Re: Innate Immune system explained, a series of posts: important, Brent, explains complement cascade



note: this is part two, I'm copying an entire section...most of this
stuff, from this section, isn't too inportant, but it does provide a
couple of explanations....
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B. ANATOMICAL BARRIERS, MECHANICAL REMOVAL, BACTERIAL ANTAGONISM BY
NORMAL FLORA, AND ANTIGEN-NONSPECIFIC ANTIMICROBIAL MOLECULES PRODUCED
BY THE BODY

The overall purpose of this Learning Object is:
1) to learn how anatomical barriers function as an innate immune
defense;
2) to learn how mechanical removal functions as an innate immune
defense;
3) to learn how normal flora bacteria function as an innate immune
defense; and
4) to learn how antigen-nonspecific antimicrobial chemicals produced by
the body function as an innate immune defense.

LEARNING OBJECTIVES FOR THIS SECTION



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Innate immunity refers to antigen-nonspecific defense mechanisms that a
host uses immediately or within several hours after exposure to an
antigen (def). This is the immunity one is born with and is the initial
response by the body to eliminate microbes and prevent infection.

Unlike adaptive immunity, innate immunity does not recognize every
possible antigen. Instead, it is designed to recognize a few highly
conserved structures present in many different microorganisms. The
structures recognized are called pathogen-associated molecular patterns
and include LPS from the gram-negative cell wall, peptidoglycan,
lipotechoic acids from the gram-positive cell wall, the sugar mannose
(common in microbial glycolipids and glycoproteins but rare in those of
humans), bacterial DNA, N-formylmethionine found in bacterial proteins,
double-stranded RNA from viruses, and glucans from fungal cell walls.
Most body defense cells have pattern-recognition receptors for these
common pathogen-associated molecular patterns (see Fig. 1) and so there
is an immediate response against the invading microorganism.
Pathogen-associated molecular patterns can also be recognized by a
series of soluble pattern-recognition receptors in the blood that
function as opsonins and initiate the complement pathways. In all, the
innate immune system is thought to recognize approximately 103
molecular patterns. All of this will be discussed in greater detail in
upcoming sections.

The innate immune responses involve:

phagocytic cells (neutrophils, monocytes, and macrophages);

cells that release inflammatory mediators (basophils, mast cells, and
eosinophils);

natural killer cells (NK cells); and

molecules such as complement proteins, acute phase proteins, and
cytokines.
Examples of innate immunity include anatomical barriers, mechanical
removal, bacterial antagonism, pattern-recognition receptors,
antigen-nonspecific defense chemicals, the complement pathways,
phagocytosis, inflammation, and fever. In the next several sections we
will look at each of these in greater detail.

We will now take a closer look at anatomical barriers, mechanical
removal, intraepithelial T-lymphocytes and B-1 cells, and bacterial
antagonism.


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Anatomical Barriers, Mechanical Removal, Intraepithelial T-lymphocytes
and B-1 cells, Bacterial Antagonism by Normal Flora, and
Antigen-Nonspecific Antimicrobial Molecules Produced by the Body

1. Anatomical barriers are tough, intact barriers that prevent the
entry and colonization of many microbes. Examples include the skin, the
mucous membranes, and bony encasements.

a. the skin

The skin, consisting of the epidermis (def) and the dermis (def), is
dry, acidic, and has a temperature lower than 37 degrees Celcius (body
temperature). These conditions are not favorable to bacterial growth.
Resident normal flora of the skin also inhibit potentially harmful
microbes. In addition, the dead, keratinized cells that make up the
surface of the skin are continously being sloughed off so that microbes
that do colonize these cells are constantly being removed. Hair
follicles and sweat glands produce lysozyme and toxic lipids that can
kill bacteria. Finally, beneath the skin surface is skin-associated
lymphoid tissue (SALT) that contains cells for killing microbes and
sampling antigens on the skin to start adaptive immune responses
against them.

b. the mucous membranes

Mucous membranes line body cavities that open to the exterior, such as
the respiratory tract, the gastrointestinal tract, and the
genitourinary tract. Mucous membranes are composed of an epithelial
layer that secretes mucus, and a connective tissue layer. The mucus is
a physical barrier that traps microbes. Mucus also contains lysozyme to
degrade bacterial peptidoglycan, an antibody called secretory IgA that
prevents microbes from attaching to mucosal cells and traps them in the
mucous, lactoferrin to bind iron and keep it from from being used by
microbes, and lactoperoxidase to generate toxic superoxide radicals
that kill microbes. Resident normal flora of the mucosa also inhibit
potentially harmful microbes. In addition, the mucous membrane, like
the skin, is constantly sloughing cells to remove microbes that have
attached to the mucous membranes. Beneath the mucosal membrane is
mucosa-associated lymphoid tissue (MALT) that contains cells for
killing microbes and sampling antigens on the mucosa to start adaptive
immune responses against them.

c. bony encasements

Bony encasements, such as the skull and the thoracic cage, protect
vital organs from injury and entry of microbes.

2. Mechanical removal is the process of physically flushing microbes
from the body. Methods include:

a. mucus and cilia

Mucus traps microorganisms and prevents them from reaching and
colonizing the mucosal epithelium. Mucus also contains lysozyme to
degrade bacterial peptidoglycan, an antibody called secretory IgA that
prevents microbes from attaching to mucosal cells and traps them in the
mucus, lactoferrin to bind iron and keep it from from being used by
microbes, and lactoperoxidase to generate toxic superoxide radicals
that kill microbes. Cilia on the surface of the epithelial cells
propels mucus and trapped microbes upwards towards the throat where it
is swallowed. This is sometimes called the tracheal toilet.

b. the cough and sneeze reflex

Coughing and sneezing removes mucus and trapped microbes.

c. vomiting and diarrhea

These processes remove pathogens and toxins in the gastrointestinal
tract.

d. the physical flushing action of body fluids

Fluids such as urine, tears, saliva, perspiration, and blood from
injured blood vessels also flush microbes from the body.

3. Intraepithelial T-lymphocytes and B-1 cells

a. Intraepithelial T-lymphocytes are found in the epidermis of the skin
and the mucosal epithelia. These T-lymphocytes, known as gamma delta
T-cells, have a limited diversity of antigen receptors for microbes
often encountered on the skin and mucous membranes. As such they
function more as effector cells for innate immunity rather than
adaptive immunity.

b. B-1 cells are B-lymphocytes with a limited diversity of antigen
receptors that initially produce a class of antibody called IgM against
common polysaccharide and lipid antigens of microbes. As such they
function more as effector cells for innate immunity rather than
adaptive immunity. Antibodies produced by B-1 cells are often called
natural antibodies.

4. Bacterial Antagonism (def) by Normal Flora (def)

Approximately 100 trillion bacteria and other microorganisms reside in
or on the human body. These normal body flora keep potentially harmful
opportunistic pathogens (def) in check and also inhibit the
colonization of pathogens by:

a. producing metabolic products (fatty acids, bacteriocins, etc.) that
inhibit the growth of many pathogens;

b. adhering to target host cells thus covering them and preventing
pathogens from colonizing;

c. depleting nutrients essential for the growth of pathogens; and

d. nonspecifically stimulating the immune system.

Destruction of normal bacterial flora by the use of broad spectrum
antibiotics may result in superinfections (def)or overgrowth by
antibiotic resistant opportunistic normal flora. The yeast Candida,
that causes infections such as vaginitis and thrush, and the bacterium
Clostridium difficile, that causes potentially severe
antibiotic-associated colitis (def), are opportunistic flora normally
held in check by normal flora bacteria. Antibiotic-associated colitis
is especially common in older adults. It is thought that C. difficile
survives the exposure to the antibiotic by sporulation (def). After the
antibiotic is gone, the endospores germinate and C. difficile overgrows
the intestinal tract and secretes toxin A that has a cytotoxic effect
(def) on the cells. Fortunately, C. difficile does itself respond to
certain antibiotics so antibiotic-associated colitis is treatable.

5. Antigen-Nonspecific Antimicrobial Molecules Produced by the Body

There are many antigen-nonspecific antimicrobial chemicals produced by
the host that play roles in innate body defense. Examples include the
following.

a. Hydrochloric acid and enzymes found in gastric secretions destroy
microbes that are swallowed.

b. Lysozyme , found in in tears, mucous, saliva, plasma (def), tissue
fluid, etc., breaks down peptidoglycan (def) in bacteria causing
osmotic lysis.

c. Human beta-defensins are short peptides found in blood plasma and
mucous. They forms pores in the cytoplasmic membrane of a variety of
bacteria causing leakage of cellular needs. Certain defensins also
block the fusion of viral envelopes with host cell membranes.

d. Lactic and fatty acids, found in perspiration and sebaceous
secretions (def), inhibit microbes on the skin.

e. Lactoferrin and transferrin, found in body secretions, plasma, and
tissue fluid, trap iron for use by human cells while preventing its use
by microorganisms.

f. Cytokines (def) are low molecular weight, soluble proteins that are
produced in response to an antigen and function as chemical messengers
for regulating the innate and adaptive immune systems. They are
produced by virtually all cells involved in innate and adaptive
immunity, but especially by T helper (Th) lymphocytes. The activation
of cytokine-producing cells triggers them to synthesize and secrete
their cytokines. The cytokines, in turn, are then able to bind to
specific cytokine receptors on other cells of the immune system and
influence their activity in some manner. Cytokines will be discussed in
greater detail later in this unit and in Unit 3.

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