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Inflammation & autoimmunity

This entry is part 7 of 34 in the series ALS Experimental Theory

My next steps lead me to exploring autoimmunity theory. In this post I summarize my current very basic understanding of inflammation and so called auto-immune body response. As you already know I´m not a scientist nor medical researcher but engineer conducting analysis and synthesis of information available.

I have only average person knowledge regarding what inflammation is. Since I want to be brief I can cite Wikipedia and anyone is recommended to refer other information source. I am fine with Wikipedia which says following.

Inflammation (from Latin: inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants,[1] and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.​1​

Everyone including myself has some real experience with inflammation. For instance when I was working with wood (very rare event) I had some minor splinter injury and I remember I could not pull the splinter out and my body created inflammation arround it to protect me from spreading infection and from the foreign wooden thing. Another real experience with inflammation is usual quinsy where inflammation got created in tonsils area. Here again my body protected me from the infection. The immune system reaction, despite the pain when swallowing, worked for me. In childhood I got some ATBs prescribed for sure due to fact bacterial infection is considered a major cause of this health problem. It is not really necessary to describe this on low cellular level but if anyone is interested I would recommend good book on immunity​2,3​.

The lesson learned here is simple – if something goes wrong with human body (injury, infection, foreign subject entered body) immune system reacts with inflammation and protects the body.

Now let´s move to a phenomen of our primary interest, a theory saying sometimes your immune system does the total opposite of what we all experienced in our lives. This is the famous autoimmunity theory​4​ which basically says your immune system got more or less crazy/wrong and turned its power against the poor body owner, against itself. This theory is from 1950s and is considered solid but its roots are even older. It describes chronic inflammation which does not help but which does damage. It basically says the immune system is commiting a suicide (many AI diseases can cause death) since it is inherent and inseparable part of the body. Pretty weird theory, right?

This theory is a fundamental axiom in the medical world – anything from allergy, lupus to multiple sclerosis or sometimes even ALS is basically explained using it and strangely enough all these diseases are still poorly understood, because otherwise they would be cured with better results.

As an engineer I am naturally open-minded when it comes to solving problems and I have some experience with it. Sometimes you really need to review or redefine everything in order to solve  problem. How does it compare with ALS? The disease is with us 200+ years and we still cannot cure it, people are slowly dying.

In the last few decades mankind came up with some decent technology and achieved great things but with ALS we are still in 1939. Isn´t it strange? How is it possible that the tremendous medical progress, mainly in terms of technology used, hasn´t made any substantial difference in our abilities to help ALS patients? What should we do?

My engineering mentality says: “Damn! Let´s review all again and again and again, when no luck then let´s also review those axioms!”. It looks to me the main problem is not in technology but in way people are thinking about the problem. People just need to be doing some mistake. But how can one without all the detailed medical knowledge attack autoimmunity theory? Well I need to study a bit and also turn to someone else and just try to think in new pioneering way. In my case it is not just foolish decision, it is something against my rational as well as intuitive thinking. I have big concerns regarding how it is being communicated to ill people. Everytime I hear some medical representative (physician, scientist) saying this awful expression “body got wrong and started to attack itself” I would break something 😉Anyway that is what most patients will hear even today. I wanted to know more on this because having feeling does not counts, it needs to be supported with some counter arguments, alternative theories. Do they exist?

Besides Anthony William, is there somebody else, more credible for science, who thinks the autoimmunity as a theory is wrong and mistaken? It looks like there is and it is also good to know there were protest voices even at those old times when this theory was a newly forming hypothesis. This is always a good sign – there could be a crossroad and some options but at the end people chose one specific route and it got established at the end, the theory prevailed. But it was perhaps not the right path. Perhaps it really is time to step back and review things. These alternative opinions are opinions of scientists and thus they have slight advantage compared to A.W. – they cannot be called pseudoscientific that easily! 😁

I gathered some literature and made a deep dive into 19th and early 20th century to see how this, for me unpopular theory, was formed. Book Intolerant Bodies – A short History Of Autoimmunity​5​ gave me excellent introduction. This book starts with explaining how people used to explain unhealthy states before modern medicine was born. Since people at that time had no idea about microbs and their role in disease causation, most issues were described using fever label. Many types of various fever like diseases were diagnosed. However then people made big jump forward in their knowledge – thanks to invention of microscope a microbial world was revealed and suddenly lots of fever type diseases were redefined because the role of pathogenic bacterial organism was identified. Of course it was not easy win because it took several decades before penicilin was invented by lucky coincidence by Mr. Flemming in 1928 and then modern antibiotics were created. During The Great War (1914-1918) thousands of soldiers were still dying because of bacterial infections. The bottom line we should remember is that technical progress enabled people to reveal the root cause of many diseases. It is no wonder that this success shifted people thinking dramatically and many health issues were attempted to explain by finding corresponding bacterium or later virus. As we know this still holds till today. Even in those times of 19th century people were struggling to find causative infectious agent for some diseases. The autoimmunity theory has actually very old roots – this fact itself is sort of 🟥red flag🟥 for me.

In the later 19th century it was believed that the immune system was unable to react against the body’s own tissues. Paul Ehrlich, at the turn of the 20th century, proposed the concept of horror autotoxicus. Ehrlich later adjusted his theory to recognize the possibility of autoimmune tissue attacks, but believed certain innate protection mechanisms would prevent the autoimmune response from becoming pathological​4​.

The problem I see is that at that time immunology was practically nonexisting yet but we already have slowly forming autoimmunity. Despite the initial controversy it looked to many scientists as the only reasonable explanation of what they saw. During 1950s it got established. In 1957 Ernst Witebsky formulated postulates for assessing diseases from autoimmunity point. He basically wrote conditions which should be met to call disease an autoimmune disease. This is the usual human reaction. Similarly Koch came with his postulates for mapping disease to causative microb. Back to autoimmunity. Much earlier there were different opponent opinions on that. For example Edmund Weil had different opinion on what is happening during Wasserman test – a blood test used to diagnose Syphilis. It is technical stuff but the original test contained a sample from someone known to have syphilis. Later on it was observed it is not needed as the reaction (complement fixation) works well when using bovine heart tissue which in turn contains cardiolipin. This is marked as a certain puzzle and despite I don´t have the necessary knowledge would see that as an important historical moment.

Distrusting assumptions of absolute specificity, Landsteiner conducted a few experiments using alternative antigens. Curiously, effective antigenic material did not need to come from someone known to be suffering with syphilis. Indeed, the disease was most readily detected when the antigen was normal bovine heart tissue, called cardiolipin, not the spirochete​5​.

It was a puzzle. What exactly could the antibodies be attacking? What was consuming them? Avoiding these questions, Landsteiner discreetly moved on to other problems in immunology, but his observations later prompted Edmund Weil, the professor of hygiene in Prague, a satellite city of Vienna, to suggest that the diagnostic antibodies were directed, in fact, against decomposed tissue products. The Wassermann reaction would therefore indicate both syphilitic and other damage to organs, and not primarily detect the presence of the foreign microorganism. Rather than a specific test for syphilis, then, perhaps the Wassermann reaction was demonstrating an immune response to the body’s own damaged tissues. Weil’s further study of this strange phenomenon was prevented by his untimely death​5​.

This test was later replaced but if I got it correctly it influenced the way people think about antibodies in the context of autoimmune disease. If antibodies react with own tissues (e.g. some organ) it is considered an autoreactive and improper behavior. I think this paradigm is present in current days and it can be actually wrong in the same way fever was wrong or nothing explaining label. Autoimmunity can be similar case. As I wrote earlier the old question of how our immune system distinguishes “self” from “foreign” is quite old and these early autoreactive explanations are old as well. Much much later important observations in immunology were made. I mean mainly the observation of the various immune system cells like B Lymphocytes, all the T cells and antigen presenting cells (APCs). The initially relatively simple idea based on presence of antibodies evolved with the growing knowledge into complex process. Today the immune reaction is thought to consist of whole cascade of actions and I would say immunity has its layered and component based architecture similar to what one can see in complex software systems. There are specific components specialized on specific task but together they provide the very complex service – keeping us alive. It really is fascinating. My personal observation from what I read is that during the last several decades people could make a mistake regarding autoimmunity. It looks to me autoimmunity was bend and upgraded in certain way to somehow absorb all the new observations instead of keeping the whole history and strictly validating the theory as a whole, including the fundamentals. I´m just asking, how do today patients with rheumatoid arthritis or multiple sclerosis benefit from these theoretical upgrades? The problem is autoimmune theory does not help, it is not root cause leading and this is the biggest reason why I´m sceptical about its correctness besides the flagrant accusation of our miraculous body from incompetency.

My thoughts are my thoughts but what about opponents in the scientific world? I´m very pleased I actually found opinion camps which are not mutually exclusive and which try to think differently about problems known as autoimmune diseases.

Danger Theory

In 1994 scientist Polly Matzinger proposed different model describing how our immunity works. It is called danger model​6​ or danger theory. I see her contribution really interesting and also appealing. The question which puzzles other for century, i.e. how immunity distinguishes between self and foreign obtained for many surprising new answer. If I got it correctly then science even never proved the mechanism and moment when the body actually learns to tolerate itself from foreign. They have just hypothesis on this, yet they say people through physicians their body is corrupted and turned against itself.

The immune system does not care about self and non-self.

— Polly Matzinger (1994)

The new theory basically says our immune system has means of detecting danger or damage and if such signals are detected then proper reaction including that “autoreaction” takes place. The signals are mostly chemical, so substances or molecules which are excreted by damaged, destroyed or infected cells. Bigger role and importance was given to APCs. As usually this kind of revolutional answer on above question indeed provokes old-schoolers. As always! Science just does not like big changes, big jumps or big thought shifts from obvious reasons. People had always problem with admitting they can be wrong. That is why progress always comes with new generation. Regarding the new theory I can say it sounds more acceptable as it can lead to the ultimate answer – we only need another big jump in the capability of revealing source of the damage and danger, like in old times people identified bacteria bugs by inventing microscopy.

Instead, danger theorists seek the molecular ontology of damage, the atomic form of an otherwise metaphysical nemesis. Thus, pathology is not monist exaggeration or alteration of normal physiology; rather, it is opposed to the normal, discontinuous with it. In danger theory, disturbance of function is subordinated to the lesion. Forestalling the self, disregarding reactivity and idiosyncrasy, danger models return us to the conventional—and reductive—microbiological view of disease​5​.

If interested please read more about it here​7​. Also note the slight similarity with the early 20th century ideas of Edmund Weil or Ludwig Fleck. Can this be kind of thought reconnection after long years?

Human Microbiom Theory

Another quite new and promising theory mentions a possibly great importance of the overall microbial environment in our bodies, mainly the intestinal tract. There are new observations in how various microbs affect our immunity. I think I read about term immunity modulation. For example I found work of Amy Proal who is considering certain disbalance or damage in the huge and often unexplored network of microbial relationships and which can give rise to autoimmune behavior​8​.

She inspired me and I further studied other sources​9​. It is all step forward away from those terrible explanations patients have received since 1950 if not earlier. The price of knowledge is always high, just imagine people were cured with mercury or arsenic in past when suffering with syphilis (both are poisons, hands away ☠).

Summary

I need to say I´m satisfied. My research on autoimmunity actually revealed the old-school doctrine, which often significantly harms patient psyche and their self perception , is not the only scientifically recognized paradigm. There are very promising theories on the horizon which will need to reveal the truth. A possibly good source of the latest autoimmunity related findings can be the Mosaic book​10​. I have it as well but did not go through that yet in more detail – will need to do that, it is the most expensive book I have ever bought! I´m sure its time will come yet, there is lot of work in front of me.

During this work I also found out ALS is by some sources actually not considered autoimmune but my mother was told that. In her case the no chance reputation of this disease played big and very sad role – please do not allow this pattern, there are alternative and much more optimistic theories!

References

  1. 1.
    Inflammation. Wikipedia. Accessed August 2020. https://en.wikipedia.org/wiki/Inflammation
  2. 2.
    Sompayrac LM. How the Immune System Works. 6th ed. Wiley-Blackwell; 2019.
  3. 3.
    Klenerman P. The Immune System: A Very Short Introduction. OUP Oxford; 2017.
  4. 4.
    Autoimmunity. Wikipedia. Accessed August 2020. https://en.wikipedia.org/wiki/Autoimmunity
  5. 5.
    Anderson W, Mackay IR. Intolerant Bodies: A Short History of Autoimmunity. Johns Hopkins University Press; 2014.
  6. 6.
    Danger Model. Wikipedia. Accessed December 2020. https://en.wikipedia.org/wiki/Danger_model
  7. 7.
    Matzinger P. The Danger Model: A Renewed Sense of Self. Science. Published online April 12, 2002:301-305. doi:10.1126/science.1071059
  8. 8.
    Proal A. Re-thinking the theory of autoimmunity in the era of the microbiome. MicrobeMinded. Accessed September 2020. http://microbeminded.com/2018/04/16/re-thinking-the-theory-of-autoimmunity-in-the-era-of-the-microbiome/
  9. 9.
    Finlay BB, Finlay JM. The Whole-Body Microbiome: How to Harness Microbes―Inside and Out―for Lifelong Health. The Experiment; 2019.
  10. 10.
    Perricone C, Shoenfeld Y, eds. Mosaic of Autoimmunity: The Novel Factors of Autoimmune Diseases. Academic Press; 2019.
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