Innate Immune System- An Introduction

The innate immune system is one of the two main immunity strategies in vertebrates, along with the adaptive immune system. The innate immune system is also the dominant immune system response found in plants, fungi, insects, and primitive multicellular organisms.

The innate immune system provides a preconfigured response to broad groups of situations and stimuli, such as pathogens (disease-causing organisms) and tissue damage. The innate immune system responds in the same general way to every pathogen it encounters, regardless of its specificity or identity. The innate immune system is also called the nonspecific immune system because of this feature.

The major functions of the innate immune system are to:

• recruit immune cells to infection sites by producing chemical factors, including chemical mediators called cytokines
• activate the complement cascade to identify bacteria, activate cells, and promote clearance of antibody complexes or dead cells
• identify and remove foreign substances present in organs, tissues, blood and lymph, by specialized white blood cells
• activate the adaptive immune system through antigen presentation
• act as a physical and chemical barrier to infectious agents; via physical measures such as skin and chemical measures such as clotting factors in blood, which are released following a contusion or other injury that breaks through the first-line physical barrier

The innate immune system consists of several components, such as:

• anatomical barriers: physical, chemical and biological barriers that prevent or limit the entry of pathogens into the body, such as skin, mucous membranes, gut flora, and tears
• cellular components: white blood cells that perform various functions, such as phagocytosis (engulfing and destroying microbes), cytotoxicity (killing infected cells), inflammation (increasing blood flow and permeability), and antigen presentation (displaying fragments of pathogens to activate adaptive immunity), such as neutrophils, macrophages, dendritic cells, natural killer cells, and mast cells
• molecular components: soluble proteins and molecules that have various roles in recognizing and eliminating pathogens, such as complement proteins, cytokines, chemokines, interferons, defensins, and acute-phase proteins

The innate immune system is essential for the survival of vertebrates, as it provides immediate protection against infections and tissue damage. It also prepares the body for a more specific and effective response by the adaptive immune system. However, the innate immune system has some limitations, such as:

• lack of specificity: the innate immune system cannot distinguish between different types of pathogens or remember previous encounters with them
• lack of diversity: the innate immune system has a limited number of receptors and molecules that can recognize pathogens
• lack of regulation: the innate immune system can cause excessive inflammation or tissue damage if not controlled properly

In this article, we will discuss some of the main components of the innate immune system in more detail: complement system, cytokines, natural killer cells, neutrophils, and macrophages. We will also explain how they interact with each other and with the adaptive immune system to provide a comprehensive defense against pathogens.

The complement system is a group of plasma proteins that work together to enhance the innate immune response against microbes. The complement proteins are normally inactive in the blood, but they can be activated by three different pathways: the classical pathway, the alternative pathway, and the lectin pathway. All three pathways converge to form a common enzyme called C3 convertase, which cleaves the C3 protein into two fragments: C3a and C3b. C3a is an anaphylatoxin that stimulates inflammation by binding to receptors on mast cells and basophils, causing them to release histamine and other mediators. C3b is an opsonin that coats the surface of microbes and enhances their phagocytosis by neutrophils and macrophages. C3b also forms part of another enzyme called C5 convertase, which cleaves the C5 protein into two fragments: C5a and C5b. C5a is another anaphylatoxin that has similar effects as C3a, but also acts as a chemotactic factor for neutrophils and monocytes. C5b initiates the formation of the membrane attack complex (MAC), which consists of C5b, C6, C7, C8, and multiple copies of C9. The MAC inserts into the membrane of bacteria and some viruses, creating pores that disrupt their integrity and cause cell lysis. The complement system is regulated by several mechanisms to prevent damage to host cells. One of these mechanisms is the presence of complement regulatory proteins on host cell surfaces, such as decay-accelerating factor (DAF) and CD59, which inhibit the formation or activity of C3 convertase and MAC, respectively. Another mechanism is the inactivation of complement fragments by plasma proteases, such as factor I and carboxypeptidase B. The complement system plays an important role in innate immunity by promoting inflammation, opsonization, and lysis of microbes. It also links innate and adaptive immunity by enhancing antibody-mediated responses and stimulating antigen presentation by dendritic cells.

Cytokines are small proteins that are secreted by various cells of the immune system and have diverse effects on other cells. They act as messengers between different types of immune cells and coordinate their activities. Some cytokines are produced mainly by innate immune cells, such as macrophages, dendritic cells (DCs), and natural killer (NK) cells, and mediate inflammation and modify adaptive immune responses. Some of these cytokines are:

• Tumor necrosis factor (TNF): TNF is produced by macrophages and DCs in response to microbial products or tissue damage. TNF has multiple effects on inflammation and immunity, such as:

  • Activating endothelial cells to express adhesion molecules and secrete chemokines, which facilitate the recruitment of leukocytes from blood into tissues.
  • Stimulating the production of other cytokines, such as interleukin-1 (IL-1) and interleukin-6 (IL-6), by various cells.
  • Increasing the production of neutrophils in the bone marrow and enhancing their phagocytic activity.
  • Inducing apoptosis (programmed cell death) of some types of infected or abnormal cells, such as tumor cells.
  • Mediating systemic effects of inflammation, such as fever, loss of appetite, and muscle wasting.

• Interleukin-1 (IL-1): IL-1 is also produced by macrophages and DCs in response to microbial products or tissue damage. IL-1 has similar effects as TNF on inflammation and immunity, such as:

  • Activating endothelial cells to express adhesion molecules and secrete chemokines.
  • Stimulating the production of other cytokines, such as IL-6 and IL-12, by various cells.
  • Increasing the production of neutrophils in the bone marrow and enhancing their phagocytic activity.
  • Inducing fever and acute-phase protein synthesis by the liver.
  • Enhancing the activation and differentiation of T cells and B cells.

• Interleukin-6 (IL-6): IL-6 is produced by macrophages, DCs, endothelial cells, fibroblasts, and other cells in response to TNF or IL-1. IL-6 has multiple effects on inflammation and immunity, such as:

  • Inducing fever and acute-phase protein synthesis by the liver.
  • Stimulating the production of antibodies by B cells.
  • Promoting the differentiation of T helper cells into Th17 cells, which secrete cytokines that enhance inflammation and immunity against extracellular bacteria and fungi.
  • Inhibiting the differentiation of T helper cells into T regulatory cells, which suppress immune responses.

• Interleukin-12 (IL-12): IL-12 is produced by macrophages and DCs in response to microbial products or NK cell-derived interferon-gamma (IFN-γ). IL-12 has important effects on adaptive immune responses, such as:

  • Stimulating the production of IFN-γ by NK cells and T cells.
  • Promoting the differentiation of T helper cells into Th1 cells, which secrete cytokines that enhance cell-mediated immunity against intracellular microbes.
  • Enhancing the cytotoxic activity of NK cells and cytotoxic T lymphocytes (CTLs).

• Interleukin-18 (IL-18): IL-18 is produced by macrophages and DCs in response to microbial products or tissue damage. IL-18 has similar effects as IL-12 on adaptive immune responses, such as:

  • Stimulating the production of IFN-γ by NK cells and T cells.
  • Promoting the differentiation of T helper cells into Th1 cells or Th17 cells.

These cytokines function in innate immune responses to different classes of microbes, such as bacteria, viruses, fungi, or parasites. They also modify adaptive immune responses that follow the innate immune response by influencing the activation, differentiation, and function of T cells and B cells. By doing so, they help to tailor the immune response to the specific type of pathogen encountered.

NK cells are one type of innate lymphoid cells that have cytotoxic functions and secrete IFN-γ, similar to CTLs. NK cells defend against intracellular microbes by killing infected cells and providing a source of the macrophage-activating cytokine IFN-γ.

NK cell recognition of infected cells is regulated by a combination of activating and inhibitory receptors. Inhibitory receptors recognize class I MHC molecules, because of which NK cells do not kill normal host cells but do kill cells in which class I MHC expression is reduced, such as virus-infected cells.

Activating receptors recognize ligands that are induced or upregulated on infected or stressed cells, such as viral proteins, heat-shock proteins, or stress-induced molecules. Some activating receptors also bind to antibodies that coat infected cells, triggering a process called antibody-dependent cellular cytotoxicity (ADCC).

NK cells kill target cells by releasing granules that contain perforin and granzymes. Perforin forms pores in the target cell membrane, allowing granzymes to enter and induce apoptosis. NK cells also express Fas ligand (FasL), which binds to Fas on the target cell and triggers apoptosis.

NK cells secrete IFN-γ in response to IL-12 and IL-18 produced by macrophages and DCs. IFN-γ activates macrophages to enhance their microbicidal activity and stimulates the production of other inflammatory cytokines. IFN-γ also promotes the differentiation of CD4+ T cells into Th1 cells, which help to eliminate intracellular pathogens.

NK cells are important for the early defense against viral infections, before adaptive immune responses are generated. They also play a role in controlling some bacterial and parasitic infections, as well as tumor surveillance. NK cell deficiency is associated with increased susceptibility to viral infections and some malignancies.

Neutrophils are the most abundant type of white blood cells in the blood and the first line of defense against microbial infections. They are short-lived cells that rapidly migrate from the blood into the tissues where they encounter and eliminate pathogens. Neutrophils are attracted to the site of infection by various signals, such as cytokines, chemokines, complement fragments, and microbial products. These signals bind to specific receptors on the surface of neutrophils and activate them to undergo a process called chemotaxis, which is the directional movement of cells along a chemical gradient.

Once they reach the site of infection, neutrophils use different mechanisms to kill and remove the invading microbes. One of these mechanisms is phagocytosis, which is the engulfment and internalization of microbes into membrane-bound vesicles called phagosomes. The phagosomes then fuse with lysosomes, which contain various enzymes and reactive oxygen species (ROS) that degrade and destroy the microbes. Another mechanism is degranulation, which is the release of granules containing antimicrobial proteins and peptides from the cytoplasm of neutrophils. These granules can damage the membranes and walls of bacteria and fungi, or form extracellular traps that immobilize and kill microbes. A third mechanism is the production of nitric oxide (NO), which is a gas molecule that can diffuse across membranes and inhibit microbial growth and metabolism.

Neutrophils play a crucial role in innate immunity by eliminating pathogens and preventing their spread to other tissues. However, neutrophils can also cause tissue damage and inflammation if they are activated inappropriately or excessively. Therefore, neutrophils are tightly regulated by various factors, such as anti-inflammatory cytokines, apoptotic signals, and clearance by macrophages. Neutrophils also interact with other cells of the immune system, such as macrophages, dendritic cells, natural killer cells, and T cells, to coordinate and modulate the immune response. Neutrophils can present antigens to T cells, secrete cytokines that influence adaptive immunity, and enhance antibody production by B cells.

In summary, neutrophils are essential components of the innate immune system that migrate from blood into inflammatory sites and phagocytose microbes. They also use other mechanisms to kill pathogens, such as degranulation, extracellular traps, and nitric oxide production. Neutrophils are regulated by various factors to prevent tissue damage and inflammation, and they communicate with other immune cells to shape the adaptive immune response.

Macrophages are large phagocytic cells that reside in various tissues and organs of the body. They are derived from monocytes that circulate in the blood and migrate into tissues in response to inflammatory signals. Macrophages play a crucial role in innate immunity by engulfing and destroying microbes, as well as presenting antigens to adaptive immune cells.

Macrophages also produce a variety of cytokines that have different effects on inflammation and tissue repair. Some of these cytokines are:

• TNF: This cytokine activates endothelial cells to express adhesion molecules and chemokines that recruit more leukocytes to the site of infection. TNF also induces fever and stimulates the production of acute-phase proteins by the liver. TNF can also induce apoptosis of infected or damaged cells, as well as tumor cells.
• IL-1: This cytokine has similar effects as TNF on endothelial cells, fever, and acute-phase proteins. IL-1 also stimulates the production of IL-6 by various cells, which mediates systemic effects such as increased antibody production and activation of T cells.
• IL-6: This cytokine is mainly produced by macrophages in response to TLR stimulation by microbial products. IL-6 has multiple effects on inflammation and immunity, such as inducing fever, stimulating acute-phase protein synthesis, enhancing B cell differentiation and antibody production, and promoting Th17 cell differentiation.
• IL-12: This cytokine is produced by macrophages and dendritic cells in response to intracellular pathogens such as bacteria and viruses. IL-12 stimulates the production of IFN-γ by NK cells and T cells, which activates macrophages to kill phagocytosed microbes more efficiently. IL-12 also promotes Th1 cell differentiation, which enhances cell-mediated immunity against intracellular pathogens.
• IL-18: This cytokine is produced by macrophages and other cells in response to microbial products or cellular stress. IL-18 synergizes with IL-12 to induce IFN-γ production by NK cells and T cells. IL-18 also enhances Th1 cell differentiation and cytotoxicity.
• IL-10: This cytokine is produced by macrophages and other cells in response to various stimuli, such as microbial products, anti-inflammatory cytokines, or regulatory T cells. IL-10 has anti-inflammatory effects by inhibiting the production of pro-inflammatory cytokines such as TNF, IL-1, IL-6, and IL-12 by macrophages and other cells. IL-10 also suppresses the activation of Th1 cells and enhances the function of regulatory T cells.
• TGF-β: This cytokine is produced by macrophages and other cells in response to tissue damage or infection. TGF-β has anti-inflammatory effects by inhibiting the proliferation and activation of T cells and B cells. TGF-β also promotes tissue repair by stimulating fibroblast proliferation and collagen synthesis, as well as angiogenesis.

Macrophages are essential for innate immunity against various types of microbes, as well as for modulating adaptive immunity and tissue repair. By producing different cytokines, macrophages can tailor their responses to different situations and stimuli. Macrophages are also involved in maintaining homeostasis and tolerance in healthy tissues by clearing apoptotic cells and debris, as well as producing anti-inflammatory cytokines such as IL-10 and TGF-β.

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