Kurzgesagt – In a Nutshell
Sources – The Immune System Explained
– Your immune System consists of hundreds of tiny and two large organs, it has its own transport network spread throughout your body.
The Immune System is one of the most complex systems in our body. This website by the Australian government provides a good general overview:
#What are the organs of the immune system?, 2020
https://www.ncbi.nlm.nih.gov/books/NBK279395/
Quote: “Primary lymphoid organs: These organs include the bone marrow and the thymus. They create special immune system cells called lymphocytes.
Secondary lymphoid organs: These organs include the lymph nodes, the spleen, the tonsils and certain tissue in various mucous membrane layers in the body (for instance in the bowel). It is in these organs where the cells of the immune system do their actual job of fighting off germs and foreign substances.”
– Every day it makes hundreds of billions of fresh cells organized like an army, with soldiers, captains, intelligence officers, heavy weapons and crazy suicide bombers.
Most of the immune cells are produced in bone marrow. Around 500 billion mature blood cells are produced daily in the bone marrow only.
#Fliedner et al., Structure and Function of Bone Marrow Hemopoiesis: Mechanisms of Response to Ionizing Radiation Exposure, 2004.
Quote: “The ultimate objective of bone marrow hematopoiesis is to maintain in the peripheral blood a constant level of the different blood cell types (erythrocytes, granulocytes, platelets, lymphocytes, etc.). All of them have their particular turnover kinetics (such as granulocytes 120 × 109/d, erythrocytes 200 × 109/d or thrombocytes 150 × 109/d), are semi-autonomous in their steady state regulatory mechanisms and dependent on a life-long supply of mature cells from a stem cell pool with unlimited replicative and pluripotent differentiative potential.”
– Immediately the first stage of your defense kicks in: The cells that survived the impact or are hurt or dieing scream in panic, releasing an onslaught of chemical alarm signals that awaken your immune system.
Generally our body has two different ways of immune responses. The adaptive immune response tackles infections, but it can take up to a week before being effective. In order to get an immediate response our body relies on the innate immune system to protect us:
#Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Innate Immunity.
https://www.ncbi.nlm.nih.gov/books/NBK26846/
Quote: “Our ability to avoid infection depends in part on the adaptive immune system (discussed in Chapter 24), which remembers previous encounters with specific pathogens and destroys them when they attack again. Adaptive immune responses, however, are slow to develop on first exposure to a new pathogen, as specific clones of B and T cells have to become activated and expand; it can therefore take a week or so before the responses are effective. By contrast, a single bacterium with a doubling time of one hour can produce almost 20 million progeny, a full-blown infection, in a single day. Therefore, during the first critical hours and days of exposure to a new pathogen, we rely on our innate immune system to protect us from infection.”
Once a cell is damaged or killed so called pathogen associated immunostimulants are released to call for help:
#Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Innate Immunity.
https://www.ncbi.nlm.nih.gov/books/NBK26846/
Quote: “The innate immune system relies on the recognition of particular types of molecules that are common to many pathogens but are absent in the host. These pathogen-associated molecules (called pathogen-associated immunostimulants) stimulate two types of innate immune responses—inflammatory responses (discussed below) and phagocytosis by cells such as neutrophils and macrophages. Both of these responses can occur quickly, even if the host has never been previously exposed to a particular pathogen.”
This article gives a good overview on the way dying cells alert the immune system and how they distinguish between dangers to our body and cell death that doesn’t harm us:
#How dying cells alert the immune system to danger, 2008
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763408/
Quote: “Cell death is potentially dangerous to the host and therefore the immune system has evolved mechanisms to detect and respond to this process. It accomplishes this important task by having the innate immune system monitor tissues for cells that are disintegrating. Upon detecting the release of intracellular contents, an inflammatory response is rapidly mobilized. This provides initial defence and also attempts to clear and repair the damage. In parallel, DCs are stimulated to mature and stimulate adaptive immune responses if immunogenic antigens are present“
– The first cells to show up are Macrophages.
#Preparing the First Responders: Building the Inflammatory Transcriptome from the Ground Up, 2014
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041192/
Quote: “For example, cells of the innate immune system, such as neutrophils, macrophages and dendritic cells, serve as the body’s first line of defense against infection and other insults.”
The British Society for Immunology provides a good introduction to macrophages:
#Macrophages, British Society for Immunology,
https://www.immunology.org/public-information/bitesized-immunology/cells/macrophages
Quote: “Macrophages are specialised cells involved in the detection, phagocytosis and destruction of bacteria and other harmful organisms.”
– If an average cell were the size of a human, a Macrophage would be the size of a black Rhino – a stoic cell in principle, but you wouldn’t want to annoy it. Bacteria annoy them.
The average size of macrophages found in human is about 21 micrometers:
#Cell size of alveolar macrophages: an interspecies comparison, 1997
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1470168/
Quote: “Comparatively, the AM from monkeys (15.3 +/- 0.5 microns, n = 7) and human volunteers (21.2 +/- 0.3 microns, n = 10) were larger than those from rats and hamsters.”
As the size for an average human cell, we took the average size of a red blood cell since they are the most abundant cells in the human body:
#Scientists bust myth that our bodies have more bacteria than human cells, 2016
The average size of a red blood cell is around 8 micrometers, however they are the smallest cells in the human body, so the average size will be larger than that. For the sake of simplicity, we took 10 microns.
#Dimensions of red blood cell (shape is basically a circular disc), Bionumbers, Harvard, 2020
https://bionumbers.hms.harvard.edu/bionumber.aspx?id=100798&ver=7
Quote: “The human erythrocyte, which may be regarded as typical, is basically a circular disc, with a diameter of approximately 8 x 10^-4 cm, and a thickness of 2 x 10^-4 cm. “
Average human: 1.75 m
Average black Rhino: 2.8 m – 3.8 m = 3.3 m
#Black Rhino
https://rhinos.org/about-rhinos/rhino-species/black-rhino/
Quote: “Length: 10- 12.5 ft (3.0-3.8m) length of head and body”
Human cells come in a wide range of sizes, so we are not aiming to make a definitive comparison here. It is an approximation to give an idea about the relative sizes of the two cell types.
Human / Black Rhino = 3.3/1.75 ~ 2
Macrophage / Average Human cell = 21/10 ~2
– Within seconds the large cells attack and begin killing them without mercy. They stretch out parts like the arms of an octopus and grab the bacteria to swallow them whole and digest them alive.
The process of how macrophages kill and digest bacteria is called Phagocytosis.
#Macrophages, Arizona State University,
https://askabiologist.asu.edu/macrophage
Quote: “Macrophages don’t eat cells the same way you might eat your food. Instead, the eating machines engulf viruses and bacteria. This is called phagocytosis.”
Phagocytosis isn’t only responsible for killing bacteria but also to kill sick cells.
#Phagocytosis: A Fundamental Process in Immunity, 2017
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5485277/
Quote: “Phagocytosis is an elegant but complex process for the ingestion and elimination of pathogens, but it is also important for the elimination of apoptotic cells and hence fundamental for tissue homeostasis.”
– A Macrophage can eat 100 bacteria before it is exhausted.
The name macrophage stems from ancient Greek and literally means “large eater”, so it is no surprise that they can eat up to 100 dishes before they die.
#Macrophage - New World Encyclopedia
https://www.newworldencyclopedia.org/entry/Macrophage#Life_cycle
Quote: “Macrophages can digest more than 100 bacteria before they finally die due to their own digestive compounds.”
#Who Claims You?, Jae Choe, 2005
Quote: “These big cells (as the name correctly implies) can “eat” the invading bacteria and other pathogens. For instance, one macrophage can “eat” to kill up to 100 bacteria before it itself dies away.
– But there are too many enemies, so the Macrophages call for reinforcements. In your blood hundreds of thousands of Neutrophils pick up their signals and move to the battlefield. Neutrophils are intense suicide warriors that only live to kill.
Macrophages activate Neutrophils with the help of the secretion of the signalling proteins chemokines:
#Kumar et al. , Partners in crime: neutrophils and monocytes/macrophages in inflammation and disease, 2018
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820413/
Quote:”Upon a microbial attack, a typical host immune response involves the activation of tissue-resident macrophages, which leads to the secretion of chemokines such as IL-8 that facilitate the recruitment of neutrophils to the gut.”
#Silverstein and Rabadan, How many neutrophils are enough (redux, redux)?, 2012
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533502/
Quote: “Accordingly, 5 × 10^6 neutrophils/ml — the average concentration in human blood — is required for these cells to explore 1 ml of a stirred bacterial suspension in 10 minutes (i.e., 2 × 10–8 ml/neutrophil/min × 5 × 106 neutrophils × 10 min = 1 ml).”
Average neutrophil count in a milliliter of human blood is 5 million. With an average blood volume of 5 liters, this would add up to ~25 billion neutrophils.
– They are so enthusiastic about killing that they kill themselves a few days after birth so they don’t have time to accidentally destroy your body from the inside.
#Brinkmann and Zychlinsky, Beneficial suicide: why neutrophils die to make NETs, 2007.
https://www.nature.com/articles/nrmicro1710
Quote: “Neutrophils are essential effector cells of the innate immune system. They mature in the bone marrow and, when terminally differentiated, they are released into the bloodstream, where they have a half-life of only a few hours. Under normal conditions, neutrophils constitute around 60% of all the white blood cells in humans. In healthy individuals most neutrophils are destined to be cleared without ever executing their function”
– As soon as Neutrophils arrive, they begin vomiting deadly chemicals at bacteria or devour them.
#Conquering Neutrophils, 2016
https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1005682
Quote: “Upon phagocytosis of bacteria, neutrophils and macrophages produce an oxidative (respiratory) burst resulting in the rapid release of highly bactericidal ROS, including superoxide anion, hydrogen peroxide, and hydroxyl radicals. ROS damage DNA—proteins and enzymes to which most bacteria are highly susceptible.“
– They are so careless in their attacks, that they are causing real damage to your own cells – but collateral damage is not their concern now. Or ever. Some Neutrophils go so far to push their suicide button and explode, casting wide and toxic nets made from their own DNA, filled with deadly chemicals, that trap and kill bacteria. Sometimes they can continue fighting after that, even though they are sort of dead already, this is how much fun they have killing.
#Neutrophil Clearance: when the party’s over, cleanup begins
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3151332/
Quote:Ultimately, however, neutrophils succumb via an expanding repertoire of possible death pathways (Fig. 2 and text box). Most importantly, these all result in the expression and/or exposure of signaling and recognition structures that can, under normal conditions, promote removal of the dying cells.
– While the battle rages, your blood vessels let fluid stream into the battlefield, like a dam opening up towards a valley. You notice this as inflammation, your thumb swells up a little and gets red and warm. The fluid brings a silent killer into the battle zone: millions of complement proteins, a sort of automated liquid weapon that stuns and kills bacteria by ripping holes into them – we made a whole video explaining them in detail.
#Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The front line of host defense.
https://www.ncbi.nlm.nih.gov/books/NBK27105/#A159
Quote: “Inflammatory responses are operationally characterized by pain, redness, heat, and swelling at the site of an infection, reflecting three types of change in the local blood vessels. The first is an increase in vascular diameter, leading to increased local blood flow—hence the heat and redness—and a reduction in the velocity of blood flow, especially along the surfaces of small blood vessels. The second change is that the endothelial cells lining the blood vessel are activated to express adhesion molecules that promote the binding of circulating leukocytes. The combination of slowed blood flow and induced adhesion molecules allows leukocytes to attach to the endothelium and migrate into the tissues, a process known as extravasation, which we will describe in detail later. All these changes are initiated by the cytokines produced by activated macrophages. Once inflammation has begun, the first cells attracted to the site of infection are generally neutrophils. They are followed by monocytes, which differentiate into more tissue macrophages. In the later stages of inflammation, other leukocytes such as eosinophils and lymphocytes also enter the infected site. The third major change in the local blood vessels is an increase in vascular permeability. Instead of being tightly joined together, the endothelial cells lining the blood vessel walls become separated, leading to exit of fluid and proteins from the blood and their local accumulation in the tissue. This accounts for the swelling, or edema, and pain—as well as the accumulation of plasma proteins that aid in host defense.”
You can watch our previous two videos to learn more on this topic:
The Immune System Explained
https://www.youtube.com/watch?v=zQGOcOUBi6s
The Bombs in your Blood
https://www.youtube.com/watch?v=BSypUV6QUNw
– We are reaching a crossroad now. If things go well your first line of defense kills the invaders quickly. But sometimes, the enemies are too strong and would overwhelm your defenses eventually, which means certain death for you, the human.
#Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The front line of host defense.
https://www.ncbi.nlm.nih.gov/books/NBK27105/#A159
Quote: ”IInnate immunity provides a front line of host defense through effector mechanisms that engage the pathogen directly, act immediately on contact with it, and are unaltered in their ability to resist a subsequent challenge with either the same or a different pathogen. These mechanisms often succeed in preventing an infection from becoming established. If not, they are reinforced through the recruitment and increased production of further effector molecules and cells in a series of induced responses that we will consider later in this chapter. These induced innate responses often fail to clear the infection. In that case, macrophages and other cells activated in the early innate response help to initiate the development of an adaptive immune response.”
– This is the hour of the Dendritic cell, your Immune System’s intelligence officer. While your soldiers were bashing in heads, it was collecting samples by ripping bacteria into tiny parts and covering itself in it. Like a soldier decorating itself in the guts of a dead enemy. The cell leaves the battlefield and enters the superhighway of your immune system that connects all your tissues, with your immune headquarters: Your lymph nodes.
#Dendric Cells, British Center for Immunology, 2020
https://www.immunology.org/public-information/bitesized-immunology/cells/dendritic-cells
Quote:”DCs are specialised to capture and process antigens, converting proteins to peptides that are presented on major histocompatibility complex (MHC) molecules recognised by T cells.”
#Lymph Nodes
https://www.cancer.gov/publications/dictionaries/cancer-terms/def/lymph-node
Quote:”Lymph nodes filter substances that travel through the lymphatic fluid, and they contain lymphocytes (white blood cells) that help the body fight infection and disease.”
– The Dendritic cell coming from the battlefield is looking for a Helper T cell, which is a sort of all purpose commander cell within your immune army. But not any Helper T Cell, one that happens to have just the right weapon for the bacteria that infected your wound. So it goes around and rubs itself, still covered in bacteria parts, against every Helper T Cell it meets. Most T cells are a bit disgusted and not interested. But after a few hours, something clicks. A Helper T Cell recognizes the bacteria parts. This cell is the weapon that is needed right now! The Dendritic Cell is overjoyed and activates the Helper T Cell.
#T-cell activation, British Society for Immunology, 2020
Quote:”T cells are generated in the Thymus and are programmed to be specific for one particular foreign particle (antigen). Once they leave the thymus, they circulate throughout the body until they recognise their antigen on the surface of antigen presenting cells (APCs).”
#Helper T Cells and Lymphocyte Activation, 2020
https://www.ncbi.nlm.nih.gov/books/NBK26827/
Quote: “Naïve T cells require at least two signals for activation. Both are provided by an antigen-presenting cell, which is usually a dendritic cell: signal 1 is provided by MHC-peptide complexes binding to T cell receptors, while signal 2 is mainly provided by B7 costimulatory proteins binding to CD28 on the T cell surface. If the T cell receives only signal 1, it is usually deleted or inactivated. When helper T cells are initially activated on a dendritic cell, they can differentiate into either TH1 or TH2 effector cells, depending on the cytokines in their environment: TH1 cells activate macrophages, cytotoxic T cells, and B cells, while TH2 cells mainly activate B cells.”
Following image demonstrates lymph transport along lymphatic vessels:
#Shang et al., Pathophysiology of aged lymphatic vessels, 2019.
– Ok wait. How come your immune system has a cell that has a weapon against the specific bacteria that infected you? Well, your immune system has a perfect weapon against every possible disease in the universe. Against the black death, the corona virus or an infection that will emerge in 100 years on Mars. We’ll talk about this a bit more in the next video because it’s very complex, so for now, just know that you have billions of unique Helper T Cells, that each have weapons against every possible enemy.
#Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. Principles of innate and adaptive immunity.
https://www.ncbi.nlm.nih.gov/books/NBK27090/
Quote: “Instead of bearing several different receptors, each recognizing a different surface feature shared by many pathogens, each naive lymphocyte entering the bloodstream bears antigen receptors of a single specificity. The specificity of these receptors is determined by a unique genetic mechanism that operates during lymphocyte development in the bone marrow and thymus to generate millions of different variants of the genes encoding the receptor molecules. Thus, although an individual lymphocyte carries receptors of only one specificity, the specificity of each lymphocyte is different. This ensures that the millions of lymphocytes in the body collectively carry millions of different antigen receptor specificities—the lymphocyte receptor repertoire of the individual. During a person's lifetime these lymphocytes undergo a process akin to natural selection; only those lymphocytes that encounter an antigen to which their receptor binds will be activated to proliferate and differentiate into effector cells.”
-Your heavy weapons are incredibly effective, but they are not fast. The activated Helper T Cell begins to clone itself, over and over again. One becomes two, two become four, until there are thousands of them.
#Moro-Garcia et al., Influence of Inflammation in the Process of T Lymphocyte Differentiation: Proliferative, Metabolic, and Oxidative Changes, 2018
https://www.frontiersin.org/articles/10.3389/fimmu.2018.00339/full
Quote: “In several of these stages, T lymphocytes are subjected to exponential growth in successive encounters with the same antigen.”
– Now they split into two groups. The first group quickly moves to help out your soldiers.
#Helper T-cells, Britannica, 2020
https://www.britannica.com/science/helper-T-cell
Quote: “Helper T cells are not a uniform group of cells but rather can be divided into two general subpopulations—TH1 and TH2 cells—that have significantly different chemistry and function. These populations can be distinguished by the cytokines (chemical messengers) they secrete. TH1 cells primarily produce the cytokines gamma interferon, tumour necrosis factor-beta, and interleukin-2 (IL-2), while TH2 cells mainly synthesize the interleukins IL-4, IL-5, IL-6, IL-9, IL-10, and IL-13. “
#Nurieva and Chung, Understanding the development and function of T follicular helper cells, 2010.
– But now the Helper T Cells arrive – one of them comes to the tired Macrophage and whispers something, using special chemical signals. In a heartbeat, the demoralized soldier feels fresh again. But there is something else: A hot, white anger. The Macrophage knows what it needs to do: Kill! Invigorated, it throws itself against the enemies once again. All over the battlefield this begins to happen.
Macrophages are able to tackle most pathogens without a hand from T-cell, however in case of more severe infections they need activating signals from T cells. Among the two types of Helper T cells we talked about above, TH-1 can activate macrophages. There are two required signals for the activation to happen; one with the characteristic cytokine IFN-γ and the other through CD40 ligand expressed by the TH1 cell which sensitizes the macrophage to respond to IFN-γ.
#Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. Macrophage activation by armed CD4 TH1 cells.
https://www.ncbi.nlm.nih.gov/books/NBK27153/
Quote: “Once activated, the macrophage can kill intracellular and ingested bacteria. Activated macrophages can also cause local tissue damage, which explains why this activity must be strictly regulated by antigen-specific T cells. TH1 cells produce a range of cytokines and surface molecules that not only activate infected macrophages but can also kill chronically infected senescent macrophages, stimulate the production of new macrophages in bone marrow, and recruit fresh macrophages to sites of infection. Thus, TH1 cells have a central role in controlling and coordinating host defense against certain intracellular pathogens. It is likely that the absence of this function explains the preponderance of infections with intracellular pathogens in adult AIDS patients.”
– Meanwhile, the second group of Helper T Cells was working on activating another line of defense: B Cells, your Antibody factories. Antibodies are protein superweapons that look like tiny crabs with two pincers to grab enemies. Just like the Helper T Cells, there are B Cells in your body that are able to make just the right Antibodies for every possible enemy. And the Helper T Cell is looking for exactly these B Cells. After a day or two, the right B Cell is found and begins to clone itself. As soon as enough clones have been made, each B Cell begins pumping out up to 2000 antibodies per second.
#B-Cells, British Society for Immunology, 2020
https://www.immunology.org/public-information/bitesized-immunology/cells/b-cells
Quote: “B cells are at the centre of the adaptive humoral immune system and are responsible for mediating the production of antigen-specific immunoglobulin (Ig) directed against invasive pathogens (typically known as antibodies).”
#Immunological memory, 2001
https://www.ncbi.nlm.nih.gov/books/NBK27158/
Quote: “When an animal is first immunized with a protein antigen, helper T-cell memory against that antigen appears abruptly and is at its maximal level after 5 days or so. Antigen-specific memory B cells appear some days later, because B-cell activation cannot begin until armed helper T cells are available, and B cells must then enter a phase of proliferation and selection in lymphoid tissue.“
#B Cells and Antibodies, Molecular Biology of the Cell. 4th edition, 2002
https://www.ncbi.nlm.nih.gov/books/NBK26884/
Quote: “Effector B cells can begin secreting antibody while they are still small lymphocytes, but the end stage of their maturation pathway is a large plasma cell (see Figure 24-7B), which continuously secretes antibodies at the astonishing rate of about 2000 molecules per second.”
– About a week after you injured yourself and bacteria invaded, your second line of defense finally arrives in full force. The tiny army begins to saturate the battlefield, pinching and stunning desperate bacteria. The antibodies clump them together and make them unable to move or fight, while your soldiers massacre the defenseless victims. The tide is turning fast. As the last enemies are cleaned up, your soldiers realize that they are no longer needed and begin to kill themselves to save resources.
#Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The course of the adaptive response to infection.
https://www.ncbi.nlm.nih.gov/books/NBK27125/
Quote: “When an infection is effectively repelled by the adaptive immune system, two things occur. The first is the removal of most of the effector cells, as part of the restoration of tissue integrity. The immune system has well-developed mechanisms for getting rid of cells that have outlasted their usefulness. Most unwanted effector cells die by apoptosis, a process used by all multicellular eukaryotic organisms to remove unwanted cells.”
– But not all of them – a few Helper T Cells remain and turn into memory cells. They will guard the tissue for years, making sure the same bacteria will never again gain a foothold here.
#Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The course of the adaptive response to infection.
https://www.ncbi.nlm.nih.gov/books/NBK27125/
Quote: “However, some of the effector cells are retained, and these provide the raw material for memory T-cell and B-cell responses. These are crucially important to the operation of the adaptive immune system, as we will argue in Chapter 15. The memory T cells, which we will consider at the end of this chapter, are retained virtually forever. However, the mechanisms underlying the decision to induce apoptosis in the majority of effector cells and retain only a few are not known. It seems likely that the answer will lie in the cytokines produced by the environment or by the T cells themselves.”
– Similarly, a few B Cells will stay alive and keep producing a low amount of antibodies, making you immune against this bacteria, maybe for the rest of your life.
#Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. Immunological memory.
https://www.ncbi.nlm.nih.gov/books/NBK27158/
Quote: “When an animal is first immunized with a protein antigen, helper T-cell memory against that antigen appears abruptly and is at its maximal level after 5 days or so. Antigen-specific memory B cells appear some days later, because B-cell activation cannot begin until armed helper T cells are available, and B cells must then enter a phase of proliferation and selection in lymphoid tissue. By one month after immunization, memory B cells are present at their maximal levels. These levels are then maintained with little alteration for the lifetime of the animal. ”