I. THE INNATE IMMUNE SYSTEM
D. 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 Intraepithelial T-lymphocytes and B-1 cells function as an innate immune defense;
4) to learn how normal flora bacteria function as an innate immune defense; and
5) to learn how antigen-nonspecific antimicrobial chemicals produced by the body function as an innate immune defense.
Innate immunity is an antigen-nonspecific defense mechanisms that a host uses immediately or within several hours after exposure to almost any microbe. 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 molecules shared by groups of related microbes that are essential for the survival of those organisms and are not found associated with mammalian cells. These unique microbial molecules are called pathogen-associated molecular patterns or PAMPS and include LPS from the gram-negative cell wall, peptidoglycan and lipotechoic acids from the gram-positive cell wall, the sugar mannose (a terminal sugar common in microbial glycolipids and glycoproteins but rare in those of humans), bacterial and viral unmethylated CpG DNA, bacterial flagellin, the amino acid N-formylmethionine found in bacterial proteins, double-stranded and single-stranded RNA from viruses, and glucans from fungal cell walls. In addition, unique molecules displayed on stressed, injured, infected, or transformed human cells also act as PAMPS. (Because all microbes, not just pathogenic microbes, possess PAMPs, pathogen-associated molecular patterns are sometimes referred to as microbe-associated molecular patterns or MAMPs.)
Most body defense cells have pattern-recognition receptors for these common PAMPSand 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 of these microbial molecular patterns.
The innate immune responses do not improve with repeated exposure to a given infection and involve the following:
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.
We will now take a closer look at anatomical barriers, mechanical removal, intraepithelial T-lymphocytes and B-1 cells bacterial antagonism, and non-specific body defense chemicals.
D. 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 (def) and toxic lipids that can kill bacteria. Epithelial cells also produce defensins (def) and cathelicidins (def) to kill microbes. Beneath the epidermis of the skin are Langerhans' cells - immature dendritic cells (def) - that phagocytose and kill microbes, carry them to nearby lymph nodes, and present antigens of these microbes to T-lymphocytes to bergin adaptive immune responses against them. Finally, intraepithelial T-lymphocytes (def) and B-1 lymphocytes (def) are associated with the epidermis and the mucosal epithelium. These cells recognize microbes common to the epidermis and mucous membranes and start immediate adaptive immune responses against these commonly encountered microbes.
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 (def) to degrade bacterial peptidoglycan, an antibody called secretory IgA (def) that prevents microbes from attaching to mucosal cells and traps them in the mucous, lactoferrin (def) to bind iron and keep it from from being used by microbes, and lactoperoxidase (def) 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 Langerhans' cells - immature dendritic cells (def) - that phagocytose and kill microbes, carry them to nearby lymph nodes, and present antigens of these microbes to T-lymphocytes to bergin adaptive immune responses against them. Intraepithelial T-lymphocytes (def) and B-1 lymphocytes (def) are associated with the epidermis and the mucosal epithelium. These cells recognize microbes common to the epidermis and mucous membranes and start immediate adaptive immune responses against these commonly encountered microbes.
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 (def) to degrade bacterial peptidoglycan, an antibody called secretory IgA (def) that prevents microbes from attaching to mucosal cells and traps them in the mucus, lactoferrin (def) o bind iron and keep it from from being used by microbes, and lactoperoxidase (def) 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 and the microbes are killed in the stomach. 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
Most of the T-lymphocytes (def) and B-lymphocytes (def) in the body are involved in the adaptive immune responses that will be discussed in Unit 5. In adaptive immunity, specific receptors on T-lymphocytes (T-cell receptors or TCRs) and B-lymphocytes (B-cell receptors or BCRs) recognize specific antigens (def) of specific microbes.
Intraepithelial T-lymphocytes and B-1 cells, on the other hand, are subpopulations of T-cells and B-cells that possess a more limited diversity of receptors and are designed to directly recognize the more common microbes that enter the epidermis or the mucosal epithelia. As such, they function more as effector cells for innate immunity rather than adaptive immunity.
a. Intraepithelial T-lymphocytes (def) 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. While they can recognize both peptide and non-peptide antigens via their T-cell receptor (TCR) similar to the lymphoid T-lymphocytes involved in adaptive immunity, they can also recognize pathogen-associated molecular patterns (PAMPs) by using restricted TCRs. As such they function more as effector cells for innate immunity rather than adaptive immunity. They help defend the body by producing cytokines (def), activating phagocytes, and killing infected cells.
b. B-1 lymphocytes, or B-1 cells (def) are found mostly in the peritoneal (def) and pleural cavities (def). B-1 cells have a limited diversity of antigen receptors that initially produce a class of antibody molecule (def) called IgM against common polysaccharide and lipid antigens of microbes and against PAMPs. 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 so as to cover them and preventing pathogens from colonizing;
c. depleting nutrients essential for the growth of pathogens; and
d. non-specifically 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. For example, 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. In the case of Candida infections, the Candida resists the antibacterial antibiotics because being a yeast, it is eukaryotic, not prokaryotic like the bacteria. Once the bacteria are eliminated by the antibiotics, the Candida has no competition and can overgrow the area. 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 body 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 (def), found in in tears, mucous, saliva, plasma (def), tissue fluid, etc., breaks down peptidoglycan (def) in bacteria causing osmotic lysis.
c. Human defensins (def)) are short cationic peptides 29-34 amino acids long that are directly toxic by forming pores in the cytoplasmic membrane of a variety of microorganisms causing leakage of cellular needs. They also activate cells for an inflammatory response. Defensins are produced by leukocytes, epithelial cells, and other cells. They are also found in blood plasma and mucus. Certain defensins also block the fusion of viral envelopes with host cell membranes.
d. Cathelicidins (def) are proteins produced by skin and mucosal epithelial cells. The two peptides produced upon cleavage of the cathelicidin are directly toxic to a variety of microorganisms. One pepitide also can bind to and neutralize LPS from gram-negative cell walls to reduce inflammation.
e. Lactic and fatty acids, found in perspiration and sebaceous secretions (def), inhibit microbes on the skin.
f. Lactoferrin (def) and transferrin (def), found in body secretions, plasma, and tissue fluid, trap iron for use by human cells while preventing its use by microorganisms.
g. 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 activate and deactivate phagocytes and immune defense cells, increase or decrease the functions of the different immune defense cells, and promote or inhibit a variety of nonspecific body defenses. For example, inflammatory cytokines promote inflammation, chemokines allow leukocytes to adhere to the inner wall of capillaries, squeeze out into the surrounding tissue, and be attracted to the infection site, and type-I interferons prevent viral replication within infected host cells.
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