Chapter 1: Overview of the Human Immune System
Learning Objectives
By the end of this chapter you will be able to:
- Define Immunology
- Describe the functions of the immune system
- Describe the features of the immune system, including:
- The innate and adaptive responses
- The three lines of immunological defense
- Explain the role of the lymphatic tissues in both returning fluid to the circulatory system and in monitoring for infection
- Define hematopoiesis and name the two major lineages of immune cells
- Explain how the immune system exists in a balance between immune response and immune tolerance
- Describe how an imbalance in immune homeostasis lead to immunological disorders
Case Study
JD is 45 years old and is considered a heavy smoker, having consumed an average 30 cigarettes per day for 20 years. JD was diagnosed with chronic obstructive pulmonary disease (COPD) and presents with respiratory symptoms, reduced exercise tolerance, and frequent respiratory infections. Frequent infection resulted in chronic bronchitis, a condition where the airway epithelial tissue has eroded and become inflamed. Sputum analysis of coughed up phlegm identified large numbers of immune cells called neutrophils within the airway space. A blood test revealed elevated antibody levels but also identified antibodies that specifically attach to collagen and elastin, proteins on the surface of human airway epithelial cells.
- What examples of immune defense impairment are described in this case study?
- Why does the respiratory airway produce mucus when mucus plugs could obstruct the airway and impair normal breathing?
- Why is it concerning that JD is producing antibodies against human tissues?
Answers to these questions are at the end of the chapter.
1.1 The Immune System and its Functions
We exist in a world of microorganisms that are invisible to the human eye but impact our health in remarkable ways. Most microorganisms are harmless to a healthy person. However some, classified as pathogens, have evolved alongside us for million of years to adapt ways of overcoming our defenses, evading our immune system and causing debilitating or even life threatening infection.
What is Immunology?
Immunology is the study of immune barriers and responses that form the immune system to protect us from infection by microorganisms. Immunology also involves the study of dysfunction that may occur in the immune response as well as medical methodologies that aim to use or modulate components of our immune system to promote health.
Since pathogens are diverse and have independently developed many ways to infect the human body, the immune system has adapted a layered approach that uses a series of strategies to prevent infection.
Some of these strategies include:
Surface Barriers: These barriers may include physical barriers, like the skin and secreted mucus, or chemical barriers, like sebum (oil), enzymes, salty or acidic body fluids and antimicrobial substances. Even the harmless microbes that inhabit our body surface and form the microbiome create a protective barrier from infection.
Immune Sensing and Communication: Most immune cells as well as epithelial cells, which line the surface of the body, have special receptor proteins on the cell surface that allow them to recognize characteristic patterns associated with infection. Some patterns, called pathogen associated molecular patterns (PAMPs) include molecules that are typically found on the surface of pathogens but are not normally in the human body. Other patterns, called damage associated molecular patterns (DAMPs) indicate cell damage that might be resulting from infection or may place a person at greater risk for infection. On sensing PAMPs and/or DAMPs, immune cells communicate the risk of infection to other cells by secreting cytokines.
Inflammation and Fever: Large numbers of immune cells are found in the bloodstream. When a pathogen is found in the body tissues, the affected cells secrete cytokines to temporarily remodel the local blood vessel through inflammation. Specifically, during inflammation, blood vessels swell and become leaky, allowing more immune cells to flow into the affected tissue and combat the infection. Cytokines released into the bloodstream can spread the inflammation to other parts of the body. Some of these cytokines will also migrate to the brain and increase the body temperature to induce a fever. Higher body temperatures will slow down the growth of bacteria and viruses as the environment become unfavourable for growth.
Phagocytosis: Many immune cells will sense PAMPs or DAMPs and, upon detecting these foreign patterns, consume the target through the process of phagocytosis. During phagocytosis, the surface of the immune cell wraps around the foreign material to create a bubble inside the cell, called a phagosome. Within the phagosome, the foreign cell or substance is degraded with the aid of acid and digestive enzymes.
Adaptive Response: The adaptive immune response is highly specific to the offending pathogen. Typical responses may induce cells that directly engage and eliminate pathogens and infected cells as well as indirect elimination using antibodies. Adaptive responses typically require a period of time to initiate, following exposure to the pathogen or a vaccine antigen. However, after the initial adaptive response, immunological memory may be established to ensure a rapid and effective response on each subsequent future exposure.
1.2 Features of the Immune System
The immune response is most easily imagined at the level of a single tissue, but in reality the immune response spans the entire body and consists of integrated and cooperating tissues and organs. Central components of the immune system include the lymphatic system, which drains fluid form tissues and monitors this fluid for infection, and the hematopoietic cells that produce immune cells and regulates the balance between immune response and immune tolerance.
Lymphatic System
The human heart pumps blood through the body under high pressure. This causes blood fluid to leak into tissues, where it is then described as interstitial fluid. While most of the interstitial fluid is reabsorbed into the bloodstream, approximately 3L of fluid accumulates in the tissues and is absorbed by lymphatic vessels. The fluid is then filtered within lymph nodes and other lymphastic tissues before returning to the bloodstream.
The lymphatic tissues are a major site for the production and storage of immune cells, as well as monitoring for evidence of infection in the interstitial fluid.
Hematopoietic Cells
After birth, most of our immune cells are produced through the process of hematopoiesis that primarily occurs in the red bone marrow. In children, this process occurs in long bones. Hematopoiesis is mostly restricted to the cranial and pelvic bones in adults.
Hematopoiesis starts with a hematopoietic stem cell, which is called a pluripotent cell because it can produce red blood cells (erythrocytes), platelets (thrombocytes) and white blood cells (leukocytes). Leukocytes are the primary immune cells and they become specialized to form two specific stem cell populations, myeloid stem cells and lymphoid stem cells.
Myeloid Cells: Stem cells in these lineages produce red blood cells and platelets, as well as white blood cells that perform phagocytosis and mediate inflammation.
Lymphoid Cells: Stem cells in these lineages form the lymphocytes (T-cells and B-cells) and natural killer (NK) cells, which are largely associated with the development of immunity.
More details on hematopoiesis are available in Chapter 2.
1.3 Classification of immune defenses
Innate and adaptive immune systems
The immune system is often divided into two branches: (1) The innate immune system and (2) the adaptive immune system. The innate immune system is not specific to any particular pathogen and is largely developed at birth. The adaptive immune system involves responses that are develop after exposure to a pathogen and generate a stronger and more tailored response upon future exposures. This enhanced subsequent response involves a phenomenon called immunological memory and is responsible of the state that we usually refer to as “immunity” following infection or vaccine immunization.
Table 1.1 – Features of Innate and Adaptive Immune systems
| Innate Immunity | Adaptive Immunity |
| Includes body’s barriers, such as skin, mucus, sebum oil (“First line of defense“). | Involves cellular and antibody mediated immune responses (“Third line of defense“) |
| Includes rapid induced chemical and cellular responses (“Second line of defense“). | Initially triggered by the innate immune response. The adaptive response may be delayed by days/weeks. |
| Immune response is largely the same for every pathogen encountered (non-specific). | Immune response is specifically enhanced toward a particular pathogen (specific) after initial exposure to that pathogen (secondary response). |
| Immune response is the same each time a pathogen is encountered (no immunological memory). | After first exposure to pathogen, the immune response is stronger against subsequent exposures (immunological memory). |
The three lines of defense
The immune system is also frequently described as having three lines of defense, where some immunological defenses are ubiquitous, meaning they are always present, while others are induced only when the immune response is triggered by infection or another source.
The first line of defense involves surface barriers, listed above. Skin, sebum, mucus and other barriers are formed before infection and are ubiquitously present. However, these barriers may be fortified during infection. For example, a respiratory infection may result in enhanced mucus secretion that is coughed out as phlegm.
The second line of defense involves cells and chemicals that are ubiquitously present but may also be rapidly induced during infection. The ubiquitous components make up the primary defense during the first four hours of infection. The induced response becomes more prominent after the first few hours. An example of this transition is seen in immune cells. Tissues often have resident immune cells that are already present and patrol for infectious agents. However, following infection these resident cells will become exhausted and a large number of new immune cells will be recruited from the bloodstream.
The third line of defense coincides with the adaptive immune response. If an infection becomes serious enough that it cannot be overcome by the innate defense mechanisms, specialized immune cells (e.g. monocytes, macrophages, dendritic cells) will interact with T-cells to trigger a stronger and more tailored response against the pathogen. The third line of defense involves enhanced stimulation of immune cells and production of antibodies or both. Helper T-cells secrete cytokines to induce and coordinate the adaptive immune response. B-cells secrete antibodies that mark a foreign cell or agent for immune destruction. Cytotoxic T-cells perform surveillance of all cells and eliminate cells that are infected or become tumor cells that might cause cancer.
Table 1.2 – Three Lines of Immune Defense
| Line of Defense |
Pathogen-Specific? |
Innate/ Acquired |
Mechanism and Outcomes |
| First | No | Innate |
Surface barriers provide ubiquitous defense.
|
| Second | No | Innate |
Ubiquitous and induced defenses that include phagocytes, inflammation, fever, complement activation
– Secreted chemicals like defensins that damage bacterial cell membrane
– Phagocytes and innate immune cells – Cytokines that induce fever and inflammation – Complement proteins |
| Third | Yes | Adaptive | Induced response that involves T-lymphocytes, B-lymphocytes and antibodies. Produces stronger and pathogen-specific response as well as immunological memory to establish future immunity. |
Immune Response and Immune Tolerance
The immune system needs to balance two opposing challenges, which are associated with inducing a rapid and effective response to infection while simultaneously minimize the immune response to human tissues and the harmless microbes of our microbiome.
A rapid immune response can be achieved through pre-formed immune components in their inactive forms. Examples of pre-formed components include leukocytes stored within lymph nodes and immune proteins that circulate in an inactive form. Infected cells and immune cells also release chemicals called cytokines that can rapidly accumulate in the tissues or bloodstream. Cytokines are potent inducers of the immune response.
In direct opposition to the immune response is the process of immune tolerance or immune homeostasis. Immune tolerance involves the suppression of the immune response. Immune tolerance is critical in suppressing immune cells following the resolution of an infection, preventing immune responses against human cells and tissues, and suppressing immune responses against harmless commensal microbes of the human microbiome. Immune tolerance is achieved by directly killing lymphocytes that react to human tissues during their development. In addition, specialized cells called regulatory T-cells detect and suppress the local immune responses to commensal microbes and ones own cells and tissue. Immune tolerance involves immune checkpoints where immune cells are inactivated through physical binding and the secretion of immunosuppressive cytokines, such as interleukin 10 (IL-10).
Disorders of the Immune System
The immune system is complex and multifaceted. Any disruption to the immune barriers and immune responses resulting in immunodeficiency increases the risk for infection. For example, broken skin resulting from trauma or a burn injury can contribute to infection. Malnutrition that affects immune cell production can impair a person’s ability to mount a productive immune response. An individuals immune response fluctuates based on various factors including genetics, age, chronic stress and the environment.
An overactive immune response (hypersensitivity) can also contribute to immune disorders. Immune response to harmless substances in our environment results in allergies, while immune responses to harmless microbes on the body surface create inflammatory conditions. In some cases, human tissues may be inadvertently or even specifically targeted by the immune system, resulting in an autoimmune condition. Finally, an inability to control the intensity of the immune response during an infection or to resolve the immune response after infection can contribute to persistent and potentially lethal impairment of health.
Summary
- The immune system functions to defend against pathogens by
- Forming barriers to infection along the body surface
- Sensing an infection and communicating between cells and tissues to develop a response
- Inducing inflammation and fever as responses to infection in order to recruit cells to the site of infection and impair the growth and dispersal of microbes
- Engaging cells that consume foreign particles and microbes by phagocytosis
- Inducing an adaptive immune response that produces a pathogen-specific response as well as a long-term immunological memory
- The immune system is body-wide and the lymphatic system is an important component of the immune system
- The lymphatic system drains fluid from the tissues
- Lymph nodes and lymphatic tissues filter and monitor lymphatic fluid
- Immune cells of the myeloid and lymphoid cell lineages are produced by hematopoiesis in the bone marrow
- The immune system forms a balance between immune response and immune tolerance
- The immune response aims to rapidly eliminate pathogens from the body
- Immune tolerance aims to prevent immune responses to self tissues and harmless microbes within the microbiome
- This balance is established by killing self-reactive lymphocytes during development as well as having cytokine signals that indicate whether an immune response should be enhanced or suppressed
- Immune disorders can result from either under-activity or over-activity of the immune response
- Under-activity of the immune response is called immunodeficiency and can result in more frequent or more severe infection
- Over-activity of the immune response is called hypersensitivity, resulting in persistent inflammation or autoimmune disease
Chapter Review
Case Study Review
A slimy substance secreted by mucous membranes. They serve to moisten, lubricate and protect the gastrointestinal, respiratory and genitourinary tracts of the body.
Pathogen associated molecular patterns (PAMPs) are the general features that our innate immune system uses to identify foreign agents, like bacteria and viruses. PAMPs are different from "antigens", which are molecules that are specifically identified by cells and antibodies of the adaptive immune system.
