Multicellular organisms, including plants, vertebrates, and invertebrates, have an intrinsic method of defending themselves against microbial infections. Since these methods are always present, ready to recognize and eliminate microbes, they are called innate immune systems or (natural or native immunity).
The innate immune system consists of different components. The only commonality is that they recognize and respond to microbes but do not react against non-microbial substances. Host cells damaged by microbes also trigger this type of immunity.
Innate immunity differs from adaptive immunity, where adaptation occurs after stimulation to encounter with microbes before it can be effective. Likewise, both microbes and non-microbial antigens can trigger adaptive immunity.
Table of Contents
Components of Innate Immune System
The innate immune system consists of epithelia, which provide barriers to infection, cells in the circulation and tissues, and several plasma proteins. These components play different but complementary roles in blocking the entry of microbes and eliminating microbes that enter the host’s tissues.
Epithelial Barriers
The continuous epithelia provide physical and chemical barriers against infection. It also protects the standard portals of entry of microbes, namely, the skin, gastrointestinal, and respiratory tract. The three significant interfaces between the body and the external environment are the skin, the gastrointestinal tract, and the respiratory tract.
Microbes may enter hosts from the external environment through these interfaces by physical contact. ingestion, and breathing. All three portals of entry are lined by continuous epithelia that physically interfere with the entry of microbes.
Epithelial cells also produce peptide antibiotics that kill bacteria. In addition, epithelia contain a type of lymphocyte called intraepithelial lymphocyte, belonging to the T cell lineage. However, this lymphocyte expresses antigen receptors of limited diversity. Intraepithelial lymphocytes presumably serve as sentinels against infectious agents that attempt to breach the epithelia. However, the specificity and functions of these cells still need to be better understood.
A population of B lymphocytes. B-1 cells resemble intraepithelial T cells in the limited diversity of their antigen receptors. B-1 cells are not present in epithelia but mainly in the peritoneal cavity, where they may respond to microbes and microbial toxins that pass through the walls of the intestine. Most of the circulating IgM antibodies found in the blood of normal individuals, called natural antibodies, are the products of B-1 cells, and many of these antibodies are specific for carbohydrates present in the cell walls of many bacteria.
Phagocytes: Neutrophils and Monocytes/Macrophages
Neutrophils and monocytes are two types of circulating phagocytes recruited to the site of infection, where they recognize and ingest microbes for intracellular killing.
Neutrophils and macrophages recognize microbes in the blood and extravascular tissues by surface receptors specific to microbial products. Several types of receptors are specific for different structures or patterns frequently found on microbial molecules.
Neutrophils and macrophages express receptors that recognize other microbial structures and promote phagocytosis and killing of the microbes. These receptors include one that recognizes N-formylmethionine-containing peptides (produced by microbes but not host cells), mannose receptors (mentioned earlier), integrins (mainly one called Mac-1), and scavenger receptors (specific for several pathogen and host molecules).
Neutrophils or polymorphonuclear leukocytes or PMNs
These are the most abundant leukocytes in the blood, numbering 4000 to 10,000 per mm3. In response to infections, neutrophil production from the bone marrow increases rapidly, and their number may rise to 20,000 per mm3 of blood. Cytokines, known as colony-stimulating factors, act on bone marrow stems in response to infections and stimulate the production of neutrophils; neutrophils are the first cell type to respond to most bacterial and fungal infections. They ingest microbes in the circulation and enter the sites of infection, where they also ingest microbes and die after a few hours.
Monocytes/Macrophages
These are less abundant than neutrophils, numbering 500 to 1000 per mm3 of blood. They, too, ingest microbes in the blood and tissues. Unlike neutrophils, monocytes that enter extravascular tissues survive in these sites for extended periods; in the tissues, these monocytes differentiate into cells called macrophages. Blood monocytes and tissue macrophages are two stages of the same cell lineage, often called the mononuclear phagocyte system. Resident macrophages are present in connective tissues and every organ in the body, serving the same function as mononuclear phagocytes newly recruited from the circulation.
Macrophages also express cytokine receptors, such as interferon-y (IFN-y), produced during innate and adaptive immune responses.
The process of coating microbes for efficient recognition by phagocytes is called opsonization. The recognition of microbes by neutrophils and macrophages leads to phagocytosis of the microbes and activation of the phagocytes to kill the ingested microbes.
Phagocytosis is a process in which the phagocyte extends its plasma membrane around the recognized microbes; the membrane closes up. It pinches off, and the particle internalizes in a membrane-bound vesicle called a phagosome. The phagosomes and lysosomes fuse to form phagolysosomes. At the same time, phagocyte receptors bind the microbe and ingest it. The receptors deliver signals that activate several enzymes in the phagolysosomes.
One of these enzymes, phagocyte oxidase, converts molecular oxygen into superoxide anion and free radicals. The enzyme-inducible nitric oxide synthase catalyzes arginine to nitric oxide (NO), a microbicidal substance. The third set of enzymes are lysosomal proteases, which break down microbial proteins.
In addition to killing phagocytosed microbes, macrophages perform several functions that play essential roles in defense against infections. Macrophages produce cytokines that are important mediators of host defense. These secrete growth factors and enzymes to remodel injured tissue and replace it with connective tissue. Macrophages also stimulate T lymphocytes and respond to the products of T cells; these reactions are important in cell-mediated immunity.
Natural Killer (NK) Cells
These cells are a class of lymphocytes that respond to intracellular microbes by killing infected cells and producing macrophage-activating cytokine, IFN-gamma. Natural killer cells comprise about 10% of the lymphocytes in the blood and peripheral lymphoid organs. These cells contain abundant cytoplasmic granules and express characteristic surface markers, but they do not express immunoglobulins or T cell receptors, the antigen receptors of B and T lymphocytes, respectively. NK cells recognize host cells that have been altered by microbial infection.
Two prominent families of NK cell inhibitory receptors are the killer cell immunoglobulin-like receptors (KIRs), so-called because they share structural homology to immunoglobulin molecules, and receptors consisting of a protein called CD94 and a lectin submit called NKG2. Both families of inhibitory receptors contain structural motifs called immunoreceptor tyrosine-based inhibitory motifs (ITIMs) in their cytoplasmic domains, which become phosphorylated on tyrosine residues when the receptors bind MHC I molecules.
When NK cells activate, they respond in two ways. First, activation triggers the discharge of proteins in the NK cells’ cytoplasmic granules toward the infected cells. These NK cell granule proteins include molecules that make holes in the plasma membrane of the infected cells and other molecules that enter the infected cells and activate enzymes that induce apoptotic death.
Second, activated NK cells synthesize and secrete the cytokine IFN-y. IFN-y activates macrophages to become more active at killing phagocytosed microbes. Thus, NK cells and macrophages function cooperatively to eliminate intracellular microbes: macrophages -st microbes and produce IL-12. IL-12 activates NK cells to secrete IFN-y and IFN-y, which, in turn, activates the macrophages to kill the ingested microbes.
Thus, hosts and microbes are engaged in a constant evolutionary struggle:
- The host uses CTLs to recognize MHC-displayed viral antigens.
- Viruses shut off MHC expression.
- NK cells have evolved to respond to the absence of MHC molecules.
Whether the host or the microbe wins this kind of evolutionary struggle, of course, determines the outcome of the infection.
Cytokines of Innate Immunity
Macrophages and other cells produce proteins called cytokines in response to microbes mediating many of innate immunity’s cellular reactions. Cytokines are soluble proteins that mediate immune and inflammatory reactions and are responsible for communications between leukocytes and other cells.
| Cytokines | Sources | Principle Cellular targets and biologic effects |
| Tumor Necrosis factor (TNF) | Macrophages, T cells | Endothelial cells (inflammation, coagulation) Neutrophils: activation Hypothalamus: fever Liver: synthesis of acute phase proteins Muscle, fat: catabolism (cachexia) Many cell types: apoptosis |
| Interleukin-1 (IL-1) | Macrophages, endothelial cells, some epithelial cells | Endothelial cells: activation (inflammation, coagulation) Hypothalamus: fever Liver: synthesis of acute phase proteins |
| Chemokines | Macrophages, endothelial cells, T lymphocytes. Fibroblasts, platelets | Leukocytes: chemotaxis, activation |
| Interlukin-12 (IL-12) | Macrophages, dendritic cells | NK cells and T cells: IFN-γ synthesis, increased cytolytic activity T cells: TH1 differentiation |
| Interferon-γ (IFN-γ) | NK cells, T lymphocytes | Activation of macrophagesStimulation of some antibody response |
| Type I IFNs (IFN-ɑ, IFN-β) | IFN-ɑ: MacrophagesIFN-β: Fibroblasts | All cells: antiviral state, increased class I MHC expression NK cells: activation |
| IL-10 | Macrophages. T cells (mainly TH2) | Macrophages: inhibition of IL-12 production, reduced expression of costimulators and class II MHC molecules |
| IL-6 | Macrophaegs, endothelial cells T cells | Liver: synthesis of acute phase proteins B cells: proliferation of antibody-producing cells |
| IL-15 | Macrophages, others | Nk cells: proliferation T cells: proliferation |
| IL-18 | Macrophages | NK cells and T cells: IFN-γ synthesis |
The Complement System
The complement system is a group of circulating and membrane-associated proteins essential in defense against microbes. Many complement proteins are proteolytic enzymes, and complement activation involves the sequential activation of these enzymes, sometimes called an enzymatic cascade.
This cascade may be activated by one of three pathways. The alternative pathway is triggered when some complement proteins are activated on microbial surfaces, which is impossible to control because microbes lack complement regulatory proteins. This pathway is a component of innate immunity.
Antibodies binding to microbes or other antigens triggers the classical pathway. Thus, it is a component of the humoral immunity.
The lectin pathway activates when mannose-binding lectin, a plasma protein, binds to terminal mannose residues on the surface glycoproteins of microbes. This lectin activates proteins of the classical pathway. However, the initiation occurs without antibodies. Thus, it is a component of innate immunity.
Other Plasma Proteins of Innate Immunity
Several circulating proteins, including complement proteins, defend against infections. Plasma mannose-binding lectin (MBL) is a protein that recognizes microbial carbohydrates and can coat microbes for phagocytosis or activate the complement cascade by the lectin pathway.
Surfactant proteins in the lung protect the airways from infection. C-reactive protein (CRP) binds to phosphorylcholine on microbes and coats the microbes for phagocytosis by macrophages, which express a receptor for CRP.
The circulating levels of many of these plasma proteins increase rapidly after infection. This protective response is called the acute phase response to infection.
Innate immune responses to different microbes may vary and are designed to eliminate these microbes in the best way possible. Phagocytes, the complement system, and acute phase proteins combat extracellular bacteria and fungi. Defense against intracellular bacteria and viruses is mediated by phagocytes and NK cells. The cytokines provides the communication between the phagocytes and NK cells.
Evasion of Innate Immunity by Microbes
Pathogenic microbes have evolved to resist the mechanisms of innate immunity and are thus able to enter and colonize their hosts. Some intracellular bacteria resist destruction inside phagocytes. Listeria monocytogenes produces a protein that enables it to escape from phagocytic vesicles. Then these enter the cytoplasm of infected cells. Here it is no longer susceptible to reactive oxygen intermediates and nitric oxide (produced mainly in phagolysosomes).
The cell wall of mycobacteria contains a lipid that inhibits the fusion of vesicles containing ingested bacteria with lysosomes. Other microbes have cell walls that are resistant to the actions of complement proteins.
References
- Abbas, A. K., & Lichtman, A. H. (2006). Basic immunology: Functions and disorders of the immune system. Elsevier Saunders.
- Aristizábal B, González Á. Innate immune system. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18. Chapter 2. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459455/
