Unit II: Introduction
Our initial immune defenses rely on types of cells and molecules that have performed admirably for hundreds of millions of years. Early in the history of life, organisms developed mechanisms to ask whether a particular cell was “self or nonself” and “friend or foe.” As life diversified, different groups of organisms developed specialized molecules with restricted distribution. For example, bacteria expressed molecules that were not expressed by protozoa or by algae—or by trees or by humans.
Over time, these group-specific markers enabled one group (e.g., multicellular animals) to encode and synthesize receptors able to recognize and bind molecules that are characteristic of other groups (e.g., bacteria). As a result, organisms encoded within their genomes a series of “hard-wired” receptors capable of a type of self or nonself distinction.
On recognizing and binding to a nonself intruder, initiate a series of enzymatic reactions that might directly destroy the intruder or at least render it more susceptible to some other means of destruction. Other receptors are placed on the surface of certain host cells that move around in the body. These cells, generically termed phagocytes, often have janitorial duties: clearing the body of debris. But when, in the course of their duties, their receptors detect the presence of nonself, phagocytes undergo a change of personality.
They become angry and aggressive. Like a mild-mannered Clark Kent, they “step into a telephone booth” and emerge as Superman, with powers to attack and destroy the intruders they have intercepted. It is on these soluble and membrane-bound hard-wired receptors that the human innate immune system is built.
We live in a microbial world. Our bodies are constantly surrounded by vast numbers of microbes (Table 3.1). In addition to the microbes themselves, the molecules they produce and some molecules from other environmental sources (e.g., venoms) can also injure body cells and tissues. The body has several mechanical, chemical, and biologic barriers that provide the first line of defense against the entry of microbes into the aseptic, nutrient-rich environment of our tissues. These barriers can be thought of as the moats and thick walls that provided the initial protection to the inhabitants of castles under enemy attack.
Table 3.1.Our Microbial Environment
|Skin||103 per cm2||1012 total|
|Scalp||106 per cm2|
|Nasal mucus||107 per gram|
|Saliva||108 per gram|
|Feces||>108 per gram|
|Alimentary tract||—||1014 total|
The initial mechanical barriers that protect the body against invasive microbes include the epidermis and keratinocytes of the skin; the epithelium of the mucous membranes of the gastrointestinal, respiratory, and urogenital tracts; and the cilia in the respiratory tract (Fig. 3.1). These mechanical barriers also incorporate several chemical and biologic barriers that minimize or prevent entry of potential pathogenic organisms into the body.
Figure 3.1.Protective barriers of the body.
The barriers of the body represent the first line of defense and prevent or retard the entry cells and molecules into the body.
The epidermis or outer layer of the skin varies in thickness from 0.05 to 1.5 mm depending on location (Fig. 3.2). The outermost of the five layers of the epidermis or stratum corneum is composed of dead, tightly layered, and cornified squamous cells. Produced by keratinocytes of the lower four layers, cells of the stratum corneum provide a watertight barrier that prevents our dehydration and provides a microbe-inhospitable dry environment on the surface of our skin. Continuously dividing keratinocytes and constant sloughing of the superficial epidermal layer removes microbes attached to cutaneous surfaces.
Figure 3.2.Skin contains various defense mechanisms.
The epidermis provides a dry, watertight barrier continually sloughing dead cells (keratinocytes). Dermal glands bathe the epidermis with microcidal molecules as well as with sebum and sweat producing an acidic pH and deposit salt on the surface of the skin. The dermis contains additional defense molecules and phagocytic molecules (e.g., neutrophils, macrophages) that attack invaders. Commensal microbes secrete fatty acids that inhibit colonization by other microbes.
B. Mucous membranes
The epithelium of mucous membranes lines all of the body’s cavities that come into contact with the environment, such as the respiratory, gastrointestinal, and urogenital tracts (Fig. 3.3). This epithelium contains goblet cells that secrete mucus. It is estimated that 4 L of mucus are secreted within the gastrointestinal tract alone on a daily basis (although much of it is resorbed in the large intestine). In the respiratory tract, the mucus traps inhaled bacteria, fungi, and other particles.
In the gastrointestinal tract, the mucus and mucous membranes help to protect the epithelial cells and underlying tissues from damage by digestive enzymes and to propel ingested matter through the tract. Mucosal surfaces of the moist epithelium facilitate the exchange of molecules with the environment while also resisting microbial invasion. Additionally, the sloughing of the intestinal epithelial cells has a protective effect similar to that of the sloughing of keratinocytes in the skin.
Figure 3.3.Defense mechanisms of the mucous membranes.
Mucus entraps microbes and particulate matter (which, in the respiratory tract, is swept out by cilia). Protective commensal microbes are present, and numerous microcidal molecules, enzymes, and acids are produced.
C. Respiratory tract
Air turbulence caused by hairs within the nostrils deposits particles larger than 10 mm in the nasal mucosa. The hairlike cilia of the epithelia lining the respiratory tract passages help the tract clean by moving the secretions containing trapped microbes and particles outward for expulsion by coughing and sneezing. The rhythmically beating cilia of the respiratory epithelium are commonly disrupted by chronic smoking and chronic alcohol consumption, leading to an increased risk of respiratory infections.
The importance of the mucus secreted by the membranes of the respiratory system is illustrated by the genetic disorder cystic fibrosis. Cystic fibrosis is caused by a mutant gene that encodes a defective chloride ion channel, leading to abnormally thickened and viscous secretions that can obstruct the respiratory tract. As a result, individuals with cystic fibrosis have recurrent respiratory infections with bacteria such as Pseudomonas aeruginosa.
D. Urinary tract
Similar to the outward movement of secretions of the respiratory tract, urination helps to inhibit movement of microbes from the environment up into the bladder and kidneys. The periodic voiding of sterile urine provides an externally directed fluid pressure that inhibits the inward movement of microbes along the urinary tract. This simple protective mechanism can be disrupted by the therapeutic insertion of a catheter, which increases the risk of urinary tract infections by facilitating entry of microbes into the urinary tract.
Urinary tract infections due to catheterization account for nearly half of all hospital nosocomial infections. The female urogenital tract is also protected by the acidic secretions of the vagina and the presence of microcidal molecules secreted by the mucous membranes.
Chemical and Environmental Barriers
The acidic pH of the skin, stomach, and vagina serves as a chemical barrier against microbes. Microcidal molecules such as ?-defensins, ?-defensins, cathelicidin, RNases, DNases, and lysozyme, which are secreted by various cell types, also provide protective environment barriers.
Most pathogens are very sensitive to an acidic environment where an acid pH inhibits the growth of potential pathogens.
The skin contains oil and sweat glands (sebaceous and sudoriferous glands, respectively), some of whose products are slightly acidic. In general, the skin has a pH of about 5.5. Sebum is a mix of lipids produced by the sebaceous glands. Excessive sebum secretion is often associated with oily skin and acne, particularly in adolescents, as it can clog skin pores (entrapping and retaining microbes) and create less favorable pH levels for microbial growth.
Compared to the colon, the stomach has very few bacteria because of its acidic environment (normal pH of 1.0 to 3.0). The acidic environment of the stomach prevents the colonization of the intestines by ingested microbes.
The acidic environment of the vagina and cervical os in healthy women is normally pH 4.4 to 4.6. This acidic environment is the result of lactic acid production by the commensal bacteria Lactobacilli spp. (see Section IV).
B. Microcidal action of secreted molecules
Several tissues that are in contact with the environment synthesize and secrete various microcidal molecules that act to inhibit or kill microbes that are attempting to colonize. A few of the primary microcidal molecules are discussed here.
The skin is protected in part by several antimicrobial peptides secreted by various cell types found within the skin. Among these are ?-defensins, ?-defensins, and cathelicidin. All are able to inhibit microbial growth by direct action on the microbes, perhaps by damaging the microbial membranes and causing lysis. They can also act as chemoattractants for cells of the innate immune system and facilitate the ingestion and destruction of microbes by phagocytes. Fatty acids released by some of the commensal microbes that are present on the skin also act to inhibit growth by some other bacteria.
Other molecules with enzymatic activity are present in the skin as well. Sweat contains lysozyme, an enzyme that breaks down peptidoglycan (a constituent of most bacterial cell walls). Also present in the skin are molecules that act on the RNA and DNA of a wide range of microbes.
RNases and DNases, in fact, are powerful enough to require the wearing of protective gloves while performing molecular biology procedures—not to protect the hands but to protect the material that is being manipulated from destruction by the enzymes on the skin. Finally, the evaporation of sweat creates a slightly salty environment that inhibits growth of many bacteria.
2. Respiratory tract
To protect the mucosal surfaces of the lungs, some cells of the respiratory epithelium secrete microcidal molecules such as ?-defensins. These and other molecules in the respiratory tract can attach to microbes and make them more susceptible to ingestion and destruction by phagocytic cells.
3. Gastrointestinal tract
The gastrointestinal tract defends against pathogens in many ways. In addition to the low pH of the stomach, some epithelial cells secrete microcidal molecules such as ?-defensins and cryptidin that help to destroy many potential pathogens. Approximately 22 different digestive enzymes are released from the salivary glands, stomach, and small intestine. Among these is lysozyme found in saliva. These enzymes help the digestive process but are also effective in killing and degrading many potential pathogens that may be ingested.
4. Lacrimal secretions
Lacrimal glands are small almond-shaped structures, located above the outer corner of the eye, that produce tears. As part of protecting the eyes, the secretions of lacrimal glands contain lysozyme.
Biologic Barriers: Commensal Microbes
Commensal microbes are those that exist in a symbiotic relationship with the body. The skin and the gastrointestinal tract are colonized by more than 500 commensal bacterial and other microbial species that are estimated to make up more than 95% of the cells present in a normal human body (Table 3.2). Commensal microbes colonizing the skin and gastrointestinal tracts “defend” their territory and inhibit the establishment of other potentially pathogenic microbes. In the gastrointestinal tract, these microbes also assist in the digestive process.
Table 3.2.Commensal Microbes
|Body Area||Common Organisms (Bacteria unless Otherwise Noted)|
|Upper respiratory tract|
|Urogenital tract||Urethral opening|
Clinical Application: Nosocomial infection
A 60-year-old woman is evaluated in the hospital for a 1-day history of fever, redness, and tenderness at the catheter insertion site. The woman was recently diagnosed with leukemia and started receiving chemotherapy several days ago. Physical examination is remarkable for high fever in addition to redness and tenderness at the catheter insertion site on her left arm. Blood cultures reveal a positive result for methicillin-resistant Staphylococcus aureus.
This patient has a nosocomial (hospital-acquired) infection in addition to her underlying immunocompromised condition (due to chemotherapy for the leukemia). The catheter should be removed immediately and the patient should be treated with intravenous antibiotics.
Commensal microbes are not pathogenic (disease-causing) except under special circumstances. For example, commensal microbes can cause disease in people who are immunocompromised (i.e., their immune systems do not function effectively). The introduction of medical devices, such as catheters, into the body can also cause commensal bacteria from the skin to enter areas of the body that are normally sterile. Any disruption of the normal flora of the body may lead to disease.
Pseudomembranous colitis is a condition caused by Clostridium difficile, a pathogenic bacterium that produces a toxin that damages the gastrointestinal tract and causes watery diarrhea, abdominal cramps, and fever. The condition may occur after a course of broad-spectrum antibiotic therapy. One explanation for the condition is that the use of antibiotics reduces the levels of normal commensal bacteria of the gastrointestinal tract, thus permitting the establishment and overgrowth by C. difficile.
- The body has several mechanical, chemical, and biologic barriers that provide the first line of defense against the entry of microbes and toxic molecules.
- The initial mechanical barriers that protect the body against invasive microbes include the epidermis and keratinocytes of the skin; the epithelium of the mucous membranes of the gastrointestinal, respiratory, and urogenital tracts; and the cilia in the respiratory tract.
- The slightly acidic pH of the skin and vagina is inhibitory to microbial growth. The high acidity of the stomach is highly inhibitory.
- Microcidal molecules inhibit microbial growth. Present in the skin are molecules such as RNases and DNases, defensins, and cathelicidin. Some cells of the respiratory epithelium secrete
- ?-defensins; some epithelial cells secrete ?-defensins and cryptidins.
- Commensal microbes are those that exist in a symbiotic relationship with the body. Commensal microbes colonizing the skin and gastrointestinal tracts inhibit the establishment of other potentially pathogenic microbes.