Kurzgesagt – In a Nutshell
Kurzgesagt – In a Nutshell
Embedded Files
Sources – Autoimmune
Sources – Autoimmune
We thank the following expert for her input and critical reading:
Jen Gommerman
Immunology Professor, University of Toronto
—Your immune system is an omnipresent terrifying entity made from billions of nuclear weapons and kamikaze bombers, saturating every little tissue, bone and fluid in your body. It scans, patrols, and when it finds an enemy — it kills.
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.”
Here, the “nuclear weapons” are a metaphor for B cells, central cells of the adaptive immune system that produce antibodies capable of neutralizing each specific invading virus or bacteria. Their specificity makes them extremely effective.
#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).”
The “kamikaze bombers” are a metaphor for neutrophils, as they trigger their own death in multiple ways as part of their immune function.
#Braton, Donna L.; Henson, Petar M. (2011): “Neutrophil Clearance: when the party’s over, cleanup begins”, Trends in Immunology, vol. 32, 8, 350–357
https://pmc.ncbi.nlm.nih.gov/articles/PMC3151332/
Quote: “Fig. 2. Possible death pathways for neutrophils and impact on resolution or perpetuation of inflammation. Recruited neutrophils succumb to various death pathways within tissues (blue boxes). Based on signaling for their recognition by macrophages, and the stage at which they are removed, inflammatory consequences will vary across a continuum from anti-inflammatory and immunosuppressive to pro-inflammatory and immunogenic.”
—This is the betrayal of autoimmunity – diseases like Type 1 diabetes, multiple sclerosis, celiac disease, lupus and Crohn's disease and many more. Literally every tissue can be affected, from your nerves to your thyroid or joints.
Type 1 diabetes, multiple sclerosis, celiac diseases and lupus are all considered autoimmune disorders. Other common autoimmune diseases are lupus and psoriasis. Any tissue can be affected by an autoimmune disease. For example, multiple sclerosis affects the protective cover of your nerves, Hashimoto’s disease affects your thyroid gland, and rheumatoid arthritis affects —among others— the tissue lining your joints. We are aware that Crohn's Disease is not strictly an autoimmune disease. It involves an abnormal immune response similar to what happens in autoimmune diseases. However, unlike other autoimmune diseases, the process is not primarily driven by autoantibodies against the body’s own tissues. Instead, the immune system appears to launch an inappropriate response—often against harmless bacteria in the gut. However, it is generally listed alongside other autoimmune conditions so we decided to include it.
#Cleveland Clinic: “Autoimmune Diseases” (retrieved 2025)
https://my.clevelandclinic.org/health/diseases/21624-autoimmune-diseases
—While there is usually a certain amount of genetic risk for autoimmunity, to get an actual autoimmune disease you also need a colossal case of bad luck on top of that.
Nobody knows what causes the immune system to start attacking healthy cells. There are genetic factors that make developing an autoimmune disease more likely, but these are usually complex a not sufficient to cause the disease by themselves.
#Pisetsky, David S. (2023): “Pathogenesis of autoimmune disease”, Nature Reviews Nephrology, 19, 509–524
https://www.nature.com/articles/s41581-023-00720-1
https://sostelemedicina.ucv.ve/documentos/manuales/pathogenesis-of-autoimmune-disease.pdf
Quote: “Autoimmune diseases are a diverse group of conditions characterized by aberrant B cell and T cell reactivity to normal constituents of the host. These diseases occur widely and affect individuals of all ages, especially women.[...]In general, autoimmune disease results from an interplay between a genetic predisposition and environmental factors. Genetic predisposition to autoimmunity is complex and can involve multiple genes that regulate the function of immune cell populations. Less frequently, autoimmunity can result from single-gene mutations that affect key regulatory pathways.”
—In total your body produces about 100,000 different proteins, or shapes.
#NHS National Genomics Education Programme: “Proteins” (retrieved 2025)
https://www.genomicseducation.hee.nhs.uk/genotes/knowledge-hub/proteins/
Quote: “Proteins are large molecules composed of one or more chains of amino acids, the sequence of which is determined by DNA. The human body has over 100,000 different proteins performing many different functions.”
However, the number of different proteins can range from tens of thousands to millions depending on how you count.
#Ponomarenko, Elena A. et al. (2016): “The Size of the Human Proteome: The Width and Depth”, International journal of analytical chemistry, 7436849
https://pmc.ncbi.nlm.nih.gov/articles/PMC4889822/
Quote: “The size of the human proteome is a matter of debate, and numbers in the literature range from as few as 20,000 to several million. The huge discrepancy between these numbers is not a scientific controversy, but more a matter of definition. Thanks to the human genome project, we can now estimate the number of protein-coding genes to be in the range of 19,587–20,245 (refs. 1,3,4). Thus, if a single representative protein from every gene is used as the definition of the proteome, the estimated size is just ~20,000. This number may decrease somewhat, as it has been difficult to find an expressed protein encoded by some of these putative protein-coding genes. However, if one considers that many genes are transcribed with splice variants, the number of human proteins increases to ~70,000 (per Ensembl3). In addition, many human proteins undergo PTMs that can strongly influence their function or activity. These PTMs include glycosylation, phosphorylation and acetylation, among a few hundred others (Fig. 1a), giving rise to many hundreds of thousands of additional protein variants; furthermore, though many proteins are unmodified, some fraction of proteins are already annotated with multiple modifications (Fig. 1b).”
—Your immune system evolved to constantly check the proteins of your cells and look for shapes that are not you – and to kill whatever is attached to them violently and brutally.
Dendritic cells patrol your body taking pieces of pathogens. They then present those pieces to T cells, which kick off the adaptive immune response against those pathogens.
#Liu, Kang (2015): “Dendritic Cells”, Encyclopedia of Cell Biology, 741–749
https://pmc.ncbi.nlm.nih.gov/articles/PMC7148618/
Quote: “Dendritic cells (DCs) are professional antigen presenting cells that inform the fight against invasive pathogens while enforcing tolerance to self and harmless environmental antigens. They capture pathogens and receive signals from pathogens that influence the outcome of immune responses.”
—Autoimmunity is when your soldier cells suddenly think that your own healthy and natural proteins belong to an enemy.
#Institute for Quality and Efficiency in Health Care (2023): “In brief: How does the immune system work?”
https://www.ncbi.nlm.nih.gov/books/NBK279364/
Quote: “The immune system can be activated by a lot of different things that the body doesn’t recognize as its own. These are called antigens. Examples of antigens include the proteins on the surfaces of bacteria, fungi and viruses. When these antigens attach to special receptors on the immune cells (immune system cells), a whole series of processes are triggered in the body. [...]
The body’s own cells have proteins on their surface, too. But those proteins don’t usually trigger the immune system to fight the cells. Sometimes the immune system mistakenly thinks that the body's own cells are foreign cells. It then attacks healthy, harmless cells in the body. This is known as an autoimmune response.”
—We explained this in more detail in this video – but in a nutshell: This is such a critical danger to your survival that your body created an entire murder university to prevent this from happening. Here, young immune cells go through ruthless training: if they recognize the shapes of your own proteins, they are executed immediately. But sometimes—through sheer, dumb luck one makes it through.
#Kurzgesagt – In a Nutshell (2021): “You Are Immune Against Every Disease
—Right at this moment you have probably a few million cells patrolling your body that have the potential to trigger an autoimmune disease.
Approximately 1 in 600 T-cells is autoreactive
#Lohse, Ansgar W. et al. (1996): “Estimation of the Frequency of Self-reactive T cells in Health and Inflammatory Diseases by Limiting Dilution Analysis and Single Cell Cloning”, Journal of Autoimmunity, vol.9, 5, 667-675 https://www.sciencedirect.com/science/article/abs/pii/S0896841196900876
Quote: “Autoreactive T cells have recently been detected not only in autoimmune diseases but also in healthy individuals, but their frequency is thought to be low. The aim of our study was to estimate the frequency of self-reactive T cells by using limiting dilution analyses of peripheral blood lymphocytes. Assessment of self-reactivity in this study was defined as T-cell proliferation to autologous non-T cells in the absence of foreign antigens. When culture conditions were optimized by adding interleukin 2, healthy individuals showed a frequency of self-reactive T cells ranging from 1/60 to 1/600.”
Though this was one of the few first studies to quantify it, there have been more recent publications with similar findings, and it is now accepted that autoreactive cells are relatively common.
There are around 500 × 109 T cells in the human body.
#Sender, Ron et al. (2023): “The total mass, number, and distribution of immune cells in the human body” , Proceedings of the National Academy of Sciences U.S.A, vol.120, 44
https://www.pnas.org/doi/10.1073/pnas.2308511120
Quote:“Cell type–specific tissue distribution of immune cells in the human body. Estimates of immune cell populations by cell type and tissue grouped by primary tissues and systems. For each cell type, the distribution across the systems is depicted in the absolute number of cells (A), absolute mass of cells (B), and relative number of cells (C)."
So the total number of autoreactive cells in a human body is approximately:
500 × 109/ 600 = 8 × 108 = 800 million
The body has additional ways to detect and kill autoreactive cells even after they are released from the thymus. We thank our expert Jen Gommerman for the following comment:
Quote: “There are other ways to deal with these self-reactive lymphocytes if they are released from the bone marrow/thymus (ie, if they graduate from murder university without being detected as self-reactive).”
For more information on the topic:
#Vignali, Dario A.A.; Collison, Lauren W.; Workman, Creg J. (2008): “How regulatory T cells work”, Nature Reviews Immunology, vol. 8, 523-532
—Another way to trigger autoimmunity is through your enemies: Some bacteria and viruses have evolved proteins that are extremely similar to the ones in your own body. Because they just have to if they want to interact with your cells – and to stay hidden.
In order to avoid being detected by the immune system, bacteria and viruses may evolve to display human-like proteins on their surface. In doing this, they may trigger autoreactive immune cells.
#Rojas, Manuel (2018): “Molecular mimicry and autoimmunity”, Journal of Autoimmunity, vol. 95, 100-123
https://www.sciencedirect.com/science/article/pii/S0896841118305365
Quote: “Molecular mimicry is one of the leading mechanisms by which infectious or chemical agents may induce autoimmunity. It occurs when similarities between foreign and self-peptides favor an activation of autoreactive T or B cells by a foreign-derived antigen in a susceptible individual. However, molecular mimicry is unlikely to be the only underlying mechanism for autoimmune responses; other factors such as breach in central tolerance, non-specific bystander activation, or persistent antigenic stimuli (amongst others) may also contribute to the development of autoimmune diseases.”
—We see this everywhere in nature, from butterflies that look like bark or crocodiles that disappear in muddy water.
#Butterfly conservation: “Moth Camouflage” (retrieved 2025)
https://butterfly-conservation.org/moths/why-moths-matter/what-are-moths/moth-camouflage
#World Nature Photography Awards “Our 2022 Winners: Jens Cullmann, Germany - Gold Winner and grand prize”
—The trigger can be anything that activates your defenses. A common cold, the flu, a tiny wound.
Specific viruses like the flu (influenza) virus have been associated with the development of specific autoimmune diseases. However, any process that triggers an inflammatory reaction can also trigger an autoimmune disease.
#Sundaresan, Bhargavi et al. (2023): “The Role of Viral Infections in the Onset of Autoimmune Diseases”, Viruses, vol.15, 3, 782
https://pmc.ncbi.nlm.nih.gov/articles/PMC10051805/
Quote: “Dysregulated inflammasome activation has been implicated in the development of various autoimmune diseases, for example, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, and Sjögren syndrome, which have been well reviewed elsewhere [62,69,72]. Mostly microbial triggers have been described in activating the inflammasome; however, viruses, fungi and parasites have also been described in inflammasome activation. To date, the NLRP3 inflammasome in macrophages was shown to be activated by different viruses or viral proteins, such as the hepatitis C virus core protein, the viroporin of the COVID-19 causing severe acute respiratory syndrome coronavirus (SARS-CoV-2), the influenza virus M2 ion channel, and the viroporin 2B of the encephalomyocarditis virus. Further, NLRP9b, which is expressed in intestinal epithelial cells (IECs), was described as a sensor of short double-stranded RNA from rotaviruses. Additionally, other virus-unspecific signals that are released upon tissue injury can lead to the activation of inflammasomes.”
#Pisetsky, David S. (2023): “Pathogenesis of autoimmune disease”, Nature Reviews Nephrology, 19, 509–524
https://www.nature.com/articles/s41581-023-00720-1 https://sostelemedicina.ucv.ve/documentos/manuales/pathogenesis-of-autoimmune-disease.pdf Quote: “Gene variants can create a predisposition to immune dysregulation in patients, but environmental factors seem to be necessary to induce B and/or T cell autoreactivity and clinical disease manifestations. The number and kind of these factors are unknown and, for the individual patient, they may be multiple and act over time. [...]
Of environmental factors, interaction with microorganisms remains the most likely direct trigger of autoimmune disease through at least two different mechanisms. The first is through molecular mimicry based on structural similarity between self and foreign molecules [...]
The second mechanism is through nonspecific stimulation of the immune system. In general, infection exposes the host to pathogen associated molecular patterns (PAMPs), which can bind to pattern recognition receptors to stimulate innate immune responses and potentiate adaptive immune responses.The action of PAMPs such as endotoxin or lipopolysaccharide can affect multiple cell types, enhancing responses to self as well as to foreign molecules by enhancing the stimulation of B or T cell responses. These responses can be elicited by different infections that can be symptomatic or asymptomatic.”
—Any sort of infection floods your body with cytokines, signals that tell your body “this is a real fight, take this seriously” which truly wakes up your immune system.
#Cleveland Clinic: “Cytokines” (retrieved 2025)
https://my.clevelandclinic.org/health/body/24585-cytokines
Quote: “Cytokines are signaling proteins that help control inflammation in your body. They allow your immune system to mount a defense if germs or other substances that can make you sick enter your body. Too many cytokines can lead to excess inflammation and conditions like autoimmune diseases.
Cytokines are proteins that function as chemical messengers in your immune system. Your immune system is a network with several parts that work together to protect your body from threats, like germs that can make you sick. It contains immune cells that fight invading pathogens (like viruses and bacteria), allergens and other harmful substances that enter your body. Cytokines signal those immune cells to fight the invaders.”
—Intelligence cells start to gather proteins – shapes – from the battlefield. These shapes are the physical information of what is going on and are carried to your lymph nodes, information distribution centers. Here, your heavy weapons, T cells, pass through, taking a look at the shapes that are being presented here. If they recognize the shape of an invader they activate the whole immune system and a few days later the attacker will be wiped out.
The intelligence agents are dendritic cells.
#British Society for Immunology (2020): “Dendritic Cells”
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.”
Dendritic cells can activate T cells in the lymph nodes by presenting them with the appropriate antigen. When this happens, T cells power up macrophages, B cells and other T cells.
#Alberts, Bruce et al. (2002): “Helper T Cells and Lymphocyte Activation”, Molecular Biology of the Cell
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.”
—Maybe an intelligent officer picked up a piece of one of your healthy cells that died in the battle, or maybe a bacteria had a protein pretty similar to one of yours. And by sheer, extremely bad luck, a few months ago a single T Cell that can recognize this shape survived the murder university. And today exactly this T cell happened to pass exactly this lymph node and is activated.
Infections can trigger autoimmune reactions in a few different ways. In this video we mention epitome spreading and molecular mimicry. In epitome spreading, an antigen-presenting cell (APC) like a dendritic cell accidentally presents T cells, a protein made by your own body as if it were from a pathogen. In molecular mimicry, a protein from the pathogen is so similar to one produced by your body that T cells cannot tell them apart.
#Sundaresan, Bhargavi et al. (2023): “The Role of Viral Infections in the Onset of Autoimmune Diseases”, Viruses, vol.15, 3, 782
Quote: “Figure 1. Mechanisms by which virus infections cause autoimmune diseases. (a) Epitope spreading. 1. Viruses infect the host´s cells. 2. Viral antigens are presented to T-helper cells by APCs. 3. T-helper cells release cytokines, which can affect cytotoxic T lymphocytes (CTLs). 4. CTLs release granzymes, which attack infected cells. 5. Hidden self-antigens leak from damaged cells. 6. APCs present these antigens to autoreactive T cells. 7. Therefore, autoreactive T cells attack other uninfected cells carrying these self-antigens. (b) Molecular mimicry. T cell receptors (TCR) can recognize and react towards both viral antigens and self-antigens that have structural or sequential homology. (c) Bystander activation. Infected cells present viral antigens to virus-specific T cells. T cells identify infected cells and release cytotoxic granules, causing cell death of infected and nearby, uninfected cells. The inflammatory milieu leads to the activation of bystander cells within the tissue.”
—This single T cell now starts a big immune reaction against your own body. It clones itself thousands of times, gathers other cells for support and streams into your tissue.
Helper T cells proliferate after activation
#Moro-García, Marco et al. (2018): “Influence of Inflammation in the Process of T Lymphocyte Differentiation: Proliferative, Metabolic, and Oxidative Changes” Frontiers in Immunology, vol. 9
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.00339/full
Quote:“The activation of lymphocytes after recognizing a peptide in the context of a MHC molecule (priming of naïve T lymphocytes) carries a series of processes of various types (genetics, proliferative, differentiation, biochemical) that lead to the formation of specific clones of effective lymphocytes, some of which will remain for long time in the form of memory cells. Before antigen exposure, the frequency of naive T lymphocytes specific for any antigen is 1 in 105 to 106 lymphocytes. After antigen exposure, [...] the number of specific [Helper T] cells increases up to 1 in 100 [Helper T cells] may increase up to 5,000-fold.”
Helper T cells differentiate and activate other immune cells.
#Alberts, Bruce et al. (2002): “Helper T Cells and Lymphocyte Activation”, Molecular Biology of the Cell
https://www.ncbi.nlm.nih.gov/books/NBK26827/
Quote: “When an antigen-presenting cell activates a naïve helper T cell in a peripheral lymphoid tissue, the T cell can differentiate into either a TH1 or TH2 effector helper cell. These two types of functionally distinct subclasses of effector helper T cells can be distinguished by the cytokines they secrete. If the cell differentiates into a TH1 cell, it will secrete interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) and will activate macrophages to kill microbes located within the macrophages' phagosomes. It will also activate cytotoxic T cells to kill infected cells. Although, in these ways, TH1 cells mainly defend an animal against intracellular pathogens, they may also stimulate B cells to secrete specific subclasses of IgG antibodies that can coat extracellular microbes and activate complement.
If the naïve T helper cell differentiates into a TH2 cell, by contrast, it will secrete interleukins 4, 5, 10, and 13 (IL-4, IL-5, IL-10, and IL-13) and will mainly defend the animal against extracellular pathogens. A TH2 cell can stimulate B cells to make most classes of antibodies, including IgE and some subclasses of IgG antibodies that bind to mast cells, basophils, and eosinophils. These cells release local mediators that cause sneezing, coughing, or diarrhea and help expel extracellular microbes and larger parasites from epithelial surfaces of the body.”
—When the misguided immune cells arrive they see nothing but enemies! The proteins they are looking for are everywhere! Which can only mean that there is a full on invasion going on! They spread out and start attacking and killing your tissue.
The immune cells recognise and attack cells with the autoantigen, that is, your own cells.
—How bad is this? Well, it depends. There are more than 100 different autoimmune diseases and basically any tissue can be affected.
#Cleveland Clinic: Autoimmune diseases (retrieved 2025)
https://my.clevelandclinic.org/health/diseases/21624-autoimmune-diseases
Quote: “There are more than 100 different autoimmune diseases. They can affect almost any tissue or organ in your body, depending on where your immune system malfunctions[.]”
—In Multiple Sclerosis your immune cells are attacking the insulation of your nerve cells making them short circuit or slow down dramatically. Causing numbness, muscle cramps, problems with your vision and concentration.
The cause of multiple sclerosis is not fully understood, but it is likely an autoimmune disorder triggered by a virus. It affects myelin, the insulation of neurons. It can cause a great variety of symptoms that vary widely from person to person in type and severity.
#MSD Manual (Consumer Version) (2024): “Multiple Sclerosis (MS)”
https://www.msdmanuals.com/home/brain-spinal-cord-and-nerve-disorders/multiple-sclerosis-ms-and-related-disorders/multiple-sclerosis-ms
Quote: “The term “multiple sclerosis” refers to the many areas of scarring (sclerosis) that result from destruction of the tissues that wrap around nerves (myelin sheath) in the brain and spinal cord. This destruction is called demyelination. Sometimes the nerve fibers that send messages (axons) are also damaged. [...] The cause of multiple sclerosis is unknown, but a likely explanation is that people are exposed early in life to a virus (possibly a herpesvirus or retrovirus) or some unknown substance that somehow triggers the immune system to attack the body’s own tissues (autoimmune reaction). The autoimmune reaction results in inflammation, which damages the myelin sheath and the underlying nerve fiber.”
If multiple sclerosis affects nerves that carry sensory information, you may experience numbness or pain, including muscle cramps. Muscle cramps can also appear due to muscle weakness and spasms if the motor nerves are affected. If the nerves that control the movement of the eyes or the optic nerves are affected, you may experience blurry vision, double vision or vision loss.
Multiple sclerosis may also cause cognitive symptoms, like concentration and memory problems, trouble finding words or difficulty processing information.
#Multiple Sclerosis Trust (2018): “Thinking and memory problems”
https://mstrust.org.uk/information-support/health-wellbeing/thinking-and-memory-problems Quote: “Cognitive problems in MS are the result of nerve damage in the brain interrupting the transmission of electrical messages, reducing the speed and accuracy of the information. It can be helpful to think of the nervous system as a telephone exchange - if the insulation on some of the wires is damaged and other wires are broken, this results in some wrong numbers and some calls not getting through at all.
[...]
You may find it difficult to concentrate or find your mind wanders, particularly if lots of people are talking at once. This can make it harder to follow the thread of a conversation or give you a feeling of 'information overload' if only some of what you are being told is relevant.”
—In Type 1 Diabetes your immune system kills the cells that produce your insulin in your pancreas, starving your cells from glucose and turning your blood into acid.
#MSD Manual (Consumer Version) (2023): “Diabetes Mellitus (DM)”
https://www.msdmanuals.com/home/hormonal-and-metabolic-disorders/diabetes-mellitus-dm-and-disorders-of-blood-sugar-metabolism/diabetes-mellitus-dm?#Types-of-Diabetes_v772819
Quote: “In type 1 diabetes (formerly called insulin-dependent diabetes or juvenile-onset diabetes), the body's immune system attacks the insulin-producing cells of the pancreas, and more than 90% of them are permanently destroyed. The pancreas, therefore, produces little or no insulin. [...]
In people with type 1 diabetes, the symptoms often begin abruptly and dramatically. A serious condition called diabetic ketoacidosis, a complication in which the body produces excess acid, may quickly develop. [...] Without treatment, diabetic ketoacidosis can progress to coma and death, sometimes very quickly”
—In Rheumatoid Arthritis yourIn Rheumatoid Arthritis angry cells invade your joints and literally start to dissolve cartilage and bone.
#MSD Manual (Consumer Version) (2024): “Rheumatoid Arthritis (RA)”
https://www.msdmanuals.com/home/bone-joint-and-muscle-disorders/joint-disorders/rheumatoid-arthritis-ra
Quote: “The exact cause of rheumatoid arthritis is not known. It is considered an autoimmune disease. Components of the immune system attack the soft tissue that lines the joints (synovial tissue) and can also attack connective tissue in many other parts of the body, such as the blood vessels and lungs. Eventually, the cartilage, bone, and ligaments of the joint erode (wear away), causing deformity, instability, and scarring within the joint.”
#MSD Manual (Professional Version) (2024): “Rheumatoid Arthritis (RA)”
https://www.msdmanuals.com/professional/musculoskeletal-and-connective-tissue-disorders/joint-disorders/rheumatoid-arthritis-ra
Quote: “Released inflammatory mediators and various enzymes contribute to the systemic and joint manifestations of rheumatoid arthritis, including cartilage and bone destruction. [...]
In chronically affected joints, the normally thin synovium proliferates, thickens, and develops many villous folds. The synovial lining cells produce various materials, including collagenase and stromelysin, which contribute to cartilage destruction, and interleukin-1 (IL-1) and TNF-alpha, which stimulate cartilage destruction, osteoclast-mediated bone absorption, synovial inflammation, and prostaglandins (which potentiate inflammation).”
#Gravallese, Ellen M,; Firestein, Gary S. (2023): “Rheumatoid Arthritis — Common Origins, Divergent Mechanisms”, The New England Journal of Medicine, vol. 388, 6, 529-542
https://www.binasss.sa.cr/feb23/41.pdf
Quote: “The rheumatoid synovium [(joint lining)] is characterized by expansion of tissue at the interface with cartilage and bone. This expanding tissue, known as pannus, resembles a locally invasive tumor and extends over the surface of cartilage. Pannus also invades the bone marrow space directly or through pores in cortical bone. In active rheumatoid arthritis, the extracellular matrix of cartilage, ligaments, and tendons is destroyed by [enzymes] that are produced by synovial cells, especially fibroblasts, and by chondrocytes themselves. The inflammatory cytokine milieu — most notably, interleukin-1β and TNF — directly activates these cells to produce matrix metalloproteinases, including collagenases, stromelysins and gelatinases, and ADAMTS5, which contribute to cartilage and joint destruction. Bone destruction requires the action of osteoclasts, which differentiate through the combined actions of the receptor activator of RANKL, and proinflammatory cytokines, especially TNF and interleukin-6.”
—Lupus con be a body-wide Blitzkrieg that attacks literally every part of your body causing painful, unpredictable and widespread destruction with a variety of bad symptoms.
#MSD Manual (Professional Version) (2025): ”Systemic Lupus Erythematosus (SLE)”
Quote: “Clinical findings vary greatly. SLE [(Systemic Lupus Erythematosus, or Lupus)] may develop abruptly with fever and multisystem involvement or insidiously over months or years with episodes of arthralgias and malaise. Manifestations referable to any organ system may appear. Periodic exacerbations (flares) may occur.”
—And almost all autoimmune diseases come with crushing fatigue and exhaustion. Because when you are sick, your immune system tells your body to shut down and rest. Even if the immune system is itself the attacker, it still sends out the same orders. It feels like you have the flu but the real enemy is your own body.
#Zielinski, Mark R.; Systrom, David M.; Rose, Noel R. (2019) : “Fatigue, Sleep, and Autoimmune and Related Disorders”, Frontier is Immunology, vol. 10, 1827 https://pmc.ncbi.nlm.nih.gov/articles/PMC6691096/
Quote: “Autoimmune disease induces enhancement in cytokines such as IL-1β, TNF-α, IL-6, IL-12, IL-23, and IFN-γ, especially by T helper cells and macrophages. [...]
Cytokines regulate normal physiological functions including mood, cognition, and sleep, and their expression varies over the course of the day and in response to local activity. Consequently, it is likely that dysregulation in inflammatory cytokines and their receptors in autoimmune disease serves to disrupt the normal physiological homeostasis of cytokines and contribute to fatigue.”
Cytokines also regulate the acute phase response in the course of an infection, producing the sense of lethargy and fatigue we normally associate with “feeling sick”.
#Wrotek, Sylwia et al. (2021): “Let fever do its job: The meaning of fever in the pandemic era.”
Evolution, Medicine, and Public Health, vol. 9, 1, 26-35 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717216/pdf/eoaa044.pdf
Quote: “In addition to the local inflammatory response to infection, the systemic defensive responses to infection are known as the acute phase response [13, 89]. Besides fever, other components include mobilization of leukocytes; production of a variety of protective proteins (acute phase proteins); reduced blood levels of iron, zinc, and manganese; reduced erythrocyte production (beyond simple iron deficiency); reduced appetite (anorexia); breakdown of muscle protein and fat (cachexia or hypercatabolism); and the uncomfortable, motivation-sapping sickness symptoms and behaviors we associate with infection, including lethargy, depression and aches. The acute phase response is induced and regulated by the infected individual’s own pro-inflammatory cytokines and other mediators acting on specific cell receptors”
—The worst part about autoimmunity is that it never stops. Your immune system is a self enforcing machine of destruction.. The more “enemies” your initial autoimmunity cells encounter the more cells they clone and activate. So its nature prevents lasting peace.
There is no cure for autoimmune diseases. Treatment is focused on reducing symptoms and improving quality of life for the patient.
#Cleveland Clinic: “Autoimmune Diseases” (retrieved 2025)
https://my.clevelandclinic.org/health/diseases/21624-autoimmune-diseases
Quote: “There’s no cure for autoimmune diseases. They’re chronic (long-term) conditions that usually last your whole life. Some autoimmune diseases enter remission, a long period of time between symptom flares. This isn’t the same as a cure, but it might mean the symptoms impact your daily routine less often. [...]
Although there are no cures for these diseases, many of their symptoms can be treated, and sometimes they go into remission. Stay in touch with your healthcare provider about any advances in understanding and treating autoimmune diseases.”
#Celichowska, Magdalena et al. (2024): “Methods of Prevention and Mitigation of Autoimmune Diseases - A Review of The Literature” , Quality in Sport, vol. 17, p. 53121 https://apcz.umk.pl/QS/article/view/53121
Quote: “There is still no cure for autoimmune diseases, although various prevention and mitigation strategies can help manage these conditions and improve quality of life for affected individuals.”
New and better treatments for many autoimmune diseases are an area of intense area of research, with many new strategies in the pipeline
#Fugger, Lars; Torp Jensen, Lise; Rossjohn, Jamie (2020): “Challenges, Progress, and Prospects of Developing Therapies to Treat Autoimmune Diseases”, Cell, vol.181, 1, 63-80 https://www.cell.com/cell/fulltext/S0092-8674(20)30269-5
Quote: “Figure 2 Graphical Summary of Current Therapies, Pipeline of Interventions Being Tested in Clinical Trials, and Potential New Treatment Strategies for Autoimmune Diseases Described in the Text”
Successive encounters of the autoantigen increase the scale of the immune response, creating a vicious circle that produces worsening of symptoms if the sickness is left untreated. These reactions are long-term because the immune system includes the autoantigen in a sort of “enemies archive” and keeps long-lived T cells and B cells specialized in fighting “enemies” with that antigen.
#Ratajczak, Weronika (2018): “Immunological memory cells”, Central European Journal of Immunology, vol.43, 2, 194-203
https://pmc.ncbi.nlm.nih.gov/articles/PMC6102609/
Quote: “Immunological memory is a unique property of the immune system as it can “store” information about a stimulus and can mount an effective response when the stimulus is encountered again. This response – a secondary immune response – is quicker and stronger than the primary response. It takes a smaller stimulus to trigger a secondary response and, what is more, it occurs even after many years since the first exposure. Immunological memory is an important mechanism that protects the organism from bacteria, viruses, fungi and parasites. It plays a significant role in understanding autoimmune diseases and is one of the decisive factors of successful treatment in transplantology. It is also crucial in vaccine therapy. The secondary immune response is dependent on many subpopulations of memory cells within T and B lymphocytes and NK (natural killer) cells.”
—But up to one in ten people in the industrialized world suffers from them.
There is no global data available for the overall autoimmune disease prevalence. But there are some studies specific to countries, such as the example below for the UK:
#Conrad, Nathalie et al. Incidence, prevalence, and co-occurrence of autoimmune disorders over time and by age, sex, and socioeconomic status: a population-based cohort study of 22 million individuals in the UK. The Lancet. 2023.
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(23)00457-9/abstract
Quote: “Autoimmune diseases affect approximately one in ten individuals, and their burden continues to increase over time at varying rates across individual diseases.”
As well as global estimates. These estimates are from 2010, so the current numbers may be even higher, due to the increasing prevalence of autoimmune diseases.
#Cooper, Glinda S.; Bynum, Milele LK; Somers, Emily C. (2010): “Recent Insights in the Epidemiology of Autoimmune Diseases: Improved Prevalence Estimates and Understanding of Clustering of Diseases”, Journal of autoimmunity, vol. 33, 197–207.
https://pmc.ncbi.nlm.nih.gov/articles/PMC2783422/
Quote: “Previous studies have estimated a prevalence of a broad grouping of autoimmune diseases of 3.2%, based on literature review of studies published between 1965 and 1995, and 5.3%, based on national hospitalization registry data in Denmark. We examine more recent studies pertaining to the prevalence of 29 autoimmune diseases, and use these data to correct for the underascertainment of some diseases in the hospitalization registry data. This analysis results in an estimated prevalence of 7.6–9.4%, depending on the size of the correction factor used.”
—So why did they stick around? Well when it comes to genes, we often have to work with trade offs – At their core autoimmune diseases always mean that your immune system is more aggressive – and while this is mostly bad, until recently in human history, this was pretty great.
#Harroud and Hafler. Common genetic factors among autoimmune diseases. Science. 2023
https://medcell.org/tbl/files/neurogenetics/reading.pdf
Quote: “Genetic diversity and variation are shaped by evolutionary forces, including negative selection, a process by which alleles with detrimental effects on fitness are removed from the population. Therefore, the presence of common genetic variants that substantially increase the risk of autoimmune diseases implies that these variants may have provided a beneficial evolutionary trade-off. Considering the immune system’s role in combating infections and the strong impact of host genetics on susceptibility to infectious diseases, it has been proposed that autoimmune risk alleles have been preserved at high frequency in the population because of their role in improving resistance to infections (43).
The canonical example of this antagonistic pleiotropy, genotypes with opposing effects on different traits, is variation of the hemoglobin subunit-b (HBB) locus that protects against malaria but causes sickle cell anemia when inherited in a recessive manner. Similarly, genetic variations in the MHC region, which is responsible for a large proportion of the inherited risk for autoimmune diseases, are expectedly also linked with susceptibility to various infections because of the roles of the encoded proteins in antigen presentation and T cell receptor composition (44). Recently, a systematic analysis of genetic effects on infectious and autoimmune disorders confirmed that variants associated with both trait categories were significantly more prevalent than expected [by >100-fold (43)] (Fig. 3).”
—In the past infectious diseases were the most common cause of death. Terrible pandemics ravaged our cities regularly, sometimes decimating communities.
#Aminov, Rustam (2017): “History of antimicrobial drug discovery: Major classes and health impact”, Biochemical Pharmacology, vol.133, 4-19 https://www.sciencedirect.com/science/article/abs/pii/S0006295216303318?via%3Dihub
Quote: “The introduction of antibiotics into clinical practice revolutionized the treatment and management of infectious diseases. Before the introduction of antibiotics, these diseases were the leading cause of morbidity and mortality in human populations.”
#Our World in Data (2023): “What were the death tolls from pandemics in history?”
https://ourworldindata.org/historical-pandemics
—Researchers analyzed DNA samples from London cemeteries before, during, and after the Black Death pandemic that killed about half of the population. They found that individuals with gene variants that increase the risk for Crohn’s disease seemed to have died at a much lower rate. What helped them against a deadly disease back then might make us vulnerable to autoimmunity today.
#Klunk, J., Vilgalys, T.P., Demeure, C.E. et al. Evolution of immune genes is associated with the Black Death. Nature 611, 312–319 (2022).
https://doi.org/10.1038/s41586-022-05349-x
Quote: “Infectious diseases are among the strongest selective pressures driving human evolution1,2. This includes the single greatest mortality event in recorded history, the first outbreak of the second pandemic of plague, commonly called the Black Death, which was caused by the bacterium Yersinia pestis3. This pandemic devastated Afro-Eurasia, killing up to 30–50% of the population4. To identify loci that may have been under selection during the Black Death, we characterized genetic variation around immune-related genes from 206 ancient DNA extracts, stemming from two different European populations before, during and after the Black Death. Immune loci are strongly enriched for highly differentiated sites relative to a set of non-immune loci, suggesting positive selection. We identify 201 variants that are highly differentiated within the London dataset. Combining evidence from during the Black Death, our replicate population in Denmark, and function evidence, rs2549794 near ERAP2 emerges as the strongest candidate for positive selection. The selected allele at rs2549794 is associated with the production of a full-length (versus truncated) ERAP2 transcript, variation in cytokine response to Y. pestis and increased ability to control intracellular Y. pestis in macrophages. Finally, we show that protective variants overlap with alleles that are today associated with increased susceptibility to autoimmune diseases, providing empirical evidence for the role played by past pandemics in shaping present-day susceptibility to disease. ”
—And then a hot second ago we changed our world. Hygiene, antibiotics, vaccines and modern medicine revolutionized our lives and how we die. So much so that most of us don’t even think a lot about infectious diseases – and this is great. But now we are left with genes that make our immune systems more aggressive for no good reason.
#Harroud and Hafler. Common genetic factors among autoimmune diseases. Science. 2023
https://medcell.org/tbl/files/neurogenetics/reading.pdf
Quote: “Throughout history, human immune systems have adapted in response to environmental pressures, perhaps none greater than those imposed by infectious agents. Their genetic imprint favoring more robust immune responses came at the cost of a higher shared genetic risk of various autoimmune diseases. The transition from high levels of infection to lower pathogen exposure in recent times has led to a mismatch between this history of selection and our current environments, contributing to the high disease burden of chronic autoimmune conditions. Furthermore, ancient DNA has also been used to trace the historical origins of autoimmune disease– associated variants (50) and revealed that loci from extinct hominins such as Neanderthals and Denisovans are enriched for innate and adaptive immunity genes (51).”
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