In the previous tutorial, we went over a general outline of the components of the innate immune
system, and the first thing we mentioned was barrier surfaces. So now let’s get a closer
look at some of the structural, chemical, and biological barriers our bodies have established
to protect our internal tissues from the outside world that is teeming with pathogens.
Despite having some key differences, all barrier surfaces have a few common features.
The first is that barrier surfaces are generally lined by epithelial cells that are connected by
tight junctions. Tight junctions are intercellular connections that form between adjacent cells,
which prevent large particles and microbes from passing through to the other side. As long as an
epithelial barrier isn’t compromised, it should be sealed off to most pathogens. Another common
feature is that all barrier surfaces have a distinct microbiome, meaning a combination
of bacteria, viruses, and fungi. Although the thought of your body crawling with microbes
may seem a little disconcerting, or even a little disgusting, the microbes that live with us, which
are called commensals, actually prevent pathogens from being able to colonize and enter the body.
Many commensals also play important roles during homeostasis, like helping to train the developing
immune system, as well as aiding with digestion and vitamin production in the case of the gut
microbiome. Be sure to visit my microbiology series for more details on these things.
Now despite the fact that barrier surfaces are covered in beneficial microbes,
another common feature they share is the production of certain chemicals and proteins
designed to target and destroy pathogens. These can include antimicrobial enzymes like lysozyme,
which can break down the peptidoglycan in bacterial cell walls, and secretory phospholipase
A2 , which can disrupt bacterial cell membranes by hydrolyzing membrane phospholipids.
These also include small peptides called antimicrobial peptides or AMPs
that can directly kill pathogens. There are three main families of AMPs: defensins,
cathelicidins, and histatins. Defensins are short, amphipathic peptides about 30-40 amino acids in
length. These peptides have a positively charged region, as well as a hydrophobic region that can
insert into bacterial, viral, and fungal membranes and disrupt them. Defensins are some of the most
abundant AMPs in mammals, and humans make more than 21 different types of defensins, although
plants and other animals can also make them. Cathelicidins are produced as pro-peptides, which
means an inactive protein precursor, and must be cleaved in order to be activated. Once cleaved,
the carboxy-terminal region functions similarly to a defensin, as it is also an amphipathic,
cationic peptide that disrupts pathogen membranes. Finally, there are the histatins,
which are found in saliva. Histatins are particularly effective against pathogenic fungi.
So now that we know the basics these surfaces have in common, let’s go through some of
the most important barrier surfaces that keep our insides in and the outside out.
Let’s start with the skin. The average adult human has two square meters of skin covering their body,
which not only makes skin the largest organ in the body, but it is also a massive surface area the
body needs to keep closed off to pathogens. The skin microbiome mainly consists of Gram-positive
bacteria like Corynebacterium, Staphylococcus, and Propionibacterium. These skin-colonizing bacteria
have multiple strategies to prevent colonization of pathogens like Staphylococcus aureus, a species
of Staphylococci which is sometimes commensal, but can also act as an opportunistic pathogen. These
can include direct strategies like production of antibiotics and proteases that can kill S. aureus,
as well as indirect ones, like stimulating AMP production by skin cells.
The skin itself is made up of multiple layers of specialized epithelial cells
called keratinocytes, as we learned right at the start of the anatomy and physiology series.
The 15-20 outermost layers of keratinocytes make up the region known as the stratum corneum,
named as such because these keratinocytes have undergone a form of programmed cell death called
cornification. Having multiple layers of dead cells as the outermost barrier of the body helps
protect against viral infections, as viruses need to infect living cells in order to proliferate.
The stratum corneum also houses a harsh chemical environment which is inhospitable to potential
invaders, including urea, lactate, amino acids, and fatty acids, all of which contribute to
an acidic environment. Not only does the low pH discourage microbial colonization,
but some defensins actually function optimally at a lower pH. Beneath the stratum corneum,
keratinocytes make a type of defensin called beta-defensins, which are stored in lipid-rich
organelles called lamellar bodies and are released into the extracellular space. Another important
contributor to skin barrier defense is a unique population of skin-resident dendritic cells,
called Langerhans cells. Langerhans cells extend their dendrites into the stratum corneum to sample
antigen. During homeostasis, Langerhans cells promote regulatory T cell development in the skin.
However, if they sense an infection, they can quickly help mobilize both an innate
and an adaptive immune response. In addition, Langerhans cells are tolerant to the normal skin
microbiome, meaning that they do not launch an immune attack in response to these microbes.
Another important barrier surface with a colossal surface area is the respiratory tract,
which some estimates place at being over 100 square meters, inhaling about 10,000
L of air per day. The airway epithelium needs to protect against inhaled pathogens and particles,
while still being permeable enough to allow for gas exchange.
One way to do this is with a lining of mucus that traps inhaled pathogens and keeps them
from crossing the epithelium into deeper tissues. In a process known as the mucociliary escalator,
tiny hairs on airway epithelial cells called cilia constantly beat upwards, pushing mucus
up from the lungs to the larynx, where it is either coughed up or swallowed, forcing
any potential pathogens to then pass through the harsh chemical conditions of the stomach.
Airway epithelial cells also make lamellar bodies full of beta-defensins and other chemicals that
are released into the pulmonary surfactant, thus making it difficult for pathogens to colonize.
The nasal microbiota closely resembles that of the skin, but as we move further into the
upper respiratory tract, it begins to diversify and include Moraxella,
Dolosigranulum, Haemophilus, and Streptococcus. Although the lungs have their own microbiome,
it is understood that the upper respiratory tract is a major initial reservoir of pathogens causing
lower respiratory tract infections. This means that the upper respiratory tract microbiome is
important for preventing colonization of pathogens that could spread to the lower respiratory tract.
Airway epithelial cells express a wide range of pattern recognition receptors,
and are often the first to sound the alarm when an infection is detected,
producing cytokines and chemokines to recruit immune cells to the site of infection.
However, some immune cells live in the respiratory tract, even during quiescence, or dormancy.
Alveolar macrophages, found in the alveolar space of the lungs, are one of the resident
immune cell types in the airways, and the main phagocytic type in the lungs.
During periods of homeostasis, in other words not during an infection, alveolar macrophages
are important scavengers, using their phagocytic capacity to ingest inhaled particles, antigens,
and microbes. They also keep pulmonary surfactant clean by phagocytosing proteins within the fluid.
Another major barrier surface requiring constant surveillance and strong defenses
is the gastrointestinal tract. Innate immune defense of the gastrointestinal tract
begins in the mouth. Saliva contains defensins and antimicrobial enzymes like lysozyme
and secretory phospholipase A2. Any microbes that survive the saliva then pass through the stomach.
The stomach produces gastric acid and digestive enzymes like proteases and lipases. Although the
primary role of these digestive enzymes is to break down food particles, they serve a dual
purpose in that they are also able to destroy many microbes that may have been ingested.
Most pathogens don’t survive transit through the stomach, but those that do move to the intestines.
Like the airway epithelium, the intestinal epithelium lines a massive surface area that
is optimized for nutrient absorption and faces a similar challenge of needing to protect these
border regions from infection. One way the gut achieves this is by peristalsis, the constant,
unidirectional movement of intestinal contents until they are flushed out of the body. The
constant movement makes it more difficult for pathogens to attach to and colonize the intestinal
epithelium. The intestinal epithelium is coated in a layer of mucus, which helps lubricate surfaces
and also makes attachment and colonization more difficult. Now shifting from pathogens back to
commensal bacteria, the mucus layer, generated by specialized epithelial cells called goblet cells,
is a source of nutrition for many gut commensals. The intestinal microbiome is probably the best
characterized of all the human microbiomes. Gut microbes play many beneficial roles in our bodies,
including helping to digest complex carbohydrates, synthesizing nutrients like bile acids and some
vitamins, and establishing ecological niches that help prevent the colonization of pathogens.
Although the body maintains tolerance towards symbiotic bacteria, meaning that it doesn’t attack
them the way it would attack pathogens, these bacteria are important for priming the developing
mucosal immune system and helping it to function properly during infection with true pathogens.
If a pathogen is able to make it past the gut microbiome and the mucus layer into the gut
epithelium, it has a few other forces to reckon with. For one thing, although the intestinal
epithelium is only one cell layer thick, the lining regenerates every four to five days.
When epithelial cells die, they slough off and become part of the intestinal contents, eventually
being expelled from the body. The rapid turnover means that many pathogens infecting intestinal
epithelial cells will be shed and destroyed before they even have time to spread from cell to cell.
Every intestinal crypt also contains several Paneth cells,
which are specialized intestinal epithelial cells that make antimicrobial peptides and lysozyme.
Paneth cells also make alpha-defensins called cryptdins that are secreted into the intestinal
lumen after being cleaved by proteases. Sitting beneath the intestinal epithelium is
the lamina propria, which is full of immune cells, including the gut-associated lymphoid tissue
like Peyer’s patches. Peyer’s patches contain an additional important type of epithelial cell
called the M cell. M cells can transport antigens from the intestinal lumen to immune cells
on the basolateral side. Although some microbes can subvert this pathway to gain access to the
lamina propria, this is also an important way to provide antigen-presenting cells
such as dendritic cells with luminal antigen to activate lymphocytes in the Peyer’s patches.
The last barrier surface we will discuss is the female reproductive tract,
which is an often-overlooked site of important barrier biology. Like mucus in other parts of
the body, cervical mucus can trap invading pathogens. The vaginal microbiome plays a
particularly important role in preventing yeast infections and bacterial vaginosis.
Lactobacillus species are the dominant colonizers of the female reproductive tract.
These bacteria metabolize glycogen to lactic acid, acidifying the vaginal tract and making
it inhospitable for many other species to grow. They also produce hydrogen peroxide,
which is an effective antimicrobial against many other bacterial species.
Reductions in vaginal Lactobacillus species have been associated with more frequent yeast
and bacterial infections, suggesting that it is directly inhibiting outgrowth of pathogens.
So that covers the basics regarding barrier surfaces. To review, the most common features of
all barrier surfaces include a protective coating of commensal bacteria, epithelial cells joined by
tight junctions which make antimicrobial peptides, and an arsenal of different chemical defenses.
And with barrier surfaces covered, it’s time to move on to the complement system.