Theoretical Immunology

[Leonard]

After my encounters with the immunologists and some material I received from Russian academics, my thinking on autoimmunity has progressed. I see no reason to withhold you the latest thinking (update 9 Jan):



I hope now (to be able) to build a coalition of immunologists, neurologists and other medical experts as well as policy makers and engage with them in further discussion. One of the first tasks would be to integrate the thinking in the various documents.

I know, the thinking does not offer us an immediate solution. But I am solemnly convinced that in order to find a solution for our problem, we first need to understand our disease. Without having at the very least a basic understanding, we will continue to be peddling in the mud, try all sort of things in big RCTs and find expensive medications with only very marginal benefits.

You may think this guy is living in a tunnel but I do certainly believe in the concepts described in the above documents. And I am not alone there, my views are shared - at least in principle as a new very interesting horizon for thinking - by some of the world most esteemed immunologists and neurologists. It shows to me that the world can change. The big challenge now is to get a wider buy-in from the medical world and get change to happen.

If there are any important new milestones or events, I will certainly report them here. In the meanwhile, if you have any good ideas, please don't hesitate and let me have them.

[Leonard]

The thinking in this recent article is completely aligned with the above thinking.
And it offers hope that some day there may be an effective therapy for us.
It talks about the 'holy grail' for the reversal or abrogation of autoimmunity.
https://www.tandfonline.com/doi/full/10 ... 19.1593085

But I think conceptually the thinking still misses one very important rather fundamental point.
And that is that autoimmunity is caused by a protein soup of herpes and HERV, partly foreign and partly self.
Ab2 alfa beta and gamma anti-antibodies or regulatory antibodies are misguided because of different binding characteristics of the soup.
See for instance https://www.future-science.com/doi/10.2 ... -2020-0142

The complexity of classes of anti-idiotype antibodies (Ab2s) is enormous. And these in turn relate or interact with many other bioregulators and hormones and can alter the biological activity of antigens which makes the picture even more complicated.
See for instance https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7345059/

Issues such as age and antigen concentration mechanisms, age and induction of (life-long) tolerance, immunity hump, age and antibody titers, concentration/exposure of antibodies and induction of immune response and immunization, and dysregulation/deregulation all play a role in the regulatory system. And of course, the important role of cellular health/fitness comes around the corner here as well including issues such as cellular morphology and compartmentalization, aberration of spindles, chromatid cohesion, chromosome alignment, membrane permeability, protein stability of SNPs, and mitochondrial dynamics.

The idiotypic regulatory system is also coupled to brain regions that are associated with reflex immune responses (nervus vagus) and can be mapped out as an immunological homunculus, and is embedded in the immune-neuroendocrine system where anti-idiotypic antibodies can mimic structural and functional properties of some bioregulators and thereby alter the effects of biologically active endogenous or exogenous immunogenic agents via the anti-idiotypic principle. Hence, a system emerges of almost infinite complexity.

While it may not be possible to understand the system in full depth, it might be possible to analyse and define characteristics of the idiotypic regulatory system, dynamics, eigenvalues etc. And, as part of that effort, to rethink the concept of autoimmunity in the presence of the herpes/HERV protein soup, integrate the documents in the above postings and amalgamate the thinking.

The challenge now is to get a wider intellectual buy-in into the thinking and to get this sort of work underway. And maybe, on the fringes of the analysis, we find a solution for our problem.

[Leonard]

This very recent article is very interesting and would seem to be fully aligned with the thinking on this thread:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691656/

Integrate it all, and we arrive at a total break-through. It is a new theory of evolution and the important role of viruses therein, a new theory of immunity with a central role for cellular health and fitness, and a new overall system characterization with on the fringes of that analysis perhaps some ideas on how to overcome disease or prevent getting diseased.

[Leonard]

Autoimmunity: an explanatory model and questions

See the figure on the uneven pages together with the text on the next page

A number of key questions emerge about the workings of the immune system and the role of herpes

[Leonard]

Einstein said: "We cannot solve our problems with the same thinking we used when we created them".
A pair of fresh eyes is badly needed.

Current views in medicines need a complete overhaul or reassessment, some issues need a new horizon for thinking.
And most important of all, one needs a holistic view across the boundaries of all the various medical disciplines.

I am trying to offer this pair of fresh eyes and a new horizon for thinking.
Under the link, you find my view on the etiology of autoimmune diseases (update V1.1 Feb 23, 2021).

[Leonard]

On the other thread on Ultimate outcome, expectation VS reality! (viewtopic.php?f=1&t=31865) we find an interesting discussion about the role of EBV in MS, and about a possible entirely new approach to stop MS progression. This is my two cents on the subject…

A renowned virologist, he is close to retirement so can speak more freely, told me that we see virtually zero cases of MS in EBV seronegative people. He argues that, if you consider that still some 5-10% of the world population is seronegative for EBV and do the maths, this is a very very very strong indication that EBV is involved in MS.

EBV is known as an onco virus. It is also causal for many types of cancers. Some attribute over 90% of all cancers in the world to EBV. Autoimmune disease then, like MS, is a form of hyper-immunization. This latter form of immunization including the epitope spreading possibly helps to counter the growth of cancers. Immortalized EBV B cells spreading and secreting antibodies (Ab3s) with special epitopes are part of the picture. Epidemiological statistics would seem to confirm such line of thinking.

Besides EBV, there are other herpes viral strains that may be involved in MS and that is Zoster (the Varicella-Zoster virus or VZV) and the herpes simplex virus (HSV-1). Zoster is an inflammatory virus. But Zoster is also known for its role in vasculopathy, which may cause vascular insufficiencies and even edema. See chapter 2 of the document on Theoretical Immunology and Chronic Disease above. viewtopic.php?f=1&t=15188&start=900#p260052

I believe that MS is then caused by a combination of EBV that transactivates HERV, possibly with a stimulus from Zoster or simplex antigens.

If the herpes spreading occurs in the head, this will normally start in the oro- and nasopharynx. Here also lie the origins of MS. This recent conceptual figure on viewtopic.php?f=1&t=31694&p=261053#p261051 suggests this as well: the bad EBV B cells originate from the tonsils, part of the nasopharynx. I think with that the figure is a perfect confirmation of the line of thinking on this thread.

But MS is more than just the bad EBV B cells (that cause the progression), see the posting below the figure. The herpes virus spreads in the head, giving the swollen lymphe nodes, agitated skin, stiff muscles etc. Via the Virchow-Robin space, it will spread into the CNS. That may be both Zoster and EBV at the same time, with quite different implications.

But ultimately, they set on MS in the CNS (the mito-ROS and nerve cell ATP failure, IFN and cytokine, T cell intervention and lesions). See Annex I of the document on Theoretical Immunology and Chronic Disease on the origins of MS viewtopic.php?f=1&t=15188&start=900#p260052 and see also the document on Autoimmunity explained on the origins of an MS relapse viewtopic.php?f=1&t=15188&start=915 .

As shown in the presentation by Atara Bio to ECTRIMS (viewtopic.php?p=260405#p260405), “the defective elimination of EBV infected B cells by cytotoxic CD8+ T cells results in the accumulation of EBV infected autoreactive B cells in lymphoid structures and within the CNS”. I do not exclude that ATA188 could indeed transform MS treatment. The company clearly sees a big multibillion dollar market ahead of them, as indicated in the same presentation.

Another option to deplete the immortalized EBV B cells would be to reset the T/B immune system (and a whole lot more) by HSCT. Some doctors give repeated light cycles of cyclophosphamide (4 - 8 times, you don’t even lose your hair) to achieve the same thing. The risk of developing a cancer seems slightly increased.

In my perhaps limited view, long term use of Valacyclovir could do the trick as well. Literature talks about a half-life of immortalized EBV B cells of 11 months when using Valacyclovir. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2772668/
The advantage here over EBV B cell depleting techniques would be that EBV is arrested when it starts to lyse, and therefore that damage is prevented at the very base. But clearly, there may not be so much money in the game...
Post script: For me, the Valacyclovir is not the right thing. See also the next posting.

[Leonard]

After taking Valacyclovir for a few days, I stopped with it because of unexplained symptoms. It comes back to memory that some years ago when I also tried Valacyclovir, the same or similar symptoms were felt. In particular a deep overall fatigue, effects on the eyes and a ‘narrowed consciousness’ (self-diagnosed). Without going into further detail, I have decided that at least for myself, taking this viral inhibitor is not right thing do.

I think patients with MS should be extremely cautious when taking Valacyclovir, notwithstanding the fact that some patients seem to have good experiences with it. I know that I do have a very high herpes load (the EBV, Zoster and simplex antibody count is very high, way above normal, between 10,000 and 100,000 where the normal value is around 500). But the herpes is locked up in the cells in a fragile cellular equilibrium with the immune regulation. We should refrain from doing anything that might distort that ‘viral homeostasis’.

[DIM]

May I ask you Leonard, for how many days and what dosage, could this be Herxheimer reaction?
From my research the first few days on Valacyclovir there are symptoms as brain fog, fatigue etc that go away as the time passes.
And if you stop it how you are you going to fight the viral load?
There are many supplements that help with HEV family, first and most important Artemisinin which is quite expensive but works with most HEVs and Cancer.
Then Monolaurinic acid, Curcumin, EGCG, Resveratrol, Luteolin, Fisetin, Astragalus and many more (most of them increase remyelination, is it random?) but I am not sure if they have same results with Valacyclovir.

[Leonard]

Hi DIM,

I decided to start slowly and used 2 x 125 mg Valacyclovir daily for 4 days. It may indeed have unleashed some sort of Herxheimer reaction that might eventually wane. But there is risk as well in continuing the experiment on my own because we don’t know what exactly happens to the delicate herpes viral equilibrium in the cells and what could be the possible consequences.

I found a study on Valacyclovir and MS. The end-date of the study was 2 years. This simple observation shows that those who did the experiments must have lacked a deeper understanding of the disease. If Valacyclovir decreases immortalized EBV B cells in 11 months time by half, you would expect to see a halt of progression after say 3 – 4 years.

I trust my body controls the high herpes load, albeit through an autoimmune disease. I know it sound paradoxical but the idea is that autoimmune disease would protect against cancers caused by herpes EBV. The next posting explains my thinking.

Now, am I the only one who can imagine this? I don’t believe so. I found some evidence on the Internet that murky practices in effect may hold back innovation (in the field of epitope assembly). Simply because the implications for the sector, both clinicians and pharmaceuticals, would be too big. OMG, if this is really true, this is getting very serious. Many things to think about...

Regards, Leo

[Leonard]

Theoretical Immunology and Chronic Disease

Part II

Thinking along the Path of Evolution

The thinking about our immunity started from the top. 'Top down’ approaches are dependent on the selection of known markers like T and B cell protective immunity, thus creating a bias in study design and focus. Obviously, technological limitations stood in the way of more accurate and detailed classification schemes at the time.

But our immunity developed from the ‘bottom up’, starting in our cells and clusters of cells. These cells evolved over billions of years in a harsh pathogenic environment and along the way took much foreign genetic material on board, in particular from viruses. Single cell immunity probably mastered evolution from the very beginning.

All the way through viruses left lasting copies of their DNA/RNA behind that provided material for the make-up and composition of our present day cells. And as we shall see, it is precisely these foreign species that nowadays help provide strong recognition of pathogenic elements, resilience and protection, i.e. immunity.

Some 2.2 billion years ago, when the oxygen level in the Earth’s atmosphere surged from 2% to 20%, bacteria were included that eventually became the mitochondria. The mitochondria are the powerhouses of the cell and by using oxygen provide the core of our ATP based energy metabolism. The sudden embryonic growth of our brains then -what makes us as humans- may be attributed to the action of retroviral elements which happened some 6 million years ago. Most foreign elements are now fully domesticated.

In our present world, the immune system is often seen as a system for defense against the non-self pathogens. In reality, it is a physiological system that has a much wider task, that is to maintain the health of the organism, of the tissue and of the cells. The system is deeply intertwined with the cellular biology, in fact started from there. And by accepting foreign elements, the system has enabled evolution to occur.


Our immunity is much more subtle than what may be seen from the rough mechanistic models at the macroscopic systemic level. That bias in our current mindset impedes our thinking, prevents new insights from being discovered and with that obstructs the emergence of a new level of understanding of, and with that, the resolution of chronic diseases.

Cellular microbiology is central in health and sickness. The health and fitness of the cell are the key driving factor that decide between health and disease at cellular, tissue, organ and at whole body level. The intra-cellular regulatory network is the front guard of our immunity and able to manage and maintain a highly complex immune homeostasis, for instance with herpes viruses that affect most people on Earth.

But if the herpes viruses get irritated enough, and depending on the regulatory fitness and the epigenetic state of the cells, a situation may arise where the cellular immunity is no longer able to contain the viral-related activity within the cell and outside help is sought. That is when signals to the outside are given and the systemic immune system intervenes. Normally, the systemic immunity controls the situation and silences the alarm bells. But under certain conditions, with repeated boosting of a response of a mix of herpes viral strains, the situation may result in a hyper-immunization and overt autoimmune disease.


In medical thinking, over the last century we have developed concepts, concepts and concepts. This is the normal way of working in any field -not only in medicine-, to simplify matters and enable us to get our head around problems. But after many decades, it shows now that clinical data provide little support for the theory underlying some of these medical concepts. In other words, it shows that concepts may be wrong or are dubious at best. Such is the case for instance for cancers where it lacks support for somatic mutation as the causal event in the origin of the vast majority of cancers.

On the contrary, there is increasing evidence that herpes EBV is the causal factor for the majority of cancers. Some experts attribute more than 90% of all cancers to EBV. If you start from this presumption and combine this with the thinking about HERV transactivation by EBV, you immediately get a very different view on chronic diseases such as cancers and autoimmunity. And you start to see – which may sound paradoxical at first sight - why cancers and autoimmunity may not be so different and indeed may even have a common denominator, namely chronic stimulation by herpes EBV and HERV.


On our path to discovery of new medical insights, we should not start from thinking of specific cancers e.g. Hodgkin and then work our way from the top down. Instead, we should start from the deeper origins of biological life and work our way from the bottom up. We should start our thinking from a highly complex and interwoven intra-cellular biology and micro-regulation. And we should start the thinking about our immunity from low level to highly advanced cellular immunity in cells or clusters of cells that must have existed a long long time before the descent of the antibody based system and the emergence of higher immune layers including of T and B cells some 300 million years ago.

Normally, the situation inside the cell is controlled by the cellular idiotypic regulatory network and in fact it does this quite well, a process called physiological autoimmunity. There is a lot of micro-regulation ongoing inside the cell; the concept of ‘tolerance’ – so often put forward in the medical literature and part of our current thinking - may have been misleading us and put us on the wrong foot. We must take the matter from the bottom up: the understanding of our immunity must follow the evolutionary path that allowed foreign species to invade and leave copies of their genetic material behind but developed protection and immunity for the dangerous from the very early stages onwards.

Einstein said: “We cannot solve our problems with the same thinking we used when we created them“. In other words, we need a new view with a pair of fresh eyes. Current thinking on our immunology starts completely from the higher layers of immunity with T and B cells. But if we want to get to the bottom of things, we should start from cellular immunity and follow the immunological path upwards as biological life developed. And as we learn fill the gaps in our thinking from there.

It is considered that concept and thinking presented immediately below is one out of many - E pluribus unum. To fully unravel the working mechanisms at an intracellular level is probably an impossibility. But it is an alternative view that goes beyond current thinking and might help unlock the stalemate seen in the medical world.


Internal cellular regulation comes in various stages. In the early stage, there is a vast amount of micro-regulation by what is sometimes referred to as Ab2 antibodies. These antibodies are really more regulatory bodies which can take many forms, mimic interferons, can be herpes specific, mimic Ab1s and anti Ab1s etc etc. It is believed that these regulatory bodies and the internal cellular regulatory fabric preceded any other forms of antibodies that call for outside help (e.g. by killer cells or macrophages).

But it is also possible -even likely- that out of these early regulatory bodies, other more potent antibodies emerged that solicit this intervention from the outside. The antibodies (Ab1s) are believed to guide early killer cells and macrophages. And trigger the oxidative stress mechanism to kill the bad cell in a multicellular cluster. It forms an early form of immunity of tissue. The other antibodies (Ab3s) which are believed to have evolved later in evolutionary time protect an organism against diseases such as lymphomas. It prepares the organ and or whole body organism by activating the latest and highest layer of the immune system for EBV related problems and is sometimes referred to as hyper-immunization.

The hyper-immunization in the case of autoimmune disease should be seen as a sort of reaction of the immune system to get prepared for EBV related problems i.e. for cancers or lymphomas that might emerge caused by EBV interaction with HERV in the genome. This lines up with the thinking of some esteemed auto-immunologists who believe that it is tumor that induces autoimmune disease. The common denominator would be EBV and HERV. Albeit that what we are talking about here would be a very early form of tumor -a pre-cancer- that we may see in our bodies thousands of times a day.

An immune response against a tumor involves the recognition of tumor-specific epitopes, which consist of point-mutations in common self-proteins, aberrantly spliced or modified proteins, or proteins that normally are only expressed during early embryonic development (i.e. carcinoembryonic antigens). Particularly when the immune response against the tumor is strong and succeeds in eliminating the malignant cells, there is an obvious risk of epitope spreading and further escalation into autoimmune disease. There are numerous examples of such “paraneoplastic” syndromes and collateral damage, for example vitiligo (i.e. the killing of normal melanocytes) in patients with melanoma after a successfully boosted anti-tumor immune response.

Many people have immortalised EBV B cells that through oxidative stress mechanisms remove (bad) cells as they grow old. And for us as MS patients, the epitope spreading mechanism may be triggered not primarily by cancerous developments but by very similar herpes/HERV related mechanisms of (combined) self-antigens and antigens presentation.

Epidemiological studies would suggest that people with autoimmune diseases have in general less risk of cancer. In other words, autoimmune disease protects. Where epitope spreading by immortalised EBV B cells provides certain elements of that protection. Having said that, this does not necessarily mean that the epitopes spread in MS/autoimmune disease are identical to (anti-)cancer epitopes. But similarity of epitopes will be there (common herpes/HERV relationship) and the spreading mechanism by B cells is the same. This observation may have important implications for EBV B cell depletion therapy.

Not only the matter of epitope spreading is important, the matter of epitope assembly/synthesis is interesting as well. Normally, the idiotypic regulatory network does well in dealing with the normal low level physiological autoimmunity, and in fact in dealing with EBV induced HERV self-antigens. But when there is high EBV load and persistent simultaneous pressure of Zoster or simplex and their antigens couple with (EBV induced HERV) self-antigens in the cell, there is an abnormal presentation. This may lead to the highly specific antibodies referred to as Ab3s. And apparently the system has learned (to suppress cancer development?) to spread these epitopes by B cells to protect. And overt autoimmune disease shows up.


This document describes the evolutionary path of biological life with a very important role for viruses in the evolution of our cells, how our cells live in peace with those viruses and take genes from them, and what happens to our immunity if a normal herpes viral cellular equilibrium in the cell is distorted. By e.g. vaccination, lowered immunity as a result of a vascular insufficiency, or failing epigenetic control.

It is argued that a mild level of autoimmunity is normal to clear the cells from permanent low level waste and repair as necessary. But if this mild level is replaced by a high concentration of auto-antibodies caused by excessive intra-cellular viral transactivation with prolonged contacts of (self-)antigens from various herpes strains and the internal cellular regulatory network cannot keep control of the situation, this may set on overt chronic diseases like malignancies and -on the other side as a protective measure- autoimmune diseases.


As part of the overall immune regulatory system, the issue of epitope spreading was hot in the 1990s but around the turn of the century, the interest declined. The reasons for this decline remain vague. A disappearing target with a large variety of peptides is not exactly the dream of a pharmaceutical company who have invested heavily in interferons, monoclonal antibodies and the like and would thereby risk to cannibalize a revenue stream of many 10s of billions of dollars. And for a variety of reasons funding dried up.

Innovation in this field will have winners and losers and would risk to bend very major revenue streams, career expectations and a whole lot more. Change will therefore have to face enormous barriers. And murky practices might impede innovation.

It reminds me of the situation where we stood in 1990 when the liberalisation of the telecom sector was first discussed by governments. Governments faced major obstacles. But in the end they did it. The US Government dismantled AT&T and made room for the new Internet ecosystem to emerge. In Europe governments collectively took the decision to open up the market for competition in 1998, a decision against the interests of the incumbent industry which -I am sure- they could only have taken collectively. And we know now the result of the opening up with the new vibrant Internet economy and society.

Likewise, governments will have to think with us how to lift the barriers and facilitate a "liberalization" of the medical sector. And with that open up the sector and the thinking and bring us closer towards the resolution of chronic diseases. For all of us and for themselves to control escalating cost in health care.

[Leonard]

Chronic degenerative diseases (including MS) require a new perspective, a new contextualization and interpretation to help us challenge how we view these diseases. As these diseases are all born out of cellular action with a common underlying herpes-viral denominator, we should try to understand the diseases as a class, as much as individual pathologies.

The essay below elaborates on my thinking and calls for action. It occurs to me that we are caught in a catch 22 situation where researchers are reluctant to engage in research into an entirely new direction outside their comfort zone while policy people can not engage and wait for the results of researchers. We must break out of this situation.

[Leonard]

I refer you to the other thread on the subject matter:
viewtopic.php?f=1&t=32024

"In the past decade, there has been growing recognition that disease prevalence, course and outcomes in women and men are influenced by both biologic sex and gender. ... This FOA seeks research that will expand the current understanding of the sex and gender factors that drive these crucial differences."

I suspect the NIH is thinking in the direction of SNPs/point mutations as well, to explain the gender bias and a whole lot more.

It is the SNPs/point mutations in the X/Y sex chromosomes that explain the gender bias. These react to the interferons produced in the cells and with that determine the anti-viral state of the cells.

This initiative by the NIH is hopeful because I think that if there is one organisation in the world that can change the current paradigm, or at the very least give an important impetus to change, it will be the NIH.

[Leonard]

The prevalence of MS is increasing worldwide because people and their 80 billion cells are ever less able to contain herpes viruses. viewtopic.php?f=1&t=31375
Besides MS, lack of herpes control causes chronic diseases such as cancers and - as a protective measure - autoimmune diseases.

Chronic diseases are on the rise worldwide. Cases will double by 2035. With dramatic consequences and escalating cost of health care.

There are a number of reasons for distorting or losing control of the herpes cellular viral homeostasis, see step 2 of the last page of the essay: vaccinations (at least some as Hepatitis B), hypoperfusion, loss of epigenetic control, degraded acquired cellular fitness.


For the underlying theory, start reading from the previous page (61):
viewtopic.php?f=1&t=15188&start=900#p260052

I was reading the book by Stephanie Kelton on the Deficit Myth, elaborating a Modern Monetary Theory. Great book, looks at the problem through a new lens, very convincing! As she describes in her book, the new ideas on MMT came first in the early 1990s, so it took almost 30 years to surface and get into the public domain. And as with the MMT, it may take time to accomplish the mega challenge of a paradigm change in medicine. But I don't think the world can afford to wait another 30 years. Medical specialists and researchers need to get out of their comfort zone and build a coalition of interested and motivated people to push the new ideas forward.

I have been in contact with a very experienced media company which has done many proposals in the field of medicine and - I am sure - could put a beautiful narrative together. The ideas are there, and I have clear indications that money for further work will be there as well. But we need a coalition of the willing - I have got a few names of medical specialists so far, renowned medical professionals in their field. If there are medical professionals or researchers reading here who would be interested to participate in a coalition, please send me a personal message on this forum. Your name will be protected and only be made public later (in the context of the study) after your reaffirmation to participate in the coalition and the mutual consent of the group.

[Leonard]

Bernie Sanders always says: "Change never comes from the top down. It always comes from the bottom up." If we are going to take advantage of the space that the new thinking opens up, it is going to be because enough of us - readers like you - help to shift the debate in a new direction. Through the new viral lens, we can see an alternative and more hopeful set of possibilities. It's our future. It's our health. And it's our health system. We can make it work for us.

I have prepared the following documents for you to forward, to print, to spread the word, to take with you and handover to your doctor, for doctors to discuss with colleagues, for policymakers to prepare new policies, for the mainstream media to cover this as a new subject, etc etc. I am sure that if you all who read here help to disseminate the message, the transformation won't be very far away.

Open letter on our societal health


On changing the paradigm


Channeling the thinking in medicine


Thinking along the path of evolution

[Leonard]

The following essay explains the beneficial effects of regular fasting on our health.



The relevant papers can be found by googling on the Internet. More about that later.