Although innate immunity does not generate antigen specific protective immunity and does not rely on specific pathogen recognition, it, nevertheless, provides a powerful line of defense. In addition, to the physiologic barriers of protection, the innate system has both cells and proteins (such as, cytokines and complement) at its disposal. Phagocytic leukocytes, such as polymorphonuclear neutrophilic leukocytes (neutrophils), and macrophages along with NK cells are the primary cellular components to combat microbes. The inter action of the invading microbe with these cells and other cells throughout the body triggers the release of complement and numerous cytokines. Many of these cytokines are proinflammatory molecules such as interleukin-1 (IL-1), tumor necrosis actor-alpha (TNF-α), interleukin-6 (IL-6), and the interferons, and are induced through TLR interactions. Armed with these special tools, the host initiates its defense against the invading pathogen.

A. Microbial Sensors

When a pathogen enters the skin, it is confronted by macro phages and other phagocytic cells possessing “microbial sensors.” There are three major groups of microbial sensors: (1) TLRs, (2) NOD-like receptors (NLRs), and (3) RIG-1–like helicases and MDA-5. The TLRs are the best studied of the microbial sensors. They are a family of evolutionary con served pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs). They constitute a first line of defense against a variety of pathogens and play a critical role in initiating the innate immune response. TLRs are type 1 transmembrane proteins with an extracellular domain, a single transmembrane α-helix, and a cytoplasmic domain. TLR recognition of these specific microbial patterns leads to a signal transduction cascade that generates a rapid and robust inflammatory response marked by cellular activation and cytokine release.

To date, 10 human TLRs have been identified, and each receptor appears to be involved in the recognition of a unique set of microbial patterns. For example, TLR2 recognizes various ligands (eg, lipoteichoic acid) expressed by gram positive bacteria, whereas TLR3 engages double-stranded RNA (dsRNA) in viral replication. TLR1 and TLR6 recognize multiple diacyl peptides (eg, mycoplasma), whereas TLR4 is specific for gram-negative lipopolysaccharides (LPS). TLR5, on the other hand, recognizes bacterial flagellin, and TLR7 and TLR8 interact with single-stranded RNA (ssRNA) in viral replication and TLR9 binds bacterial and viral DNA. At present, TLR10 remains an orphan receptor.

Another large family of innate receptors, NLRs, are located in the cytoplasm and serve as intracellular sensors for microbial products. They activate the nuclear factor kappa light chain–enhancer of activated B cells (NF-κB) pathway and drive inflammatory responses similar to the TLRs. The third group of microbial sensors is the RIG-1–like helicases and melanoma differentiation-associated protein 5 (MDA5). These are cytoplasmic sensors of viral ssRNA. The engagement of ssRNA with these sensors triggers the production of the type 1 IFNs. These IFNs are highly effective inhibitors of viral replication.

B. Cellular Components and Phagocytosis

The key elements of effective innate immunity are responses that are rapid, nonspecific, and of short duration. These features are the hallmark of the phagocytic process. During infection, circulating phagocytic cells increase and can participate in chemotaxis, migration, ingestion, and microbial killing. Any antigen (microorganism) that enters the body through the lymphatics, lung, or bloodstream is engulfed by phagocytic cells.

Therefore, phagocytes, present in the blood, lymphoid tis sue, liver, spleen, lung, and other tissues, are the cells responsible for the uptake and removal of foreign antigen. Phagocytes include (1) monocytes and macrophages; (2) granulocytes, including neutrophils, eosinophils, and basophils; and (3) dendritic cells. Monocytes are small leukocytes that circulate in the blood and mature into macrophages that can be found in almost all tissues. For example, they are known as Kupffer cells in the liver and microglial cells in the nervous tissue. Macrophages are critical cells that engulf and kill pathogens, process and present antigen, and regulate immune reactivity by producing a variety of molecules (eg, cytokines).

Granulocytes are leukocytes that contain densely staining granules. Neutrophils have a short half-life and are important phagocytic cells that destroy pathogens within intracellular vesicles. Eosinophils and basophils are less abundant and store granules containing enzymes and toxic proteins that can be released upon activation of the cells. Dendritic cells are also phagocytic and can degrade pathogens; however, their main role is to activate T cells in the adaptive immune response by acting as APCs and by producing regulatory cytokines (eg, IFN-α).

Phagocytosis is a multistep process whereby a phagocytic cell, like a neutrophil, recognizes the pathogen, ingests it, and then destroys the engulfed organism. Once a pathogen enters the blood or tissue, the phagocytic cell migrates to that site. This migration is dependent on the release of chemoattractant signals produced by either the cells of the host or the pathogen. One chemoattractant is IL-8, a potent chemotactic cytokine that attracts neutrophils. More recently IL-17 has been shown to be an effective chemoattractant. In the initial stage of the migration process, neutrophils attach to the endothelial cell surface by means of adhesion molecules, such as P-selectin. Neutrophils follow the chemokine attraction and migrate from the circulation through the endothelium into the tissues and to the site of infection. Here the neutrophil recognizes, engulfs, and internalizes the pathogen into an endocytic vesicle called a phagosome. Once inside the neutrophil, the pathogen is killed.

There are several antimicrobial mechanisms used by phagocytes to eliminate the pathogen. For example, (1) acidification occurs within the phagosome. The phagosome pH is 3.5–4.0, and this level of acidity is bacteriostatic or bactericidal. (2) Toxic oxygen-derived products are generated and include superoxide O₂⁻, hydrogen peroxide H₂O₂ , and singlet oxygen O₂ . (3) Toxic nitrogen oxides are also produced, and nitric oxide NO is formed. (4) Phagocytic cells generate anti-microbial peptides that participate in pathogen killing. In the macrophage, cathelicidin and macrophage elastase–derived peptides are found. The neutrophil, on the other hand, is rich in α-defensins, β-defensin, cathelicidin, and lactoferricin. All of these mechanisms are used by the phagocytes to destroy the pathogen. When the neutrophil completes its mission, it undergoes apoptosis and dies.

As already mentioned, phagocytosis can occur without antibody. However, phagocytosis is more efficient when antibodies are available to coat the surface of bacteria and facilitate their ingestion. This process is called opsonization and it can occur by the following mechanisms: (1) antibody alone can act as opsonin; (2) antibody and antigen can trigger the complement system (via the classic pathway) to generate opsonin; and (3) opsonin may be produced when the alternative pathway is activated and C3 is generated. Macrophages have receptors on their membranes for the Fc portion of an antibody and for the complement component C3. Both of these receptors facilitate the phagocytosis of the antibody coated pathogen.

C. Natural Killer Cells

Natural killer (NK) cells are large, granular lymphocytes morphologically related to T cells, which make up 10–15% of blood leukocytes. NK cells contribute to innate immunity by providing protection against viruses and other intracellular pathogens. NK cells have the ability to recognize and kill virus-infected cells and tumor cells. NK cells express two types of surface receptors: (1) lectin-like NK-cell receptors that bind proteins not carbohydrates and (2) killer immunoglobulin-like receptors (KIRs) that recognize the major histocompatibility complex (MHC) class I molecules. These NK-cell receptors have both activation and inhibition properties. NK cells contain large amounts of granzyme and perforin, substances that mediate the cytotoxic actions of NK cells.

In addition, when antibody production is initiated in the adaptive immune response, NK cells play a critical role in antibody-dependent cellular cytotoxicity (ADCC). In this process, specific antibody binds to the target cell surface. The NK cell has Fc receptors that bind to the attached antibody and kill the cell. This property allows the NK cell another opportunity to inhibit the replication of viruses and intracellular bacteria.

NK cells and the IFN system are both integral parts of innate immunity that communicate with each other. NK cells are one of the two primary sources of IFN-γ, a potent anti-viral and immunoregulating cytokine. Moreover, the lytic activity of NK cells is enhanced by the type 1 IFNs (IFN-α and IFN-β). These two cytokines are actually induced by the invading virus.

D. Complement System

 The complement system is another key component of innate immunity. This system consists of 30 proteins found in the serum or on the membrane of selected cells that interact in a cascade. When complement is activated, it initiates a series of biochemical reactions that ultimately culminate in cellular lysis or destruction of the pathogen. As described later in this chapter, there are three complement pathways: classic, alternative, and lectin. Even though each has a different initiating mechanism, they all result in the lysis of the offending invader. The alternative and lectin pathways serve as critical first lines of defense and provide immediate protection against microorganisms. The alternative complement path way can be activated by microbial surfaces and it can proceed in the absence of antibody. Likewise, the lectin pathway also bypasses antibody and uses a lectin, mannose-binding lectin (MBL), to initiate events. The complement proteins can achieve their defense mission in several ways, including opsonization, lysis of bacteria, and amplification of inflammatory responses through the anaphylatoxins, C5a and C3a. Complement is described in more detail later in this chapter.

Some microbes have acquired mechanisms to sabotage the complement system and evade the immune response. For example, poxviruses, such as vaccinia virus and smallpox, encode a soluble protein with complement regulatory activity that leads to inhibition of the complement system.

E. Mediators of Inflammation and the Interferons

In the section on mechanisms of innate immunity, it was mentioned that various cells and complement components of innate immunity orchestrate their effects through the production of soluble mediators. These mediators include cytokines, prostaglandins, and leukotrienes. Here in this section, the role of these mediators in inflammation is outlined. A separate detailed description on cytokines is found in the section on adaptive immune response.

Injury to tissue initiates an inflammatory response. This response is dominated mainly by soluble mediators, referred to as cytokines. Cytokines may include inflammatory and anti-inflammatory cytokines, chemokines, adhesion molecules, and growth factors. During the innate immune response, leukocytes, such as macrophages, release a variety of cytokines, including IL-1 and TNF-α, and IL-6. The other mediators released from activated macrophages and other cells include prostaglandins and leukotrienes. These inflammatory mediators regulate changes in local blood vessels. This begins with dilation of local arterioles and capillaries. During dilation, plasma escapes and accumulates in the area of injury. Fibrin is formed which occludes the lymphatic channels, limiting the spread of organisms.

A second effect of these mediators is to induce changes in the expression of adhesion molecules expressed on the sur face of endothelial cells and leukocytes. Adhesion molecules (eg, selectins and integrins) cause leukocytes to attach to the endothelial cells and thereby promote their movement across the vessel wall. Thus, cells stick to the capillary walls and then migrate out (extravasation) of the capillaries in the direction of the irritant. This migration (chemotaxis) is stimulated by proteins in the inflammatory exudate, including some chemokines. A variety of cell types, including macrophages and endothelial cells, can produce chemokines. Once the phagocytic cells migrate to the site of infection, they can initiate the engulfment of microorganisms.

Fever is another common systemic manifestation of the inflammatory response and is a cardinal symptom of infectious disease. The main regulator of body temperature is the thermoregulatory center in the hypothalamus. Among the substances capable of inducing fever (pyrogens) are endotoxins of gram-negative bacteria and cytokines (eg, IL-1, IL-6, TNF-α, and the interferons) released from a variety of cells.

The interferons (IFNs) are critical cytokines that play a key role in defense against virus infections and other intra cellular organisms, such as Toxoplasma gondii. Although the IFNs were first identified in 1957 as antiviral proteins, they are now recognized as critical immunoregulating proteins capable of altering various cellular processes, including cell growth, differentiation, gene transcription, and translation. The IFN family consists of three groups. Type I IFNs comprise numerous genes and primarily include IFN-α and IFN-β. Type II IFN consists of a single gene that produces IFN-γ. IFN-λ is a third group of IFN-like cytokines that have more recently been described. Virus infection itself triggers the production of type I IFNs. Following virus entry into a cell, the virus initiates replication and the viral nucleic acid interacts with specific microbial sensors (TLR3, TLR7, TLR 9, RIG-1, and MDA-5). This interaction triggers cellular production of IFN that is secreted from the infected cell. In contrast, the type II IFN, IFN-γ, is produced by activated NK cells in innate immune responses and by specifically sensitized T cells in adaptive immune responses. Moreover, the cytokines IL-2 and IL-12 can trigger T cells to produce IFN-γ.

The IFN system consists of a series of events leading to protection of a cell from virus replication. Once the IFN is produced by the infected cell or the activated NK cell or T cell, the IFN binds to its specific cellular receptor. The IFN receptor interaction activates the JAK, STAT signaling path ways. This process triggers activation of genes that initiate production of selected proteins that inhibit virus replication. All of the IFNs share overlapping biological activities such as antiviral actions, antiproliferative actions, and immunoregulatory actions. However, they also have unique functions that are not overlapping. For example, IFN-β is used success fully to treat patients with multiple sclerosis, whereas IFN-γ has been shown to exacerbate this disease. These potent actions of the IFNs and the advances in biotechnology are the underlying factors that have identified the clinical relevance of the IFNs. In fact, many of the IFNs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of infections, malignancies, autoimmunity, and immunodeficiency

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مواضيع ذات صلة

The Major Histocompatibility Complex

Cellular Basis of the Adaptive Immune Response

Overview of Acute-Phase Proteins

C-Reactive Protein

Hematopoietic Stimulators

The Complement System: Diagnostic Evaluation

Biological Functions of Complement Proteins

The Complement System: Alternative Pathway

The Complement System: Classic Pathway

The Complement System

Immune-Mediated Disease

Evaluation of Immunodeficiency Syndromes