Theoretical Immunology

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Leonard
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Re: A new concept for MS and other autoimmune diseases

Post by Leonard » Sat Feb 01, 2020 6:24 am

Reflections on cellular fitness

On the protective effect of childhood sun exposure


A childhood in the sun may cut the risk of getting an autoimmune disease later in life, including the risk of getting MS. Central in the new theory on health and disease is the cellular fitness. A vibrant and performant cell is better able to fend off a viral infection and make the difference between viral clearance / staying healthy on the one hand and tissue pathology / getting sick on the other hand.

Although chronic excessive sunlight increases the risk of skin cancer, the avoidance of direct sun exposure can also have serious health consequences and has demonstrated to increase the risk of many common chronic autoimmune diseases including MS. Identical (monozygotic) twins who were separated during their childhood have a different risk to develop MS. It is critial that this separation occurred prior to adolescence. After that, there no difference found anymore. Apparently, when the cell is full grown, the effect wanes. The effect is only seen when cellular growth is not yet complete.

The results of many studies would suggest that cells are, depending on certain environmental factors, either better or less able to fight against viral infection. This is where cellular fitness comes around the corner. With herpes infection very common - almost ubiquitous - under the general population and responsible for most cases of autoimmune diseases (see also earlier essay on autoimmunity and our society under the link below), defense against the herpes virus is critical.
viewtopic.php?f=1&t=15188&start=885#p258372

Although many studies and reports cover the issue of cellular fitness, most of the time the focus is wrong. As such, work considers all sort of aspect such as: cellular fitness and exercise; mitochondrial dysfunction in isolation, that is without the role of any pathogen; sun exposure and cancers and skin aging. But cellular fitness in the presence of a virus i.e. herpes is rarely covered. For instance, in this major review paper from 2018, the word viral is mentioned only once, in the text below figure 3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551641/

Notwithstanding, the herpes virus is omni-present in the general population and cellular stress is often caused by viral infection and mechanisms activated to deal with the herpes virus. The cell will determine the way to fight, and what instruments from the systemic immune system should be mobilized in order to get the best result or least possible damage. And the cell will ultimately determine its fate, including apoptosis if necessary. So the cell will decide about health or sickness of the cell and, given the process of fitness selection in infected tissue, of the surrounding tissue.

If the fitness of the cell, defined by its anti-viral properties, is the key issue, the following questions arise: What is cellular fitness? How does cellular fitness determine its anti-viral properties? Is this cellular fitness determined during the early phases of life (the main phases of cellular growth, fetal period and childhood)? Then, what are the critical life elixirs during pregnancy and childhood? How important are sun exposure, cholesterol, vitamin D?

On an intra-cellular level, we could ask questions how cellular fitness is established in cellular structure, and issues arise such as cellular morphology, aberration of spindles, chromatid cohesion, chromosome alignment, altered membrane permeability and cellular compartmentalization. Also the network of mitochondrial dynamics including fusion and fission and anti-viral properties is a big area for research. We may also ask questions about protein stability including that of MAVS / SNPs and about other intra-cellular signalling structures including redox biology that for instance activate the interferon trigger and the many signaling pathways to systemic immunity.

The decoding of the intricate network of relations constitutes a riveting scientific challenge. Despite, it is becoming ever more obvious that the amount of sunshine during the early phases of life, that is during both pregnancy and childhood, are a determining factor for one’s health for the rest of his or her life i.e. that the first 10 years of life are so important for the cellular make up that it decides about viral clearance / staying healthy or tissue pathology / getting autoimmune diseased later in life.

The photosynthesis of vitamin D has been occurring in living organisms for more that a billion years and therefore it is not surprising that the vitamin has evolved into a necessary hormone - a building block really - which acts as an indicator of overall health and well-being. And, given that the herpes virus has been with us for billions of years and probably dates back to an ancient RNA world, it is not surprising either that the interaction between cell structure, sunshine (Vit D) and viral resistance are fully intertwined in the biology of the cell.

The indoor life of our kids sitting behind their game consoles and smart phones, excessive use of sun creams and an overkill of low cholesterol diets (that may be good for elderly people above 60 years of age but not for young mothers and young kids) could have devastating effects on their health and on societal health in the future. For the well being of ourselves and our children and grand children, this is a matter that needs urgent study to clarify the situation.
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Re: A new concept for MS and other autoimmune diseases

Post by lyndacarol » Sat Feb 01, 2020 1:50 pm

Please tell me the URL for this article and the "society" mentioned at the end of paragraph #3. Thank you.

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Re: A new concept for MS and other autoimmune diseases

Post by Leonard » Mon Feb 24, 2020 2:33 am

Hallo lyndacarol,

On your question, I have added the link to the essay in the above posting.

I seem to remember you from the past when we had an exchange of ideas on this very forum on the role of insulin and cellular feeding in MS. This was in the Autumn of 2010. I had read somewhere that there is a double peak in the graph of age of onset of MS - I think it was probably in the book of Judy Graham - and in early 2011 I made the connection between the two: the double peak in the graph is caused by different mechanisms. This double peak is very fundamental and can not be explained by neurologists by simply referring to imperfection in the statistical data. It is sad that to this very day, I have not seen any plausible explanation from the medical sector that could explain this phenomenon.

The exchange laid the basis for this thread that I started in early 2011. In fact, this thread was born just a few hours after I made the connection where my believe must have been grounded in a deeper mistrust of the medical sector after the complete denial of the Zamboni findings that MS is caused by vascular narrowings in the neck. In my view, through his program with a cohort of 1600 patients, Dr. Zivadinov in Buffalo clearly demonstrated a positive correlation between MS patient and vascular narrowings in the neck. Where 80 – 90% of MS patients had vascular narrowings in their neck veins, in the control group he found only 20 % of people with narrowed veins.

Now we are almost 10 years later and obviously after this long journey we know a lot more now than what we knew back then. But unfortunately, so far the medical world has not embraced, at least not publicly, any of this thinking. Whilst
evidences are accumulating for viruses to play an etiologic role in MS and the very underlying mechanisms are becoming clear as the next posting explains.

Regards,
Last edited by Leonard on Fri Mar 20, 2020 6:00 am, edited 5 times in total.

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Where the state failed, church succeeded

Post by Leonard » Mon Feb 24, 2020 2:39 am

Protecting us against our smallest but yet our biggest enemies:
What the state can’t do even today, church has done for the last 2000 years




Autoimmunity: it all starts with a viral homeostasis

Evolution favors hosts that develop strategies to avoid or limit pathogen infections, and pathogens develop effective mechanisms to evade the host’s anti-viral defenses. This ‘arms-race’ results in a stable but dynamic equilibrium (homeostasis) between a virus and its host, whereby the virus does not significantly compromise the host’s productive capacities, nor does the host’s immune system completely block production of virus progeny. The immune system is not completely sterilizing and pathogens have adapted by using general and specific strategies to weaken the immune barrier. For these reasons, infection with a number of clinically significant human viruses invariably results in the establishment of viral persistence or latency. Or in other words, to the establishment of incurable life-long infection.

For a number of human virus adaptations, there is this tendency toward a state of balance that ensures survival of both pathogen and host. Examples are the herpes viruses including herpes simplex, the cytomegalovirus, the Varicella zoster virus and the Epstein-Barr virus. Other viruses that may lead to a chronic persistent infection are Hepatitis B and C viruses and the human immunodeficiency virus. The equilibrium level is earmarked by a constant and dynamic adjustment of regulatory pathways between the host and the pathogen where each try to control the other’s function.

The herpes virus is almost omni-present among the general population, the virus invariably results in the establishment of viral persistence or latency and the infection normally remains benign. But once key homeostatic pathways are disrupted, it can have dramatic consequences on pathogenesis and become even life threatening. Both the immune and nonimmune pathways contribute to viral homeostasis. While the immune pathways control viral homeostasis, nonimmune pathways exert a second level of control that is interrelated with immunity and that are connected to the obligate dependency of the virus on its host and plays an important role in modulating infections at the cellular level.

Here, such issues arise as to how the cell may keep the virus hostage by control on the virus transcription cycle, and what molecular breaks of the cell are used including for instance the role of mitochondria anti viral signaling proteins and single nucleotide polymorphisms (MAVS/SNPs). And when essential cellular pathways for virus multiplication are limited for instance by anti viral cytokines that induce cellular genes that subsequently limit the ability of viruses to complete their replication cycle, if these pathways are for the cell non essential for its survival and the virus becomes a hostage of the cell, what cellular factors may distort the equilibrium? Is it energy or ATP?

The combined genetic complexity exhibited by the viral and human genome provides for a multiplicity of mechanisms by which virus and host cell processes can impact on the transcription and replication cycle. Whilst a better understanding of the control system remains a formidable academic challenge, there are a few things however we could say on the meta -whole organism- level. For that, we refer back to the above postings on autoimmunity and our society and on cellular fitness where we saw that autoimmunity is caused by herpes viral infection where cellular fitness is ultimately a key factor that determines whether one remains healthy or gets sick. We may infer that gut control on (the epigenetics of) our cells and cellular fitness are extremely important.

This is where the church comes into the picture. Thousands of years of experience must have led religious leaders to see and believe that populations are healthier when fasting regularly. This may be a remainder from old times where our pre-historic ancestors were faced with famine by the end of the winter period. What is happening there? Can we explain the relationship between societal health and these practices? Practices that have a root that perhaps goes much deeper than mere religious rituals?

With this theory on viral homeostasis in hand, with a dynamic equilibrium between latent virus and immunological control through gut signaling and cellular dynamics, we may be closer to a plausible explanation for the positive health effects of fasting. As we have seen, fasting resets the gut microbiome which may be important because of enhanced signaling such as methylation which alter mitochondria DNA dynamics and thereby may help to block virus multiplication. We also note the important role of cellular starvation which may lead to new intra-cellular dynamics of mitochondrial networks and strengthen the cell’s anti-viral properties. Hence, regular fasting induces important anti viral effects and thus may help fend off autoimmune diseases in society. So where the state protects us and provides security against the more traditional enemies, religious practices may have protected us against the smallest biological species that in the end may turn out to be our biggest enemies.


Signaling pathways and a measured/proportionate immune response

The thinking in this section is based on my own experiences during my life as an MS patient. The immune response to viral infection is highly sophisticated and diverse. There are different levels of control, multiple mechanisms and cell signaling and hormone pathways involved.

I was born in 1956 with a vascular narrowing in the neck. As regards any questions that might be raised on the direction of causality, this is clearly a birth defect because my left internal jugular vein (IJV) is bigger than my right IJV, a situation that must have developed during the fetal growth when the left was trying to compensate for the blockage in the lower neck on the right. The vascular obstruction in the blood drainage likely breached the blood brain barrier and allowed viral entry into the CNS, where the virus targeted in particularly fast dividing cells such as OPCs.

Since I was born, there were exacerbations every 7 to 8 years. During these exacerbations, relatively light neurological symptoms were felt. This may have been numbness on the outer side of a knee, the little finger on one hand and later in life on two hands. Or effects on the eyes. But although some occurrences were more severe than others, the situation always restored back to normal in a matter of a few weeks to a month. Sometimes, an occurrence repeated itself in 2 subsequent years. Symptoms always showed up in the early Spring when the immune system was low and/or hormonal levels were low. Clearly, a process was running in the background to get the virus back under control and restore the cellular equilibrium.

My immune system always managed to keep control on the virus. The dynamic equilibrium between the latent virus and immunological control was maintained where apparently after an exacerbation the immune system managed to push the virus back into a deeper latent state where it took 7-8 years for it to reemerge. And I led a perfectly happy family and working life. Even when the bad gut developed in my early 40’s (which causes the second peak in the graph of age of onset), the immune system managed to maintain an effective equilibrium. But the cells were probably on a limit, the nerves must have been ‘thin’.

Then around the age of 45, I was vaccinated 3 times with Engerix B, a vaccination for Hepatitis B. This must have brutally distorted the weak but stable viral homeostasis of the cells. When the virus entered cells that were on a limit, the fitness of the intracellular machinery did not suffice to keep control. And the systemic immune system was called to help in a more forceful way. In other words, a bigger army was now mobilized to get the infection under control.

There must be numerous pathways into the systemic immune system calling for specialized troops, in particular specialized T cells, to reinstate the equilibrium. But this time, the specialized troops caused a lot more damage than all previous occurrences. Where I had two old lesions that I may relate back to specific symptoms earlier in life, this time I had two big new active lesions. The patterns of these lesions may have been different from the earlier lesions, indicating a different viral pathogen (Hepatitis vs. herpes). And the age of 47, I was diagnosed with MS. The occurrence was not synchronised in any way with the 7-8 years rhythm. The flare up set in motion or accelerated a whole new process, namely that of oxidative damage.


The redox biology is intertwined with the viral homeostasis

Oxidative damage is an emerging general mechanism of system injury caused by viral infection. Oxidative damage can be caused by direct effects of virus on cells and indirect effects of host inflammatory responses. As such, this form of injury can affect both infected and uninfected cells and thus may help limit viral replication and spread.

Oxidative stress, primarily due to increased generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS), is a feature of many viral infections and is a key activator of many signaling pathways. ROS and RNS are seen to modulate the permissiveness of cells to viral replication, regulate host inflammatory and immune responses, and cause oxidative damage to both host tissue and progeny virus.

The lipid-rich nervous system is particularly susceptible to lipid peroxidation, an autocatalytic process that damages lipid-containing structures and yields reactive by-products, which can covalently modify and damage cellular macromolecules.

Oxidative injury is a component of acute encephalitis caused by herpes simplex virus type 1 and reovirus, neurodegenerative disease caused by human immunodeficiency virus and murine leukemia virus, and subacute sclerosing panencephalitis caused by measles virus.

Changes in the redox homeostasis in infected cells are one of the key events linked to inflammation and subsequent tissue damage. A moderate level of oxidative stress is essential for cell survival and could be induced and modulated to produce an adaptive cellular response that is beneficial for cell survival and protects the cell against subsequent severe challenges that otherwise would trigger widespread oxidative damage and cell death. Oxidative damage in virus-infected tissues modulates the permissiveness of cells to viral replication and cause damage to both host tissue and progeny virus. These oxidative modifications play regulatory roles in protein function and conditions. As such, stressors when used at appropriate dosages can elicit a moderate or non-lethal level of oxidative stress in the absence of cytotoxicity and cell death and protect tissue against injuries.

But to what extent oxidative stress plays a beneficial role for the host by limiting viral replication is not understood for most neurodegenerative diseases and indeed neurotropic viral infections. A better understanding of the role of oxidative stress in viral infections may lead to improved treatment strategies that will reduce the extent of tissue damage during viral infections without impeding the antiviral response of the host. Furthermore, such studies may contribute to an enhanced understanding of the pathogenesis of neurodegenerative diseases such as MS for which viruses play an etiologic role.



Refs:

Viruses: Hostages to the Cell
https://www.ncbi.nlm.nih.gov/pubmed/10998321

Multiplexed imaging of immune cells in staged multiple sclerosis lesions by mass cytometry
https://elifesciences.org/articles/48051

Role of oxidative damage in the pathogenesis of viral infections of the nervous system
https://www.ncbi.nlm.nih.gov/pubmed/15944946

Oxidative stress in biological systems and its relation with pathophysiological functions: the effect of physical activity on cellular redox homeostasis
https://www.tandfonline.com/doi/abs/10. ... ode=ifra20
Last edited by Leonard on Tue Mar 17, 2020 4:02 am, edited 6 times in total.

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Re: A new concept for MS and other autoimmune diseases

Post by Leonard » Mon Mar 02, 2020 12:04 am

A new grand theory on health and disease

... might now look a bit as follows:

1. It all starts with a viral homeostasis
Redox biology is fully intertwined, multiple signaling mechanisms, pathogenic & beneficial effects of oxidative stress, autoimmunity

2. Cellular fitness: a decisive factor between health and disease
On the role of MAVS proteins & SNPs, gut microbiome signaling and cellular methylation, distortion of the cellular equilibrium by small retroviral elements and/or adjuvants

3. A measured/proportionate immune response
Heterogeneity in immune response, different levels of control, multiple cell signaling and hormone pathways, inflammation and physiological trauma’s, lesion patterns, chronic activation of immune responses

4. The unfolding
iNOS, EBV B cells and the RNA interference complex, superoxide, peroxynitrite, lack of exercise and cellular fitness

5. Special cases
- Multiple Sclerosis BBB breach and virus
- other autoimmune diseases as Rheumatiod Arthritis
- and neurodegenerative diseases as Alzheimer’s and Parkinson’s
- cancers, EBV and cellular fitness

6. Preventive and therapeutic strategies: sunshine and cholesterol, regular fasting, fats and microglia anti-viral defense, anti-oxidants, chemo for the gut to replenish the immune system with new clean immune cells, B cell therapies etc. etc.

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Re: A new concept for MS and other autoimmune diseases

Post by Leonard » Fri May 01, 2020 7:04 am

I was looking through the pile of papers that I collected in recent years and found interesting material on the HERV.
It is the missing piece that puts it all together. I then drafted the following text:



Autoimmunity: viral recombination on the edge of the self


Over many millions, perhaps even billions of years, the herpes virus has developed clever strategies for immune evasion and immune escape, allowing viral persistence where most often the virus becomes hostage to the cell. At the same time, the human cell is the product of an equally long evolution in an adverse pathogenic environment with repetitive sequences in the genome corresponding to human endogenous retroviruses (HERVs), believed to be remnants of ancient exogenous infections.

Viruses may utilize each other. A herpes virus can transduce a retrovirus that then becomes more lymphomagenic or viruses can enhance the pathological effects of each other. It is considered that this is particularly true if cells are not fit enough to stop mutations i.e. if they can’t keep the virus quiet and effectively contained. With herpes viruses omni-present and almost as “endogenous” as the HERVs, the love-hate relationship between human cells and HERVs then becomes a triangle drama.

As we shall see in the next sections, it is here at the cross roads between the mixture of viral proteins and the fitness of the cellular surveillance and immune machinery where the basis lies for autoimmunity. In fact, the intersection brings together the two views that have dominated the discussion on the etiology of MS in recent decades: a genetic disease of Mendelian inherited proviral loci in the human genome and a disease caused by an infectious agent like the herpes virus that has “endogenously” settled itself in the cell.


The ubiquitous herpes virus


Herpes virus infections are common under the world’s population and the virus causes lifelong infection among a majority of people. In humans, the prevalence of herpes is well over 90 %. Herpes viruses encode many proteins that manipulate the host cell and immune response, thereby escaping immune control. As such, herpes viruses have the capacity to establish latent and recurrent infections and may persist in a quiescent but persistent form. In this respect, the herpes viruses are almost as “endogenous” as HERVs which are present in 100% of the population.

Epidemiological observations provide clear evidence of herpes strains in the development of autoimmune diseases. Herpes strains may trigger pro-inflammatory and autoimmune neurological processes. With the negative argument, that is the virtual non-existence of MS in EBV seronegative people (still 5-10% of population), epidemiological analysis confirms a strong relationship of MS with EBV.

Herpes viruses can escape antibody clearance while cell-mediated immune response is essential to control infection.
Herpes viral strains have different primary target cells which is probably the product of a long evolution. The virus appears “to have studied” cellular pathways that control protein turnover and craftily manipulate multiple such pathways.

Myelin basic protein as well as fast divinding cells as OPC’s appear an attractive target for herpes virinae. Varicella-Zoster and EBV are capable of infecting the endothelial cells of the Blood Brain Barrier (BBB) and have been linked to inducing a breach in the BBB, in particular if a weak barrier function is present for instance because of vascular narrowing.

A particularly interesting herpes strain is the EBV. EBV that has been with us for only 40 – 100 million years, the shortest of all herpes strains persists for life and continues to replicate. As a herpes virus, the EBV has a broad range of antiviral immune effector mechanisms. A clever strategy developed by the virus allows it to gain access to the memory B cell pool and establish viral persistence independent of viral reactivation and re-infection. EBV establishes latency in memory B cells.

It may be possible that these immortalized B cells play a role in the immune control of EBV related lymphoma’s. Conversely, there appears to be a causative association in immune suppressed or immune compromised people between neoplastic diseases and EBV.

In an evolutionary context there is still some pathogenicity left for EBV. EBV is considered a major cause of lymphomas. The putative involvement of the HERV protein in EBV-related growth stimulation of B cells raises the possibility that immunization against the HERV protein, or prevention of its expression via transduction of anti-sense constructs, might inhibit EBV lymphomagenesis. Patients with MS have high immortalized EBV B cell concentration but at the same time lower risk on developing cancers which would seem to confirm such relationship. Other intriguing experiments would seem to point to the involvement of EBV and HERV to stimulate growth of the B cells. The benefactor allegedly is EBV.


The human endogenous retrovirus


Eukaryotic cells probably have been exposed to retroviral elements since their very beginning. Human Endogenous Retroviruses (HERVs) - selfish genes of retroviruses - are believed to be remnants of ancient exogenous infections. HERVs are mobile subcellular structures that span the divide between self and foreign. Approximately an 8% of the genome has a retroviral origin.

HERVs entered the germ line during evolution and as retroviruses were able to replicate and retrotranspose, increasing their copy number and spreading all over the genome. During evolution, most of the HERV proviruses have undergone extensive mutations and are unable to replicate. Nowadays, they reside in the genome of all human cells and are transmitted in Mendelian fashion. Retroviral elements are prime providers of genetic flexibility. In the animal kingdom and in plants, they often are dominating genetic components.

In evolution, disease equates negative selection. The persistence of (H)ERVs in a lineage can stretch over several hundred million years. Hence there is ample time to establish a stable host-viral sequence interaction with a minimum of negative selection, i.e. disease. A large majority of HERV prove not pathogenic. Although most retroviral genes may be assumed to have been ’pacified’, in rare cases HERV pathogenicity will not be eliminated and retroviruses can carry with them a number of mechanisms optimized to suit a free-living exogenous virus or potentially semi-endogenous viruses such as herpes, making them potentially dangerous to the host.

Some HERVs have retained open reading frames putatively encoding functional proteins. These proteins might show antigenic properties involving the immune system. HERVs have been associated with several pathologies as cancer and autoimmune diseases. HERVs RNAs proteins and virions have been found in different tumor tissues, in rheumatoid arthritis and in MS. As such, some HERV might be exerting its role in MS pathogenesis through activation of innate immunity and subsequent release of pro-inflammatory cytokines.

Interactions between the host and HERVs are manifold. More than half of the human genome has probably undergone reverse transcription before incorporation. Previous HERV integrations may protect against new ones in several ways. Many defense mechanisms against damage from newly acquired retroelements must exist. Methylation and inhibitory RNA are two of them.

HERVs are a genetic factor in the pathogenesis of autoimmune diseases; there is enough information to justify a correlation of human diseases with HERV.

HERVs in combination with “semi-endogenous” herpes viruses as opposed to exogenous retroviruses may trigger immune-mediated response in which case we talk about autoimmunity. The association of TRIM5 with MS is a clear confirmation that a retrovirus plays a role in the etiology of MS.


Interaction of (semi-)endogenous viruses: repackaging RNA material


It is not unlikely that HERV and herpes viruses may utilize each other. In fact there is the potential of interactions between highly prevalent selfish genes/retroviruses and ubiquitous semi-endogenous viruses like the herpes viruses or the Hepatitis B and C viruses. The correlation of MS with both HERV and EBV would also seem to confirm such thinking.

Interestingly, demethylation of the HERV resulted in significant increased levels of HERV expression in cells previously completely silent. Retro elements are generally epigenetically silenced in cells. This is where the microbiome comes into the picture.

Besides variation in methylation there is evidence for a second mechanism of HERV action, referred to as “ERV breakout”. Starting from humble beginnings, may be after a temporary demethylation, one quasispecies member may provide functional capsids and partially functional enzymes. Another quaisispecies may provide the envelop proteins. It is conceivable that such particles can copackage RNAs from each other and other more or less defective members of the quasispecies.

During reverse transcription these particles recombine and reintegrate. Once the process starts, it is self optimizing, and may generate particles that trigger the immune reaction of the cell and let the cell call for help from the immune system.

Or it may generate an infectious exogenous retrovirus, or the production of retrovirus like particles, in some cases progressing to a replicatory avalanche. This is reminiscent of the self optimizing nature of tumour cells, once they start to escape from extraneous control of cell division. A “breakout” process involving both mutation and recombination occurs regularly in leukemogenesis.

The repackaging of these RNA is astonishing. It is possible that such a protein can be created via somatic mutation and provide the capsids. The envelop protein may be supplied via one or several of the known env open reading frame (ORF) genes. Some expert groups maintain that they can grow the respective virus in human cells.

It cannot be excluded that other semi-endogenous viruses such as herpes/EBV contribute to disease and more in particular alarming the immune system through recombination (repertoire of proviral sequences involving for instance other herpes strains, associations between close SNPs).

Some recombinant products or viruses may have new properties, some being pathogenic due to access to a new target in the cell. This may result in immune suppression or immune stimulation, with a “breakout” of viral species.

We cannot exclude the contribution of other viruses to putative infectivity through recombination. The relevant determinant of infectivity in the organism is not the individual locus, but the repertoire of proviral sequences.
How does HERV ultimately effect the immune system? In general HERVs are defective. However, some are able to produce proteins that may be able to start an infectious-like process, either through complementation or recombination with herpes strains. Here it may be the entire HERV repertoire that determines infectivity and not the individual locus. If activated the endogenous viruses could trigger the adaptive immune system or, equally likely, the innate immune system. This in turn could lead to the stimulation of an adaptive immune response, and ultimately to a broad range of cellular components.

It is noteworthy that elements that contribute to a new and potentially dangerous mix of viral components and proteins apparently also contribute to the detection mechanisms to render such a mixture harmless. And perhaps it is not so surprising from an evolutionary point of view that such signaling mechanisms are close to the pathogenic generators.


The crucial role of MAVS/SNPs in antiviral detection and signaling


Some polymorphisms are associated with disease while others are associated with protection. HERV SNPs are highly associated with disease and are most significant risk factors, other SNPs are associated with disease protection. A genetic test of fifty endogenous retroviral loci for association with MS showed SNP markers near a specific endogenous retroviral locus, incidently – as we would expect – located on the X-chromosome.

Genetic variation is associated with disease. As a type of genetic variation occurring with certain regularity and frequency, the Single Nucleotide Polymorphism (SNP) is attracting more attention for its association with diseases. The effect of Mitochondrial Antiviral Signaling proteins (MAVS) coding-region SNPs exhibited functional alterations or in an inhibited immune response, or in some cases the opposite effect.

MAVS acts as a common adaptor molecule and can recognize foreign RNA, including viral RNA, leading to the induction of type I interferons. Therefore, MAVS are thought to be crucial molecules in antiviral innate immunity. MAVS gene have a crucial role in antiviral signaling. MAVS are functionally associated with susceptibility to viral infection.

Variations in the MAVS genes result in susceptibility to infectious diseases. Loss of MAVS blocked IFN induction by viral infection. And hence, genetic variation of MAVS may result in susceptibility to diseases. The distribution of MAVS in the mitochondria is vital for its role in antiviral signaling.

Studies have reported that several viruses escape antiviral response by degrading Mitochondrial Antiviral Signaling proteins (MAVS). Loss of MAVS blocked IFN induction by viral infection. Studies confirm that there is a positive correlation between the amount of MAVS and its antiviral role. Variations in the MAVS gene result in susceptibility to infectious diseases.

Certain HERV copies are thought to be associated with the recognition of viral components. As such, the HERV-W on chromosome Xq22.3 that contains an almost complete open reading frame, is believed to be a genetic marker for viral entrapment. This would explain the gender differential prevalence in autoimmune diseases and indeed in MS. The HERV, via a polymorphism, would be the (a) major etiological factor of MS.

While HERV play an etiological role in MS, SNPs around one retroviral locus showed highly significant association with disease. Significant associations of the HERV/Fc1 polymorphism with MS was observed. For RR and SP the strength of the association was further enhanced as you would expect. The progressive form is a different mechanism.

TRIM5 encodes an ubiquitin ligase that restricts the replication of many retroviruses to a varying degree. SNPs in gene TRIM5 were inversely correlated with disease. Conversely, SNPs around one retroviral locus, HERV-Fc1, showed highly significant association with disease. Significant associations for the same disease occur at opposite alleles of the same polymorphism.

The human genome contains several sets of genes encoding dozens of proteins constituting anti-retroviral defense mechanisms. Such genes are known to restrict the replication of viruses, protecting the host from exogenous retroviral infection. Recognition of viral components may also recognize products of endogenous proviruses.

Variants of innate immune system-associated molecules are reported to associate with various clinical diseases including cancer, infectious diseases and autoimmune diseases. Hundreds of articles focus on the genetic variation of Toll-like receptor (TLR) family which recognize various components of pathogens on the cell surface or in intracellular vesicles. Activation of the innate immune system could be done by stimulating Toll-like receptors in the endosomes. Thus, TLRs may be triggered by HERVs.

Other mechanisms have also been proposed. However reports about Retinoic acid-inducible gene-I (RIG-I)-like Receptors (RLRs), pattern recognition receptors, are much less common. Polymorphisms have been associated with resistance to various diseases.

Semi-endogenous viruses such as herpes/EBV contribute to disease, alarming the immune system through recombination with HERV repertoire of proviral sequences. EBV activates HERV-W/MSRV/sycyntin-1 in cells and antigens from other herpesviruses as VZV are able to induce higher activity in peripheral lymphocytes. The cellular equilibrium might be distorted by other ‘semi endogenous’ viruses as Hepatitis. Some recombinant products or viruses may have new properties, some being pathogenic due to access to a new target in the cell. This may result in immune suppression or immune stimulation.

Infections by a combination of (semi-)endogenous viruses often develop into running battles between the immune system and the viruses, with the virus repertoire mutating repeatedly to avoid the immune system, and the immune system repeatedly catching up. One can see the episodic nature of MS as such as running battle.
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Re: A new concept for MS and other autoimmune diseases

Post by Leonard » Fri May 01, 2020 7:22 am

I think that after my 10,000 hours I am getting into the flow of things. I am sure this is not an immediate solution for us or for MS but to know what it is is the first step towards prevention and effective therapies.

Based on the last few pages of this thread, the new grand theory might now look as follows:

1. The viral homeostasis
the redox homeostasis; immune homeostasis

2. Autoimmunity: viral recombination on the edge of the self
herpes virus and integrated retroviral elements; human endogenous retrovirus; protein/RNA recombination

3. Viral recognition and cellular response
MAVS and SNPs; cellular fitness; microbiome and methylation; heterogeniety of response and physiological trauma's

4. Unfolding
The oxidative stress mechanism; other compensatory reactions

A1. An example: MS
Last edited by Leonard on Sat May 09, 2020 8:35 am, edited 1 time in total.

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Leonard
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Re: A new concept for MS and other autoimmune diseases

Post by Leonard » Sat May 09, 2020 8:34 am

Critics might argue that herpes is a double stranded DNA virus and that it may not unravel that easily in the cellular machinery. And therefore that interaction with the HERV resulting in a repackaging of RNA material is not obvious.

But it has been known for some time that herpes viruses integrate smaller retroviruses in their genome. This is not entirely surprising as these viruses and retroviral elements are the result of billions of years of biological evolution.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC48371/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC190089/

If herpes, or perhaps also Hepatitis, a (semi-endogenous) virus that is absorbed by the cell is not sufficiently contained and controlled and may be partially unpacked (in preparation for replication), it is these integrated retroviral elements that may escape intra-cellular control and mate with other species from HERV proviruses putting the RNA reassembling process to work.

To this end, it is believed that cellular immunity does not only involve activation of phagocytes, T-lymphocytes and release of cytokines. But more importantly, that cell-mediated immunity probably has another very important component directed towards the internal machinery of the cell rather than to call for help from the outside. And that, when cellular antiviral recognition would detect viral recombinant activity, the cell would first try to quieten the process and regain control without alerting outside components. Which fit cells apparently do better than unfit cells.

My own experience with MS periodic light exacerbations would suggest such a course of events.

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Re: A new concept for MS and other autoimmune diseases

Post by Leonard » Sun May 10, 2020 2:13 am

In the years prior to my MS diagnosis and the major flare up, I had an agitated skin in the neck when shaving. I remember that a doctor from my employer where I was for an annual check up suggested to start using an after shave.
[Post script: Now that my memory comes back, I also had a stiff neck and enormous pressure on the nose, as if I had developed an allergy that I had never had before, and may be I had even a bit of an edema on my head. It felt like that. I had it for several subsequent years, the worst was always in the spring. I now think it was the nasopharynx and -maybe- the space above it... ]

I now think it was a sign of microbleedings caused by the Varicella Zoster virus (VZV), a herpes strain. And that it may have been part in the break of an already weakened Blood Brain Barrier because of vascular narrowings.

A few years before, I had been vaccinated three times for Hepatitis B (Engerix B). Apparently now the cells had lost control over herpes. This loss of cellular homeostasis may have been triggered by components of the Hepatitis B virus but also by vaccine adjuvants (see Vaccine Safety Conference Session 13 on https://forbetterscience.com/2019/06/26 ... l-academy/
to find it, scroll a bit down on this page).

From the literature, I learn that as part of complex interactions between herpes viruses and HERV, EBV retroviral elements may activate HERV in cells where antigens from other herpes viruses as VZV are able to induce higher activity. And clearly, the RNA recombination product may trigger immune reaction via MAVS/SNP recognition (essentially this is autoimmunity).

But activation of the innate immune system could also be done by Toll-like receptors if they recognize components of pathogens in intracellular vesicles. Or activation might occur if stimulated by vaccine adjuvants. OMG, this would imply that vaccination schemes will need to be (re-)examined to see whether adjuvants might disturb an (already weak) herpes/HERV viral homeostasis in the cell with possibly catastrophic consequences.

You may think this is all a bit far-fetched. And maybe it is. But if there is only the slightest chance that there is some truth in all this, it would be worthwhile to go after it and explore the matter with greatest urgency.

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Re: A new concept for MS and other autoimmune diseases

Post by Leonard » Thu Jun 04, 2020 3:56 am

Theoretical Immunology and Chronic Disease

A New Horizon for Thinking



Biological life on earth has evolved over several billion years on the basis of relatively stable DNA double helix structures. The development of the directly autocatalytic mechanisms fundamental to living systems began with the evolution of families of molecules that could catalyze their own replication. With time, a family of cooperating RNA catalysts probably developed the ability to direct synthesis of polypeptides. DNA is likely to have been a late addition where the accumulation of additional protein catalysts allowed more efficient and complex cells to evolve.

RNA stored both genetic information and catalyzed the chemical reactions in primitive cells. Only later in evolutionary time did DNA take over as the genetic material and proteins became the major catalyst and structural component of cells. Despite, the transition out of the RNA world was never complete; RNA still catalyzes several fundamental reactions in modern-day cells.

A complex network of RNA-mediated interactions dominated cell metabolism in the RNA world where both viral and cellular RNAs recombine with each other. Mechanisms not only contribute to the evolution of RNA viruses but also lead to the generation of recombinant cellular RNAs. Such recombination events between cellular RNAs may result in formation of biologically active molecules. As we shall see, even today ancient elements are still shaping immune response.


About 8 - 9 % of our genome is composed of sequences with viral origin, namely Human Endogenous Retroviruses (HERVs). HERVs are relics of ancient infections that affected the primates' germ line along the last 100s of millions of years, and became stable elements at the interface between self and foreign DNA. Most of HERVs pathogenicity has been erased over time.

Despite, HERV products including RNA, cytosolic DNA, and proteins are still able to modulate and be influenced by the host immune system. HERV expressed products have been shown to modulate innate immunity effectors, being related to on the one side inflammatory and autoimmune disorders and on the other side to immune suppression which might cause cancers.

At the same time, our cells may be infected by ubiquitous viruses such as herpes that are not eliminated but become hostage to the cell, that is they establish themselves inside the cell as latent “semi-endogenous” sequences. These viruses may carry “open” retro-elements. When the cellular immunity is insufficient or other infectious agents distort the cellular viral equilibirum, RNA from retro-viral elements from herpes may recombine with RNA from the entire HERV repertoire into new viral or RNA species. It is believed that here, on the edges of the self, lie the origins for autoimmune diseases, cancers and neurodegenerative diseases.


As a first line of defense against these new pathogenic products, in the course of evolution our cells have developed natural surveillance and detection triggers in the form of point mutations or Single Nucleotide Polymorphism (SNP). SNPs in HERVs are relatively common; and, as you would expect, they are often located in or close to those retro viral loci. Autoimmune diseases then show SNP markers near a specific endogenous retroviral locus located on the X-chromosome which explains the gender bias.

Mitochondrial Antiviral Signaling proteins (MAVS) coding-region SNPs act as common adaptor molecule and can recognize foreign RNA, including viral RNA, leading to an anti-viral response. As such, MAVS genes have a crucial role in antiviral signaling while genetic variation of MAVS results in susceptibility to diseases. The distribution of MAVS in or near the mitochondria is vital for its role in antiviral signaling.

Upon viral challenge, MAVS initiate a cascade of signaling events eventually leading to the production of type I and III interferons which in turn trigger the transcription of interferon-stimulated genes to restrict viral spread. The processes are dynamically regulated, resulting in a downstream signal for the anti-viral state. The sensing of viruses and signaling pathways are tightly regulated, determining the duration and magnitude of immune responses to ensure viral clearance and immune homeostasis. Dysregulation may lead to various inflammatory and autoimmune diseases.

Upon viral challenge, if cells are fit enough, the debris and pro-viral content will be effectively contained and controlled inside the cell, and cells will revert back to a silent state, for years. This cellular fitness is influenced by various factors including critical life-elixirs during the early phases of cellular growth such as Vitamin D during pregnancy and childhood.

Later in life then, cellular fitness later is influenced by the gut microbiome which co-evolved with the genome for more than 2 billion years and controls the epi-genetic state of the cells such as the methylation and acetylation state. Our modern lifestyle, our poor diet and in particular the widespread use of antibiotics may negatively affect the microbiome. Cellular fitness might also be negatively affected in cellular redox signaling pathways by insufficient enzymatic anti-oxidant activity through for instance a short of trace elements caused by soil depletion and hydroponic plant growth.

On the positive side, fasting resets the microbiome and improves the epi-genetic state of the cells whilst cellular starvation induces new mitochondrial dynamics which enhances the cell’s antiviral properties. Hence, fasting is a lot more than just a religious tradition as it augments cellular state and cellular fitness and directly contributes to a healthier society. Other factors influence cellular and mitochondrial fitness.

Also vaccinations and the use of adjuvants are suspect as they may distort the cellular immune homeostasis.


Besides the cellular fitness, there are numerous other influences that may affect the effectiveness of the response to viral challenge such as the fitness of the microglia, and the immortalized nature of memory B cells. For that, in the course of evolution, the basal cellular early signaling and oxidant mechanisms in worms developed into higher layers and adaptive immune mechanisms in vertebrates.

If the pathogen can not be contained in the early phase after the ‘danger’ signal from the cells, other weapons of immunity are called in a sequential immune response. Cytokines will call for outside help, escalating the immune ladder and mobilizing more heavy armory as antibodies and T/B lymphocytes.

The cross reaction of these immune cells with infected and expressed cells will result in tissue damage and lesions. At all times, it is believed that a complex immune homeostasis is maintained where immune intervention is believed to be proportionate to the danger resorting maximum immune response with minimum tissue damage done. However, in the interaction between the basal oxidative stress mechanism and higher layer immune lymphocytes, correction mechanisms may lead to cell and tissue damage and cell apoptosis.


In the case of MS, when the cellular equilibrium is challenged by a pathogen or immunity is low, the herpes in the nasopharynx will be reactivated. Slowly, the virus will percolate into the CNS where Zoster, an omni-present herpes strain, will breach an already weakened Blood-Brain Barrier enabling herpes virinae including herpes Zoster and Epstein-Barr to anchor in Oligodendrocyte Precursor Cells (OPCs) which are fast dividing cells as well as in axons. If these latter cells can not contain the virus effectively and RNA recombination occurs with HERV, the cellular signaling cascade will start and launch an inflammatory stage. The autoimmune mechanism will trigger intervention by rogue T cells which damage myelin and nerve cells. In the progressive stage, EBV immortalized B cells and highly local inducible nitric oxide in damaged tissue cause high oxidative stress followed by further mitochondrial and eventually cell starvation. Then, over time, the diffuse control of muscles and the declining ability to recharge the ion-pump and compensatory mechanisms cause muscle relearning and gradual mobility impairment.

But besides MS, the theory sketched gives rise to all sorts of autoimmune diseases and comorbidities depending on where in the body the inflammatory activity and highly localised oxidative stress develop as a result of prior viral anchoring and cellular trigger. Other neurodegenerative disease like Alzheimer's and Parkinson's are also believed autoimmune and to find their causal factor in the immune theory sketched above. Epidemiological research then has clearly shown that even cancers are seen to be inversely dependent upon the exposure to sunlight and the acquired cellular fitness during the early years of life.


The growth of autoimmune and neurodegenerative diseases is alarming. At the same time we see an emerging epidemic of lymphomas worldwide. Increasingly strong evidence would suggest that the trend is linked to some characteristics of our modern lifestyle, notably the countless environmental triggers that we are exposed to every day. Several of these influences of cellular fitness have been mentioned above. Our modern Western lifestyle over the last 50 years – in the anthropocene - has led us down a very dangerous path.

The thorough in-depth understanding of cellular immunity, the role and trigger functions of cellular surveillance and the influences of cellular fitness on our immunity are key to divert the dangerous path we have entered as a society. This analysis presents a coherent framework for thinking to stimulate insightful discussion. It is offered to interested parties to investigate the alternatives, connect interdependent innovations and insights that enhance the theory and proposes ways forward.

Given what is at stake, public intervention and consultation would also seem logical. It is the task of government, any government, to provide security for its citizens. Governments from around the world should initiate new medical health initiatives. The scourge of chronic diseases which will soon affect well over 25 percent of our societies and is growing fast merits an urgent effort at scale to clarify and address the underlying causes.

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Re: Theoretical Immunology in a Global Crisis

Post by Leonard » Fri Aug 07, 2020 7:52 am

On the basis of the last dozen postings or so, I started to put together a document, a sort of a thesis if you wish. But then, after I collated the postings, I felt a need to add other things where there were holes or where things got insufficient attention. With that, unfortunately, the document got bigger and bigger.

I admit that as part of the process I still had to go through a learning curve. And perhaps things are still not perfectly in balance, as such you should see it as work in progress. Nonetheless, as the document has already spread is some circles, I see no reason to withhold you the document in its current draft status. You find the document here below (V2.2 26 Aug 2020):



In the middle of last month, I was offered the opportunity to present my view on autoimmunity and cellular fitness to about 60 (auto)immunologists from across the whole world, many of them professors in the field. My presentation was said to be I quote very very very interesting. I think many of them will now dwell on the new thinking. You find the presentation below:




I see that slowly, very slowly, the new thinking gains traction in the circles of immunologists. Also national patient organizations of MS and rheumatoid arthritis are showing interest. I guess these latter are in a sort of limbo and don’t know anymore where to go or what to do. That is hopeful because I think that helps set conditions for change.

If anyone reading here would like to comment, please do so. You find my email address on the first page of the presentation. Thanks a whole lot. I think we are making important progress.
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Re: Theoretical Immunology in a Global Crisis

Post by Scott1 » Fri Aug 07, 2020 4:45 pm

Hi Leo,
It would be interesting to watch a video of the presentation you gave. A running commentary would add color to your presentation slides.

Regards,

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Re: Theoretical Immunology in a Global Crisis

Post by Petr75 » Sat Aug 08, 2020 1:55 am

Hi Leo.
You worked a lot of time on it .. good work.

It is, however, possible to get the main idea into a few sentences, or abstract?

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Re: Theoretical Immunology in a Global Crisis

Post by Leonard » Sun Sep 13, 2020 7:11 am

Hi Scott,
I don't think it would be the appropriate thing to do to share the video of the presentation here. Sorry for that. I normally attach great value to openness, but in this case maybe better not. We need these people for our cause. I believe ongoing discussions are best held in the private sphere of these immunologists.

Hi Petr,
Last week, I gave a presentation to the group for a second time. I think the presentation captures the main idea in a single slide, see the link.


My first encounter with the group of immunologists tells me how far the sector has to come. And these are just the immunologists who don't even own MS, who are just bystanders, let alone the neurologists who created an enormous world around MS and - I believe- have become by and large the prisoners of their own perceptions.
It is encouraging to see that the new horizon for thinking starts to make some waves in the circles of immunologists. We can only hope for the best that things will eventually change.

Regards,

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Re: Theoretical Immunology in a Global Crisis

Post by Leonard » Wed Oct 07, 2020 9:18 am

On the basis of the above work and some further input, I prepared the attached draft paper on autoimmunology.
It complements the above document on Theoretical Immunology.




For many professionals, after some initial enthusiasm, the new thinking is probably a bridge too far. A British professor captured the situation very well when he said: "The world isn't ready for this'.

If there are professionals reading here who would like to engage into further discussion, please send me a PM or an email with your name, contact points, affiliation and expertise.

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