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Immunology: Foundations
and Frameworks
Last Updated: August 16, 2022
access_time 14 min
Learning Objectives (4) After completing this brick, you will be able to: ● Discuss the main purposes of the immune system. ● 1 ● Briefly explain how the innate immune system works, and describe how antigens are transferred from the innate to the adaptive immune system (dendritic cells). ● 2 ● Briefly describe the main purpose of the adaptive immune system, and explain how the two arms (cellular and humoral) work. ● 3 ● Describe what happens after an immune response is finished. ● 4 CASE CONNECTION You are explaining to TJ, a 39-year-old man who just recovered from a leg wound and infection, the intricate workings of the innate and adaptive immune systems. You get the feeling he is really interested in the topic as you explain how these systems performed individually and as a pair to secure his recovery. “Well, let me ask you this. If there’s all this activation, presentation, signaling, differentiation,
ramping up, death, and destruction, how do things stop? What puts on the brakes? Why isn’t my leg completely eaten away?” How would you respond to TJ? Consider your answer as you read, and we’ll revisit at the end of the brick. What Is the Immune System? How do we survive in a complex environment filled with harmful organisms that thrive on colonizing us? Our heroic defender is the immune system, a network of organs and cell lines that exist with the mission of protecting the body from harm. While we often recognize the pathogen-fighting capabilities of the system, we can sometimes forget that the immune system is also crucial in ensuring the body is kept safe from itself, as in when our cells transform into cancer cells. On the dark side, sometimes our immune system can get overactive, reacting against our own normal body tissue. Taken together, the immune system is both critical for survival and a vital topic for new medical research. Immune System Functions
and the adaptive immune system, characterized by slower but more targeted responses (Figure 1). Figure 1 CREDIT: ©ScholarRx These two branches play crucial roles individually. In addition, communication between the two branches allows for coordinated, stronger immune responses. We’ll look at each in turn.
Innate Immune System The innate immune system is the older, more archaic branch of the immune system. It is fast, nonspecific, and inherited—but by that virtue it does not change during an organism’s lifetime. It includes physical components that act as barriers, such as your skin and epithelial layers, as well as molecular and cellular components, such as mast cells, phagocytes, complement proteins, natural killer (NK) cells, eosinophils, basophils, and dendritic cells. We’ll discuss each of these briefly here.
Skin and Epithelial Barrier
The barriers created by the innate immune system, primarily the epithelial barriers like skin and the linings of your gastrointestinal and respiratory tracts, are usually the first line of defense that any pathogen wanting to infect the body must bypass. While these act partially as physical barriers, they also act as holding areas for many sentinel cells that wait for pathogens to get through—including mast cells and dendritic cells.
Cellular Components and Complement System
Natural killer cells Can recognize virus-infected cells, irreparably damaged or cancer cells, and antibody-bound cells to induce their apoptosis. Neutrophils A type of phagocyte. Recognizing and destroying microbes by phagocytosis. Once inflammation is signaled, neutrophils will generally be first on the scene. However, they survive for only a few hours in tissue. Antibodies and phagocytes are “complemented” by complement proteins, a key portion of the innate immune system produced primarily by the liver. Although complex in function, complement proteins basically act by attacking pathogens, signaling immune cells, and neutralizing pathogens and their toxins. Adaptive Immune System The adaptive immune system is “new” on an evolutionary timescale. It includes B and T lymphocytes, their products (which includes primarily antibodies and cytokines), and the lymphatic system. It is significantly slower in its response than the innate immune system. What it lacks in speed, however, it more than makes up for in strength and specificity of response—and its ability to hold a grudge.
Features
The adaptive immune system is a specialized system. We aren’t born with a fully functioning adaptive immune system; it requires exposure to many antigens over time to produce full variation. This system has several general features: ● Specificity and specialization: Each antibody produced is specific to an antigen, and the system can cater its response to different types of pathogens. ● Diversity: The adaptive immune system can respond to an extremely diverse number of antigens with limited starting genetic material. ● Memory: Although the first response may take longer, the adaptive immune system can remember an antigen and ramp a faster response on re-infection. ● Clonal expansion: Once a target is identified, cells producing antibodies against an antigen begin ramping up production until the target is neutralized. ● Contraction and homeostasis: Following target neutralization, response is ramped down and excess immune cells killed, returning to a homeostatic level. ● Nonreactivity to self: Through multiple selective processes, cells that react to the host are destroyed before maturation. Together, these features allow the adaptive immune system to perform specific targeted responses to a huge load of antigens and prevent reinfection in the future, without requiring a constant massive immune response.
Branches
B cells mount an accelerated future response in case of re- infection. Antibodies secreted by plasma cells achieve their function through four main mechanisms: They directly inactivate pathogens. They label pathogens for destruction and phagocytosis. They aggregate to form an insoluble antibody-antigen complex (ie, agglutination). They activate the complement system. T cells will become “memory” T-helper cells , which can be reactivated by APC in case of re-infection. Regulatory T cells are special CD4+^ T cells that have the important function of modulating the activity of other T cells, ensuring that their activation does not go out of control. Cytotoxic T cells survey the body for infected or neoplastic cells and destroy them by inducing apoptosis. Memory T cells persist in the circulation, remembering the past response to a pathogen and quickly repeating it during a re-infection. Cytokines like interleukin- and tumor necrosis factor are circulating signaling molecules secreted by immune cells that control what type of immune response takes place. While many are pro-inflammatory, some actually downregulate inflammation. After the Immune Response After an immune response, a complex network of anti-inflammatory mediators and immune cells modulate healing.
In acute infections, neutrophils will die within hours, though macrophages will survive in tissue much longer. These dying leukocytes will accumulate alongside dead tissue and pathogens, eventually forming pus. As a localized infection continues and becomes more chronic, the area can be walled off by the surrounding healthy cells, creating a physical barrier to the pathogen and inflammation. This is the idea behind abscess formation. In disseminated or systemic infections, no localized barrier can be formed, and the immune system must fight a more widespread battle. Eventually, if an immune response resolves, pro-inflammatory cell signaling will decrease. As cytokine production does finally drop, chemotaxis of immune cells will slow, and the innate immune system will allow for inflammation to decrease and tissue healing to begin. Once in the tissue and signaled with markers of infection resolution, macrophages play a role in proper tissue healing. They do this by phagocytosing dead pathogens and tissues, signaling local cells to initiate repair, and signaling special wound-healing cells to enter the damaged tissue. The adaptive immune system functions similarly as an infection resolves. Once activating signals for B cells decrease, a process of contraction takes place. The vast majority of plasma cells will die off through apoptosis. Some plasma cells migrate to the bone marrow,
● The innate immune system includes tissue barriers, the complement system, phagocytes, mast cells, NK cells, eosinophils, basophils, and dendritic cells. ● The innate immune system is fast, heritable, and nonspecific. ● Dendritic cells act as the primary bridge between the innate and adaptive immune system. ● The adaptive immune system is made up of lymphocytes and antibodies. ● The adaptive immune system is slow but is specific, specialized, and diverse and has memory function. ● The humoral adaptive immune system, made up of B cells and antibodies, produces antibodies that indirectly and directly attack pathogens. ● The cellular adaptive immune system contains CD
cells that modulate the immune system, CD
cells that directly attack cells, and regulatory T cells that downregulate the immune response of CD
and CD
cells. ● After an immune response, a complex network of anti- inflammatory mediators and immune cells modulate healing.
Cytokines
Last Updated: August 19, 2020
access_time 13 min
Learning Objectives (3) After completing this brick, you will be able to: ● Define cytokines and chemokines and describe their general functions. ● 1 ● Describe the role of proinflammatory cytokines in response to antigen. ● 2
● Describe the role of anti-inflammatory cytokines in downregulating the immune response. ● 3 CASE CONNECTION You are seeing CA in the urgent care center. Twenty-four hours ago, CA cut her finger on a sharp knife. “Since yesterday, my finger has gotten really red and painful, and there’s a greenish drainage soaking the bandage. It’s really gross.” As you remove the bandage, you note a 3-cm laceration of the left index finger with surrounding erythema and purulent material. “That pus might be gross,” you say. “But it’s important. Pus is a collection of dead white blood cells that the body has sent to help you fight that infection.” CA asks, “How does my body know where to send those infection-fighting cells?” How would you answer CA’s question? Consider your answer as you read, and we’ll revisit at the end of the brick. What Are Cytokines? Cytokines are circulating messengers of the body whose function is to enable communication among its many cells. “Cytokine” is a catch-all
In this discussion, we will not cover all of the numerous cytokines but instead will focus on some that are most crucial to normal body processes and the defense against pathogens. Cytokines That Enhance the Immune Response Cytokines play a key role in modulating cell-mediated immunity. This is the wing of the adaptive immune system modulated by T cells, rather than B cells or antibodies. When immune cells such as macrophages encounter antigens, one of their main responses is to secrete proinflammatory cytokines. Much of modulation of cell- mediated immunity occurs via circulating cytokines. On encountering a pathogen, how does an immune cell such as a T cell or macrophage begin secreting cytokines? Invading pathogens have molecular patterns that can be recognized by cell receptors. After antigen binding, these receptors will begin signaling to an intracellular complex called the inflammasome. The inflammasome is a massive molecular machine that when assembled will activate enzymes such as caspase 1. Caspase 1 will activate inflammatory cytokines such as interleukin 1β (IL-1β) and IL-18 and cause their secretion. This cytokine secretion recruits other immune cells to amplify the inflammation.
Cytokines generally intensify the immune response but do so using a variety of mechanisms. Below we will highlight a few of the most important.
Increased T-Cell Proliferation and Differentiation
IL-12 is a key component of the innate immune system, produced by macrophages and antigen-presenting cells after encountering a pathogen or a damaged cell (Figure 1). It stimulates naive (unstimulated) T cells to become helper T cells, which are essential in mediating immune responses against intracellular bacterial and viral infections. These cells will amplify the response by secreting multiple cytokines, including IL-2 and interferon-γ, cytokines involved in the activation of macrophages and cytotoxic T cells. Different subtypes of helper T cells are associated with secretion of different cytokines.
Chemotaxis is the movement of cells in response to a chemical stimulus. It’s important for neutrophils to get to a site of infection or inflammation, and the below cytokines help them get there. Chemokines ( chemo tactic cyto kines ) are a small family of cytokines that go by a series of names like CCL14 and CCL20, which you don’t need to remember. What is key is that their main function is to cause inflammatory cell (especially neutrophil) migration to an infection site in response to a stimulus. Chemokines are classified as either homeostatic or inflammatory. Homeostatic chemokines maintain basal leukocyte migration. On the other hand, inflammatory chemokines are produced because of inflammation and recruit immune cells to address the inflamed area. IL-8 is a type of chemokine also known as neutrophil chemotactic factor. IL-8 enhances neutrophil migration by increasing the expression of adhesion molecules, thereby anchoring the neutrophil to the endothelium at the infected site. It then induces the neutrophils to phagocytose pathogens and can also perform an oxidative burst, which breaks down the extracellular matrix and basement membrane, allowing the neutrophil to reach its intended target.
Antiviral Activity
Interferons (IFNs) are a group of related cytokines whose effects include antiviral activity, growth regulatory properties, and inhibition of angiogenesis. IFN-α and IFN-β have potent antiviral properties that have been studied in the treatment of hepatitis B, where increased expression of antiviral genes induced by IFNs help clear the virus. CLINICAL CORRELATION IFN-α is used to treat malignant melanoma, chronic hepatitis B and C, and condyloma acuminatum (genital warts). IFN-β is used to slow the advance of multiple sclerosis, although its mechanism is unknown.
Fever and the Acute Phase Response
We usually think of fever as a symptom of infection, but an elevated body temperature is also an important host defense, because most pathogens don’t grow as well at higher body temperatures. Several cytokines act as pyrogens, molecules that cause fever by acting on the hypothalamus, the thermoregulatory center of the brain. They raise the setting on the body’s thermostat, increasing the body temperature to help rid the body of the infection.
