J Innate Immunity

[Angelique Syria]

Theimmune system fights germs on the skin, in the tissues of the body, and in bodily fluids such as blood. It is made up of the innate (general) immune system and the adaptive (specialized) immune system. These two systems work closely together and take on different tasks.

Bacteria or viruses that enter the body can be stopped right away by phagocytes, also known as scavenger cells. These special white blood cells (leukocytes) enclose germs and "digest" them, making them harmless. The remains of the germs move to the surface of the phagocytes, where they can be detected by the adaptive immune system.

Several proteins (enzymes) help the cells of the innate immune system. A total of nine different enzymes activate each other in a kind of chain reaction: One enzyme in the first stage alerts several enzymes in a second stage, each of which activates several enzymes in a third stage, and so on. This allows the immune response to grow stronger very quickly.

The natural killer cells are the third major part of the innate immune system. Their main job is to identify cells that have been infected by a virus, as well as abnormal cells that may turn into (or have turned into) tumor cells. To do this, they search for cells with an abnormal surface, and then destroy the cell surface using substances called cytotoxins.

B cells (B lymphocytes) are made in the bone marrow, where they mature into specialized immune system cells. They take their name from the "B" in "bone marrow." Like the T cells, there are many different types of B cells that match particular germs.

B cells are activated by T helper cells: T helper cells send signals to B cells that match the same germs as they do. This stimulates the B cells to make copies of themselves and turn into plasma cells. The plasma cells quickly make very large amounts of antibodies and release them into the blood. Because the T helper cells only activate the B cells that match the attacking germs, the body only makes the exact antibodies that are needed.

The different cells of the adaptive immune system communicate either directly or through soluble chemical messengers such as cytokines (usually proteins). These chemical messengers are made by various cells in the body.

Antibodies (proteins with sugar groups attached to them) travel around the body in the bloodstream. They are made by the immune system to fight germs and foreign substances. Antibodies can quickly recognize germs and other potentially harmful substances, and then attach to them. This makes the "intruders" harmless and attracts other immune system cells to help. Antibodies are made by B cells. Germs and substances that can trigger the production of antibodies are called "antigens."

An antibody only attaches to an antigen if it matches exactly, like a key in the lock of the antibody. In this way, antibodies recognize matching germs and trigger the fast response of the adaptive immune system.

Humans are exposed to millions of potential pathogens daily, through contact, ingestion, and inhalation. Our ability to avoid infection depends in part on the adaptive immune system (discussed in Chapter 24), which remembers previous encounters with specific pathogens and destroys them when they attack again. Adaptive immune responses, however, are slow to develop on first exposure to a new pathogen, as specific clones of B and T cells have to become activated and expand; it can therefore take a week or so before the responses are effective. By contrast, a single bacterium with a doubling time of one hour can produce almost 20 million progeny, a full-blown infection, in a single day. Therefore, during the first critical hours and days of exposure to a new pathogen, we rely on our innate immune system to protect us from infection.

Innate immune responses are not specific to a particular pathogen in the way that the adaptive immune responses are. They depend on a group of proteins and phagocytic cells that recognize conserved features of pathogens and become quickly activated to help destroy invaders. Whereas the adaptive immune system arose in evolution less than 500 million years ago and is confined to vertebrates, innate immune responses have been found among both vertebrates and invertebrates, as well as in plants, and the basic mechanisms that regulate them are conserved. As discussed in Chapter 24, the innate immune responses in vertebrates are also required to activate adaptive immune responses.

In vertebrates, the skin and other epithelial surfaces, including those lining the lung and gut Figure 25-39), provide a physical barrier between the inside of the body and the outside world. Tight junctions (discussed in Chapter 19) between neighboring cells prevent easy entry by potential pathogens. The interior epithelial surfaces are also covered with a mucus layer that protects these surfaces against microbial, mechanical, and chemical insults; many amphibians and fish also have a mucus layer covering their skin. The slimy mucus coating is made primarily of secreted mucin and other glycoproteins, and it physically helps prevent pathogens from adhering to the epithelium. It also facilitates their clearance by beating cilia on the epithelial cells (discussed in Chapter 22).

It is still uncertain how defensins kill pathogens. One possibility is that they use their hydrophobic or amphipathic domains to insert into the membrane of their victims, thereby disrupting membrane integrity. Some of their selectivity for pathogens over host cells may come from their preference for membranes that do not contain cholesterol. After disrupting the membrane of the pathogen, the positively-charged peptides may also interact with various negatively-charged targets within the microbe, including DNA. Because of the relatively nonspecific nature of the interaction between defensins and the microbes they kill, it is difficult for the microbes to acquire resistance to the defensins. Thus, in principle, defensins might be useful therapeutic agents to combat infection, either alone or in combination with more traditional drugs.

The pathogen-associated immunostimulants are of various types. Procaryotic translation initiation differs from eucaryotic translation initiation in that formylated methionine, rather than regular methionine, is generally used as the first amino acid. Therefore, any peptide containing formylmethionine at the N-terminus must be of bacterial origin. Formylmethionine-containing peptides act as very potent chemoattractants for neutrophils, which migrate quickly to the source of such peptides and engulf the bacteria that are producing them (seeFigure 16-96).

In addition, the outer surface of many microorganisms is composed of molecules that do not occur in their multicellular hosts, and these molecules also act as immunostimulants. They include the peptidoglycan cell wall and flagella of bacteria, as well as lipopolysaccharide (LPS) on Gram-negative bacteria (Figure 25-40) and teichoic acids on Gram-positive bacteria (see Figure 25-4D). They also include molecules in the cell walls of fungi such as zymosan, glucan, and chitin. Many parasites also contain unique membrane components that act as immunostimulants, including glycosylphosphatidylinositol in Plasmodium.

The various classes of pathogen-associated immunostimulants often occur on the pathogen surface in repeating patterns. They are recognized by several types of dedicated receptors in the host, that are collectively called pattern recognition receptors. These receptors include soluble receptors in the blood (components of the complement system) and membrane-bound receptors on the surface of host cells (members of the Toll-like receptor family). The cell-surface receptors have two functions: they initiate the phagocytosis of the pathogen, and they stimulate a program of gene expression in the host cell for stimulating innate immune responses. The soluble receptors also aid in the phagocytosis and, in some cases, the direct killing of the pathogen.

Many of these cleavages liberate a biologically active small peptide fragment and a membrane-binding larger fragment. The binding of the large fragment to a cell membrane, usually the surface of a pathogen, helps to carry out the next reaction in the sequence. In this way, complement activation is confined largely to the particular cell surface where it began. The larger fragment of C3, called C3b, binds covalently to the surface of the pathogen. Once in place, it not only acts as a protease to catalyze the subsequent steps in the complement cascade, but it also is recognized by specific receptors on phagocytic cells that enhance the ability of these cells to phagocytose the pathogen. The smaller fragment of C3 (called C3a), as well as fragments of C4 and C5 (see Figure 25-41), act independently as diffusible signals to promote an inflammatory response by recruiting phagocytes and lymphocytes to the site of infection.

The classical pathway is activated by IgG or IgM antibody molecules (discussed in Chapter 24) bound to the surface of a microbe. Mannan-binding lectin, the protein that initiates the second pathway of complement activation, is a serum protein that forms clusters of six carbohydrate-binding heads around a central collagen-like stalk. This assembly binds specifically to mannose and fucose residues in bacterial cell walls that have the correct spacing and orientation to match up perfectly with the six carbohydrate-binding sites, providing a good example of a pattern recognition receptor. These initial binding events in the classical and lectin pathways cause the recruitment and activation of the early complement components. In the alternative pathway, C3 is spontaneously activated at low levels, and the resulting C3b covalently attaches to both host cells and pathogens. Host cells produce a series of proteins that prevent the complement reaction from proceeding on their cell surfaces. Because pathogens lack these proteins, they are singled out for destruction. Activation of the classical or lectin pathways also activates the alternative pathway through a positive feedback loop, amplifying their effects.

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