement activation, the IgM and some subclasses of IgG participate. Protein antigens from extracellular bacteria also activate the cellular adaptive immune response, which is mediated by CD4+ T cells. These CD4+ T cells produce cytokines that induce local inflammation, increase phagocytosis, as well as microbicidal activities of macrophages and neutrophils. The Th17 cells are also involved in recruiting monocytes and neutrophils, promoting local inflammation. Similarly, there is an induction of the Th1 immune response that contributes to the macrophages activation with ample phagocytic capacity and the production of the cytokines, such as IFN-γ [179].

media/F1.png

Figure 1.

Immune response against bacteria. Mechanisms of the innate immune response to eradicate bacteria are (A) phagocytosis, (B) inflammatory response, and (C) participation of the complement system. Description in the text.

In the case of infection by intracellular bacteria, they have the ability to survive and replicate within phagocytic cells, which causes the circulating antibodies to be inaccessible to intracellular bacteria. The innate immune response against these bacteria is mediated primarily by phagocytes and NK cells [180]. Among the phagocytes involved are neutrophils and then macrophages. However, these pathogens are resistant to degradation, but their products are recognized by TLRs and NLR receptors that are responsible for activating more phagocytes. NK cells are also activated in this type of infections and participate by stimulating the production of cytokine IL-12 by DCs and macrophages. Also, the NK cells produce IFN-γ, which promotes the death of phagocytic intracellular bacteria. But usually this immune response is ineffective against infection. In contrast, the adaptive immune response against infections by intracellular bacteria is mediated by CD4+ T cells that help recruit and activate phagocytes that kill the pathogen, and the response of cytotoxic CD8+ T cells that kills the infected cells. Both subpopulations of T cells respond through the antigen presentation by MHC type I and II. All this to eradicate the infection of the host [181].

5.2. Immune response against fungi

Most fungi are present in the environment, so animals including humans are exposed and then can inhale spores or yeasts [182]. The mechanisms for defense against the fungi comprise of both innate and adaptive immune responses. TLRs recognize several PAMPs, so that TLR1, TLR2, TLR3, TLR4, TLR6, and TLR9 have been implicated in the recognition of PAMPs from fungi. Activation of TLR4 and CD14 by recognition of conidia derived from some fungi has been shown to increase the production of inflammatory molecules such as TNF-α. Meanwhile, the TLR2 may recognize conidia and hyphae, as well as β-glucans from pathogenic fungi Coccidioides. TLR2 activation induces oxidative pathways in polymorphonuclear (PMN) cells with the release of gelatinases and inflammatory cytokines. TLR6 is involved in the recognition of Candida albicans, which is involved in the production of IL-23 and IL-17A, which promote Th17 responses. TLRs can be combined to recognize a large number of fungal structures and thus generate a broader response against the various fungal structures [183, 184].

The NLRs are involved in detection of fungal structures, such as Aspergillus fumigatus hyphal fragments, and once activated the production of IL-1β and IL-18 is induced by the formation of a multimeric complex known as inflammasome [182, 185].

Type C lectin receptors (CTLRs) make up a receptors family that can recognize several molecules like proteins, carbohydrates, and lipids. Among these receptors, the best studied are dectin-1, dectin-2, dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), macrophage inducible C-type lectin, and mannose receptor (MR) involved in the recognition of some structures of the fungi [186]. Dectin-1 recognizes β-glucan and promotes its phagocytosis, it can also interact with TLR2 to induce the activation of NF-κB and the production of reactive oxygen species [187]. Dectin-1 activation can also induce mast cells to produce proinflammatory and TH2-polarizing cytokines, such as IL-4 and IL-13. Dectin-2 also activates NF-κB. In addition, dectin-2 promotes Th17 polarization by inducing IL-17A, which is crucial in neutralizing some fungi. The MR recognizes mannose, fucose, or N-acetylglucosamine residues present in fungi. MR generates a Th17 response and promotes fungi phagocytosis [183]. The response that occurs through the activation of these receptors includes the binding to fungi and their phagocytosis, the induction of antifungal effector mechanisms and the production of soluble mediators such as cytokines, chemokines, and inflammatory lipids [187].

The immunity against fungi requires the recruitment and activation of phagocytosis, which is mediated through factors that induce inflammatory molecules such as proinflammatory cytokines and chemokines. The PRRs interaction with fungal structures plays an important role in the control of infections against these pathogens, since this interaction is determinant for the generation of the profile of cytokines or chemokines that influence the immune response. For example, the interaction of Candida albicans with TLR4 or TLR2 generates a Th1 or Th2 response, respectively. Therefore, these interactions of the different fungal structures and the PRRs generate different responses polarizing toward one or the other depending on the cytokine profile that could be generated after these interactions (Figure 2) [188].

media/F2.png

Figure 2.

Immune response against fungi. PRRs, such as TLR2, 4, 6, NLRs, dectins-1 and 2, and RM, are involved in the recognition of some structures of the fungi. The activation of these receptors includes the binding to fungi and their phagocytosis. Description in the text.

5.3. Immune response against viruses

In an infectious process, the most common host response is to generate inflammation. Viruses in the absence of cytopathologic damage at early stages of infection inhibit the induction of acute phase protein response because early monocytes are not activated. By contrast, the participation of NK cells against the virus play an important role in the host’s defense, they recognize cells infected by viruses in an antigen-independent manner, exert cytotoxic activities and rapidly produce large amounts of IFN-γ that participate in the activation of the adaptive immune cell [5]. Type I interferons are the major cytokines responsible for defending the human host against viral infections. It has been shown that interferons do not exert their antiviral effects by direct action on viruses, but they help in the gene activation that results in the production of antiviral proteins, which participate as mediators in the inhibition of viral replication, as well as mediating the effects of suppressor T cells [189].

The adaptive immune response against this type of infection is primarily composed of the humoral immune response with the antibody production directed against viral antigens. However, the cellular immune response is the most important for virus eradication. T CD4+ cells recognize antigens presented by MHC-II molecules on the surface of APCs [190]. Subsequently, T CD4+ cells perform multiple effector functions including direct activation of antigen-specific macrophages and B cells, as well as cytokine-dependent activation of T CD8+ cells. T CD8+ cells eliminate virus-infected cells and secrete cytokines such as TNF-α and IFN-γ, which also participate in the inhibition of viral replication. Thus, both the innate immune response and the adaptive immune response in their cellular and humoral involvement eradicate viral infections in most cases (Figure 3). However, certain viruses have developed mechanisms of immune evasion to survive longer and thus be able to replicate without any problem until causing serious damage to the host [191].

media/F3.png

Figure 3.

Immune response against viruses. (A) Innate immune response: NK cells recognize cells infected by viruses in an antigen-independent manner, exert cytotoxic activities and rapidly produce large amounts of IFN-γ to eliminate infected cells. (B) Antibody production directed against viral antigens. T CD8+ cells eliminate virus-infected cells and secrete cytokines such as TNF-α and IFN-γ. Description in the text.

5.4. Immune response against parasites

Due to there being a large variety of parasites and that each of their life cycles are very complex, in this section, we will focus on the immune response against helminth parasites. This is because more than 1 billion people are currently infected with helminth parasites worldwide [192], making them one of the most prevalent infectious agents responsible for many diseases in both animals and humans [193]. The investigation of these parasitic infections is not only of direct relevance to human and animal health but also because they present a constant and important challenge to the host immune system, since both in humans and animals, helminth parasites establish chronic infections [194] associated with a significant downregulation of the immune response.

The first defense barrier during intestinal helminth parasites infection is the mucus layer secreted by the host’s intestine, either in a larval stage during the early infectious process or as adult parasites during the reproductive phase of infection. Thus, helminth parasites will interact with the mucus layer and in many cases will have to cross it to reach the epithelial layer and thus thrive and reproduce within it [192].

The immune response against helminth parasites involves both the innate and adaptive immune response [195, 196]. Helminth parasite antigens are capable of inducing the DCs maturation, leading to the expression of MHC class II [197, 198], promoting the development of a Th1 type cellular immune response (Figure 4A) [199]. Several studies have shown that during intestinal infection by helminth parasites, there is an increase in the levels of gene expression of TLR4 and TLR9 [200], with a significant increase of proinflammatory cytokines such as IL-12, INF-γ, IL-1β, TNF-α, nitric oxide (NO), and prostaglandin (PG)-E2 [201207].

media/F4.png

Figure 4.

Immune response against parasites. (A) Th1 immune response: helminth parasites antigens induce maturation of DCs by polarizing a Th1 immune response, which is mainly characterized by the release of IL-12, INF-γ, GM-SCF, NO, PGE2, IL-1β, and TNF-α, which together with eosinophilia (derived from the Th2 immune response) enhance intestinal inflammatory response, resulting in the development of intestinal pathology, creating a favorable environment for the helminth parasites survival. (B) Th2 immune response: helminth parasites antigens activate T cells that together with IL-10 induce a Th2 immune response characterized by the release of IL-4, IL-5, IL-10, and IL-13 favoring helminth parasites antigens expulsion.

Helminth parasite antigens also induce Th2 immune response (Figure 4B) trough CD4+ T cells [208], and DCs activation, leading to the secretion Th2 cytokines, such as IL-10 [209], IL-4, IL-5 [210], and IL-13 which stimulate IgE synthesis, inducing mast cell and eosinophil hyperplasia, triggering immediate hypersensitivity reactions, promoting the helminth parasites expulsion from the intestine [197, 208, 211213]. However, mast cells rapidly expand in the mucosa, where helminth parasites antigens can directly induce their degranulation, releasing effector molecules such as histamine, serine proteases [197], TNF-α, LTC4, LTB4 [213], IL-4, IL-13 [201], which together with the eosinophils contributes to the intestinal inflammation development [214, 215].

Acknowledgements

Thanks to the authors who collaborated in the writing of this chapter: Dr. en C. José Luis Muñoz, Dra. en C. Pamela Castro, Dr. en C. Oscar Gutiérrez, Dra. en C. Alejandra Moreno and Dr. en C. Juan Francisco Contreras; as well as the Universities involved: Cuauhtémoc University Aguascalientes, Autonomous University of Nuevo Leon, Autonomous University of Zacatecas, Autonomous University of Durango Campus Zacatecas and University of Guadalajara. Thanks to the Cuauhtémoc University Aguascalientes for financial support for chapter publication.

References

1 - Williams AE. Basic Concepts in Immunology. In: Immunology: Mucosal and Body Surface Defences. Chichester, UK: John Wiley & Sons, Ltd; 2011. p. 1-19. DOI: 10.1002/9781119998648.ch1
2 - Koenderman L, Buurman W, Daha MR. The innate immune response. Immunology Letters. 2014;162(2 Pt B):95-102. DOI: 10.1016/j.imlet.2014.10.010
3 - Lamb TJ. Notes on the immune system. In: Lamb TJ, editor. Immunity to Parasitic Infection. Chichester, UK: John Wiley & Sons, Ltd; 2012. p. 13-57. DOI: 10.1002/9781118393321.ch1
4 - Williams AE. The Innate Immune System. In: . Immunology: Mucosal and Body Surface Defences. Chichester, UK: John Wiley & Sons, Ltd; 2011. p. 20-40. DOI: 10.1002/9781119998648.ch2
5 - Tosi MF. Innate immune responses to infection. The Journal of Allergy and Clinical Immunology. 2005;116(2):241-249. DOI: 10.1016/j.jaci.2005.05.036
6 - Beutler B. Innate immunity: An overview. Molecular Immunology. 2004;40(12):845-859. DOI: 10.1016/j.molimm.2003.10.005
7 - Chung PY, Khanum R. Antimicrobial peptides as potential anti-biofilm agents against multidrug-resistant bacteria. Journal of Microbiology, Immunology, and Infection. 2017;S1684-1182(17)30080-4. DOI: 10.1016/j.jmii.2016.12.005
8 - de la Fuente-Núñez C, Silva ON, Lu TK, Franco OL. Antimicrobial peptides: Role in human disease and potential as immunotherapies. Pharmacology & Therapeutics. 2017 pii: S0163-7258(17)30105-5. DOI: 10.1016/j.pharmthera.2017.04.002
9 - Mishra B, Reiling S, Zarena D, Wang G. Host defense antimicrobial peptides as antibiotics: Design and application strategies. Current Opinion in Chemical Biology. 2017;38:87-96. DOI: 10.1016/j.cbpa.2017.03.014
10 - Yutin N, Wolf MY, Wolf YI, Koonin EV. The origins of phagocytosis and eukaryogenesis. Biology Direct. 2009;4(9):1-9. DOI: 10.1186/1745-6150-4-9
11 - França CN, Izar MCO, Hortêncio MNS, do Amaral JB, Ferreira CES, Tuleta ID, Fonseca FAH. Monocyte subtypes and the CCR2 chemokine receptor in cardiovascular disease. Clinical Science (London, England). 2017;131(12):1215-1224. DOI: 10.1042/CS20170009
12 - de Jong E, Strunk T, Burgner D, Lavoie PM, Currie A. The phenotype and function of preterm infant monocytes: Implications for susceptibility to infection. Journal of Leukocyte Biology. 2017;102(3):645-656. DOI: 10.1189/jlb.4RU0317-111R
13 - Jakubzick CV, Randolph GJ, Henson PM. Monocyte differentiation and antigen-presenting functions. Nature Reviews Immunology. 2017;17(6):349-362. DOI: 10.1038/nri.2017.28
14 - Hu S, Wei W, Korner H. The role of monocytes in models of infection by protozoan parasites. Molecular Immunology. 2017;88:174-184. DOI: 10.1016/j.molimm.2017.06.020
15 - Gordon S. Macrophage neutral proteinases and chronic inflammation. Annals of the New York Academy of Sciences. 1976;278:176-189. DOI: 10.1111/j.1749-6632.1976.tb47028.x
16 - Raggatt LJ, Wullschleger ME, Alexander KA, Wu AC, Millard SM, Kaur S, Maugham ML, Gregory LS, Steck R, Pettit AR. Fracture healing via periosteal callus formation requires macrophages for both initiation and progression of early endochondral ossification. The American Journal of Pathology. 2014;184(12):3192-3204. DOI: 10.1016/j.ajpath.2014.08.017
17 - Wynn TA, Vannella KM. Macrophages in tissue repair, regeneration, and fibrosis. Immunity. 2016;44(3):450-462. DOI: 10.1016/j.immuni.2016.02.015
18 - Gu Q, Yang H, Shi Q. Macrophages and bone inflammation. Journal of Orthopaedic Translation. 2017;10:86-93. DOI: 10.1016/j.jot.2017.05.002
19 - Wynn TA, Chawla A, Pollard JW. Macrophage biology in development, homeostasis and disease. Nature. 2013;496(7446):445-455. DOI: 10.1038/nature12034
20 - XQ W, Dai Y, Yang Y, Huang C, Meng XM, BM W, Li J. Emerging role of microRNAs in regulating macrophage activation and polarization in immune response and inflammation. Immunology. 2016;148(3):237-248. DOI: 10.1111/imm.12608
21 - Tan HY, Wang N, Li S, Hong M, Wang X, Feng Y. The reactive oxygen species in macrophage polarization: Reflecting its dual role in progression and treatment of human diseases. Oxidative Medicine and Cellular Longevity. 2016;2016:2795090. DOI: 10.1155/2016/2795090
22 - Suzuki K, Meguro K, Nakagomi D, Nakajima H. Roles of alternatively activated M2 macrophages in allergic contact dermatitis. Allergology International. 2017;66(3):392-397. DOI: 10.1016/j.alit.2017.02.015
23 - Gordon S, Martinez FO. Alternative activation of macrophages: Mechanism and functions. Immunity. 2010;32(5):593-604. DOI: 10.1016/j.immuni.2010.05.007
24 - Gordon S, Plüddemann A, Martinez Estrada F. Macrophage heterogeneity in tissues: Phenotypic diversity and functions. Immunological Reviews. 2014;262(1):36-55. DOI: 10.1111/imr.12223
25 - Taylor PR, Martinez-Pomares L, Stacey M, Lin HH, Brown GD, Gordon S. Macrophage receptors and immune recognition. Annual Review of Immunology. 2005;23:901-944. DOI: 10.1146/annurev.immunol.23.021704.115816
26 - Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K. Development of monocytes, macrophages and dendritic cells. Science. 2010;327(5966):656-661. DOI: 10.1126/science.1178331
27 - Kraal G, van der Laan LJ, Elomaa O, Tryggvason K. The macrophage receptor MARCO. Microbes and Infection. 2000;2(3):313-316. DOI: 10.1016/S1286-4579(00)00296-3
28 - Zhang L, Wang CC. Inflammatory response of macrophages in infection. Hepatobiliary & Pancreatic Diseases International. 2014;13(2):138-152. DOI: 10.1016/S1499-3872(14)60024-2
29 - Auffray C, Sieweke MH, Geissmann F. Blood monocytes: Development, heterogeneity, and relationship with dendritic cells. Annual Review of Immunology. 2009;27:669-692. DOI: 10.1146/annurev.immunol.021908.132557
30 - Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325(5940):612-616. DOI: 10.1126/science.1175202
31 - Serbina NV, Jia T, Hohl TM, Pamer EG. Monocyte-mediated defense against microbial pathogens. Annual Review of Immunology. 2010;26:421-452. DOI: 10.1146/annurev.immunol.26.021607.090326
32 - Boltjes A, Van Wijk F. Human dendritic cell functional specialization in steady-state and inflammation. Frontiers in Immunology. 2014;5(131):1-13. DOI: 10.3389/fimmu.2014.00131
33 - Liu K, Victora GD, Schwickert TA, Guermonprez P, Meredith MM, Yao K, Chu FF, Randolph GJ, Rudensky AY, Nussenzweig M. In vivo analysis of dendritic cell development and homeostasis. Science. 2009;324(5925):392-397. DOI: 10.1126/science.1170540
34 - Waskow C, Liu K, Darrasse-Jèze G, Guermonprez P, Ginhoux F, Merad M, Shengelia T, Yao K, Nussenzweig M. The receptor tyrosine kinase Flt3 is required for dendritic cell development in peripheral lymphoid tissues. Nature Immunology. 2008;9(6):676-683. DOI: 10.1038/ni.1615
35 - Corcoran L, Ferrero I, Vremec D, Lucas K, Waithman J, O’Keeffe M, Wu L, Wilson A, Shortman K. The lymphoid past of mouse plasmacytoid cells and thymic dendritic cells. Journal of Immunology. 2003;170(10):4926-4932. DOI: 10.4049/jimmunol.170.10.4926
36 - Colonna M, Trinchieri G, Liu YJ. Plasmacytoid dendritic cells in immunity. Nature Immunology. 2004;5(12):1219-1226. DOI: 10.1038/ni1141
37 - Borregaard N. Neutrophils, from marrow to microbes. Immunity. 2010;33(5):657-670. DOI: 10.1016/j.immuni.2010.11.011
38 - Teng TS, Ji AL, Ji XY, Li YZ. Neutrophils and immunity: From bactericidal action to being conquered. Journal of Immunology Research. 2017;2017:9671604. DOI: 10.1155/2017/9671604
39 - Cowland JB, Borregaard N. Granulopoiesis and granules of human neutrophils. Immunological Reviews. 2016;273(1):11-28. DOI: 10.1111/imr.12440
40 - Kobayashi SD, Malachowa N, DeLeo FR. Influence of microbes on neutrophil life and death. Frontiers in Cellular and Infection Microbiology. 2017;7:59. DOI: 10.3389/fcimb.2017.00159
41 - Dąbrowska D, Jabłońska E, Garley M, Ratajczak-Wrona W, Iwaniuk A. New aspects of the biology of neutrophil extracellular traps. Scandinavian Journal of Immunology. 2016;84(6):317-322. DOI: 10.1111/sji.12494
42 - Ruhnau J, Schulze J, Dressel A, Vogelgesang A. Thrombosis, neuroinflammation, and Poststroke infection: The multifaceted role of neutrophils in stroke. Journal of Immunology Research. 2017;2017:5140679. DOI: 10.1155/2017/5140679
43 - Liu T, Wang FP, Wang G, Mao H. Role of neutrophil extracellular traps in asthma and chronic obstructive pulmonary disease. Chinese Medical Journal. 2017;130(6):730-736. DOI: 10.4103/0366-6999.201608
44 - Garley M, Jabłońska E, Dąbrowska D. NETs in cancer. Tumour Biology. 2016;37(11):14355-14361. DOI: 10.1007/s13277-016-5328-z
45 - Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nature Reviews Immunology. 2013;13(3):159-175. DOI: 10.1038/nri3399
46 - Boyce JA, Friend D, Matsumoto R, Austen KF, Owen WF. Differentiation in vitro of hybrid eosinophil/basophil granulocytes: Autocrine function of an eosinophil developmental intermediate. The Journal of Experimental Medicine. 1995;128(1):49-57. DOI: 10.1084/jem.182.1.49
47 - Lopez AF, Begley CG, Williamson DJ, Warren DJ, Vadas MA, Sanderson CJ. Murine eosinophil differentiation factor. An eosinophil-specific colony- stimulating factor with activity for human cells. The Journal of Experimental Medicine. 1986;163(5):1085-1099. DOI: 10.1084/jem.163.5.1085
48 - Rothenberg ME, Pomerantz JL, Owen WF Jr, Avraham S, Soberman RJ, Austen KF, Stevens RL. Characterization of a human eosinophil proteoglycan, and augmentation of its biosynthesis and size by interleukin 3, interleukin 5, and granulocyte/macrophage colony stimulating factor. The Journal of Biological Chemistry. 1988;263(27):13901-13908 PMID: 2458354
49 - Lopez AF, Sanderson CJ, Gamble JR, Campbell HD, Young IG, Vadas MA. Recombinant human interleukin 5 is a selective activator of human eosinophil function. The Journal of Experimental Medicine. 1988;167(1):219-224 PMID: 2826636
50 - Takatsu K, Takaki S, Hitoshi Y. Interleukin-5 and its receptor system: Implications in the immune system and inflammation. Advances in Immunology. 1994;57:145-190. DOI: 10.1016/S0065-2776(08)60673-2
51 - Sanderson CJ. Interleukin-5, eosinophils, and disease. Blood. 1992;79(12):3101-3109 PMID: 1596561
52 - Collins PD, Marleau S, Griffiths-Johnson DA, Jose PJ, Williams TJ. Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. The Journal of Experimental Medicine. 1995;182(4):1169-1174. DOI: 10.1084/jem.182.4.1169
53 - Dent LA, Strath M, Mellor AL, Sanderson CJ. Eosinophilia in transgenic mice expressing interleukin 5. The Journal of Experimental Medicine. 1990;172(5):1425-1431. DOI: 10.1084/jem.172.5.1425
54 - Tominaga A, Takaki S, Koyama N, Katoh S, Matsumoto R, Migita M, Hitoshi Y, Hosoya Y, Yamauchi S, Kanai Y. Transgenic mice expressing a B cell growth and differentiation factor gene (interleukin 5) develop eosinophilia and autoantibody production. The Journal of Experimental Medicine. 1991;173(2):429-437. DOI: 10.1084/jem.173.2.429
55 - Foster PS, Hogan SP, Ramsay AJ, Matthaei KI, Young IG. Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. The Journal of Experimental Medicine. 1996;183(1):195-201. DOI: 10.1084/jem.183.1.195
56 - Kopf M, Brombacher F, Hodgkin PD, Ramsay AJ, Milbourne EA, Dai WJ, Ovington KS, Behm CA, Köhler G, Young IG, Matthaei KI. IL-5-deficient mice have a developmental defect in CD5+ B-1 cells and lack eosinophilia but have normal antibody and cytotoxic T cell responses. Immunity. 1996;4(1):15-24. DOI: 10.1016/S1074-7613(00)80294-0
57 - Flood-Page P, Phipps S, Menzies-Gow A, Ong Y, Kay AB. Effect of intravenous administration of an anti-IL-5 mAb (Mepolizumab) on allergen-induced tissue eosinophilia, the late-phase allergic reaction and the expression of a marker of repair/remodeling in human atopic subjects. Journal of Allergy and Clinical Immunology. 2003;111(2):S261. DOI: 10.1016/S0091-6749(03)80933-8
58 - Rothenberg ME. Eosinophilic gastrointestinal disorders (EGID). The Journal of Allergy and Clinical Immunology. 2004;113(1):11-28. DOI: 10.1016/j.jaci.2003.10.047
59 - Gleich G, Loegering DA. Immunobiology of eosinophils. Annual Review of Immunology. 1984;2(1):429-459. DOI: 10.1146/annurev.iy.02.040184.002241
60 - Weller PF. Eosinophils: Structure and functions. Current Opinion in Immunology. 1994;6(1):85-90. DOI: 10.1016/0952-7915(94)90038-8
61 - Rothenberg ME. Eosinophilia. New England Journal of Medicine. 1998;338(22):1592-1600. DOI: 10.1056/NEJM199805283382206
62 - Mishra A, Hogan SP, Lee JJ, Foster PS, Rothenberg ME. Fundamental signals that regulate eosinophil homing to the gastrointestinal tract. The Journal of Clinical Investigation. 1999;103(12):1719-1727. DOI: 10.1172/JCI6560
63 - Humbles AA, Lu B, Friend DS, Okinaga S, Lora J, Al-Garawi A, Martin TR, Gerard NP, Gerard C. The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(3):1479-1484. DOI: 10.1073/pnas.261462598
64 - Pope SM, Zimmermann N, Stringer KF, Karow ML, Rothenberg ME. The eotaxin chemokines and CCR3 are fundamental regulators of allergen-induced pulmonary eosinophilia. Journal of Immunology. 2005;175(8):5341-5350. DOI: 10.4049/jimmunol.175.8.5341
65 - Kita H. The eosinophil: A cytokine-producing cell? The Journal of Allergy and Clinical Immunology. 1996;97(4):889-892. DOI: 10.1016/S0091-6749(96)80061-3
66 - Sher A, Coffman RL, Hieny S, Cheever AW. Ablation of eosinophil and IgE responses with anti-IL-5 or anti-IL-4 antibodies fails to affect immunity against Schistosoma Mansoni in the mouse. Journal of Immunology. 1990;145(11):3911-3916
67 - Horie S, Okubo Y, Hossain M, Sato E, Nomura H, Koyama S, Suzuki J, Isobe M, Sekiguchi M. Interleukin-13 but not interleukin-4 prolongs eosinophil survival and induces eosinophil chemotaxis. Internal Medicine. 1997;36(3):179-185. DOI: 10.2169/internalmedicine.36.179
68 - Bochner BS, Schleimer RP. The role of adhesion molecules in human eosinophil and basophil recruitment. The Journal of Allergy and Clinical Immunology. 1994;94(3):427-438. DOI: 10.1016/0091-6749(94)90195-3
69 - Zimmermann N, Hershey GK, Foster PS, Rothenberg ME. Chemokines in asthma: Cooperative interaction between chemokines and IL-13. The Journal of Allergy and Clinical Immunology. 2003;111(2):227-242. DOI: 10.1067/mai.2003.139
70 - Rothenberg ME, Hogan SP. The eosinophil. Annual Review of Immunology. 2006;24:147-174. DOI: 10.1146/annurev.immunol.24.021605.090720
71 - Venge P, Byström J, Carlson M, Hâkansson L, Karawacjzyk M, Peterson C, Sevéus L, Trulson A. Eosinophil cationic protein (ECP): Molecular and biological properties and the use of ECP as a marker of eosinophil activation in disease. Clinical and Experimental Allergy. 1999;29(9):1172-1186. DOI: 10.1046/j.1365-2222.1999.00542.x
72 - Agosti JM, Altman LC, Ayars GH, Loegering DA, Gleich GJ, Klebanoff SJ. The injurious effect of eosinophil peroxidase, hydrogen peroxide, and halides on pneumocytes in vitro. The Journal of Allergy and Clinical Immunology. 1987;79(3):496-504. DOI: 10.1016/0091-6749(87)90368-X
73 - Wu W, Chen Y, Hazen SL. Eosinophil peroxidase nitrates protein tyrosyl residues. Implications for oxidative damage by nitrating intermediates in eosinophilic inflammatory disorders. Journal of Biological Chemistry. 1999;274(36):25933-25944. DOI: 10.1074/jbc.274.36.25933
74 - MacPherson JC, Comhair SA, Erzurum SC, Klein DF, Lipscomb MF, Kavuru MS, Samoszuk MK, Hazen SL. Eosinophils are a major source of nitric oxide-derived oxidants in severe asthma: Characterization of pathways available to eosinophils for generating reactive nitrogen species. Journal of Immunology. 2001;166(9):5763-5772. DOI: 10.4049/jimmunol.166.9.5763
75 - Shi HZ, Humbles A, Gerard C, Jin Z, Weller PF. Lymph node trafficking and antigen presentation by endobronchial eosinophils. The Journal of Clinical Investigation. 2000;105(7):945-953. DOI: 10.1172/JCI8945
76 - MacKenzie JR, Mattes J, Dent LA, Foster PS. Eosinophils promote allergic disease of the lung by regulating CD4(+) Th2 lymphocyte function. Journal of Immunology. 2001;167(6):3146-3155. DOI: 10.4049/jimmunol.167.6.3146
77 - Mawhorter SD, Kazura JW, Boom WH. Human eosinophils as antigen-presenting cells: Relative efficiency for superantigen- and antigen-induced CD4+ T-cell proliferation. Immunology. 1994;81(4):584-591 PMID: 7518797
78 - Handzel ZT, Busse WW, Sedgwick JB, Vrtis R, Lee WM, Kelly EA, Gern JE. Eosinophils bind rhinovirus and activate virus-specific T cells. Journal of Immunology. 1998;160(3):1279-1284 PMID: 9570544
79 - Shi HZ. Eosinophils function as antigen-presenting cells. Journal of Leukocyte Biology. 2004;76(3):520-527. DOI: 10.1189/jlb.0404228
80 - Butterworth AE. The eosinophil and its role in immunity to helminth infection. Current Topics in Microbiology and Immunology. 1977;77:127-168 PMID: 336298
81 - Fabre V, Beiting DP, Bliss SK, Gebreselassie NG, Gagliardo LF, Lee NA, Lee JJ, Appleton JA. Eosinophil deficiency compromises parasite survival in chronic nematode infection. Journal of Immunology. 2009;182(3):1577-1583. DOI: 10.4049/jimmunol.182.3.1577
82 - Huang L, Gebreselassie NG, Gagliardo LF, Ruyechan MC, Lee NA, Lee JJ, Appleton JA. Eosinophil-derived IL-10 supports chronic nematode infection. Journal of Immunology. 2014;193(8):4178-4187. DOI: 10.4049/jimmunol.1400852
83 - Huang L, Gebreselassie NG, Gagliardo LF, Ruyechan MC, Luber KL, Lee NA, Lee JJ, Appleton JA. Eosinophils mediate protective immunity against secondary nematode infection. Journal of Immunology. 2015;194(1):283-290. DOI: 10.4049/jimmunol.1402219
84 - Huang L, Beiting DP, Gebreselassie NG, Gagliardo LF, Ruyechan MC, Lee NA, Lee JJ, Appleton JA. Eosinophils and IL-4 support nematode growth coincident with an innate response to tissue injury. PLoS Pathogens. 2015;11(12):e1005347. DOI: 10.1371/journal.ppat.1005347
85 - Siracusa MC, Saenz SA, Hill DA, Kim BS, Headley MB, Doering TA, Jessup HK, Siegel LA, Kambayashi T, Dudek MC, Kubo M, Cianferoni A, Spergel JM, Ziegler SF, Comeau MR, Artis D. TSLP promotes IL-3-independent basophil hematopoiesis and type 2 inflammation. Nature 2011;477(7363):229-233. DOI: 10.1038/nature10329
86 - Kim S, Shen T, Min B. Basophils can directly present or cross-present antigen to CD8 lymphocytes and alter CD8 T cell differentiation into IL-10-producing phenotypes. Journal of Immunology. 2009;183(5):3033-3039. DOI: 10.4049/jimmunol.0900332
87 - Hida S, Tadachi M, Saito T, Taki S. Negative control of basophil expansion by IRF-2 critical for the regulation of Th1/Th2 balance. Blood. 2005;106(6):2011-2017. DOI: 10.1182/blood-2005-04-1344
88 - Wakahara K, Baba N, Van VQ, Bégin P, Rubio M, Ferraro P, Panzini B, Wassef R, Lahaie R, Caussignac Y, Tamaz R, Richard C, Soucy G, Delespesse G, Sarfati M. Human basophils interact with memory T cells to augment Th17 responses. Blood. 2012;120(24):4761-4771. DOI: 10.1182/blood-2012-04-424226
89 - Wada T, Ishiwata K, Koseki H, Ishikura T, Ugajin T, Ohnuma N, Obata K, Ishikawa R, Yoshikawa S, Mukai K, Kawano Y, Minegishi Y, Yokozeki H, Watanabe N, Karasuyama H. Selective ablation of basophils in mice reveals their nonredundant role in acquired immunity against ticks. The Journal of Clinical Investigation. 2010;120(8):2867-2875. DOI: 10.1172/JCI42680
90 - Knol EF, Olszewski M. Basophils and mast cells: Underdog in immune regulation? Immunology Letters. 2011;138(1):28-31. DOI: 10.1016/j.imlet.2011.02.012
91 - Cromheecke JL, Nguyen KT, Huston DP. Emerging role of human basophil biology in health and disease. Current Allergy and Asthma Reports. 2014;14(1):408. DOI: 10.1007/s11882-013-0408-2
92 - Yamada T, Sun Q, Zeibecoglou K, Bungre J, North J, Kay AB, Lopez AF, Robinson DS. IL-3, IL-5, granulocyte-macrophage colony-stimulating factor receptor alpha-subunit, and common beta-subunit expression by peripheral leukocytes and blood dendritic cells. The Journal of Allergy and Clinical Immunology. 1998;101(5):677-682. DOI: 10.1016/S0091-6749(98)70177-0
93 - MacGlashan D Jr, White JM, Huang SK, Ono SJ, Schroeder JT, Lichtenstein LM. Secretion of IL-4 from human basophils. The relationship between IL-4 mRNA and protein in resting and stimulated basophils. Journal of Immunology. 1994;152(6):3006-3016 PMID: 8144899
94 - Gibbs BF, Haas H, Falcone FH, Albrecht C, Vollrath IB, Noll T, Wolff HH, Amon U. Purified human peripheral blood basophils release interleukin-13 and preformed interleukin-4 following immunological activation. European Journal of Immunology. 1996;26(10):2493-2498. DOI: 10.1002/eji.1830261033
95 - Yuk CM, Park HJ, Kwon BI, Lah SJ, Chang J, Kim JY, Lee KM, Park SH, Hong S, Lee SH. Basophil-derived IL-6 regulates TH17 cell differentiation and CD4 T cell immunity. Scientific Reports. 2017;7:41744. DOI: 10.1038/srep41744
96 - Min B, Prout M, Hu-Li J, Zhu J, Jankovic D, Morgan ES, Urban JF Jr, Dvorak AM, Finkelman FD, LeGros G, Paul WE. Basophils produce IL-4 and accumulate in tissues after infection with a Th2-inducing parasite. The Journal of Experimental Medicine. 2004;200(4):507-517. DOI: 10.1084/jem.20040590
97 - Schroeder JT, MacGlashan DW, Lichtenstein LM. Human basophils: Mediator release and cytokine production. Advances in Immunology. 2001;77:93-122. DOI: 10.1016/S0065-2776(01)77015-0
98 - Perrigoue JG, Saenz SA, Siracusa MC, Allenspach EJ, Taylor BC, Giacomin PR, Nair MG, Du Y, Zaph C, van Rooijen N, Comeau MR, Pearce EJ, Laufer TM, Artis D. MHC class II-dependent basophil-CD4+ T cell interactions promote T(H)2 cytokine-dependent immun. Nature Immunology. 2009;10(7):697-705. DOI: 10.1038/ni.1740
99 - Yoshimoto T, Yasuda K, Tanaka H, Nakahira M, Imai Y, Fujimori Y, Nakanishi K. Basophils contribute to T(H)2-IgE responses in vivo via IL-4 production and presentation of peptide-MHC class II complexes to CD4+ T cells. Nature Immunology. 2009;10(7):706-712. DOI: 10.1038/ni.1737
100 - Lantz CS, Min B, Tsai M, Chatterjea D, Dranoff G, Galli SJ. IL-3 is required for increases in blood basophils in nematode infection in mice and can enhance IgE-dependent IL-4 production by basophils in vitro. Laboratory Investigation. 2008;88(11):1134-1142. DOI: 10.1038/labinvest.2008.88
101 - Chen K, Xu W, Wilson M, He B, Miller NM, Bengten E, Edholm ES, Santini PA, Rath P, Chiu A, Cattalini M, Litzman J, Bussel J, Huang B, Meini A, Riesbeck K, Cunningham-Rundles C, Plebani A, Cerutti A. Immunoglobulin D enhances immune surveillance by activating antimicrobial, pro-inflammatory and B cell-stimulating programs in basophils. Nature Immunology. 2009;10(8):889-898. DOI: 10.1038/ni.1748
102 - Galli SJ, Tsai M. Mast cells in allergy and infection: Versatile effector and regulatory cells in innate and adaptive immunity. European Journal of Immunology. 2010;40(7):1843-1851. DOI: 10.1002/eji.201040559
103 - Wedemeyer J, Tsai M, Galli SJ. Roles of mast cells and basophils in innate and acquired immunity. Current Opinion in Immunology. 2000;12(6):624-631. DOI: 10.1016/S0952-7915(00)00154-0
104 - Galli SJ, Maurer M, Lantz CS. Mast cells as sentinels of innate immunity. Current Opinion in Immunology. 1999;11(1):53-59. DOI: 10.1016/S0952-7915(99)80010-7
105 - Palker TJ, Dong G, Leitner WW. Mast cells in innate and adaptive immunity to infection. European Journal of Immunology. 2010;40(1):13-18. DOI: 10.1002/eji.200990325
106 - Mekori YA, Metcalfe DD. Mast cells in innate immunity. Immunological Reviews. 2000;173:131-140. DOI: 10.1034/j.1600-065X.2000.917305.x
107 - Urb M, Sheppard DC. The role of mast cells in the defence against pathogens. PLoS Pathogens. 2012;8(4):e1002619. DOI: 10.1371/journal.ppat.1002619
108 - Abraham SN, St John AL. Mast cell-orchestrated immunity to pathogens. Nature Reviews Immunology. 2010;10(6):440-452. DOI: 10.1038/nri2782
109 - Suurmond J, Rivellese F, Dorjée AL, Bakker AM, Rombouts YJ, Rispens T, Wolbink G, Zaldumbide A, Hoeben RC, Huizinga TW, Toes RE. Toll-like receptor triggering augments activation of human mast cells by anti-citrullinated protein antibodies. Annals of the Rheumatic Diseases. 2015;74(10):1915-1923. DOI: 10.1136/annrheumdis-2014-205562
110 - Rossi FW, Prevete N, Rivellese F, Lobasso A, Napolitano F, Granata F, Selleri C, de Paulis A. HIV-1 Nef promotes migration and chemokine synthesis of human basophils and mast cells through the interaction with CXCR4. Clinical and Molecular Allergy. 2016;14(1):15. DOI: 10.1186/s12948-016-0052-1
111 - Marone G, Varricchi G, Loffredo S, Galdiero MR, Rivellese F, de Paulis A. Are basophils and mast cells masters in HIV infection? International Archives of Allergy and Immunology. 2016;171(3-4):158-165. DOI: 10.1159/000452889
112 - Kawakami T, Galli SJ. Regulation of mast-cell and basophil function and survival by IgE. Nature Reviews Immunology. 2002;2(10):773-786. DOI: 10.1038/nri914
113 - Rivellese F, Nerviani A, Rossi FW, Marone G, Matucci-Cerinic M, de Paulis A, Pitzalis C. Mast cells in rheumatoid arthritis: Friends or foes? Autoimmunity Reviews. 2017;16(6):557-563. DOI: 10.1016/j.autrev.2017.04.001
114 - Anthony RM, Rutitzky LI, Urban JF Jr, Stadecker MJ, Gause WC. Protective immune mechanisms in helminth infection. Nature Reviews Immunology. 2007;7(12):975-987. DOI: 10.1038/nri2199
115 - Bischoff SC. Role of mast cells in allergic and non-allergic immune responses: Comparison of human and murine data. Nature Reviews Immunology. 2007;7(2):93-104. DOI: 10.1038/nri2018
116 - Galli SJ, Nakae S, Tsai M. Mast cells in the development of adaptive immune responses. Nature Immunology. 2005;6(2):135-142. DOI: 10.1038/ni1158
117 - Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M. Mast cells as “tunable” effector and immunoregulatory cells: Recent advances. Annual Review of Immunology. 2005;23:749-786. DOI: 10.1146/annurev.immunol.21.120601.141025
118 - de Queiroz MR, de Sousa BB, da Cunha Pereira DF, Mamede CCN, Matias MS, de Morais NCG, de Oliveira Costa J, de Oliveira F. The role of platelets in hemostasis and the effects of snake venom toxins on platelet function. Toxicon. 2017;133:33-47. DOI: 10.1016/j.toxicon.2017.04.013
119 - Rendu F, Brohard-Bohn B. The platelet release reaction: granules’ constituents, secretion and functions. Platelets. 2001;12(5):261-273. DOI: 10.1080/09537100120068170
120 - Christopher D, Hillyer MD, Shaz BH, Zimring JC, Abshire TC. Transfusion Medicine and Hemostasis Clinical and Laboratory Aspects. 1st ed. USA: Academic Press. Elsevier Science; 2009. 775 p. DOI: 0.1016/B978-0-12-374432-6.00156-1
121 - Saboor M, Ayub Q, Ilyas S, Moinuddin. Platelet receptors; an instrumental of platelet physiology. Pakistan Journal of Medical Sciences. 2013;29(3):891-896. DOI: 10.12669/pjms.293.3497
122 - Saluk J, Bijak M, Ponczek MB, Wachowicz B. The formation, metabolism and the evolution of blood platelets. Postępy Higieny i Medycyny Doświadczalnej (Online). 2014;68:384-391. DOI: 10.5604/17322693.1098145
123 - Deppermann C, Kubes P. Platelets and infection. Seminars in Immunology. 2016;28(6):536-545. DOI: 10.1016/j.smim.2016.10.005
124 - Varga-Szabo D, Pleines I, Nieswandt B. Cell adhesion mechanisms in platelets. Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28(3):403-412. DOI: 10.1161/ATVBAHA.107.150474
125 - Spits H, Di Santo JP. The expanding family of innate lymphoid cells: Regulators and effectors of immunity and tissue remodeling. Nature Immunology. 2011;12(1):21-27. DOI: 10.1038/ni.1962
126 - Lim AI, Li Y, Lopez-Lastra S, Stadhouders R, Paul F, Casrouge A, Serafini N, Puel A, Bustamante J, Surace L, Masse-Ranson G, David E, Strick-Marchand H, Le Bourhis L, Cocchi R, Topazio D, Graziano P, Muscarella LA, Rogge L, Norel X, Sallenave JM, Allez M, Graf T, Hendriks RW, Casanova JL, Amit I, Yssel H, Di Santo JP. Systemic human ILC precursors provide a substrate for tissue ILC differentiation. Cell. 2017;168(6):1086-1100. DOI: 10.1016/j.cell.2017.02.021
127 - Suffiotti M, Carmona SJ, Jandus C, Gfeller D. Identification of innate lymphoid cells in single-cell RNA-Seq data. Immunogenetics. 2017;69(7):439-450. DOI: 10.1007/s00251-017-1002-x
128 - Bernink JH, Mjösberg J, Spits H. Human ILC1: To be or not to be. Immunity. 2017;46(5):756-757. DOI: 10.1016/j.immuni.2017.05.001
129 - Spits H, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, Koyasu S, Locksley RM, McKenzie AN, Mebius RE, Powrie F, Vivier E. Innate lymphoid cells--a proposal for uniform nomenclature. Nature Reviews Immunology. 2013;13(2):145-149. DOI: 10.1038/nri3365
130 - Artis D, Spits H. The biology of innate lymphoid cells. Nature. 2015;517(7534):293-301. DOI: 10.1038/nature14189
131 - Klose CS, Artis D. Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis. Nature Immunology. 2016;17(7):765-774. DOI: 10.1038/ni.3489
132 - Lanier LL. NK cell recognition. Annual Review of Immunology. 2005;23:225-274. DOI: 10.1146/annurev.immunol.23.021704.115526
133 - Freud AG, Becknell B, Roychowdhury S, Mao HC, Ferketich AK, Nuovo GJ, Hughes TL, Marburger TB, Sung J, Baiocchi RA, Guimond M, Caligiuri MA. A human CD34(+) subset resides in lymph nodes and differentiates into CD56 bright natural killer cells. Immunity. 2005;22(3):295-304. DOI: 10.1016/j.immuni.2005.01.013
134 - Chan A, Hong DL, Atzberger A, Kollnberger S, Filer AD, Buckley CD, McMichael A, Enver T, Bowness P. CD56bright human NK cells differentiate into CD56dim cells: Role of contact with peripheral fibroblasts. Journal of Immunology. 2007;179(1):89-94. DOI: 10.4049/jimmunol.179.1.89
135 - Cerwenka A, Lanier LL. Natural killer cells, viruses and cancer. Nature Reviews Immunology. 2001;1(1):41-49. DOI: 10.1038/35095564
136 - Walzer T, Dalod M, Robbins SH, Zitvogel L, Vivier E. Natural-killer cells and dendritic cells: “l’union fait la force”. Blood. 2005;106(7):2252-2258. DOI: 10.1182/blood-2005-03-1154
137 - Parisi L, Bassani B, Tremolati M, Gini E, Farronato G, Bruno A. Natural killer cells in the orchestration of chronic inflammatory diseases. Journal of Immunology Research. 2017;2017:4218254. DOI: 10.1155/2017/4218254
138 - Benlagha K, Kyin T, Beavis A, Teyton L, Bendelac A. A thymic precursor to the NK T cell lineage. Science. 2002;296(5567):553-555. DOI: 10.1126/science.1069017
139 - Erazo-Borrás LV, Álvarez-Álvarez JA, Trujillo-Vargas CM. Invariant NKT lymphocytes: Ontogeny, phenotype and function. Inmunología. 2014;33(2):51-59. DOI: 10.1016/j.inmuno.2014.01.004
140 - Lee PT, Benlagha K, Teyton L, Bendelac A. Distinct functional lineages of human Vα24 natural killer T cells. The Journal of Experimental Medicine. 2002;195(5):637-641. DOI: 10.1084/jem.20011908
141 - Bollino D, Webb TJ. Chimeric antigen receptor-engineered natural killer and natural killer T cells for cancer immunotherapy. Translational Research. 2017;187(2017):32-43. DOI: 10.1016/j. trsl.2017.06.003
142 - Werling D, Jungi TW. TOLL-like receptors linking innate and adaptive immune response. Veterinary Immunology and Immunopathology. 2003;91(1):1-12. DOI: 10.1016/S0165-2427(02)00228-3
143 - Uthaisangsook S, Day NK, Bahna SL, Good RA, Haraguchi S. Innate immunity and its role against infections. Annals of Allergy, Asthma & Immunology. 2002;88(3):253-264. DOI: 10.1016/S1081-1206(10)62005-4
144 - Häcker G, Redecke V, Häcker H. Activation of the immune system by bacterial CpG-DNA. Immunology. 2002;105(3):245-251. DOI: 10.1046/j.0019-2805.2001.01350.x
145 - Bianchi ME. DAMPs, PAMPs and alarmins: All we need to know about danger. Journal of Leukocyte Biology. 2007;81(1):1-5. DOI: 10.1189/jlb.0306164
146 - Carta S, Castellani P, Delfino L, Tassi S, Venè R, Rubartelli A. DAMPs and inflammatory processes: The role of redox in the different outcomes. Journal of Leukocyte Biology. 2009;86(3):549-555. DOI: 10.1189/jlb.1008598
147 - Wakefield D, Gray P, Chang J, Di Girolamo N, McCluskey P. The role of PAMPs and DAMPs in the pathogenesis of acute and recurrent anterior uveitis. The British Journal of Ophthalmology. 2010;94(3):271-274. DOI: 10.1136/bjo.2008.146753
148 - Muzio M, Mantovani A. Toll-like receptors. Microbes and Infection. 2000;2(3):251-255. DOI: 10.1016/S1286-4579(00)00303-8
149 - Kaisho T, Akira S. Toll-like receptors and their signaling mechanism in innate immunity. Acta Odontologica Scandinavica. 2001;59(3):124-130. DOI: 10.1080/000163501750266701
150 - Li K, Qu S, Chen X, Wu Q, Shi M. Promising targets for cancer immunotherapy: TLRs, RLRs, and STING-mediated innate immune pathways. International Journal of Molecular Sciences. 2017;18(2):404. DOI: 10.3390/ijms18020404
151 - Gao D, W1 L. Structures and recognition modes of toll-like receptors. Proteins. 2017;85(1):3-9. DOI: 10.1002/prot.25179
152 - Brodsky IE, Medzhitov R. Targeting of immune signalling networks by bacterial pathogens. Nature Cell Biology. 2009;11(5):521-526. DOI: 10.1038/ncb0509-521
153 - Lavelle EC, Murphy C, O’Neill LA, Creagh EM. The role of TLRs, NLRs, and RLRs in mucosal innate immunity and homeostasis. Mucosal Immunology. 2010;3(1):17-28. DOI: 1038/mi.2009.124
154 - Satoh T, Kato H, Kumagai Y, Yoneyama M, Sato S, Matsushita K, Tsujimura T, Fujita T, Akira S, Takeuchi O. LGP2 is a positive regulator of RIG-I- and MDA5-mediated antiviral responses. Proceedings of the National Academy of Sciences of the United States of America. 2010;107(4):1512-1517. DOI: 10.1073/pnas.0912986107
155 - Barnum SR. Complement: A primer for the coming therapeutic revolution. Pharmacology & Therapeutics. 2017;172:63-72. DOI: 10.1016/j.pharmthera.2016.11.014
156 - Kolev M, Le Friec G, Kemper C. Complement-tapping into new sites and effector systems. Nature Reviews Immunology. 2014;14(12):811-820. DOI: 10.1038/nri3761
157 - Hawksworth OA, Coulthard LG, Woodruff TM. Complement in the fundamental processes of the cell. Molecular Immunology. 2017;84:17-25. DOI: 10.1016/j.molimm.2016.11.010
158 - Bubeck D. The making of a macromolecular machine: Assembly of the membrane attack complex. Biochemistry. 2014;53(12):1908-1915. DOI: 10.1021/bi500157z
159 - Mevorach D, Mascarenhas JO, Gershov D, Elkon KB. Complement-dependent clearance of apoptotic cells by human macrophages. The Journal of Experimental Medicine. 1998;188(12):2313-2320. DOI: 10.1084/jem.188.12.2313
160 - Prieto GA, Cotman CW. Cytokines and cytokine networks target neurons to modulate long-term potentiation. Cytokine & Growth Factor Reviews. 2017;34:27-33. DOI: 10.1016/j.cytogfr.2017.03.005
161 - McInnes IB. Cytokines. In: Firestein GS, Budd RC, Gabriel SE, McInnes IB, O’Dell JR, editors. Kelley and Firestein’s Textbook of Rheumatology. 10th ed. Philadelphia, PA. Elsevier. Health Sciences; 2016. p. 396-407. DOI: 10.1016/B978-0-323-31696-5.00026-7
162 - Gadina M, Gazaniga N, Vian L, Furumoto Y. Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases. Journal of Autoimmunity. 2017. pii: S0896-8411(17):pii: S0896-8411(17)30411-0. DOI: 10.1016/j.jaut.2017.06.006
163 - Kakar S. Cytokines evolution: Role in various diseases. Current Medicine Research and Practice. 2017;5(4):176-182. DOI: 10.1016/j.cmrp.2015.07.002
164 - Proudfoot AE, Bonvin P, Power CA. Targeting chemokines: Pathogens can, why can’t we? Cytokine. 2015;74(2):259-267. DOI: 10.1016/j.cyto.2015.02.011
165 - Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein 1 (MCP-1): An overview. Journal of Interferon & Cytokine Research. 2009;29(6):313-326. DOI: 10.1089/jir.2008.0027
166 - Rollins BJ. Chemokines. Blood. 1997;90(3):909-928 PMID: 9242519
167 - Baggiolini M. Chemokines and leukocyte traffic. Nature. 1998;392(6676):565-568. DOI: 10.1038/33340
168 - Charo IF, Ransohoff RM. The many roles of chemokines and chemokine receptors in inflammation. The New England Journal of Medicine. 2006;354(6):610-621. DOI: 10.1056/NEJMra052723
169 - Chen C, Chu SF, Liu DD, Zhang Z, Kong LL, Zhou X, Chen NH. Chemokines play complex roles in cerebral ischemia. Neurochemistry International. 2017. DOI: 10.1016/j.neuint.2017.06.008
170 - Kelner GS, Kennedy J, Bacon KB, Kleyensteuber S, Largaespada DA, Jenkins NA, Copeland NG, Bazan JF, Moore KW, Schall TJ, Zlotnik A. Lymphotactin: A cytokine that represents a new class of chemokine. Science. 1994;266(5189):1395-1399 PMID: 7973732
171 - Kotas ME, Medzhitov R. Homeostasis, inflammation, and disease susceptibility. Cell. 2016;160(5):816-827. DOI: 10.1016/j.cell.2015.02.010
172 - Nathan C. Points of control in inflammation. Nature. 2002;420(6917):846-852. DOI: 10.1038/nature01320
173 - Medzhitov R. Inflammation 2010: New adventures of an old flame. Cell. 2010;140(6):771-776. DOI: 10.1016/j.cell.2010.03.006
174 - Yano T, Kurata S. Intracellular recognition of pathogens and autophagy as an innate immune host defence. Journal of Biochemistry. 2011;150(2):143-149. DOI: 10.1093/jb/mvr083
175 - Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454(7203):428-435. DOI: 10.1038/nature07201
176 - Vergnolle N. The inflammatory response. Drug development research. 2003;59(4):375-381. DOI: 10.1002/ddr.10306
177 - Gilroy DW, Lawrence T, Perretti M, Rossi AG. Inflammatory resolution: New opportunities for drug discovery. Nature Reviews Drug Discovery. 2004;3(5):401-416. DOI: 10.1038/nrd1383
178 - Headland SE, Norling LV. The resolution of inflammation: Principles and challenges. Seminars in Immunology. 2015;27(3):149-160. DOI: 10.1016/j.smim.2015.03.014
179 - Curtis MM, Way SS. Interleukin-17 in host defence against bacterial, mycobacterial and fungal pathogens. Immunology. 2009;126(2):177-185. DOI: 10.1111/j.1365-2567.2008.03017.x
180 - Barth K, Remick DG, Genco CA. Disruption of immune regulation by microbial pathogens and resulting chronic inflammation. Journal of Cellular Physiology. 2013;228(7):1413-1422. DOI: 10.1002/jcp.24299
181 - Kara EE, Comerford I, Fenix KA, Bastow CR, Gregor CE, McKenzie DR, McColl SR. Tailored immune responses: Novel effector helper T cell subsets in protective immunity. PLoS Pathogens. 2014;10(2):e1003905. DOI: 10.1371/journal.ppat.1003905
182 - Romani L. Immunity to fungal infections. Nature Reviews Immunology. 2011;11(4):275-288. DOI: 10.1038/nri2939
183 - Williams PB, Barnes CS, Portnoy JM. Innate and adaptive immune response to fungal products and allergens. The Journal of Allergy and Clinical Immunology. In Practice. 2016;4(3):386-395. DOI: 10.1016/j.jaip.2015.11.016
184 - Taghavi M, Khosravi A, Mortaz E, Nikaein D, Athari SS. Role of pathogen-associated molecular patterns (PAMPS) in immune responses to fungal infections. European Journal of Pharmacology. 2017;808:8-13. DOI: 10.1016/j.ejphar.2016.11.013
185 - Saïd-Sadier N, Padilla E, Langsley G, Ojcius DM. Aspergillus fumigatus stimulates the NLRP3 inflammasome through a pathway requiring ROS production and the Syk tyrosine kinase. PloS One. 2010;5(4):e10008. DOI: 10.1371/journal.pone.0010008
186 - Hardison SE, Brown GD. C-type lectin receptors orchestrate antifungal immunity. Nature Immunology. 2012;13(9):817-822. DOI: 10.1038/ni.2369
187 - Kimura Y, Chihara K, Honjoh C, Takeuchi K, Yamauchi S, Yoshiki H, Fujieda S, Sada K. Dectin-1-mediated signaling leads to characteristic gene expressions and cytokine secretion via spleen tyrosine kinase (Syk) in rat mast cells. The Journal of Biological Chemistry. 2014;289(45):31565-31575. DOI: 10.1074/jbc.M114.581322
188 - Brown GD. Innate antifungal immunity: The key role of phagocytes. Annual Review of Immunology. 2011;29:1-21. DOI: 10.1146/annurev-immunol-030409-101229
189 - Thimme R, Lohmann V, Weber F. A target on the move: Innate and adaptive immune escape strategies of hepatitis C virus. Antiviral Research. 2006;69(3):129-141. DOI: 10.1016/j.antiviral.2005.12.001
190 - Koziel MJ. Cellular immune responses against hepatitis C virus. Clinical Infectious Diseases. 2005;41(Suppl 1):S25-S31. DOI: 10.1086/429492
191 - Accapezzato D, Visco V, Francavilla V, Molette C, Donato T, Paroli M, Mondelli MU, Doria M, Torrisi MR, Barnaba V. Chloroquine enhances human CD8+ T cell responses against soluble antigens in vivo. The Journal of Experimental Medicine. 2005;202(6):817-828. DOI: 10.1084/jem.20051106
192 - Grencis RK, Humphreys NE, Bancroft AJ. Immunity to gastrointestinal nematodes: Mechanisms and myths. Immunological Reviews. 2014;260(1):183-205. DOI: 10.1111/imr.12188
193 - McSorley HJ, Maizels RM. Helminth infections and host immune regulation. Clinical Microbiology Reviews. 2012;25(4):585-608. DOI: 10.1128/CMR.05040-11
194 - Zaph C, Cooper PJ, Harris NL. Mucosal immune responses following intestinal nematode infection. Parasite Immunology. 2014;36(9):439-452. DOI: 10.1111/pim.12090
195 - Bruschi F, Chiumiento L. Immunomodulation in trichinellosis: Does Trichinella really escape the host immune system? Endocrine, Metabolic & Immune Disorders Drug Targets. 2012;12(1):4-15. DOI: 10.2174/187153012799279081
196 - Ashour DS. Trichinella spiralis immunomodulation: An interactive multifactorial process. Expert Review of Clinical Immunology. 2013;9(7):669-675. DOI: 10.1586/1744666X.2013.811187
197 - Ilic N, Worthington JJ, Gruden-Movsesijan A, Travis MA, Sofronic-Milosavljevic L, Grencis RK. Trichinella spiralis antigens prime mixed Th1/Th2 response but do not induce de novo generation of Foxp3+ T cells in vitro. Parasite Immunology. 2011;33(10):572-582. DOI: 10.1111/j.1365-3024.2011.01322.x
198 - Sofronic-Milosavljevic L, Ilic N, Pinelli E, Gruden-Movsesijan A. Secretory products of Trichinella spiralis muscle larvae and immunomodulation: Implication for autoimmune diseases, allergies, and malignancies. Journal of Immunology Research. 2015;2015:523875. DOI: 10.1155/2015/523875
199 - Gruden-Movsesijan A, Ilic N, Colic M, Majstorovic I, Vasilev S, Radovic I, Lj S-M. The impact of Trichinella spiralis excretory-secretory products on dendritic cells. Comparative Immunology, Microbiology and Infectious Diseases. 2011;34(5):429-439. DOI: 10.1016/j.cimid.2011.08.004
200 - Kim S, Park MK, Yu HS. Toll-like receptor gene expression during Trichinella spiralis infection. The Korean Journal of Parasitology. 2015;53(4):431-438. DOI: 10.3347/kjp.2015.53.4.431
201 - Gentilini MV, Nuñez GG, Roux ME, Venturiello SM. Trichinella spiralis infection rapidly induces lung inflammatory response: The lung as the site of helminthocytotoxic activity. Immunobiology. 2011;216(9):1054-1063. DOI: 10.1016/j.imbio.2011.02.002
202 - Ilic N, Colic M, Gruden-movsesijan A, Majstorovic I, Vasilev S, Sofronic-Milosavljevic LJ. Characterization of rat bone marrow dendritic cells initially primed by Trichinella spiralis antigens. Parasite Immunology. 2008;30(9):491-495. DOI: 10.1111/j.1365-3024.2008.01049.x
203 - Muñoz-Carrillo JL, Contreras-Cordero JF, Muñoz-López JL, Maldonado-Tapia CH, Muñoz-Escobedo JJ, Moreno-García MA. Resiniferatoxin modulates the Th1 immune response and protects the host during intestinal nematode infection. Parasite Immunology. 2017;39(9):1-16. DOI: 10.1111/pim.12448
204 - YR Y, Deng MJ, WW L, Jia MZ, Wu W, Qi YF. Systemic cytokine profiles and splenic toll-like receptor expression during Trichinella spiralis infection. Experimental Parasitology. 2013;134(1):92-101. DOI: 10.1016/j.exppara.2013.02.014
205 - Ming L, Peng RY, Zhang L, Zhang CL, Lv P, Wang ZQ, Cui J, Ren HJ. Invasion by Trichinella spiralis infective larvae affects the levels of inflammatory cytokines in intestinal epithelial cells in vitro. Experimental Parasitology. 2016;170:220-226. DOI: 10.1016/j.exppara.2016.10.003
206 - Muñoz-Carrillo JL, Muñoz-Escobedo JJ, Maldonado-Tapia CH, Chávez-Ruvalcaba F, Moreno-García MA. Resiniferatoxin lowers TNF-α, NO and PGE2 in the intestinal phase and the parasite burden in the muscular phase of Trichinella spiralis infection. Parasite Immunology. 2017;39(1):1-14. DOI: 10.1111/pim.12393
207 - Andrade MA, Siles-Lucas M, López-Abán J, Nogal-Ruiz JJ, Pérez-Arellano JL, Martínez-Fernández AR, Muro A. Trichinella: Differing effects of antigens from encapsulated and non-encapsulated species on in vitro nitric oxide production. Veterinary Parasitology. 2007;143(1):86-90. DOI: 10.1016/j.vetpar.2006.07.026
208 - Ilic N, Gruden-Movsesijan A, Sofronic-Milosavljevic L. Trichinella spiralis: Shaping the immune response. Immunologic Research. 2012;52(1-2):111-119. DOI: 10.1007/s12026-012-8287-5
209 - Sofronic-Milosavljevic LJ, Radovic I, Ilic N, Majstorovic I, Cvetkovic J, Gruden-Movsesijan A. Application of dendritic cells stimulated with Trichinella spiralis excretory-secretory antigens alleviates experimental autoimmune encephalomyelitis. Medical Microbiology and Immunology. 2013;202(3):239-249. DOI: 10.1007/s00430-012-0286-6
210 - Bruschi F, Korenaga M, Watanabe N. Eosinophils and Trichinella infection: Toxic for the parasite and the host? Trends in Parasitology. 2008;24(10):462-467. DOI: 10.1016/j.pt.2008.07.001
211 - Gurish MF, Bryce PJ, Tao H, Kisselgof AB, Thornton EM, Miller HR, Friend DS, Oettgen HC. IgE enhances parasite clearance and regulates mast cell responses in mice infected with Trichinella spiralis. Journal of Immunology. 2004;172(2):1139-1145. DOI: 10.4049/jimmunol.172.2.1139
212 - Wang LJ, Cao Y, Shi HN. Helminth infections and intestinal inflammation. World Journal of Gastroenterology. 2008;14(33):5125-5132. DOI: 10.3748/wjg.14.5125
213 - Rogerio AP, Anibal FF. Role of leukotrienes on protozoan and helminth infections. Mediators of Inflammation. 2012;2012:595694. DOI: 10.1155/2012/595694
214 - Knight PA, Brown JK, Pemberton AD. Innate immune response mechanisms in the intestinal epithelium: Potential roles for mast cells and goblet cells in the expulsion of adult Trichinella spiralis. Parasitology. 2008;135(6):655-670. DOI: 10.1017/S0031182008004319
215 - Akiho H, Ihara E, Motomura Y, Nakamura K. Cytokine-induced alterations of gastrointestinal motility in gastrointestinal disorders. World Journal of Gastrointestinal Pathophysiology. 2011;2(5):72-81 PMID: 22013552