Its mechanisms include physical, chemical and biological barriers, cellular components, as well as soluble molecules. The organism first line of defense against tissue damage involves several steps closely integrated and constituted by different components of this system.
The aim of this review is to restore the foundations of this response, which has high complexity and consists of several components that converge to articulate the development of adaptive immune response. We selected some of the following steps to review: perception and molecular recognition of aggressive agents; activation of intracellular pathways, which result in vascular and tissue changes; production of a myriad of mediators with local and systemic effects on cell activation and proliferation, synthesis of new products involved in the chemoattraction and migration of cells specialized in destruction and removal of offending agent; and finally, tissue recovery with restoration of functional tissue or organ.
The immune function has been conceptually divided into innate and adaptive immunity.
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Innate immunity represents a rapid and stereotyped response to a large but limited number of stimuli. It is represented by physical, chemical, and biological barriers, specialized cells and soluble molecules, present in all individuals, irrespective of previous contact with offending agents or immunogens, and does not change qualitatively or quantitatively after contact. The main effector cells of innate immunity are macrophages, neutrophils, dendritic cells, and natural killer NK cells Table 1. Phagocytosis, release of inflammatory mediators, activation of complement system proteins, as well as synthesis of acute phase proteins, cytokines and chemokines are the main mechanisms in innate immunity.
These mechanisms are activated by specific stimuli, represented by molecular structures of ubiquitous occurrence in microorganisms, but not in human species. Molecules commonly found on the surface of microorganisms, such as lipopolysaccharides, mannose and teichoic acids constitute pathogen-associated molecular patterns PAMPs and activate the innate immune response by interaction with different receptors known as pattern recognition receptors PRR , among which is the family of Toll-like receptors TLRs.
Among the various PRRs involved in opsonization, complement activation, and phagocytosis, the TLRs are distinguished by their central role in binding to pathogens and initiating the inflammatory response. These receptors are present mainly on macrophages, neutrophils, and dendritic cells DCs. Currently, eleven different TLRs have been identified, some located in the cell membrane, others inside the cells Figure 1. Phagocytosis begins with adhesion of the phagocyte surface receptors to the pathogen, which then is internalized into vesicles called phagosomes.
Inside the phagocyte, the phagosome fuses to lysosomes, whose contents are released with consequent digestion and pathogen elimination. The absence of ROS determines serious deficiency in the destructive capacity of phagocytes, being responsible for a significant primary immunodeficiency called chronic granulomatous disease. Unlike innate response, adaptive or acquired immune response depends on activation of specialized cells the lymphocytes and soluble molecules produced by lymphocytes Table 1. The main features of acquired response are: specificity and diversity of recognition, memory, specialized response, self-restraint, and tolerance to components of the organism itself.
Although the main cells involved in acquired immune response are lymphocytes, antigen presenting cells APCs play a key role in its activation, presenting antigens associated with molecules of the major histocompatibility complex MHC to T lymphocyte TL. Dendritic cells, specialized in capturing and presenting antigens to lymphocytes, are considered a bridge between innate and adaptive immunity because they are attracted and activated by elements of innate response and permit TL sensibilization of adaptive immune response.
Dendritic cells reside in peripheral tissues, such as skin, liver, and intestine, where they capture antigens and become activated and migrate to regional lymph nodes, in which they process and present protein antigen or lipid to TLs. Immature DCs are highly efficient in capturing antigens, while mature DCs are very efficient in presenting antigens. During their lifetime, the immature DCs migrate from bone marrow into bloodstream, reaching peripheral tissues as skin, where they become residents Langerhans cells.
A curious aspect is that DCs are the first cells to arrive at a site of infection, preceding even the neutrophils. After contact with antigen, DCs become activated and migrate through lymphatic vessels to secondary lymphoid organs Figure 3. Therefore, DCs are essential for the initiation and coordination of the acquired immune response. There are two pathways of DCs differentiation from a common progenitor. DCs are crucial for determining the activation and type of immunity mediated by TLs.
Antibody fc : linking adaptive and innate immunity
In general, immature DCs are tolerogenic, while mature DCs are immunostimulatory. However, in some contexts, mature DCs can expand the population of TLs regulators. Induction of tolerance or immune response depends on the set of signals received by DCs, such as activation of TLRs and cytokines present in the environment. Neutrophils are the most abundant leukocytes in peripheral blood, with an important role in the early stages of inflammatory reaction and sensitive to chemotactic agents, such as cleavage products of complement fractions C3a and C5a and substances released by mast cells and basophils.
They are among the first cells to migrate from vessels to tissues attracted by chemokines, such as IL-8, and are activated by various stimuli, such as bacterial products, complement proteins C5a , immune complex IC , chemokines, and cytokines.
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These cells also undergo degranulation, releasing three classes of granules in the extracellular environment:. Primary or azurophilic granules that contain important mediators, such as myeloperoxidase, defensins, neutrophil elastase, permeability-increasing protein, and bacterial cathepsin G. Secondary granules with components specifically secreted by neutrophils, with lactoferrin is a prime example.
Tertiary granules with cathepsins and gelatinases as main proteins. Recent studies have shown that neutrophils can also generate the so-called neutrophil extracellular traps NETs formed by granule substances and nuclear components capable of calling off the virulence factors and destroying extracellular bacteria. The NETs are present in large quantity in inflammatory sites, acting directly on microorganisms and also serving as a physical barrier that prevents spreading.
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Under normal conditions, neutrophils are cleared from the circulation and inflamed tissues by apoptosis. Disturbances in these cells apoptosis have been associated with several autoimmune conditions, especially SLE, as circulating apoptotic debris containing nuclear material could lead to the induction of a huge variety of autoantibodies.
Monocytes and macrophages are efficient phagocytes, engulfing pathogens and cellular debris. Unlike neutrophils, macrophages can remain in tissue for months to years, acting as true sentinels. Besides having a role in innate immunity, macrophages process and present antigens via MHC molecules, thus stimulating the response mediated by TL.
Recently, the existence of three subpopulations of macrophages was proposed: activated, tissue repair, and regulator macrophages. The first would be the classic macrophages with tumoricidal and microbicidal activity, which secrete large amounts of proinflammatory mediators and cytokines, present antigens to TLs, and are involved in cellular immune response. The second type, activated by IL-4, would be primarily involved in tissue repair by stimulating fibroblasts and promoting extracellular matrix deposition.
The third type would exert regulatory activity through release of IL, an anti-inflammatory cytokine. They also produce reactive oxygen species ROS , such as superoxide anion, hydroxyl radical, hydrogen peroxide H2O2 , and reactive nitrogen intermediates whose main representative is nitric oxide NO. Some microorganisms, like Mycobacterium tuberculosis , are resistant to the microbicidal action and remain viable for a long time in macrophages' phagosomes.
These macrophages become large and multinucleated giant cells and, together with lymphocytes and fibroblasts that accumulate around them, form granulomas, which are the body's attempt to prevent the spread of the pathogen. They are an important line of nonspecific defense, recognizing and lysing cells infected by viruses, bacteria and protozoa, as well as tumor cells. Furthermore, they recruit neutrophils and macrophages, activate DCs and T and B lymphocytes. The cytolysis mediated by NKs occurs through the action of the enzymes perforins, which create pores in membrane of target cells, and granzymes, which penetrate into cells and trigger cell death by apoptosis.
NK cells have activation and inhibition receptors, and the balance between the signals generated by these receptors determines NK activation. One class of receptors belongs to the immunoglobulin superfamily KIR , while the other belongs to the family of C-type lectins. In humans, there are 14 KIRs, eight activators and six inhibitors.
In general, there is dominance of inhibitory receptors, preventing lysis of host's normal cells that express MHC class I. Infected cells, especially by viruses, and tumor cells often have low expression of MHC class I proteins, becoming vulnerable to the action of NK Figure 4. From bone marrow, the progenitors migrate to peripheral tissues as immature cells and differentiate in situ according to the particular characteristics of the microenvironment.
Stimuli such as products of complement activation, basic substances, including some animals' poisons, certain neuropeptides, and several physical agents mechanical trauma, heat, and cold can activate mast cells independently of IgE binding. The binding of bacterial components to TLRs 1, 2, 4, and 6, and other specific receptors such as CD48, also activates mast cells, leading to mediators' release. After the stimulus, degranulation and release of preformed mediators occur, followed by the release of newly formed mediators.
The mediators formed following activation include platelet activating factor PAF , arachidonic acid derivatives, and a series of cytokines. These autoantibodies cause histamine release and characterize the chronic autoimmune urticaria, with clinical and histological features similar to those found in a late-phase reaction. There is experimental evidence of mast cells involvement in cardiovascular diseases, neoplastic diseases, parasitic and bacterial infections, fibrotic diseases, and autoimmune diseases.
Although notnormally presentin tissues, they can be recruited to inflammatory sites, together with eosinophils. The granules found in basophils have mediators similar to those of mast cells. Granulocytes and eosinophils are important infection-fighting cells, and their antiparasitic action helminths is one of the most powerful and effective. They are also important in allergic reactions and asthma. Eosinophils develop in the bone marrow, producing and storing various secondary proteolytic granules before leaving the marrow.
After maturation, they circulate through the bloodstream in small amounts and can be found in greater numbers in mucosal regions, such as gastrointestinal, respiratory, and genitourinary tracts. Once activated, eosinophils induce inflammation through production and release of eosinophilic cationic content of granules. The main components of these granules are: major basic protein, eosinophil cationic protein, eosinophil derived neurotoxin, and eosinophil peroxidase, which have great potential cytotoxicity on parasites, but also can cause tissue injury.
Eosinophil cationic protein and neurotoxin are ribonucleases with antiviral properties. The major basic protein presents toxicity to parasites, induces degranulation of mast cells and basophils, and activates the synthesis of remodeling factors by epithelial cells. Eosinophil cationic protein creates pores in target-cell membrane, allowing the entry of other cytotoxic molecules; inhibits TL proliferation; suppresses antibody production by LB; induces degranulation of mast cells; and stimulates secretion of glucosaminoglycans by fibroblasts.
Eosinophil peroxidase forms ROS and NO, promoting oxidative stress in target-cell and causing cell death by apoptosis and necrosis. Complement system CS consists of a family of more than 20 plasma glycoproteins, synthesized in the liver, but also by macrophages and fibroblasts. Each SC activated component acquires proteolytic activity activating the next elements in cascade. Throughout the process, there is the production of several mediators that alter vascular permeability and contribute to the development of inflammatory response.
Finally, there is formation of membrane attack complex MAC , which promotes osmotic lysis of target-cell, favoring the elimination of the infectious agent. The activation of these pathways contributes to the integration of effector mechanisms of innate and adaptive immunity Figure 5. In the innate immune response, pathogens that invade the organism encounter soluble substances of innate immune response, such as CS proteins, C-reactive protein, and others.
In adaptive immunity, CS is activated by binding of preformed antibodies to pathogen or antigen immune complex. C4bC2a complex is the C3 convertase of the classical pathway, which cleaves C3 into soluble C3a and C3b, which in turn binds to C4bC2a at the surface of microorganism. The classical pathway resembles the lectin pathway and is initiated by the binding of C1q component to two molecules of IgG or to one molecule of IgM, complexed with the target antigen immune complexes.
This binding activates the proteases R C1r and S C1s associated with C1q, cleaving components C2 and C4 and following the pathway, as described. Because the classical pathway depends on the prior production of specific antibodies attached to the surface of pathogens, it is associated with specific humoral immune response.
The alternative pathway begins with the spontaneous rupture of the C3 component into C3a and C3b fragments Figure 5. A thioester binding in fragment C3b is exposed with this cleavage, which allows their covalent binding to the surface of invading microorganisms. If there is no binding of C3b component, thioesters binding site is rapidly hydrolyzed and the fragment is inactivated. The C3bBb complex alternative pathway C3 convertase cleaves more C3 molecules and remains on the surface.
This complex is stabilized by properdin Factor P , amplifying the breakdown of C3. There is a vast literature regarding antibody effector function, indicating that it is a high impact and dynamic area. The book is also recommended as an excellent resource for academic, government and company libraries. The first two parts discuss effector mechanisms and their mediating cells including antibody-dependent cytotoxicity, the complement system, phagocytosis, natural killer and B cells. Parts III-IV cover general properties of Fc immune receptors, receptor variation amongst species, and the structural variations and glycoside modifications of the Fc domain.
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Provides a comprehensive reference of antibody functions mediated by the Fc domain Clarifies the different mechanisms of IgG activity at the level of the different model systems used Demonstrates the importance of the Fc domain, including protective mechanisms, effector cell types, genetic data, and variability in Fc domain function Covers the role of antibodies in cancer, infectious disease, and autoimmunity, and in both the setting of monoclonal antibody therapy as well as naturally raised antibodies Uniquely concentrates on the therapeutic mechanism of antibodies Industry Reviews " Fanatical About Frogs.
Alteration of polymorphonuclear neutrophil surface receptor expression and migratory activity after isolation: comparison of whole blood and isolated PMN preparations from normal and post fracture trauma patients. J Trauma 60 4 — J Immunol 6 — Defective functions of polymorphonuclear neutrophils in patients with common variable immunodeficiency. Immunol Res 60 1 — Ziegler-Heitbrock L.
Blood monocytes and their subsets: established features and open questions. Gene expression profiling reveals the defining features of the classical, intermediate, and nonclassical human monocyte subsets. Blood 5 :e16— Intravenous immunoglobulin replacement induces an in vivo reduction of inflammatory monocytes and retains the monocyte ability to respond to bacterial stimulation in patients with common variable immunodeficiencies. Int Immunopharmacol 28 1 — Clin Immunol 2 — Cell death modulation by intravenous immunoglobulin.
J Clin Immunol 30 Suppl 1 :S24— CD1 antigen presentation: how it works. Nat Rev Immunol — Human dendritic cell subsets.
Immunology 1 — Sallusto F, Lanzavecchia A. J Exp Med 4 — Inhibition of maturation and function of dendritic cells by intravenous immunoglobulin.
Blood 2 — Selective deficits in blood dendritic cell subsets in common variable immunodeficiency and X-linked agammaglobulinaemia but not specific polysaccharide antibody deficiency. Clin Immunol 1 — Amelioration of differentiation of dendritic cells from CVID patients by intravenous immunoglobulin. Am J Med 12 — PLoS One 8 10 :e Blood 10 — Blood 24 —4. Natural antibodies sustain differentiation and maturation of human dendritic cells. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood — Common variable immunodeficiency disorders: division into distinct clinical phenotypes.
B cell receptor-mediated calcium signaling is impaired in B lymphocytes of type Ia patients with common variable immunodeficiency. J Immunol — Toll-like receptor 7 and 9 defects in common variable immunodeficiency. J Allergy Clin Immunol — Modulation of the cellular immune system by intravenous immunoglobulin. Trends Immunol 29 12 — Intravenous immunoglobulin preparations have no direct effect on B cell proliferation and immunoglobulin production.
Clin Exp Immunol 1 — Autoimmun Rev 11 2 —6. Intravenous immunoglobulin induces a functional silencing program similar to anergy in human B cells. J Allergy Clin Immunol 1 —8. Intravenous immunoglobulin induces proliferation and immunoglobulin synthesis from B cells of patients with common variable immunodeficiency: a mechanism underlying the beneficial effect of IVIg in primary immunodeficiencies.
J Autoimmun 36 1 :9— Nat Immunol — Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells. Telomere-dependent replicative senescence of B and T cells from patients with type 1a common variable immunodeficiency. Eur J Immunol 41 3 — Dysregulated extracellular signal-regulated kinase signaling associated with impaired B-cell receptor endocytosis in patients with common variable immunodeficiency. J Allergy Clin Immunol 2 — Intravenous immunoglobulin replacement therapy in common variable immunodeficiency induces B cell depletion through differentiation into apoptosis-prone CD21 low B cells.
Immunol Res 60 2—3 —8. J Allergy Clin Immunol Pract 4 1 — Late-onset combined immune deficiency: a subset of common variable immunodeficiency with severe T cell defect.
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