By Dr. Marcus Judge and Dr. Ethan Kavanagh
Next Lesson - Adaptive Immunity
Core
The human body has an amazing system to defend itself against infectious disease - the immune system. It has two arms of protection: innate and adaptive immunity. The former is what we are focusing on here.
Properties of the Innate Immune System
Innate immunity is the front-line defence against any pathogen that tries to attack the body. It is referred to as "non-specific", as it protects from everything that is "non-self" (not produced by the body) equally. It is made of multiple components. These start with the physical wall of our skin, which guards against the pathogens that are always present around us. They go on to include immune cells designed to recognise non-self antigens (markers) and destroy them.
As you might expect, the innate response is fast (acting over minutes to hours). It has no antigen-specific memory, unlike the adaptive immune system. (A different process, called "trained immunity", has also been described, in which innate cells can resist reinfection better. It is beyond the scope of this article.)
In summary the innate immune system is: Fast, non-specific, standardised and has no memory.
The adaptive immune system, by contrast, is slow to start, specific to the pathogen and has memory, so a repeat exposure to the same pathogen causes a faster, stronger response.
Image: The innate physical, physiological, biological and chemical mechanisms of defence in the human body
SimpleMed original by Dr. Marcus Judge
Barriers of the Innate Immune System
Alongside holding everything together, the skin is the main physical barrier that is preventing the bacteria present everywhere from infecting humans. Its outer layer (the epidermis) replaces itself every 39 to 48 days or so. The skin is also elastic, so it can twist and stretch as our joints move. This makes it the ideal covering for the body.
Of course, the skin isn’t continuous like one big bubble around us (we need to eat, breathe and excrete waste products) so the openings and passages we use for these (the mouth, airways, gut and urinary tract) have a different lining. Lining the openings to the body are different mucous membranes (moist linings that make mucus, a sticky fluid), which can be found in tracts such as the respiratory tract. Each mucosal layer is specialised depending on its location.
For example, the respiratory epithelium is lined with cilia (explained below) and goblet cells (cells that make mucus). Goblet cells, together with small glands in the airway wall, make the mucus in the respiratory tract. The mucus traps anything that contacts the inside of your respiratory tract. The cilia then move the mucus, and everything trapped in it, up towards the throat (the pharynx). This is known as the mucociliary escalator. Cilia are finger-like projections that stick out along the mucosal membrane and beat in synchrony. This beating shifts the mucus and any trapped pathogens upward, so they can be coughed out of the body or swallowed and destroyed in the stomach.
The skin barrier has one major weakness. Once it is damaged (for example by a scrape or cut), pathogens can get into the tissue underneath much more easily. This is a particular risk with the commensal bacteria of the skin (bacteria which usually live on the skin without causing harm). These can become pathogenic (disease-causing) when they enter the body through the break in the skin. This is why it is important to clean wounds before they are closed. Cleaning stops non-sterile material from being trapped under the skin and leading to infection. The skin does have the ability to heal if it has been cut, but this takes time.
There are several different physiological barriers that the innate immune system has up its sleeve. As mentioned above, coughing is a response used by the innate immune system to remove anything harmful in the airway. Similar mechanisms apply to pathogens in other tracts for example the gastrointestinal (GI) tract. If the irritant is in the stomach, the body may expel it by vomiting (emesis). If it is in the small or large intestine, diarrhoea is used for expulsion.
One thing to remember is that these physiological responses aren’t perfect and often have side-effects. Coughing excessively can cause chronic damage or inflammation of the airways and may trigger or exacerbate asthmatic episodes. Vomiting and diarrhoea lead to loss of fluid and electrolytes (salts such as potassium and sodium). Some patients have severe diarrhoea and vomiting that is hard to control, for example in cholera. They need fluids and salts replaced to prevent dehydration and electrolyte imbalance, which in extreme cases can be fatal. The main treatment is to drink plenty of fluids, including oral rehydration solution (a drink containing water, salts and sugars). Patients who are very unwell may need fluids given through a vein in hospital. Thus, innate immune responses can cause severe complications. Some infections can also trigger these mechanisms themselves. In cholera, for example, a bacterial toxin makes the gut secrete large volumes of watery fluid.
Different bacteria have certain conditions that they thrive in. The human body tries to counteract this by altering the conditions of different environments within it. A key example of this is the stomach, where stomach acid (composed mainly of hydrochloric acid) creates an environment with a pH of around 2. This low pH does many helpful things (activating certain enzymes, de-activating proteins, breaking down food etc.) alongside damaging and killing most of the bacteria in the stomach.
Note: pH is a measure of how acidic or alkaline something is on a scale that is commonly given as 0 to 14. A pH of 7 is neutral; anything below this is acidic and anything above is alkaline. The scale is logarithmic, meaning that each whole pH unit represents a tenfold change in hydrogen ion concentration. A pH of 1 is very acidic and a pH of 14 is very alkaline. Stomach acid has a pH of about 1 to 3, so it is very acidic. When the acidity is reduced, the stomach is a less effective chemical barrier, and the risk of some gut infections, such as cholera and Salmonella (a bacterium that causes food poisoning), goes up. Acid can be reduced for several reasons. Examples are acid-suppressing drugs called proton pump inhibitors (which block the acid-making proton pump of the stomach lining) and infection with Helicobacter pylori (H. pylori), a bacterium that infects the stomach lining and, early in the infection, lowers acid output for a time.
Other examples of pH control include the skin which has a pH of about 5.5 and the vagina which has a pH of 4.5 or below (which is maintained by Lactobacilli, harmless acid-producing bacteria that live in the vagina).
Alongside pH, the body has other chemical means to prevent infection. A molecule called IgA (immunoglobulin A) is present in tears, saliva and mucous membranes and helps to fight against pathogens. IgA is an antibody, made by plasma cells (antibody-producing white blood cells) in the tissue beneath mucosal surfaces. Antibodies are made by the adaptive immune system, but IgA also acts as a chemical barrier at body surfaces. Most people with IgA deficiency have no symptoms (they are asymptomatic). Some get repeated infections of the airways and gut, and IgA deficiency is also linked with allergic disorders and autoimmune disease. Other molecules and chemicals used by the innate immune system include lysozyme (an enzyme that kills bacteria), beta defensins (small proteins that kill microbes by damaging their cell membranes) and pepsin (a digestive enzyme that can also help to kill bacteria). Mucus, mentioned earlier, also contains peptides (small pieces of protein) that kill microbes, and helps to stop bacteria from sticking to surfaces.
This barrier consists of the body’s normal flora (bacteria that normally reside in certain parts of the body). This is protective for two reasons. First, commensal bacteria in certain locations outcompete pathogenic bacteria for nutrients and other resources (including space), which stops an infection from taking hold. Second, normal flora can also produce antimicrobial chemicals and synthesise certain nutrients and vitamins that the body needs (e.g. vitamin K in the gut).
Normal flora are helpful until they move to another location where they shouldn’t be or the composition of the flora is modified by diet or immune status. In this case the commensal flora may become pathogenic. There are a few reasons bacteria can move out of place e.g. loss of skin integrity, poor dental work, when antibiotics deplete competitors (see the section "A Note on Commensals" in the linked article, An Introduction to Infection).
What if the Pathogen Gets Through?
If a microorganism is able to get past the initial barriers of the innate immune system, the cells of the innate response now come into battle. This involves the activation of the complement molecules (blood proteins that help to destroy microbes) and the phagocytic cells of the body (white blood cells that engulf and destroy microbes). Activating complement sets off a chain reaction called the complement cascade, explained in the Complement section below.
Image: The cells of the Innate Immune system. Note the macrophages, dendritic cells (cells that engulf microbes and help to start the adaptive response) and neutrophils responsible for phagocytosis (the engulfing and breakdown of foreign cells). Natural killer cells (lymphocytes that kill virus-infected and abnormal cells) are part of the innate immune system, although they also interact with T-cells and other cells of the adaptive response
Public Domain Source [Fred the Oysteri] The source code of this SVG is valid. This vector image was created with Adobe Illustrator. [https://upload.wikimedia.org/wikipedia/commons/4/44/Innate_Immune_cells.svg]
Phagocytes (white blood cells that engulf and destroy microbes) will recognise, bind to and then destroy pathogens. They engulf the microbe into a membrane-bound bubble (a phagosome). They then kill it in one of two ways. The oxygen-dependent pathway makes reactive oxygen molecules, a process known as the respiratory burst. The oxygen-independent pathway uses digestive enzymes. The main phagocytes are macrophages, monocytes and neutrophils. Monocytes circulate in the blood and become macrophages in the tissues. Dendritic cells also engulf microbes.
Microbes are recognised by pathogen-associated molecular patterns (PAMPs): molecules found on microbes, made of carbohydrates, lipids, nucleic acids and proteins, that mark them as foreign. The phagocytes have pattern recognition receptors (PRRs) on their cell surface and inside the cell (in endosomes, small membrane-bound sacs) that bind to the PAMPs so they can recognise and destroy the bacteria. Toll-like receptors are one important family of PRRs.
Image: Opsonins (molecules that coat a microbe) binding the surface of the antigen that has been identified as non-self, making the antigen-bearing pathogen more "attractive" for phagocytes to phagocytose
SimpleMed original by Dr. Marcus Judge
A process called opsonisation (literally, to "make tasty") can help phagocytosis. Substances called opsonins bind to the surface of the pathogen and to a receptor on the phagocyte. This tags the pathogen, which helps the phagocyte to attach to it and engulf it. Examples of opsonins include C3b (from the complement pathway), IgG (immunoglobulin G, an antibody), C-reactive protein (CRP) and mannose-binding lectin (MBL, a protein that binds sugars). CRP and MBL are acute phase proteins (proteins the liver makes more of during inflammation). Opsonins are especially important for clearing encapsulated bacteria (bacteria with a protective outer capsule), because the capsule helps these bacteria to avoid being engulfed.
The complement system is a group of proteins that complement (add to) the work of antibodies and phagocytes, giving the immune system a boost. It consists of more than 30 proteins, found in the blood (serum) and on cell surfaces. The most important of these are:
- C3a and C5a for recruiting phagocytes (chemoattractants, chemicals that draw cells towards them)
- C3b and C4b which are opsonins (discussed above)
- C5b - C9 help to kill pathogens (C5b is made when C5 is split). These proteins come together to form the "membrane attack complex", a pore (hole) in the cell membrane of bacteria. This pore allows water to move into the bacteria, causing them to swell and burst. This works against Gram-negative bacteria (one of the two main groups of bacteria, defined by the Gram stain). Gram-positive bacteria (the other main group) have a thick cell wall of peptidoglycan (a mesh of sugar and amino acid chains) that the complex cannot get through, so the pore does not kill them. Fungi also have a thick cell wall, so the pore cannot burst them either.
There are three pathways that activate the complement system:
- Classical - antibody-antigen complexes
- Alternative - activating surfaces (bacterial and fungal cell walls)
- MBL - Mannose Binding Lectin (a protein that binds sugars) binds to mannose (a sugar) on the surface of pathogens
All three pathways produce an enzyme called C3 convertase. This leads to the same end results: opsonins (C3b), chemoattractants (C3a and C5a) and the membrane attack complex, which can damage the plasma membrane of some cells and bacteria.
Diagram: The membrane attack complex forms in the membranes of pathogens - complement proteins come together to form a pore in the membrane, allowing water to flow into the cell, causing the cell to swell and die
Creative commons source by The Complement System Amy Lovett-Racke, PhD Associate Professor Department of Microbial Infection and Immunity Reading: The Immune System, 3rd Edition [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
Cytokines are small proteins, produced by immune cells, that act as chemical messengers. They have a very important role in regulating the immune response. They also provide a key link between the innate immune response and the adaptive immune response, which is carried out by lymphocytes (white blood cells) called T-cells and B-cells. The innate immune response, being non-specific and fast, will occur before the adaptive immune response.
Tumour necrosis factor alpha (TNF-α) is a key pro-inflammatory (inflammation-promoting) cytokine involved in triggering the inflammatory response and leads to increased permeability of the blood vessel. This allows more fluid to move into the tissues from the blood vessels, and with that fluid more immunoglobulins (antibodies) and phagocytes. TNF-α is produced by macrophages and other inflammatory cells. Along with increasing permeability, it also influences the activity of T-cells, which helps to link the innate response to the adaptive immune response.
Interleukins, such as interleukin 1 (IL-1) and interleukin 6 (IL-6) are another type of very important cytokines. IL-1 is produced mainly by macrophages and is responsible for T-cell and B-cell activation (and proliferation, meaning multiplying). IL-6 is also produced by macrophages and monocytes. Not only does IL-6 stimulate B-cell activation, but it also acts as a hepatocyte-stimulating factor. This means it tells liver cells to make more acute phase proteins (also called acute phase reactants; proteins such as CRP whose levels rise during inflammation). These increase the inflammatory response and help to recruit more immune molecules. IL-6 also stimulates haematopoiesis (the making of blood cells).
These cytokines have combined actions:
- Increase in CRP and MBL produced by the liver - these help with the activation of the complement pathways.
- Release of neutrophils from the bone marrow into the blood.
- Vasodilation, increase in vascular permeability and attracting neutrophils to a particular area.
- Cause the hypothalamus to increase body temperature, making the body temperature unfavourable for bacterial or viral growth.
These actions normally help the body to contain and clear the infection. Problems, however, start to arise when phagocytosis has been reduced due to:
- A decrease in spleen function (important for clearing encapsulated bacteria)
- A decrease in neutrophil number (could be due to chemotherapy, which is drug treatment for cancer; certain other drugs; and certain diseases that damage the bone marrow, from which neutrophils are produced)
- A decrease in neutrophil function. An example is chronic granulomatous disease, where a faulty enzyme (NADPH oxidase) stops the phagocytes from producing the respiratory burst (the oxygen-dependent killing of microbes described above). The phagocytes take up bacteria and fungi but cannot kill some of them properly, and these infections can be life-threatening.
Edited by: Dr. Marcus Judge and Dr. Ben Appleby
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