I have decided to summarize my thoughts on autoimmune processes in a dedicated post and also coin the new term to emphasize the difference from the classical autoimmunity and highlight the interdisciplinary factor which made me to think in this way. The factor name is computer science.
I have written one post about autoimmunity here but the motivation was different – I mainly needed to understand its roots and find out if there are any better interpretations of this “renowned body behavior” which is claimed as main cause of many tough diseases. I indeed found what I hoped for and then during later research I realized certain strange aspects which could in my opinion redefine the theory as a whole. Well ok, not as a whole. Good property of this new theory is how it builds on those previous – it does not deny entirely anything. It only adds another and perhaps even the last piece to the mosaic. Let´s first recap those known theories to set the proper context.
Version 1.0 is the theory which evolved from the experiments done on turn of 19th century. Initially hard to believe but in 1950s it got established. With some little upgrades (1.0.x) it holds till our days. However it has huge problems and holes – it just isn´t complete theory which would lead to explanation of the immune system behavior. As a result also the diseases which are the consequences of the behavior are not well described and cannot be effectively cured (multiple sclerosis, rheumatoid arthritis, systemic lupus are the classical examples).
Over the decades between 1950s and our presence this theory had to absorp the new findings in immunology – lot of it were made in last 50-60 years. This is mainly related to discovery of those cell types which comprise our immune systems. This story was not about just antibodies (early observation made by people) but instead about a layered and component based architecture of our miraculous immunity which was gradually revealed. So what does it say about the case when immunity “goes wrong”? Below citation can summarize well the latest state of the theory.
The human immune system does not expend a huge amount of biological “energy” on a foolproof system in which every B and T cell is carefully checked for tolerance of self. Instead, the system relies on a multilayered strategy in which each layer includes mechanisms that should weed out most self-reactive cells, with lower layers catching cells that slip through tolerance induction in the layers above. This usually works very well, but occasionally “mistakes are made,” and instead of defending us against foreign invaders, the weapons of our immune system are turned back on us1.
The cited paragraph states the immunity has the ability to create autoreactive cells (B cells) but it also has control mechanisms how to eliminate them. If I understood correctly this ability to create even autoreactive B cells is necessary – the system needs to be capable of creating any possible protein (“combination”) because this huge diversity is also out there and represents a threat (viruses, bacteria, common antigens). If the system would be able to generate, let´s say only 640 thousands combinations or even 655 360 (Why 640k?2) then it would be finite number and any additional antigen like viral antigen would probably kill us. That´s why immune system needs to be able to produce practically anything – huge number of combinations. It is assumed it is at least 100 million1. However this includes also what we all are made from – that is why our system is able to produce antibodies against our own tissues. As the textbook above says there is no need to panic, there are control mechanisms in place which will eliminate these self-reacting also known as autoreactive cells before they do big harm. That is why most people are healthy and don´t fall apart internally.
The problems arise when these control mechanisms somehow fail and these autoreactive cells can get activated which means they produce autoreactive antibodies. If we stick to our above classic examples then such unwanted antibodies can bind to myelin sheats and cause multiple sclerosis or can bind to synovial tissues, joints and cause rheumatoid arthritis.
Science roughly knows where and how such B cells are created, how they mature and what conditions need to be met for such cell to become a very potent factory sprouting antibodies. Today it is already known this is a team work among various cell types and important role play T helper cells.
- Antigen presenting cells (APCs) like B cells, dendritic cell but also macrophages, Important factor here are so called PRRs which are basically the very first signals that something is not right, an alarm for immunity.
- T helper cells (Th) – there are more types (Th1, Th2, Th17)
- T killer cells (CTLs; cyto toxic T lymphocyte)
- T Regulatory cells (TReg)
This is certainly not immunology class and I don´t need to pretend I master this but it is good to know the high-level contracts and relationships between above mentioned cells, together with many other they keep us alive! It is just unfortunate we blame them for slowly killing us as well in certain cases but that is exactly what science with this theory states. All above cell types basically need to collaborate well so that reasonably strong and accurate immune response causes the danger (e.g. viral infection) is eliminated and health is maintained or quickly restored. Before T killer cells can start killing infected cells, those APCs usually need to detect the presence of the foreign and dangerous antigen and also T helper cell needs to activate the killing mode (or give permission) in T killer cells. It is also assumed that these T cells with the right antigen recognizing receptor exist and circulate within the organism (often it takes time for them to get created first as part of adaptive immunity response; 1-2 weeks are stated). That is the reason why we are often sick for some time as we are in the period during which the cells are gradually being created. Before these specific forces arrive it is our innate immunity which needs to fight and hold the lines till “elite reinforcements” arrive. This human organism ability to create practically any combination of the receptor is what protects us but what, under some unfortunate circumstances, can result in autoimmune disease.
Although some autoimmune disorders are caused by genetic defects, the majority of autoimmune diseases occur when the layers of tolerance-inducing mechanisms fail to eliminate self-reactive cells in genetically normal individuals. In fact, you could argue that the potential for autoimmune disease is the price we must pay for having B and T cell receptors which are so diverse that they can recognize essentially any invader1.
Many people were healthy and happy and suddenly something happened and they are told they suffer with autoimmune disease. Fresh moms could tell these stories (multiple sclerosis). Isn´t it strange? What science can tell us? Nothing good, they don´t know! We can close this 1.0 version with another citation and please note the text in bold and mainly the selfconfidence science shows with respect to the mysterious and infinitely surprising microbial world.
So for autoimmune disease to occur, a person must have MHC molecules that can present a self antigen, and lymphocytes with receptors that can recognize the self antigen – but this is not enough. There also must be environmental factors that lead to the breakdown of the tolerance mechanisms which are designed to eliminate self-reactive lymphocytes. For years, physicians have noticed that autoimmune diseases frequently follow bacterial or viral infections, and immunologists believe that microbial attack may be one of the key environmental factors that triggers autoimmune disease. Now clearly, a viral or bacterial infection cannot be the whole story, because for most people, these infections do not result in autoimmunity. However, in conjunction with a genetic predisposition (e.g., the type of MHC molecules inherited) and lymphocytes with potentially self-reactive receptors, a microbial infection may be the “last straw” that leads to autoimmune disease1.
This version in my classification comprises theory presented by Polly Matzinger. We should know that initially (version 1.0) the idea was that any self-reacting lymphocytes are eliminated very early in human life (see Burnet´s work) and somehow the tolerance of self gets developed and in healthy people it remains maintained during their lives. This is quite strange right? Science has theory which can be basically described using expression “and then somehow this and that happens”. Polly Matzinger contributed to this big topic in 1994 and since that moment she tries to refine her theory.
As a graduate student, I was taught that the immune system functions by discriminating between self (defined early in life) and nonself (anything that comes later), tolerating self and attacking nonself. Although this elegantly
simple idea seemed to make a lot of sense, it had problems from the beginning and has failed over the years to explain a great number of findings. For example, what happens when “self ” changes? How do organisms go through puberty, metamorphosis, pregnancy, and aging without attacking newly changed tissues? Why do mammalian mothers not reject their fetuses or attack their newly lactating breasts, which produce milk proteins that were not part of earlier “self ”? Why do we fail to make immune responses to vaccines composed of inert foreign proteins unless we add noxious substances, collectively known as “adjuvants”? Why do we fail to reject tumors, even when many clearly express new or mutated proteins? Why do most of us harbor autoreactive lymphocytes without any sign of autoimmune disease, while a few individuals succumb?3
She described problems which previous theory is unable to well absorp and builds her danger model on “danger signals”.
Standing on the shoulders of the SNS models, the Danger model added another layer of cells and signals (2), proposing that APCs are activated by danger/alarm signals from injured cells, such as those exposed to pathogens, toxins, mechanical damage, and so forth (Fig. 1e). Although purely theoretical at the time (20), many alarm signals have since been empirically revealed (9). Alarm signals can be constitutive or inducible, intracellular or secreted, or even a part of the extracellular matrix. Because cells dying by normal programmed processes are usually scavenged before they disintegrate, whereas cells that die necrotically release their contents, any intracellular product could potentially be a danger signal when released. Inducible alarm signals could include any substance made, or modified, by distressed or injured cells. The important feature is that danger/alarm signals should not be sent by healthy cells or by cells undergoing normal physiological deaths3.
For autoimmunity, the Danger model offers a unique suggestion that would not arise from the SNS or the INS models. Starting with the view that “bad” death or cell stress can elicit an immune response, the model suggests that some autoimmune diseases may be caused by mutations in genes governing the normal physiological death and clearance processes, or by environmental pathogens or toxins that cause cellular stress or death. In these cases, the immune system is not at fault; it is doing its job of responding to alarm
signals (but, in these cases, to the detriment of the host). If we could pinpoint these mutations or environmental agents, we might be able to reduce the incidence of autoimmune diseases3.
Well it is a nice theory but what the critics say about it? The problem is with defining the original danger without ending with circular argumentation. Above is stated by the theory author, Polly Matzinger, but below I add another citation which tells us why danger model is not fully accepted.
Many immunologists found “danger theory” rather vapid and tame. To be sure, it possessed considerable appeal to those who believe the immune system ought to focus on potential harm, not fritter away its energy in discrimination of self. But Matzinger struggled to define danger and to avoid entrapment in circular logic. Some immune responses occur without tissue damage, as in the reaction to vaccines; and often tissue damage is the result, not the cause, of the immune response. In as much as whatever activates an immune reaction can be designated dangerous, there is a risk of tautology. Proponents of the danger theory boast of their inclusion of antigen-presenting cells and ordinary tissues in the greater immune network, but there is nothing to stop contextualists, who are still invested in altered self, from encompassing these, too4.
Fine, now it is my turn! LOL. It is me who is coming up with another upgrade to the theory having a critical importance for humans. Isn´t it great? Everyone can contribute to the world of science and share his thoughts thanks to the amazing technology progress. It is nice coincidence that it indeed is a technology what is behind my theory. Does it mean some advanced aritifical intelligence will tell us why and how autoimmune behavior occurs or what is causing ALS or MS and how we should treat it? Well, we are not there yet but we should rather adjust the thinking paradigm and the inspiration comes from the world of computer science which is behind all the stuff we got so quickly used to including WordPress blogs or Youtube videos, Facebook, Instagram, Twitter, TikTok and Android or iOS app for practically anything on our mobile phones.
First I would like to formalize the main points taken from the earlier theories. Let´s also classify them in a following way:
- Hard Facts (HF) – Proven findings which are just accepted, i.e. foundations.
- Assumed Facts (AF) – Strongly assumed facts, those which are believed strongly as well but are not proven.
- Hypothesis (HY) – Statements and deductions made by considering previous two categories, the real experimental ground.
|1||HF||Human organism is capable of creating self-reacting antibodies or self-reacting cells (cell immunity).|
|2||AF||The reason for existence of the self-reacting cells is assumed to be a requirement to be capable of creating any protein combination so that organism in longterm can adapt to any threat (toxin, virus, bacteria).|
|3||AF||It is also assumed the organism and its system has fail safe processes to recognize it generated autoreactive cell and it will remove it more or less quickly from the system (think about it like a factory which has its QA part of the manufacture process and defective products are detected and trashed or recycled quickly after they are produced).|
|4||HF||Many people suffer with autoimmune diseases meaning those fail safe mechanisms probably do not work well for them or in their case. In other words their immunity is somehow compromised (immunodeficient – often specifically!).|
|5||HY||Danger Theory (latest observations, PRRs, danger signals etc.).|
|6||HF||Danger theory struggles with defining the original source of danger (circular logic).|
|7||HF||85-100% of patients suffering with multiple sclerosis are all EBV positive. Epstein-Barr virus is extremely suspected by science, it is believed it plays some unknown critical role in MS development.|
|8||HF||On contrary many EBV positive people do not suffer with autoimmune disease which makes the immediate EBV conviction impossible. At least without any further theory or knowledge what can be behind such unstable or non-deterministic phenomenon.|
|9||HF||EBV virus and also some other viruses from the same “family” have unique equipment in their genetic code. It possesses a gene which can disrupt or basically disable cell ability to commit suicide (when infiltrated by a virus; if cell dies, virus is destroyed; apoptosis). This means EBV can refuse orders sent to the infected cell. It seems the virus had to very specifically adapt to the way we fight it as it knows it would die together with the cell.|
|10||HF||Problems in apoptopic processes can result in significant problems, whole system stability can be affected and more or less unpredictable consequences, meaning issues in immunity can occur, including all those weird autoimmune problems.|
I have put together above table to really emphasize the building blocks which were extracted from other works, often works of well known scientists. Now it is the time to add some spice …
What we will need is a basic understanding of some core principles on which computer science is built on.
This will enable us to think about the whole problem little bit differently and perhaps it can really help! Explaining the theory behind those principles is beyond this article – there are many software engineers out there, which will immediatelly know what is going on here. Others should consult with someone or read about it on Wikipedia etc.
So what is relevant here?
- Processes and parallel processes (multi-tasking, multi-threading)
- Critical section
- Race condition
- Memory leak
How could above mentioned computer science terms help us with autoimmunity?
The answer is simple. It can help us to fill the last piece – the definition of the source of original danger which the danger theory is missing. All science has so far is fine but it struggles with the EBV role5. It is a very very common virus so it is hard to directly convict it from causing MS or even other AI disease. It is also rational to expect there are many mutations of this virus – today COVID pandemic reminded all people including the public that viruses mutate if they rapidly spread among big populations. On the other hand it really is suspicious as all those ill people have this virus. Also it is not simple and non-dangerous virus. I recommend everyone finding some details about it – good start can be my article which will point readers to further resources. So what is this theory upgrade about?
In my opinion the autoimmune disease is just a stochastical consequence of all the facts and findings written here so far. It can be also said that the EBV and similar viruses have exploited the human defense lines quite well and thus are able to compromise the system. This is exactly how certain software bugs occur in software systems – we do not need computer virus analogy but it could be interesting too. There is a special category of errors which happen due to incorrect handling of parallel processes. Any time a user clicks on certain web page it results in multi-process or multi-threaded processing on the webserver side. The problem is that sometimes the programmer forgets to handle concurrent access to a shared resource and since that moment there are only two possible outcomes – either the latent error in the program code will not cause any problem as the concurrent and by nature inherently stochastical result was that the latent error did not fire. Just for your information EBV virus is so called latent virus which lives in human organism often for many years unspotted – it is able to survive in B memory cells. This is already about probabalities. But sometimes the problem in the code results in error which is very hard to trace due to that concurrent nature of these processes. Usually it looks like this. Sometimes error is thrown and system goes down and sometimes after restarting it works fine. So where is the problem? Why it is not working or failing consistently? (recall the inconsistency of EBV and MS factors in human organism). Well every decent software engineer knows why! This knowledge is part of the formal education. So good developer will know he has some problem in the code and he or she needs to conduct special testing and code reviewes to identify the “concurrent access” problem and fix it. Now what factors increase the probabality that the latent error in the code will actually fire? One of the most usual factors is the load of the system. If there is a higher load, for example thousands of people are viewing the same article on a given webserver the error will fire more likely than if you have website like me, where two people reading my blog at the same time is very rare. It is sad truth! The traffic is just so low on my website! LOL. In nuthsell, this is the background.
How does it link with autoimmunity and EBV? Well it should be already clear. The virus sometimes causes autoimmune disease and sometimes not. Sometimes the result is multiple sclerosis and sometimes it is something else. Science is unable to explain it. My advice is – get a computer science course!
The thing is there can be a short time window (critical section) during which an autoreactive cell exists and it hasn’t been removed by the system yet. However this is the time for lucky EBV particles! If they manage to infect the autoreactive cell within this time window, things can get pretty dangerous. Due to that anti-apoptopic gene any successive attempts of the standard immunity to remove the autoreactive cell can fail. EBV can cause the cell to be kind of immortal, which is known by science. However it is also known or mentioned in other articles, that once EBV infiltrates the target cell, it also activates it. This means the target of EBV, which is surprisingly B cell or B lymphocyte can get activated meaning it can switch to plasma B cell and rapidly start producing antibodies! But antibodies against some own tissue due to that autoreactive receptor. Is that all? No. Those autoantibodies can react with the tissue, for example myelin sheats and this will attract other immune system players and they will attack the myelin sheats which impairs the nerve function. Here the danger theory can fully connect. Long story short, the EBV and stochastical nature of parallel processes including critical section can be the original source, a root cause of the danger as per danger theory. EBV infected B cell or even astrocyte or glial cell (all confirmed to be infected) are biological equivalents of so called memory leak problem in computer science. Such memory leak problem can bring down the whole system but it also can cause only very slow increase of memory consumption so nobody ever notices the problem (if the system is restarted sooner, way before the increased memory can cause issue). It is not a big surprise that the multiple sclerosis and other diseases occur in people after infections and after facing very stressful life events. Only this compound factor explains majority of the cases. This stress can be an equivalent of the high load in software systems. Any time I hear about a woman who developed MS after giving birth I remember this. It is already known that physical stress causes degradation of immunity so that it can explain why EBV can suddenly succeed. Birth process is an extreme load on woman organism, period.
The system should still have some means how to resolve already serious issue. However this is already different story. As per my shallow knowledge NK cells are the elite cells who can step in and resolve the problem. However many people have problems with NK cells and they lack them or rather their populations are insufficient (immunodeficiency). Since NK cells are part of innate immunity I would already need to go back to those earliest theories which suspected the individual shows some problem with his or her identity. Anyway this is already too esotheric. At this point we should know, EBV and HHV-xx viruses can in theory completelly compromise your system. As I already wrote on my website, medical science ignores EBV and treats all the autoimmune diseases with suppressing the immune cells. These battle units patient needs may be actually attacked by drugs he or she is taking so immunity is suppressed and EBV, as it is known, can live and slowly reproduce within your system for many years. What do you think about it now? Yes, that is super crazy stuff. Anyway this is my hypothesis describing the rise of autoimmune process in humans. One last note – there are case studies which prove that people who suffered with infectious mononucleosis (EBV) have much much higher chance to develop multiple sclerosis. All pieces of the mosaic are fitting together. That should be scary enough for everyone … Welcome in immunity micro wars!
- 1.Sompayrac LM. How Immune System Works. 6th ed. Wiley-Blackwell; 2019.
- 2.640k Enough. QuoteInvestigator. Accessed February 2021. https://quoteinvestigator.com/2011/09/08/640k-enough/
- 3.Matzinger P. The Danger Model: A Renewed Sense of Self. Science. Published online April 12, 2002:301-305. doi:10.1126/science.1071059
- 4.Warvick A, Mackay IR. Intolerant Bodies – A Short History of Autoimmunity. 1st ed. Johns Hopkins University Press; 2014.
- 5.Cryo-electron microscopy opens a door to fight Epstein-Barr. Phys.org. Accessed July 2021. https://phys.org/news/2020-02-cryo-electron-microscopy-door-epstein-barr.html
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