Chapter 2: Innate Immune Barriers and Components
Learning Objectives
By the end of this chapter you will be able to:
- Outline physical and chemical defenses of the immune system
- Identify and assign a function to each cell of the innate immune system
Case Study
Sarah B. is 28 years old and has no history of urinary issues. Recently however, she has presented with frequent urination, pain and burning during urination, cloudy urine. Sarah has been taking antibiotics that cleared up a respiratory infection, which contributed to the death and imbalance of protective bacteria within her urinary tract. This microbial imbalance allowed Escherichia coli to attach to the bladder lining and multiply, causing irritation and inflammation. Inspection of her cloudy urine shows the presence of bacteria in urine but also mucus and white blood cells (leukocytes). Sarah’s physician prescribes her a new antibiotic that is more specific to E. coli and that concentrates within urine. The new prescription helps Sarah recover from the urinary tract infection and she progressively re-establishes a healthy population of bacteria within her urinary tract.
- How do you think some bacteria protect us from infection?
- What characteristic of urine would protect us against excessive bacterial growth?
- Why do you think it would be beneficial for Sarah to drink more water and increase her frequency of urination?
- What are the roles of mucus and white blood cells in the urine of a person with urinary tract infection?
Answers to these questions are at the end of the chapter.
2.1 Physical Immune Defenses
The human immune system takes a multi-barrier approach, where layers of physical and chemical challenges prevent microbes from invading deeper into tissues.
The skin is a superficial barrier, composed of dead cells that are tightly connected by a dense layer of keratin. Our skin is dry, salty and acidic, and is constantly being shed. These characteristics collectively make the skin difficult to penetrate.
Where the skin is replaced by more fragile but functional tissues, such as the eyes, respiratory tract, urinary tract and digestive tract, mucus acts as a physical barrier. Mucus is secreted by specialized epithelial cells called mucous membranes. Secreted mucus traps microbes in a thick and sticky matrix, which contains antimicrobial compounds. Mucus, along with the entrapped microbes, is then be flushed out of the body. The mucocilliary escalator of the upper respiratory tract is an example of this process, where epithelial cells with hair-like appendages called cilia transports mucus up and out of the airway.
Physical Barriers
Epithelial cells of the body surface (e.g. skin) and the tracts (e.g. digestive, respiratory) are tightly associated to create a barrier and have additional specialized functions based on their location.
Specialized epithelial cells include:
- Endothelial cells that line the blood and lymph vessels. Endothelial cells are especially tightly packed around the brain and spinal cord, forming the blood-brain barrier.
- Mucociliary cells that sweep mucus out of the airway.
- Sebum (oil) is a secretion from the sebaceous glands that locks moisture in the skin and protects against ultraviolet damage. This oily layer also represents a physical barrier to infection and promotes the growth of protective commensal microbes.
Mechanical Barriers
The body actively expels pathogens with mechanical barriers, such as the eyelids that protect the sensitive tissues of the eye. Secreted tears and sweat contain antimicrobial chemicals. The secretion of body fluids as well as the shedding of skin limits the time that microbes can occupy the body surface.
Goblet cells in the respiratory tract secrete mucus, which entraps microbes, while cilia extension on the epithelial surface sweeps this mucus out of the airway. A cough reflex can then eliminate these microbes from the body.
The body generally flushes microbes from the body through defecation or urination. The kidney supports this process through filtration and processing of blood plasma fluid for excretion.
Figure 2-1 Mechanical Barriers of the Immune System. Different body systems coordinate their actions to eliminate microbes from the body. [Link to Image Description]
Microbial Barriers
The human microbiome is the collection of microbes on the surface and within the tracts of the human body. While these microbes do not formally form part of the human immune system, they contribute to immune defense in the same way as our own physical and chemical barriers.
Figure 2-2 Dysbiosis. The surface of the human body is typically co-inhabited by microbes that support healthy tissues. External stressors provide an opportunity for outgrowth of opportunistic pathogens. As the opportunistic pathogens dominate the tissue, they contribute to pathology. [Link to Image Description]
Image Source: Adapted from Suhelen Egan & Melissa Gardiner, CC BY-SA 4.0, via Wikimedia Commons via Wikimedia Commons
Genetic Barriers
A person’s risk for infectious disease may depend on their unique genetic makeup. Some pathogens are specific to a species and are not transmitted from animals to humans. For viruses, this genetic barrier may be the requirement of a specific protein to bind cells. When the receptor protein is not available on human cells the cell can not be infected. Bacteriophages, viruses specific to bacteria, an example of this. Large numbers of bacteriophage are found in the human intestine, where they infect bacteria of the microbiome but do not infect human cells.
The best-described example of genetic barriers to infection in humans relates to infection by human immunodeficiency virus (HIV-1). HIV-1 requires two proteins to enter human immune cells. The first protein is called CD4 and serves as the viral receptor that attaches it to the cell surface. The second protein is a co-receptor consisting of either CCR5 early in the infection process or CXCR4 during acceleration of the disease. As many as 10% of people have a mutation in CCR5 called CCR5-delta-32 (CCR5-Δ32). This mutation makes the protein non-functional, preventing HIV-1 from infecting human cells. This premise was used to provide the first-ever cure for HIV-1 infection to a person who was known as the Berlin patient to preserve their anonymity. Bone marrow from a person with CCR5-Δ32 mutation was grafted into the Berlin patient with HIV-1 infection. Stem cells within the bone marrow produced immune cells with the mutation, which then could not be infected by the virus. The patient thereafter maintained a low viral load without needing to take antiretroviral medication.
2.2 Chemical Immune Defenses
Chemistry underlies how biological cells work and our body leverages this fact to produce chemicals aimed at preventing infection. Chemical defenses can work in variety of ways, including:
- Antimicrobial chemicals that are inhibitory or toxic to microbial pathogens.
- Chemical mediators that participate in cellular communication in order to coordinate complex responses, such as inflammation.
Antimicrobial Chemicals of the Microbiome
Microbes that inhabit the human body may cooperate with the immune system to prevent colonization by potential pathogens. Our body secretes chemicals that promote the growth and function of these beneficial commensal microbes.
- Propionibacterium acnes consumes oily sebum that is secreted by the skin and produces oleic acid as a byproduct of metabolism. The resultant mildly acidic skin restricts the growth of potential pathogens.
- Lactobacillus species consume glycogen that is secreted into the vagina. These bacteria produce lactate as a byproduct of metabolism that acidifies these tissues.
Secreted Antimicrobial Chemicals
Secreted factors throughout the human body can prevent colonization by potential pathogens.
- Body Surface
- Secreted tears contain lysozyme enzyme, which degrades the bacterial cell wall, as well as lactoferrin, which competes with microbes for iron uptake.
- Digestive Tract
- Saliva contains mucus that contains lysozyme, lactoferrin and lactoperoxidase enzyme, which speeds up the degradation of both bacteria and viruses.
- Stomach acid and digestive enzymes are destructive toward microbes.
- Respiratory Tract
- Urogenital Tract
- The inherent acidity of urine restricts microbial growth.
Antimicrobial peptides (AMP) is a classification of secreted peptides produced throughout the body that have antimicrobial properties. For example, defensin peptides are secreted by epithelial cells and disrupt the membranes surrounding bacterial and fungal cells, as well as some viruses.
2.3 Cells of the Immune System
In additions to physical and chemical barriers, an intricate combination of cellular responses and cell communication plays an important role in developing an appropriate and coordinated response to infection. This process involves (1) detection of infection by cells at the site of infection, (2) an immediate response to prevent the invasion of tissue by the pathogen, (3) cellular communication to recruit more immune cells to the site of infection, and (4) develop a body-wide systemic response if the infection cannot be contained.
The main cells of the immune system are white blood cells, called leukocytes, and these cells along with red blood cells and platelets are all produced from a shared stem cell, called a hematopoietic stem cell.
Hematopoiesis
The hematopoietic stem cells are typically found in the bone marrow and produce the non-fluid component of the blood, which is collectively called the formed elements.
The primary formed elements are:
- Erythrocytes (Red blood cells) – make up the vast majority of the formed elements produced by hematopoiesis. Function to carry oxygen to tissues.
- Leukocytes (White blood cells) – Often subdivided into cells with visible granules (granulocytes) and those without granules (agranulocytes). These cells are primarily responsible for the immune response.
- Thrombocytes (Platelets) – Fragments produced from a larger cell that are active in blood clotting and tissue repair.
Figure 2-3 Hematopoiesis. Most immune cells generated through the process of hematopoiesis. Hematopoiesis starts with the hematopoietic stem cell, which is a pluripotent cell because it can produce red blood cells (erythrocytes), platelets (thrombocytes) and white blood cells (leukocytes). Leukocytes arise from two specialized stem cells the myeloid stem cells and lymphoid stem cells. All myeloid cells and natural killer cells participate in the innate immune response. T and B lymphocytes are involved in the adaptive immune response. [Link to Image Description]
Innate Immune Cell Types
Different immune cells perform different but often overlapping functions.
Cells relevant in the immune defense include:
Neutrophils: These granulocytes are sometimes called polymorphonuclear (PMN) cells due to the fact that the cell nucleus forms into multiple connected lobes. Neutrophils are often involved in elimination of bacterial infection in the space between cells. The main way that neutrophils eliminate pathogens is by phagocytosis (process of consuming pathogens). However, neutrophils can also release their DNA as a neutrophil extracellular trap (NET). The NETs form a lattice to restrict the spread of pathogens and are also decorated with proteins that have antimicrobial properties. When neutrophils build up around a site of infection, their numbers may be so great that we can see them as purulent drainage or ‘pus’.
Eosinophils: These granulocytes specialize in defense against parasites, both single cell (protozoa) and parasitic worms (helminth). They also regulate inflammation and are involved in allergies.
Basophils and Mast Cells: These granulocytes regulate inflammation and are involved in allergies. While functionally similar these cells are quite different. Basophils reside in the bloodstream while mast cells reside in tissues.
Monocytes, Macrophages and Dendritic Cells: Monocytes are agranulocytes that circulate in the bloodstream. When the monocyte enters a body tissue it differentiates into macrophage or dendritic cell. These cells collectively form the mononuclear phagocyte system and actively consume pathogens by phagocytosis (described below). These cells also release cytokines to coordinate the immune response and engage in antigen presentation, a mechanism by which to alert the adaptive immune system to the presence of a particular pathogen.
Natural Killer (NK) Cells: These agranulocytes are unique because they are the only lymphoid cells involved in the innate response. NK cells look for abnormalities in human cells, such as might arise in virus-infected or cancer cells. Human cells use a molecular display called MHC in order to present abnormal viral or cancer proteins on their surface. Some viruses try to bypass this system by preventing MHC from reaching the cell surface. As a response to viral suppression of MHC, NK cells will kill human cells that fail to present MHC on their surface.
Other Cell Types
Platelets are also known as Thrombocytes and these formed elements are cell fragments that participate in tissue repair and blood clotting.
T- and B-Lymphocytes are cells of the adaptive immune system and will be discussed in detail in Chapter 3. These cells provide a targeted immune response to a specific pathogen and can produce memory cells that contribute to longterm immunity to infectious disease.
Blood Cell Counts
Certain immune cells accumulate in the bloodstream as needed to overcome specific infections. Conversely, reduced numbers of specific immune cell types can place a person at increased risk for a particular infection.
As such, a complete blood cell (CBC) count can be performed to aid in disease diagnosis. If a CBC test reveal an increased number of leukocytes, this may indicate an infection. CBC with differential involves specifically counting the different types of white blood cells to get even further information about the infectious disease. The suffixes –philia or –cytosis are used to represent overabundance and -penia means deficiency of cells.
For example:
- Leukocytosis – a high number of white blood cells indicates potential response to infection.
- Leukopenia – a low number of white blood cells may indicate an immunodeficiency that puts a person at risk for infection.
- Neutrophila frequently occurs in response to bacterial infection, especially those involving pus formation (pyogenic infection).
- Eosinophila may indicate parasite infection or allergy response
Summary
- Physical defenses prevent pathogens from entering the body
- Physical barriers such as the skin and mucous block access to sensitive cells and tissues
- Mechanical barriers such as urination and shedding are utilized to actively expel pathogens from the body
- The unique genetic makeup of an individual may protect them from infection acting as a genetic barrier
- Chemical defenses include antimicrobial chemicals that act directly on pathogens and chemical mediators (such as cytokines), which are utilized to induce immune responses
- All myeloid cells participate in the innate immune response
- Neutrophils, monocytes, macrophages, dendritic cells are professional phagocytes
- Monocytes, macrophages and dendritic cells are antigen presenting cells that bridge innate and adaptive responses
- Mast cells (in tissue) and basophils (in blood) are associated with inflammation including allergies
- Eosinophils are pro-inflammatory cells and are most effective against parasites
- Natural killer cells are innate immune cells that recognize and target cells that are infected or damaged by injecting toxins. They originate from the lymphoid progenitor cell.
Chapter Review
Case Study Review
specialized epithelial tissues that secrete mucus.
A slimy substance secreted by mucous membranes. They serve to moisten, lubricate and protect the gastrointestinal, respiratory and genitourinary tracts of the body.
