The Immune System

Since this course is being taught during the COVID-19 pandemic, many aspects of the course will be connected to the virus and its biology:

Objectives:

The immune system protects our bodies from being destroyed by bacteria, viruses, or its own mutated cells. It's a complex, multifaceted system. On this page, I'll try to tell part of the story of the immune system as it relates to the fundamental concepts of Bio 6B. I’m only going to describe vertebrate immune systems; other multicellular organisms also have immune systems, but they may work quite differently.

By the time you complete this unit, you should be able to:

  • Explain the basic functions of the immune system.
  • Compare and contrast innate immunity and adaptive immunity.
  • Compare and contrast humoral and cell-mediated immunity.
  • Explain some important ways that the immune systems of bats differ from those of humans, and how these differences might be connected to cellular respiration and to the ways that bats respond to viruses.
  • Explain how SARS-CoV-2 vaccines might stimulate immune responses that protect against the virus. (See the vaccines page for more on this topic.)

Immune systems: self and non-self

Your body is a collection of trillions of cells, but it’s much more than that. Those cells, along with a vast number of microbial cells, form an integrated single organism: you. Your continued existence depends on cooperation among those myriad cells, which are diverse in terms of their biochemical activities, their epigenetic signatures, and sometimes their genomes (in the case of mutated cells). This ongoing cooperation depends on cell communication, control of gene expression, control of the cell cycle, and the immune system.

The immune system has traditionally been described as distinguishing self from non-self -- in other words, identifying and destroying things that aren’t your own cells, such as pathogenic (disease-causing) bacteria or viruses. That’s part of the job, but we now realize that there is more to it than that. For one thing, your body hosts vast numbers of microorganisms that aren’t pathogens. These microbes are peaceful and often beneficial parts of your body’s ecosystem, and your immune system does not normally mount an attack against them. The immune system must recognize which microbes warrant a response, and which don’t. The immune system’s definition of “self” might include the body’s normal microbiota. 

On the other hand, the immune system sometimes attacks the body’s own cells. In some cases, this could lead to a harmful autoimmune disorder, but it’s also an essential part of the body’s cancer defense. Sometimes the immune system’s definition of “non-self” includes mutated versions of the body’s own cells. The immune system must continually be ready to recognize two kinds of problems: pathogens and cellular damage. It’s a complex task. On this page, my goal is to provide enough immunology to make some sense of the body’s response to viruses and vaccines, and also the links between the DNA damage response and the immune system.

The vertebrate immune system has two branches: innate immunity and adaptive immunity

Innate immunity

The innate immune system, the body’s first line of defense, does not rely on cells learning to produce unique antibodies to recognize specific pathogens. Instead, the innate immune system relies on a broadly applicable set of defenses that protect against many pathogens or other sources of damage. These defenses fit into four categories: barrier defenses, antimicrobial proteins, cellular innate defenses and inflammation. 

Barrier defenses: 

Skin and other body surfaces form a tight barrier that prevents most microbes from entering the tissues. If your skin is broken, it’s far more likely that your body will be invaded by pathogens. Other aspects of barrier defenses include the mucus that coats our airways and the acidity of the stomach.

Antimicrobial proteins: 

The innate immune system produces various molecular defenses that can either directly block pathogens or stimulate other aspects of the immune system to mount a response. For example, the complement system is activated in response to pathogens and assists the adaptive immune system in attacking infected cells. Similarly, interferons are released by infected cells and act as signals to other cells, regulating the expression of immune-related genes.

Cellular innate defenses: 

Cells of the innate immune system have the ability to recognize many common pathogens and destroy them. These cells use two different approaches to destroying pathogens: phagocytosis or apoptosis.

Phagocytosis is the process by which a cell engulfs another cell or piece of debris and destroys it in a lysosome. In the innate immune system, both macrophages and neutrophils act as phagocytes (cells that perform phagocytosis). When these cells encounter a “non-self” cell, they engulf it into a lysosome and destroy it with enzymes and a burst of reactive oxygen species (ROS). The ROS burst oxidizes and destroys the macromolecules of the pathogen, while also acting as a signal within the macrophage, turning on pathways such as inflammation and apoptosis.

The pathway that generates ROS in macrophages, called a respiratory burst, is different from the pathway that generates ROS as a by-product of the electron transport chain (ETC) of cellular respiration. In the ETC, superoxide is generated when electrons escape from the ETC complexes and are passed to O2 in an uncontrolled reaction. In the respiratory burst, electrons are passed from the electron donor NADPH to O2 in a reaction catalyzed by a specific enzyme (NADPH oxidase). (You have encountered NADPH before; it acts as an electron donor in photosynthesis.) The respiratory burst results in controlled superoxide production within the lysosome, destroying the pathogen while limiting damage elsewhere. Thus, reactive oxygen species are not not only a dangerous byproduct, but also play important roles in cellular defenses and signaling.

Apoptosis also plays an important role in the innate immune system, through the action of natural killer T cells. These cells also recognize cells bearing “non-self” motifs, but instead of engulfing them, they induce the cell to perform apoptosis. For example, a cell that is infected with a virus will produce viral proteins and display them on the surface of the cell as antigens. A natural killer cell can recognize the viral antigens and induce the infected cell to perform apoptosis by way of the extrinsic pathway. The “death signal” in this case is a ligand on the surface of the natural killer cell, activated in response to the “non-self” antigen. The recognition process depends on antigen display, which I’ll describe below in the section on the adaptive immune system.

Inflammation

Inflammation is a set of responses, mediated in part by signaling proteins called cytokines, that results in increased local blood flow, with leakage of fluid and immune cells from the blood vessels into an infected area. Inflammation activates a set of molecular signals that can result in the immune system attacking and destroying pathogens or damaged tissues, and initiating repair processes. The inflammation process is essential in allowing the immune system to do its job, but inflammation isn’t always well targeted in its effects, and can sometimes do more harm than good.

As was mentioned in the bats & viruses page, the innate immune systems of bats seem to function somewhat differently from those of humans. Intense exercise can cause cellular damage — either direct physical damage or oxidative damage due to reactive oxygen species (ROS). When DNA is detected in places where it doesn’t belong (either in the cytosol or outside the cell), whether due to cellular damage or infection with a virus, the DNA damage response is triggered. This pathway can stop the cell cycle and initiate DNA repair, and it can also cause inflammation. The inflammatory response helps signal the cells to repair the damage; in the case of exercise, it’s part of the way we adapt and become more fit. However, long-lasting or excessive inflammation can interfere with repair processes. Bats seem to moderate the DNA damage-induced inflammation response to either exercise or viral infection, while using other aspects of the immune system to slow the rate of viral replication.

In contrast, the human inflammatory response seems to be more likely to cause damage in the case of Covid-19 infection. One example of what appears to be an excessive and harmful innate immune response is the “cytokine storm” that sometimes occurs in patients with severe Covid-19 (see the reference under "cytokines and innate immunity" at the bottom of this page for much more detail). Perhaps someday we’ll understand how these pathways are controlled in animals such as bats, and be able to make use of the knowledge to improve human health.

Overall, the innate immune system is a fast and effective way to eliminate most potential pathogens or damaged cells. Our bodies are faced with vast numbers of viruses and microorganisms every day, and the innate immune system is constantly at work, guarding against hostile takeover. However, pathogens continually evolve; the innate system cannot recognize every potential threat. To guard against an ever-evolving array of pathogens, we need the adaptive immune system.

Adaptive immunity

This is what most people have in mind when they think of “the immune system.”  The adaptive immune system is capable of recognizing an almost unlimited range of pathogens. This recognition process relies on specific antigen receptors, which are proteins that bind to specific molecular signatures. “Antigen” simply means a molecule that an antigen receptor binds to; in the case of infection, the antigens are usually unique proteins produced by pathogens.

The adaptive immune system adapts to the presence of viruses and other pathogens by producing an endless array of different antigen receptors throughout your life, and then selectively amplifying those that bind to non-self antigens and have a protective effect. The binding of an antigen receptor to an antigen such as a viral protein can trigger an immune response that destroys the virus. Meanwhile, antigen receptors that bind to self antigens are eliminated.

Antigen receptors are essential to two different aspects of the adaptive immune system: humoral immunity and cell-mediated immunity.

Humoral immunity

The humoral immune response is mediated by antibodies, which are free-floating antigen receptors, secreted into extracellular bodily fluids by B cells (also called B lymphocytes). The secreted antibodies can bind to specific antigens, defending against pathogen through two different mechanisms:

  • In neutralization, antibodies bind to pathogens such as viruses, preventing the virus from attaching to and entering the cell. One of the goals for vaccines is to block infection by inducing the immune system to produce neutralizing antibodies.
  • In opsonization, antibodies bind to a pathogen and induce phagocytes to destroy the pathogen by phagocytosis.

Cell-mediated immunity

The cell-mediated adaptive immune response is mediated by T cell receptors, found on the surface of cytotoxic T cells (and other T cells). Like antibodies, these receptors bind to specific antigens. Unlike antibodies, the T cell receptors are not secreted, but remain bound to the surface of the cell that produces them. When a cytotoxic T cell binds to a cell bearing a viral protein, the T cell induces the infected cell to perform apoptosis, which destroys both the cell and the virus, exposing its contents to the immune system.

Antigen presentation

Unlike the humoral (antibody) response, the cell-mediated T cell response exclusively recognizes antigens on the surface of other cells. This response depends on antigen presentation by other cells. In this process, a cell chops up some of its proteins in the proteasome. Some of the resulting peptide fragments are brought into the endoplasmic reticulum, where they are attached to MHC (Major Histocompatibility Complex) proteins, inserted into vesicles, and brought to the cell surface. 

Antigen presentation by MHC class I proteins.

Thus, every cell wears a molecular signature on its surface, reflecting the proteins that are being produced inside the cell and allowing the immune system to scan for the presence of non-self antigens. 

All cells perform antigen presentation to some extent, but the immune system also has specialized antigen-presenting cells, which take in foreign proteins from outside the cell, break them into small peptides, and display them, triggering immune responses to pathogens.

Antigen receptor diversity

The adaptive immune system is based on the ability to generate an almost unlimited diversity of antigen receptors. Each antibody or T cell receptor is a protein, made up of either four (for antibodies) or two (for T cell receptors) polypeptide chains. Our genome isn’t big enough to encode millions of different antigen receptor polypeptides; instead, lymphocytes continually rearrange the genomic regions that encode these proteins. 

Recombination of immunoglobulin genes.

Image credit: Campbell Biology

Each antibody (or immunoglobulin) is made up of two heavy chain polypeptides and two light chains. Each of those polypeptides contains more than one domain, and each domain is encoded by a specific exon. In the genome, there are multiple, slightly different copies of each exon. The DNA in B cells is frequently rearranged (recombined) as the cells multiply, cutting out particular exons and joining together others. The result is that there are multiple versions (or clones) of B cells, each with its own distinct set of antibody genes. Some of these B cell clones are eliminated, and some are amplified to carry out essential immune functions.

This type of DNA rearrangement doesn’t occur in most cells.  The recombination process for immunoglobulin genes is similar to the alternative RNA splicing process that happens in many genes, but the immunoglobulin recombination process actually changes the DNA. This is important, because it creates clones of B cells that can replicate themselves and consistently produce the same immunoglobulins.

Crosstalk between the innate and adaptive responses

Innate and adaptive immunity aren't separate processes; they are are two different aspects of a single integrated immune system. For example, in the early stages of an infection, the innate system might respond by producing antimicrobial proteins such as interferons or complement proteins while initiating inflammation. In turn, these events stimulate the activities of the T cells and B cells of the adaptive immune system.

Example: cell-mediated response to coronavirus infection

This diagram shows part of the cell-mediated adaptive immune response to a coronavirus infection:

Adaptive Immune Response to Coronavirus infection.

Image credit: BioRender.

  1. Coronavirus SARS-CoV-2 attaches to a lung cell's ACE2 receptor and is brought into the cell. The virus may replicate in the cell, but at the same time, the immune response begins.
  2. The virus is brought into a vesicle, where it is recognized by proteins of the innate immune system (TLR, or toll-like receptors, and MAVS or mitochondrial antiviral-signaling protein). These receptors bind to conserved molecular signatures such as viral RNA.
  3. The activated receptors activate other proteins (IRF, or interferon regulatory factor, and NF-κB), initiating an immune response.
  4. NF-κB and IRF act as transcription factors, upregulating the expression of genes including interferons and cytokines.
  5. Cytokines and interferons activate dendritic cells of the immune system.
  6. The infected cell displays viral antigens on its surface after breaking down some viruses in its proteasomes.
  7. A T cell with the appropriate receptor, activated by the dendritic cell, induces apoptosis in the infected cell.

A shorter summary: Infected cells display viral antigens, which can be recognized by antigen receptors. Meanwhile, the infected cell activates its innate immune response, which activates the adaptive response, leading to apoptosis. This diagram shows only the cell-mediated response, but the humoral response, using antibodies, would be happening at the same time. The end point could either be apoptosis, as shown here, or phagocyosis of the infected cell. 

Review

Terms & concepts

  • Adaptive immune system (also called the acquired immune system)
  • Antigen
  • Antigen display
  • Antigen receptor
  • Antibody (also called an immunoglobulin)
  • Apoptosis in the immune response
  • B cells and T cells (also called B and T lymphocytes)
  • Cell-mediated response
  • Cytokine
  • DNA damage response
  • Humoral response
  • Inflammation
  • Innate immune system
  • MHC (Major Histocompatibility Complex) Proteins
  • Neutralizing antibodies
  • Pathogen
  • Phagocyte: a cell that commonly performs phagocytosis. (Macrophages are a type of phagocytes.)
  • Respiratory burst & ROS in the immune system

Review questions

  1. If there is an innate immune system, why is it important that we also have an adaptive immune system? If there is an adaptive immune system, why is it important that we also have an innate immune system?
  2. Compare and contrast the two main categories of antigen receptors in the adaptive immune system: B cell receptors and T cell receptors. Relate these terms to humoral immunity and cell-mediated immunity.
  3. Specific recognition of many different antigens requires a huge number of different antigen receptors. How can so many different proteins be generated from a genome of limited size?

References & further reading

On this site

Bats & viruses.

Biology of coronavirus.

Videos: 

Immune System from The Amoeba Sisters. If you like your science cute, this one's for you! A good 9-minute overview of immunity.

Immune system made easy. MEDSimplified. 25 min. Broad overview. More detail than needed for 6B.

Immune System: Innate and Adaptive Immunity Explained. Science ABC. 7-minute cartoon overview. Describes many different cell types involved in immunity. Helpful, but you don’t need to memorize all the cell types.

Reading: the immune system

Campbell, Chapter 43, The Immune System. I haven't found an online source that lays out the fundamentals as clearly and reliably as the textbook. However, the chapter contains a lot of information that I won't test you on, so you may want to skim the chapter briefly and read only the sections I've mentioned here.

Innate Immunity. A chapter in Molecular Biology of the Cell (4th edition). 

British Society for Immunology. This site is a little difficult to navigate, but it has some clear and readable articles on topics such as: What is immunology? British Society for Immunology. Antigen Processing and Presentation. British Society for Immunology. 

Cytokines & innate immunity

Type I and III interferons disrupt lung epithelial repair during recovery from viral infection. Major et al., 2020, Science. This is a current research report, and way beyond what you need to know for this class, but it has a Bio 6B connection. From the abstract: "Excessive cytokine signaling frequently exacerbates lung tissue damage during respiratory viral infection." This may be one of the ways that the human innate immune system leads us to have a worse Covid-19 outcome than bats; in bats, this aspect of the immune reaction may be less extreme. Interferons are a type of cytokine, and "interferon-induced p53 directly reduces epithelial proliferation and differentiation, increasing disease severity, and susceptibility to bacterial superinfections."

Deeper reading: Immunology

Antigen Processing and Presentation. British Society for Immunology. 

What is immunology? British Society for Immunology. 

Deeper reading: Vaccines and the immune system

Skeletal Muscle Is an Antigen Reservoir in Integrase-Defective Lentiviral Vector-Induced Long-Term Immunity. Lin et al., 2020. Molecular Therapy Methods & Clinical Development.

The Road Less Traveled: SARS-CoV-2 and Cell-Mediated Immunity. Morris, 2020. Molecular Therapy.

Deeper reading: DNA damage response and bats

This is far deeper than you’ll want to go for Bio 6B, but these are some of the articles I used in trying to understand how bats and humans respond differently to both viral infections and DNA damage. As I read these and other articles, I realized the depth of the connections between coronavirus, bats, and almost every topic of biology 6B.

As you have already seen, DNA damage stimulates a response pathway involving p53; this pathway can lead to DNA repair, cell cycle arrest, or apoptosis. In addition, the same pathway can stimulate the innate immune system and cause inflammation, along with other effects.

DNA Damage Response and Immune Defense: Links and Mechanisms. Nakad & Schumacher, 2016. “DNA damage leads to the activation of innate immunity and innate immunity causes in return DNA damage.” This chronic cycle can lead to aging and the development of tumors in humans. (But somehow, it doesn’t in bats.)

Novel Insights Into Immune Systems of Bats. Banerjee et al., 2020. Frontiers in Immunology. “Bat cells mount an antiviral response to RNA viruses, but limit the expression of inflammatory cytokines.” and “Exogenous and self-DNA sensing pathways are dampened in bat cells.”

Dampened STING-Dependent Interferon Activation in Bats. Xie et al., 2018. Cell Host & Microbe. “Compared with terrestrial mammals, bats have a longer lifespan and greater capacity to co-exist with a variety of viruses. In addition to cytosolic DNA generated by these viral infections, the metabolic demands of flight cause DNA damage and the release of self-DNA into the cytoplasm.” “Our findings [of a reduced innate immune component of the DNA damage response] shed light on bat adaptation to flight, their long lifespan, and their unique capacity to serve as a virus reservoir.”

The Toll-Like Receptor Gene Family Is Integrated into Human DNA Damage and p53 Networks. Menendez et al., 2011. PLOS Genetics.

Interactions between the tumor suppressor p53 and immune responses. Menendez et al., 2013. Current Opinion in Oncology

p53, cancer and the immune response. Blaigh et al, 2020. Journal of Cell Science.

DNA Damage Response and Immune Defense. Nastasi et al., 2020. Int. J. Mol. Sci.

DNA Damage: From Chronic Inflammation to Age-Related Deterioration. Ioanidou et al, 2016. Frontiers in Genetics.

DNA Damage Response. Clear overview of the many cellular responses to DNA damage.

 

A- A A+