Kurzgesagt – In a Nutshell

Sources – Immune#2

– You are not a person, you are a planet, made from roughly 40 trillion cells.

According to recent estimates , the total number of cells in the human body falls somewhere in the range of 29 trillion to 45 trillion. We stick to 40 billion for a higher end rounded number. Apart from these, we have another 39 trillion cells from the resident microbes in our body.

#Bianconi, Eva et al. An estimation of the number of cells in the human body, 2013.

https://pubmed.ncbi.nlm.nih.gov/23829164/

Quote:”Our current estimation of human total cell number was calculated only on a variety of organs and cell types, as listed in Appendix B, Table B1 (online only). These partial data correspond to a total number of 3.72 ±0.81 x 10^13 (Figure 2).”

#Alison Abbott, Scientists bust myth that our bodies have more bacteria than human cells, 2016

https://www.nature.com/articles/nature.2016.19136

Quote: “It's often said that the bacteria and other microbes in our body outnumber our own cells by about ten to one. That's a myth that should be forgotten, say researchers in Israel and Canada. The ratio between resident microbes and human cells is more likely to be one-to-one, they calculate. A 'reference man' (one who is 70 kilograms, 20–30 years old and 1.7 metres tall) contains on average about 30 trillion human cells and 39 trillion bacteria, say Ron Milo and Ron Sender at the Weizmann Institute of Science in Rehovot, Israel, and Shai Fuchs at the Hospital for Sick Children in Toronto, Canada.”

#R. Sender et al., Revised Estimates for the Number of Human and Bacteria Cells in the Body, 2016

https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.1002533

Quote: “We estimate the total number of bacteria in the 70 kg "reference man" to be 3.8·10^13. For human cells, we identify the dominant role of the hematopoietic lineage to the total count (≈90%) and revise past estimates to 3.0·10^13 human cells. Our analysis also updates the widely-cited 10:1 ratio, showing that the number of bacteria in the body is actually of the same order as the number of human cells, and their total mass is about 0.2 kg.”

– There is so much of you, that if your cells were human-sized, you would be 20 Mount Everest's big. For your crawly inhabitants, this makes your body an ecosystem, rich with resources and warmth and space.

If we assume an average human cell of 15 μm, sizing up this cell to a human height (165 cm), would make us around 181.5km tall. 20 times Mount Everest (8849 m) is around 180km which is more or less similar to our human-size-celled version.

#D. A. Guertin, D. M. Sabatini, Cell Size Control, 2005

http://sabatinilab.wi.mit.edu/Sabatini%20papers/Cell_Growth_REV_ELS-2006.pdf

Quote: “The overall size of any animal or organ depends on the number and size of its cells. The average animal cell size is approximately 10–20 μm in diameter. Size variation can be found in cells circulating in the blood; for instance, neutrophils are 10 μm in diameter while macrophages are 20–30 μm in diameter.”

#Britannica, Mount Everest, 2021

https://www.britannica.com/place/Mount-Everest

Quote: “Reaching an elevation of 29,032 feet (8,849 metres), Mount Everest is the highest mountain in the world”

– A bacterium consists of one cell. It can make a fully grown copy in about half an hour.

#How quickly can a bacterium grow?, Anne Trafton, MIT News Office, 2013

https://news.mit.edu/2013/how-quickly-can-a-bacterium-grow-0827

Quote: “During the 20-minute replication process, a bacterium consumes a great deal of food, rearranges many of its molecules — including DNA and proteins — and then splits into two cells.”

– A virus can turn into hundreds within hours and billions within days.

Unlike bacteria, viruses do not replicate but the infected host-cell makes many copies of the virus during one viral reproductive cycle and releases them all at once. The number of viruses released, which is called burst size, and the time it takes until the release differs from virus to virus. For example, HIV-1 can release more than 10,000 virions per T cell approximately every 24 hours. (some estimates put it even higher)

#Roizman B. Multiplication. In: Baron S, editor. Medical Microbiology, 1996. https://www.ncbi.nlm.nih.gov/books/NBK8181/

Quote: “After several hours (e.g., picornaviruses) or days (cytomegalovirus), cells infected with lytic viruses cease all their metabolic activity and lose their structural integrity. Cells infected with non-lytic viruses may continue to synthesize viruses indefinitely. The reproductive cycle of viruses ranges from 8 hrs (picornaviruses) to more than 72 hrs (some herpesviruses). The virus yields per cell range from more than 100,000 poliovirus particles to several thousand poxvirus particles.”

#Mohammadi, Pejman et al. 24 hours in the life of HIV-1 in a T cell line, 2013. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561177/

Quote: “HIV-1 infects CD4+ T cells and completes its replication cycle in approximately 24 hours.”

#Chen, Hannah Yuan et al. Determination of virus burst size in vivo using a single-cycle SIV in rhesus macaques, 2007.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2141911/

Quote: ”We applied a simple mathematical model based on computing the total number of virions produced and dividing by the total number of productively infected cells inoculated into each animal to estimate the SIV burst size in vivo. With this method, the SIV burst size ranged from 1.3 × 10^4 to 5.9 × 10^4, with a mean of 4.0 × 10^4 virions per infected cell for the first inoculation and from 1.5 × 104^ to 1.2 × 10^5, with a mean of 5.5 × 10^4 virions per infected cell for the second inoculation. [...] Our findings suggest that the SIV burst size in vivo, and by inference the HIV burst size, is much larger than the previous estimates of 10^2 to 10^3 virions per cell.”

– Even worse, for a bacterium or virus your body is a hostile ecosystem applying selective pressure. Because they go through so many generations so quickly, eventually by pure chance, there will be an individual that mutates and adapts in just the right way to resist your defenses and then multiply quickly again. In other words, you are facing a sheer endless variety of different enemies and you’re too slow to keep up with their evolution.

Any factor that increases or decreases the reproductive success of an organism causes selective pressure. High rate of reproduction does not only help viruses and bacteria to make a sheer number of copies of themselves and win the whole numbers-game over us. In fact, not all of those copies are exactly the same – there is a certain rate of mutation which introduces some ratio of novel individuals to the population in each generation.

#Michael R. Mulvey, Andrew E. Simor. Antimicrobial resistance in hospitals: How concerned should we be? 2009.

https://www.cmaj.ca/content/180/4/408.short

Quote: ”Selective pressure refers to the environmental conditions that allow organisms with certain characteristics to survive and proliferate. Exposure to an antibiotic, for example, may inhibit or kill the majority of the bacterial population who are susceptible. However, a resistant subset of organisms may not be inhibited or killed by the antibiotic (Figure 2). These bacteria may be intrinsically resistant to the antibiotic, or they may have acquired resistance. Thus, antimicrobial use selects for the emergence of resistant strains of organisms that may then proliferate and become predominant.15 Indeed, antimicrobial resistance in health care facilities and the community is largely determined and magnified by the selective pressure of antimicrobial use.16”

#The virus is under increasing selection pressure, MPG, 2021

https://www.mpg.de/16371358/coronavirus-variants

Quote: “Under what conditions can such selection pressure arise?

It can occur at the level of an individual or a population. For example, in individuals with weakened immune systems, who cannot effectively fight the virus effectively, the pathogen can “try out” new things for a longer period of time. In the end, the variants that most effectively escape the body’s defences remain.

Regions where the first wave of the pandemic was particularly strong – such as parts of South America and South Africa – also exert strong selection pressure because many people there developed immunity following Sars-CoV-2 infection. New virus variants may have an advantage here.”

– In a nutshell, you actually have two immune systems, the innate and the adaptive immune system. The innate immune system was ready when you were born. It mostly consists of general purpose soldiers, we introduced them in the last immune video.

#Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease, 2001.

https://www.ncbi.nlm.nih.gov/books/NBK27090/

Quote: “The early innate systems of defense, which depend on invariant receptors recognizing common features of pathogens, are crucially important, but they are evaded or overcome by many pathogens and do not lead to immunological memory. The abilities to recognize all pathogens specifically and to provide enhanced protection against reinfection are the unique features of adaptive immunity, which is based on clonal selection of lymphocytes bearing antigen-specific receptors. The clonal selection of lymphocytes provides a theoretical framework for understanding all the key features of adaptive immunity. Each lymphocyte carries cell-surface receptors of a single specificity, generated by the random recombination of variable receptor gene segments and the pairing of different variable chains. This produces lymphocytes, each bearing a distinct receptor, so that the total repertoire of receptors can recognize virtually any antigen. If the receptor on a lymphocyte is specific for a ubiquitous self antigen, the cell is eliminated by encountering the antigen early in its development, while survival signals received through the antigen receptor select and maintain a functional lymphocyte repertoire. Adaptive immunity is initiated when an innate immune response fails to eliminate a new infection, and antigen and activated antigen-presenting cells are delivered to the draining lymphoid tissues. When a recirculating lymphocyte encounters its specific foreign antigen in peripheral lymphoid tissues, it is induced to proliferate and its progeny then differentiate into effector cells that can eliminate the infectious agent. A subset of these proliferating lymphocytes differentiate into memory cells, ready to respond rapidly to the same pathogen if it is encountered again. The details of these processes of recognition, development, and differentiation form the main material of the middle three parts of this book.”

Learn more about the innate immune system from the previous immune video:

#Immune System Explained

https://youtu.be/nek0lyV8D9o

– The adaptive immune system carries two types of cells T Cells and B Cells that are your super weapons and are incredibly effective and deadly to your enemies. These cells are complicated to produce and take a lot of time to deploy but once they are ready, they have a real punch.

#Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease, 2001.

https://www.ncbi.nlm.nih.gov/books/NBK27092/

Quote: “There are two major types of lymphocyte: B lymphocytes or B cells, which when activated differentiate into plasma cells that secrete antibodies; and T lymphocytes or T cells, of which there are two main classes. One class differentiates on activation into cytotoxic T cells, which kill cells infected with viruses, whereas the second class of T cells differentiates into cells that activate other cells such as B cells and macrophages.”

#Cologne, Germany: Institute for Quality and Efficiency in Health Care (IQWiG); 2006-. The innate and adaptive immune systems. [Updated 2020 Jul 30].

https://www.ncbi.nlm.nih.gov/books/NBK279396/

Quote: “The adaptive immune system takes over if the innate immune system is not able to destroy the germs. It specifically targets the type of germ that is causing the infection. But to do that it first needs to identify the germ. This means that it is slower to respond than the innate immune system, but when it does it is more accurate.”

– What makes your adaptive immune system so powerful is that it has the largest library in the universe. It has an answer to everything. You have at least one of these super weapon cells inside you to fight the black death, the corona virus and the first deadly bacteria that will emerge in a city on Mars in one hundred years. This makes it possible for you to counter the ability of bacteria and viruses to change so rapidly. How is this possible? To understand what is going on here, we need to take one step back.

#Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Lymphocytes and the Cellular Basis of Adaptive Immunity.

https://www.ncbi.nlm.nih.gov/books/NBK26921/

Quote: “The most remarkable feature of the adaptive immune system is that it can respond to millions of different foreign antigens in a highly specific way. B cells, for example, make antibodies that react specifically with the antigen that induced their production. How do B cells produce such a diversity of specific antibodies? The answer began to emerge in the 1950s with the formulation of the clonal selection theory. According to this theory, an animal first randomly generates a vast diversity of lymphocytes, and then those lymphocytes that can react against the foreign antigens that the animal actually encounters are specifically selected for action. As each lymphocyte develops in a central lymphoid organ, it becomes committed to react with a particular antigen before ever being exposed to the antigen. It expresses this commitment in the form of cell-surface receptor proteins that specifically fit the antigen. When a lymphocyte encounters its antigen in a peripheral lymphoid organ, the binding of the antigen to the receptors activates the lymphocyte, causing it both to proliferate and to differentiate into an effector cell. An antigen therefore selectively stimulates those cells that express complementary antigen-specific receptors and are thus already committed to respond to it. This arrangement is what makes adaptive immune responses antigen-specific.”

– All organisms on earth are made from the same basic parts, mostly proteins.

#Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell, 2002. https://www.ncbi.nlm.nih.gov/books/NBK26864/

Quote: “Protein molecules, like DNA and RNA molecules, are long unbranched polymer chains, formed by the stringing together of monomeric building blocks drawn from a standard repertoire that is the same for all living cells. Like DNA and RNA, they carry information in the form of a linear sequence of symbols, in the same way as a human message written in an alphabetic script. There are many different protein molecules in each cell, and—leaving out the water—they form most of the cell's mass.”

#Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell, 2002. https://www.ncbi.nlm.nih.gov/books/NBK26864/

Quote: “To carry out its information-storage function, DNA must do more than copy itself before each cell division by the mechanism just described. It must also express its information, putting it to use so as to guide the synthesis of other molecules in the cell. This also occurs by a mechanism that is the same in all living organisms, leading first and foremost to the production of two other key classes of polymers: RNAs and proteins. The process begins with a templated polymerization called transcription, in which segments of the DNA sequence are used as templates to guide the synthesis of shorter molecules of the closely related polymer ribonucleic acid, or RNA. Later, in the more complex process of translation, many of these RNA molecules serve to direct the synthesis of polymers of a radically different chemical class—the proteins (Figure 1-4).”

– Proteins are the building blocks of life and can have billions of different shapes you can imagine as 3D puzzle pieces. There are billions of different puzzle pieces your enemies can use to construct their bodies.

#Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell, 2002

https://www.ncbi.nlm.nih.gov/books/NBK26830/#A409

Quote: “Since each of the 20 amino acids is chemically distinct and each can, in principle, occur at any position in a protein chain, there are 20 × 20 × 20 × 20 = 160,000 different possible polypeptide chains four amino acids long, or 20^n different possible polypeptide chains n amino acids long. For a typical protein length of about 300 amino acids, more than 10^390 (20^300) different polypeptide chains could theoretically be made. This is such an enormous number that to produce just one molecule of each kind would require many more atoms than exist in the universe.

Only a very small fraction of this vast set of conceivable polypeptide chains would adopt a single, stable three-dimensional conformation—by some estimates, less than one in a billion. The vast majority of possible protein molecules could adopt many conformations of roughly equal stability, each conformation having different chemical properties. And yet virtually all proteins present in cells adopt unique and stable conformations. How is this possible? The answer lies in natural selection. A protein with an unpredictably variable structure and biochemical activity is unlikely to help the survival of a cell that contains it. Such proteins would therefore have been eliminated by natural selection through the enormously long trial-and-error process that underlies biological evolution.”

– Why is this important? Because proteins are in a way the “language” of the microworld. Cells don’t have eyes or ears, so to tell a friend from a foe, they have to touch them and recognize if their protein is part of a friend or part of an enemy. Recognizing means that cells have countless tiny devices called receptors, that are able to connect with a specific protein puzzle piece.

#Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Chapter 15, Cell Communication.

https://www.ncbi.nlm.nih.gov/books/NBK21059/

Quote: “According to the fossil record, sophisticated unicellular organisms resembling present-day bacteria were present on Earth for about 2.5 billion years before the first multicellular organisms appeared. One reason why multicellularity was so slow to evolve may have been related to the difficulty of developing the elaborate cell communication mechanisms that a multicellular organism needs. Its cells have to be able to communicate with one another in complex ways if they are to be able to govern their own behavior for the benefit of the organism as a whole.

These communication mechanisms depend heavily on extracellular signal molecules, which are produced by cells to signal to their neighbors or to cells further away. They also depend on elaborate systems of proteins that each cell contains to enable it to respond to a particular subset of these signals in a cell-specific way. These proteins include cell-surface receptor proteins, which bind the signal molecule, plus a variety of intracellular signaling proteins that distribute the signal to appropriate parts of the cell. Among the intracellular signaling proteins are kinases, phosphatases, GTP-binding proteins, and many other proteins with which they interact. At the end of each intracellular signaling pathway are target proteins, which are altered when the pathway is active and change the behavior of the cell. Depending on the signal's effect, these target proteins can be gene regulatory proteins, ion channels, components of a metabolic pathway, parts of the cytoskeleton, and so on (Figure 15-1).”

– This is also one of the reasons we still have to deal with diseases like the flu each year – the influenza virus mutates very rapidly and so the proteins that make up its hull constantly change a tiny bit.

#Suzanne ClancyGenetics of the Influenza Virus, 2008

https://www.nature.com/scitable/topicpage/genetics-of-the-influenza-virus-716/

Quote: “In the United States, seasonal influenza epidemics typically claim the lives of about 30,000 people each year and cause hospitalization of more than 100,000 (Reid & Tautenberger, 2003). Every two or three years, more virulent strains circulate, increasing death tolls by approximately 10,000 to 15,000 individuals. These seasonal epidemics are the result of antigenic drift, a phenomenon caused by mutations in two key viral genes due to an error-prone RNA polymerase.”

Quote: “With the HA and NA genes, the influenza A genome contains eight genes encoding 11 proteins. These proteins include three RNA polymerases that function together as a complex required by the virus to replicate its RNA genome. Interestingly, these polymerases have been shown to have high error rates due to a lack of proofreading ability, which leads to high mutation rates in replicated viral genomes and therefore rapid rates of viral evolution. This high rate of mutation and evolution is one source of influenza virus genetic diversity.”

There are two mechanisms that Influenza virus can change:

Antigenic drift: These are small mutations on the two viral surface proteins, hemagglutinin (HA) and neuraminidase (NA), that produce slightly different variants. HA and NA function as antigens through which the immune system recognizes the virus. As the virus replicates, these mutations happen continuously and cause the so-called antigenic shift. Most flu shots target HA surface proteins. Since antigenic shift creates influenza variants with similar antigenic properties, antibodies against one influenza virus will likely recognize and respond to antigenically similar influenza viruses.
Antigenic shift: These are big abrupt changes that result in new HA or NA proteins. These can happen, for instance, when an animal-origin influenza virus gains the ability to infect humans. Such viruses can contain substantially different surface protein combinations than their human-subtype so that most people would not have immunity to the new virus.

High mutation rate, however, might also be working to the disadvantage of the virus. A new study suggests that mutated versions of the virus are more likely to trigger the cellular alarm and less successful at replicating themselves.

#HHMI, The Flu Virus’s Ability to Mutate May Sometimes Be Its Downfall, 2019

https://www.hhmi.org/news/the-flu-viruss-ability-to-mutate-may-sometimes-be-its-downfall

Quote: ”One of influenza virus’s main weapons is actually a double-edged sword. The virus’s ability to rapidly mutate lets it escape from the immune system’s memory and explains why people can be repeatedly re-infected with flu – unlike measles or polio. But those mutations can also blow the virus’s cover, Howard Hughes Medical Institute Investigator Jesse Bloom and colleagues reported May 8, 2019, in the Journal of Virology. ”

– The soldiers of your innate immune system have a large number of the puzzle pieces for common bacteria and viruses memorized, that’s why they are your all purpose weapons. But they are ineffective against many billions of mutations and adaptations that your enemies can develop.

#Desjardins E., Barker G., Madrenas J. (2014) Thinking Outside the Mouse: Organism-Environment Interaction and Human Immunology. In: Barker G., Desjardins E., Pearce T. (eds) Entangled Life. History, Philosophy and Theory of the Life Sciences, vol 4. Springer, Dordrecht.

https://link.springer.com/chapter/10.1007%2F978-94-007-7067-6_9

Quote: “Innate immunity, as the name suggests, is the part of the immune system that organisms possess at birth. It encompasses cells like macrophages, dendritic cells, neutrophils, natural killer cells and mastocytes.5 This part of the immune system remains active and virtually unchanged throughout the entire life of the organism. The types of mechanisms involved in innate immunity reflect the evolutionary history of the species. Innate immunity thus changes and adapts to new situations, but it does so very slowly over many generations and not during the lifetime of individual organisms.The evolutionary process by which it becomes able to respond to new challenges is much too slow to cope with the rapid evolution of infectious microorganisms. As a consequence, our species would probably not survive if the only kind of immunity we had was innate immunity.”

– Well, the cells of your adaptive immune system found a cheat code: mixing and matching their own genetic code to create this stunning variety of receptors. The details are way too complicated for this video but in a nutshell, your adaptive immune cells have the official permission to take a tiny part of their own genetic code and mix it in random ways to create billions of different receptors.

https://link.springer.com/chapter/10.1007%2F978-94-007-7067-6_9

Quote: “Unlike the innate system, the adaptive immune system constantly changes during the life of an organism as a function of antigen exposure. It does this by means of somatic selective processes that are made possible by the rapid production of variations via somatic recombination and somatic hypermutation. Somatic selection can be compared to a Darwinian selection process that happens within organisms in lines of non-reproductive cells. Some refer to this type of process as “ontogenic Darwinism” (Shanks 2004). Basically, when a pathogen invades an organism, certain cells of the innate system present the pathogen to the antibody-producing cells of the adaptive system. B and T cells produce a tremendous variety of antibodies, but only a few of them can bind to a given pathogen. Defense by antibodies is thus much more specific than innate immunity. The synthesis of a given antibody involves multiple genetic components that are shuffled together to form a complete immunoglobulin gene, which in turn specifies the structure of a given antibody. This somatic recombination process allows organisms to produce a great variety of antibodies—the system is capable of recognizing at least 100 billion different types of antigens (Shanks and Greek 2009, 188). This process of recombination also increases the probability that the system will produce at least one antibody capable of binding to any new antigen.”

#T Cells, Arizona State University

https://askabiologist.asu.edu/t-cell

Quote: “There are 25 million to a billion different T-cells in your body. Each cell has a unique T-cell receptor that can fit with only one kind of antigen, like a lock that can fit with only one shape of key. Antigens and receptors work a lot like a lock and key. Most of these antigens will never get in your body, but the T-cells that patrol your body will recognize them if they do.

The T-cell receptor fits with its antigen like a complex key. When the perfectly shaped virus antigen on an infected cell fits into the Killer T-cell receptor, the T-cell releases perforin and cytotoxins. Perforin first makes a pore, or hole, in the membrane of the infected cell. Cytotoxins go directly inside the cell through this pore, destroying it and any viruses inside. This is why Killer T-cells are also called Cytotoxic T-cells. The pieces of destroyed cells and viruses are then cleaned up by macrophages.”

– But here we hit a pretty dangerous problem – if your adaptive immune system is making weapons that can attack every possible protein puzzle piece in the universe… wouldn’t it also make some that can attack your own cells? Indeed, this happens all the time.

#Hogquist et al., Central Tolerance: Learning Self Control In The Thymus, 2005

https://www.nature.com/articles/nri1707

Quote: ”For developing T cells, many of the randomly rearranged antigen receptors are useless, because these receptors cannot bind the MHC alleles that are present in the individual. So, positive selection is a crucial step that enriches T-cell progenitors that are MHC restricted by allowing only cells that express a T-cell receptor (TCR) that can interact with self-peptide–MHC complexes to differentiate further. This step, of course, also enriches self-reactive cells, thereby making the danger of autoimmunity inherent in the adaptive immune system. Fortunately, the most strongly self-reactive progenitors are under strict control — that is, they are made self tolerant — and it is the weakly reactive progenitors that mature, populate the lymphoid organs and participate in immune responses to foreign antigens (FIG. 1).”

– This is so fundamentally dangerous to your survival that you have a whole organ that does nothing but working on preventing this: The Murder University of your Thymus. Your Thymus is a chicken wing sized organ above your heart and you probably have never heard of it.

#Shelly, S., Agmon-Levin, N., Altman, A. et al. Thymoma and autoimmunity. Cell Mol Immunol 8, 199–202 (2011).

https://www.nature.com/articles/cmi201074

Quote: “Many immunological functions of the thymus have been elucidated, including development of immunocompetent T cells, differentiation and proliferation of T-cell subsets, such as the evolution of naive T-cells into T helper cells (CD4) and cytotoxic suppressor cells (CD8), and migration of mature T cells into the circulating lymphocyte pool and peripheral tissues.2 Perhaps the most important role of the thymus, however, is the induction of immune self-tolerance that functions to prevent self-harm or autoimmunity. Additionally, the thymus is capable of secreting hormones and soluble factors, the most notable being thymolin, thymopoietin and thymosin alpha-1. These hormones function in concert to regulate numerous complex interactions controlling the production of mature and functional T cells within the thymus and peripheral tissues.”

#Araki, Tetsuro et al. “Normal thymus in adults: appearance on CT and associations with age, sex, BMI and smoking.” European radiology vol. 26,1 (2016): 15-24.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847950/

– Interestingly, your thymus is one of the reasons why your immune system gets worse as you age, because it is in a constant state of decline once you reach puberty.

#Thapa, P., & Farber, D. L. The Role of the Thymus in the Immune Response, 2019

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6446584/

Quote:”Unlike mice, humans are born with a full complement of T cells in circulation and lymphoid tissues and the human thymus is largest at birth and is most active up until puberty. After puberty, the thymus starts to involute with age and turns into fatty tissue [...] Together, the reduction in epithelial cell turnover and expression of key TEC-associated transcription factors coupled with age- and sex-related effects on thymic structural integrity and increased fat accumulation result in reduced homing of bone marrow progenitors and induction of thymopoiesis.”

– In your murder university, your immune system is putting your adaptive immune cells through an intense and deadly curriculum. Basically it is showing them all sorts of protein puzzle pieces that are used by your own cells to see how they react. When a young cell recognizes a body puzzle piece and wants to attack it, the teacher cells order them to kill themselves and they are eaten up and recycled.

#Hogquist et al., Central Tolerance: Learning Self Control In The Thymus, 2005

https://www.nature.com/articles/nri1707

Quote: “The hallmark of T-cell central tolerance is clonal deletion: that is, suicide of T-cell progenitors that have high affinity for self-antigens1. Other processes have been described, including ANERGY2 and RECEPTOR EDITING 3,4, but these are thought to have a lesser role. These three processes impair or eliminate high-affinity self-reactive cells and are considered to be negative selection mechanisms (FIG. 1). But not all central-tolerance mechanisms cripple self-reactive T cells. The positive selection of regulatory T-cell populations in the thymus enables T cells to actively restrain immune responses to motifs that are recognized as self (FIG. 1). Three main cell types have been considered as potential regulatory T-cell subsets: CD4+CD25+ REGULATORY T TReg CELLS 5,6, CD8αα+ INTESTINAL EPITHELIAL LYMPHOCYTES7 and NATURAL KILLER T NKT CELLS8. All are thought to be induced by high affinity (that is, agonist) self-peptide–MHC interactions with TCR in the thymus9. The double whammy of ‘recessive’ (that is, cell intrinsic) and ‘dominant’ (that is, trans-acting) central-tolerance mechanisms greatly reduces the threat of autoimmunity inherent in the adaptive immune system.“

– The immune system is so particular about this process that around 98% of your adaptive immune cells that enter murder university die there. 2% graduate and get to do their job of protecting you for real.

#Lynne Eldrige, An Overview of the Thymus Gland, 2020

https://www.verywellhealth.com/thymus-gland-overview-4582270

Quote: ”T cells are negatively selected for autoimmunity, and these self-attacking cells either die or are turned into regulatory cells.

Not all T cells make it through the selection process—only around 2% eventually make it through positive and negative selection. The survivors are then exposed to hormones produced by the thymus gland to complete their maturation before being released to do their job (circulating in the bloodstream or waiting in the lymph nodes for foreign invaders).”

– If this process goes wrong and cells escape that can recognize your own protein puzzle pieces, this can lead to autoimmune disease, where your immune system attacks your own body from the inside. But this is a story for another time.

Unlike the normal adaptive immune response, where foreign antigen is cleared out from the body, autoimmune response aims the adaptive immune response at self-antigens. Immune effector mechanisms are not able to fully get rid of this antigen which usually causes a sustained response. This can in turn cause chronic inflammatory injury to tissues, which can be lethal.

#Chaplin DD. Overview of the immune response, 2009.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923430/

Quote: “The immune system employs many potent effector mechanisms that have the ability to destroy a broad range of microbial cells and to clear a broad range of both toxic and allergenic substances. It is critical, therefore, that the immune response is able to avoid unleashing these destructive mechanisms against the mammalian host’s own tissues. The ability of the immune response to avoid damaging self-tissues is referred to as self-tolerance. Because failure of self-tolerance underlies the broad class of autoimmune diseases, this process has been extensively studied. It is now clear that mechanisms to avoid reaction against self-antigens are expressed in many parts of both the innate and the adaptive immune response. The mechanisms that underlie protection of normal self-tissues from immune damage will be discussed as each of the major effector arms of the host immune response is introduced.”

#Chaplin DD. Overview of the immune response, 2009.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923430/

Quote: “Perhaps more puzzling are conditions in which tissue inflammation appears to develop without any underlying infectious or noxious stimulus. Prominent in these are autoimmune diseases and atopic illnesses. These disorders appear to represent a fundamental misdirection of the immune response, resulting in tissue damage when no real danger was present. The growing spectrum of autoimmune diseases appears to represent a breakdown in self-tolerance.”