limited immune impairment: a work-in-progress

One principle I picked up over several careers was that if a group of intelligent and reasonably hard-working people have failed to solve a problem, after a sustained effort at finding a solution over a considerable length of time, finding a solution might very well require systematically violating various rules and shibboleths governing group behavior. While this has regularly been taken as simple "bloody-mindedness" (British term), it is in fact a testament to my faith that they are intelligent and hard-working, but following rules which preclude solution. Sometimes it works. (This kind of reasoning is called heuristic.)

(It is important when you do this to distinguish rules whose violation leads to mere outrage from those for which lapses lead to explosions and similar drastic phenomena. Once you have made this distinction, you may take an injunction like "Don't push that button!" to mean the opposite, as I once did. The problem defies solution because it hides in a blind spot. "If it ain't broke, I can't fix it.")

This preface is necessary to explain that I am not at all discouraged by various "proofs" that the illness cannot be viral. I expect it to violate common virological expectations. If this were an easy problem it would have been solved long ago by people without exceptional skills. This makes it intellectually interesting. What follows is not a finished piece of reasoning, it is a work-in-progress.

(I want to reassure other patients that my concentration on extreme possible outcomes below does not reflect actual likelihood. Even if statistically rare consequences are enhanced in this disease, they remain far from inevitable. My reason for such unbalanced emphasis is that these unambiguous outcomes may reveal aspects of pathology which would be lost in a typical subjective checklist approach to diagnosis. If you are overly imaginative, it might be better to skip this post.)

This line of reasoning began years ago with the simple suggestion that a virus found in prostate cancer might also be linked to a variety of mysterious problems in many organ systems. Behavior of the corresponding class of viruses in several other species pointed to infection of reproductive organs, lymphatic organs and mucosa.

In the prostate, prior to prostate cancer, there are often repeated bacterial infections, which might be due to one kind of immune impairment. There can also be a peculiar problem more common with ME/CFS than in other conditions, chronic non-bacterial prostatitis. In women, there is a parallel in a poorly understood condition called interstitial cystitis. (Why it is called this is a matter of history. At present the problem is a real mystery which could be called anything.)

Several factors, some of which I cannot yet express clearly, led me early on to the assumption we were dealing with a very limited and specific type of immune dysfunction, except in the most horribly extreme cases. One idea I can articulate is that this might serve to benefit both host and pathogen.

Specific limited local immunity would allow the virus to persist in tissues for which it has a tropism without seriously impacting host response to pathogens in general. For the host, specific and limited immunity could allow infection to confer a benefit such as increased fertility through local immune tolerance, say in the ovaries and testes. A persistent pathogen in reproductive organs might well behave in exactly this way.

The immune behavior most of interest to me here has been the adaptive immune response. Within that I have had a special interest in specific markers and what are termed "professional phagocytes". These use highly specific markers to control interactions with other cells, including other immune cells.

The shift in markers from CD19 to CD20 in both this illness and in various leukemias/lymphomas which appear to be associated caught my eye long ago. CD19 appears on mature B-cells, and is a sign they are ready to participate in interactions with other components of the immune system. These interactions typically involve direct contact, even the formation of immunological synapses. I started thinking about what might happen if a virus were passed through such contacts.

A number of people far more active and knowledgeable than myself were interested in this shift in markers. This has now resulted in clinical trials of Rituximab with very interesting results. I'm sure they did not get the idea from me. Relapses after treatment would be expected if B-cells are being reinfected by other infected components of the immune system. Infection via immunological synapses would leave little evidence of free virions.

One important distinction I made early on was that I did not expect infection to cause massive cell death. That was one giveaway which would have made infection easy to find. In particular, it would distort the numbers of different classes of cells in a complete blood count (CBC) or flow cytometry in consistent ways. There are changes, but they are maddeningly variable. My assumption has therefore been that infected cells typically survive, but with altered behavior. Cells are less often destroyed than deranged.

At the outset, I was merely creating an abstract model of pathology which would reduce the exposure of the pathogen. This would have evolved to evade immune response, but would also serve to defeat research. The simplified model was that proliferation of proviral sequences mainly took place during clonal expansion of immune cells, without active virions. When virions were passed to other cells they were passed through immunological synapses without ever appearing as free virions.

At some point I realized that the model would allow virtually the entire pathology to develop without ever expressing free virions, provided it worked with a machine-like precision rarely seen in biology. Infected B-cells could pass virus to T-cells, either directly or via an intermediary like dendritic cells. Infected monocytes would ultimately result in infected macrophages, following an immune challenge.

One key requirement of this model was that virions must be able to enter cells through receptor/coreceptor pairs which play important roles in immune response to similar viruses. For this reason I looked for evidence in published research of the virus infecting cells marked with CD4 or CD8, but lacking the XPR1 receptor already known to allow entry. A cell line with CD4, but not XPR1 did appear to be susceptible in vitro, where there is no immune system to infect. Later in vitro research showed virus infecting neurons via CD4 T-cells. Two small predictions based on the model worked out.

(I still don't know if the virus can directly infect T-8 cells, or whether it would have to infect through an intermediary. My guess is that cells with CD8 will also be directly susceptible.)

Now, it was time to stop tinkering with my toy model, and start considering how it would look if implemented in the slipshod manner of many real biological processes. Free virions would be rare, but not completely absent. They would appear sporadically in particular contexts where immune dysfunction was known. They would be maddeningly hard to trace to exogenous sources. The simple inference would be that these must be endogenous sequences, which they resemble, that somehow became activated by chance. They would be dismissed as irrelevant artifacts of disease instead of causes. This exactly describes the appearance of research on a list of diseases where progress in research has been very slow and etiology remains unknown. Whether this is due to a real underlying cause remains to be determined.

The immune system has any number of remaining mysteries. The model long taught in medical schools, in which various classes of immune cells are trained to distinguish "self" from "other", is inadequate for a very important immunological task -- protecting interfaces.

For example, in the lungs capillaries must be so close to outside air that oxygen molecules can diffuse in, and carbon dioxide molecules out, during a brief exposure while blood passes through the lungs. Outside air can contain particles and pathogens. It is literally vital that the air have intimate contact with blood in capillaries at all times. The naive model of immune response might leave all of us with asthma, because those foreign particles are all around us. Simply detecting something which is "non-self" should not by itself trigger a strong response.

Mucus secreted by the lungs turns out to be teaming with life. Literally hundreds of novel viruses have been found in the lungs of healthy people. Most of these serve to keep the population of bacteria, yeasts and fungi under control.

Digestion requires another immune interface. Bacteria essential to digestion must be allowed to thrive in the gut, close enough to capillaries in mucosa lining the gut so that fairly large molecules from food can transit tissues into the bloodstream. However, those same bacteria should never be allowed in the blood where they could cause a fatal septicemia. When you realize that these bacteria outnumber human cells in the body, you get a feel for the scale of the problem.

A third interface is the blood/brain barrier. The central nervous system can't be bothered with the attentions of blundering immune cells, it has its own community police force which recognizes that most of the chemical signaling in the brain is for purposes unrelated to immunology. Immune impairment here could have very serious consequences, like infections resulting in seizure disorders.

There have long been rare reports of cases of viral encephalitis caused by ubiquitous herpes simplex virus, which is in nearly everyone, but generally does not cause encephalitis. Recently, herpes virus was linked to medulloblastomas deep inside the brain. What is it doing there, and why isn't it eliminated before it causes a lethal tumor?

A fourth interface is the skin, which is so complicated as to be the subject of a great deal of research I have not even begun to read.

One clue that immunological interfaces are disturbed could be irritable bowel syndrome (IBS) which regularly shows up with ME/CFS. A more obvious and accessible breakdown takes place in the development of peptic ulcers, which are known to be caused by helicobacter pylori. (Are peptic ulcers at increased incidence in ME/CFS?) The problem is that h. pylori is detectable in about 50% of people, most of whom do not have ulcers. Something is disrupting normal immune system operation in the case of peptic ulcers, and these are closely associated with stress and production of glucocorticoids. (Remember the glucocorticoid receptor elements in the LTR of this class of viruses?)

The model would naturally lead to disturbed behavior by infected macrophages. These would arise naturally from infected monocytes when an immune challenge caused their transformation. What holds true in the stomach and duodenum would also be true at the end of the digestive tract, but with different pathogens and macrophages. In that case, we might have an explanation for ulcerative collitis. With an underlying viral cause we might expect the same kinds of changes to appear in both ulcerative collitis and colorectal cancer. Recent research has identified fusobacterium as a common factor in both. Have we reached the bottom of this mystery?

At the beginning of the process of digestion we find glands which add saliva to food being chewed. Infected sublingual glands and parotid glands do show up regularly in this disease. Some cases have gone on to develop cancers of these glands.

Cancer tumors do not always result from the transformation of a cell into a cancerous form. You can take laboratory animals like mice, chosen to be immunologically similar, and attempt to transplant a single tumor cell from one to another. The most likely result is that the cell will be destroyed by immune response before it results in a tumor. It takes deliberate effort to produce laboratory models of many cancers. Some are much, much harder than others.

We simply don't know how often healthy bodies eliminate single cells which transform into cancer cells. Unless the cells begin the clonal expansion of growth characteristic of cancer we don't see any effects from the elimination of single cells. They are lost in the background noise of a living body. Cancer is as much a disease of impaired immune function as any infectious disease.

One small way of testing ideas without a laboratory is to make bets with myself. One such bet occurred to me when I had reached the point just described. If cancers resulted from impaired immune response on mucosa, and so did bacteria responsible for peptic ulcers, there should be a correlation between those bacteria and certain classes of cancers. News reports about famous deaths due to pancreatic cancer prompted me to guess that exocrine pancreatic cancer (the pancreas is both an endocrine gland and an exocrine gland with a duct leading to the digestive system) would show a correlation with helicobacter pylori infection, even in the absence of peptic ulcers. This turned out to be true. A tiny bit of support for the idea, and another chance to be wrong avoided.

Another place where glands dump secretions into the digestive system is at the junction of the esophagus and the gastric cardia. Are the changes resulting in esophageal adenocarcinoma preceded by changes due to impaired immune activity in this region? The glands are there, and changes take place, but at this time I can't say if locally impaired immune response is behind the damage.

This model does seem to be generating pertinent questions.

To be continued


While a great deal has changed in news about ME/CFS, I've felt little need to modify what I have written. I have also discovered I am far from the first to reason this way.

A paper on HTLV-1 written in 2009 and published in the journal Blood/Hematology contains the following description of transmission of HTLV-1:
Naturally infected lymphocytes produce virtually no cell-free virions in vivo, and cell contact is required for efficient transmission of HTLV-1 between cells and between persons.
If a human retroviral disease can spread with so few free virions, it follows that it will be hard to find such virions. Likewise, antibodies generated in response to those virions will be reduced. This leads to questions about asymptomatic carriers. These turn out to be a big problem for HTLV-1 control. I'm far behind the leading edge of research on asymptomatic HTLV-1 carriers.

Currently, blood is screened for HIV using both serology and PCR tests. Screening for HTLV-1 uses only serology. If new work on asymptomatic carriers and proviral load is correct, we could be missing a significant fraction of HTLV-1 carriers. This would help explain the continued spread of HTLV-1.

Someone needs to tell virologists their eternal verities about viral behavior have already been falsified w.r.t. HTLV-1.
My reference above to h. pylori was only a sidelight on a very active field of research. The connection between h. pylori and gastric cancer, via direct damage to tissues, seemed obvious. I was looking for less obvious connections which might indicate a common underlying pathology not tied to local damage. These keep turning up, as in this reference to h. pylori and mitochondrial disease. We still don't know why large numbers of people have this infection while large numbers of others do not.
Very interesting following your reasoning here anciendaze (well I'm no scientist) but despite current findings and complexities faced, it's surely deep thought and reasoning needed to unravel immune and disease processes more.
We need a Steve Jobs in the medical field though. Someone who thinks out of the box. Someone who can come up with a theory that is obscure to everyone else.

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