Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Endomembrane system wikipedia , lookup
Cell culture wikipedia , lookup
Extracellular matrix wikipedia , lookup
Cellular differentiation wikipedia , lookup
Cell encapsulation wikipedia , lookup
Organ-on-a-chip wikipedia , lookup
Signal transduction wikipedia , lookup
Tissue engineering wikipedia , lookup
Lec (2) Immunology Innate Immunity RESISTANCE TO MICROBIAL DISEASE First Line of Defense Before a pathogen can invade the human body, it must overcome the resistance provided by the body’s first line of defense. The first barrier to infection is unbroken skin and mucosal membrane surfaces. These surfaces are essential in forming a physical barrier to many microorganisms because this is where foreign materials usually first contact the host. Keratinization of the upper layer of the skin and the constant renewal of the skin’s epithelial cells, which repairs breaks in the skin, assist in the protective function of skin and mucosal membranes. In addition, the normal flora (microorganisms normally inhabiting the skin and membranes) deter penetration or facilitate elimination of foreign microorganisms from the body. Secretions are also an important component in the first line of defense against microbial invasion. Mucus adhering to the membranes of the nose and nasopharynx traps microorganisms, which can be expelled by coughing or sneezing. Sebum (oil) produced by the sebaceous glands of the skin and lactic acid in sweat both possess antimicrobial properties. The production of earwax (cerumen) protects the auditory canals from infectious disease. Secretions produced in the elimination of liquid and solid wastes (e.g., urinary and gastrointestinal processes) are important in physically removing potential pathogens from the body. The acidity and alkalinity of the fluids of the stomach and intestinal tract, as well as the acidity of the vagina, can destroy many potentially infectious microorganisms. Additional protection is provided to the respiratory tract by the constant motion of the cilia of the tubules. In addition to the physical ability to wash away potential pathogens, tears and saliva also have chemical properties that defend the body. The enzyme lysozyme, which is found in tears and saliva, attacks and destroys the cell wall of susceptible bacteria, particularly certain gram-positive bacteria. Immunoglobulin A (IgA) antibody is another important protective substance in tears and saliva. 1 Lec (2) Immunology Second Line of Defense: Natural Immunity Natural immunity (inborn or innate resistance) is one of the ways that the body resists infection after microorganisms have penetrated the first line of defense. Acquired resistance, which specifically recognizes and selectively eliminates exogenous or endogenous agents, is discussed later. Natural immunity is characterized as a nonspecific mechanism. If a microorganism penetrates the skin or mucosal membranes, a second line of cellular and humoral defense mechanisms becomes operational. The elements of natural resistance include phagocytic cells, complement, and the acute inflammatory reaction. Detection of microbial pathogens is carried out by sentinel cells of the innate immune system located in tissues (macrophages and dendritic cells) in close contact with the host’s natural environment or that are rapidly reunited to the site of infection (neutrophils). Despite their relative lack of specificity, these cellular components are essential because they are largely responsible for natural immunity to many environmental microorganisms. These phagocytic cells, which engulf invading foreign material, constitute major cellular components. Tissue damage produced by infectious or other agents results in inflammation, a series of biochemical and cellular changes that facilitate phagocytosis (engulfment and destruction) of microorganisms or damaged cells. If the degree of inflammation is sufficiently extensive, it is accompanied by an increase in the plasma concentration of acute phase proteins or reactants, a group of glycoproteins. COMPONENTS OF INNATE IMMUNITY The components of the innate immune system include epithelial cells, sentinel cells in tissues (macrophages, dendritic cells, and others), NK cells, and a number of plasma proteins. 1- Epithelial Barriers The common portals of entry of microbes— the skin, gastrointestinal tract, and respiratory tract—are protected by continuous epithelia that provide physical and chemical barriers against infection. The three major interfaces between the body and the external environment are the skin and the gastrointestinal and respiratory tracts. Microbes may enter hosts from the external environment through these interfaces by external physical contact, 2 Lec (2) Immunology ingestion, and inhalation. All three of entries are lined by continuous epithelia that physically interfere with the entry of microbes. 2- Phagocytes: Neutrophils and Monocytes / Macrophages. The two types of circulating phagocytes, neutrophils and monocytes, are blood cells that are recruited to sites of infection, where they recognize and ingest microbes for intracellular killing. Neutrophils, also called polymorphonuclear leukocytes (PMNs), are the most abundant leukocytes in the blood, numbering 4000 to 10,000 per milliliter. Neutrophils are the first cell type to respond to most infections, particularly bacterial and fungal infections, and thus are the dominant cells of acute inflammation. These cells are also recruited to sites of tissue damage in the absence of infection, where they initiate the clearance of cell debris. Neutrophils live for only a few hours in tissues, so they are the early responders, but they do not provide prolonged defense. Monocytes are less abundant than neutrophils, numbering 500 to 1000 per mL of blood. They also ingest microbes in the blood and in tissues. Monocytes that enter extravascular tissues differentiate into cells called macrophages, which, unlike neutrophils, survive in these sites for long periods. Blood monocytes and tissue macrophages are two stages of the same cell lineage, which often is called the mononuclear phagocyte system (Fig. 2–8). Macrophages serve several important roles in host defense—they produce cytokines that initiate and regulate inflammation, they ingest and destroy microbes, and they clear dead tissues and initiate the process of tissue repair. 3- Dendritic Cells Dendritic cells respond to microbes by producing numerous cytokines that serve two main functions: they initiate inflammation and they stimulate adaptive immune responses. By sensing microbes and interacting with lymphocytes, especially T cells, dendritic cells constitute an important bridge between innate and adaptive immunity. 4- Mast Cells Mast cells are bone marrow–derived cells with abundant cytoplasmic granules that are present in the skin and mucosal epithelium. Mast cell granules contain vasoactive amines such as 3 Lec (2) Immunology histamine that cause vasodilation and increased capillary permeability as well as proteolytic enzymes that can kill bacteria or inactivate microbial toxins. Mast cells also synthesize and secrete lipid mediators (e.g., prostaglandins) and cytokines (e.g., TNF), which stimulate inflammation. 5- Natural Killer Cells Natural killer (NK) cells are a class of lymphocytes that recognize infected and stressed cells and respond by killing these cells and by secreting the macrophage activating cytokine IFN. NK cells make up approximately 10% of the lymphocytes in the blood and peripheral lymphoid organs. NK cells contain abundant cytoplasmic granules and express some unique surface proteins, but do not express immunoglobulins or T cell receptors, the antigen receptors of B and T lymphocytes, respectively. On activation by infected cells, NK cells empty the contents of their cytoplasmic granules into the extracellular space at the point of contact. Complement System The complement system is a collection of circulating and membrane-associated proteins that are important 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. The complement cascade may be activated by any of three pathways (Fig. 2–13). The alternative pathway is triggered when some complement proteins are activated on microbial surfaces and cannot be controlled, because complement regulatory proteins are not present on microbes (but are present on host cells). The alternative pathway is a component of innate immunity. The classical pathway is most often triggered after antibodies bind to microbes or other antigens and is thus a component of the humoral arm of adaptive immunity. The lectin pathway is activated when a carbohydrate-binding plasma protein, mannose binding lectin (MBL), binds to terminal mannose residues on the surface glycoproteins of microbes. This lectin activates proteins of the classical pathway, but because it is initiated by a microbial product in the absence of antibody, it is a component of innate immunity. Activated complement proteins function as proteolytic enzymes to cleave other complement proteins in an enzymatic cascade that can be rapidly amplified. 4 Lec (2) Immunology The central component of complement is a plasma protein called C3, which is cleaved by enzymes generated in the early steps. The major proteolytic fragment of C3, called C3b, becomes covalently attached to microbes and is able to activate downstream complement proteins on the microbial surface. The three pathways of complement activation differ in how they are initiated, but they share the late steps and perform the same effector functions. The complement system serves three functions in host defense. First, C3b coats microbes and promotes the binding of these microbes to phagocytes, by virtue of receptors for C3b that are expressed on the phagocytes. Thus, microbes that are coated with complement proteins are rapidly ingested and destroyed by phagocytes. This process of coating a microbe with molecules that are recognized by receptors on phagocytes is called opsonization. Second, some proteolytic fragments of complement proteins, especially C5a and C3a, are chemoattractants for leukocytes (mainly neutrophils and monocytes), so they promote leukocyte recruitment (inflammation) at the site of complement activation. Third, complement activation culminates in the formation of a polymeric protein complex that inserts into the microbial cell membrane, disturbing the permeability barrier and causing either osmotic lysis or apoptosis of the microbe. 5