Download Second Line of Defense: Natural Immunity

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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.
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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,
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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
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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.
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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.
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