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ipsa scientia potestas est

If knowledge itself is power, what results from profound ignorance? Whatever that is, I think it describes the way medicine has dealt with the immune system. Prior to Pasteur (ca. 1870) I would describe understanding of immunology as entirely anecdotal.

We have learned a lot since then, but haven't come quite as far as you might think. It would now be awkward to produce baseball cards for all the different types of immune cells. Nobody would expect to complete their collection, and we aren't entirely sure on which team they are playing at any given time. What has been missing from view is a coherent active system.

Added: Some private questions indicate I've failed to make a good bit of this clear. My comment about not knowing which "teams" immune cells were playing on concerned known problems with, e.g. T-suppressor cells, which are underactive in such diseases as rheumatoid arthritis and multiple sclerosis, and overactive in many cancers. (This is not late-breaking news.) These cells are then a problem in adoptive immunotheraphy for cancer because they are busy protecting tumor cells to prevent damage to "self". This has resulted in the drastic step of combining general leukocyte depletion with adoptive immunotherapy, severely damaging the entire immune system to get rid of a misbehaving minority of cells. This is a real problem because the immune system will be needed to clean up the mess as the cancer is destroyed. Careful targeting of only those cells running interference for cancer works better. It would be nice to know what is going on before and during treatment.

While there are new discoveries in immunology almost every day, those in the last few weeks illustrate just how ignorant all experts have been in the past. The biggest surprise was the discovery that the brain has a lymphatic system. This means that a great deal of conventional wisdom about "the blood-brain barrier" is flat wrong.

There are differences in the rates at which different molecules move from peripheral blood to the brain, but these are tiny non-living things. The discovery that leukocytes are moving out of the brain consistently enough to require a vascular system changes the picture dramatically. Since these cells do not originate inside the brain, there must be a steady traffic into and out of the brain. Compared to the size of some molecules kept out these cells are huge. It is like discovering your shark net lets supertankers through.

An earlier discovery, which got much less press coverage, concerned the way communication between B-cells and T-cells controls recruitment of cytotoxic T-cells to inflamed tissues, especially endothelial tissues.

(See Homeostatic regulation of T cell trafficking by a B cell–derived peptide is impaired in autoimmune and chronic inflammatory disease.)

This did not have specific relevance to the brain, but the mechanisms appear to be quite general for endothelial tissues, and these occur in many places in the body. The mechanism by which T-cells carried by peripheral blood enter tissues are sophisticated, and generally take place where vessels are small, making them harder to investigate in the absence of conspicuous lesions. Cell entry takes place in stages moving from rolling contact to stopping to invasion of tissues. All the tissues lining these vessels present laminins on their surface, which immune cells recognize. A variety of molecules like adherins and integrins perform functions in those different steps. We have just learned that some of the signals passed from B-cells to T-memory cells, etc. to control recruitment of more cytotoxic T-cells are in the form of a 14-unit peptide. This had been overlooked because it is a subunit of a normal protein. (Researchers still have not identified the enzyme which cleaves this.)

Research on autoimmune diseases has concentrated on finding antibodies to "self", and suppressing these. This has not been an unqualified success. In many cases the treatment may be worse than the disease, which limits interventions to a late stage of pathology. This pretty well rules out any means of preventing the development of autoimmune pathology. It also means thresholds for diagnosis are set high, ignoring possible preclinical conditions.

Some diseases which do not directly fit this paradigm are now being called "autoinflammatory". Questions about recruitment of cytotoxic T-cells are dead center in this research effort.

Mechanisms by which leukocytes enter lymphatic ducts are much less studied. What we know so far is that these ducts are marked by specific laminins, like most endothelial tissues, and lack the adherins and integrins active in movement from the bloodstream to tissues. Some known mechanisms for entry to lymphatic ducts also appear to be sophisticated.

What guides immune cells in their movement? In general we talk about chemotaxis. This is commonly assumed to mean they are attracted or repelled by certain molecules floating free in their local environment. This is merely part of the story because not all molecules are free. Cells also "feel" out the shapes of molecules presented on cell surfaces, and not just those commonly designated as epitopes. Experiments with immune cells moving on lung tissues have shown they follow paths marked by specific laminins. This is a common mechanism for cell membranes which also controls the entry of Schwann cells to neuromuscular junctions and glial cells to nerve synapses. When the wrong molecules are presented on the surface, those cells enter synaptic clefts, destroying the synapse. This is called "synaptic stripping".

Added: this is not simply limited to pathological conditions. The vast majority of receptors in the brain are blocked by glial cells sitting on top of them. Whenever the cell needs to form a new synapse it must change the surface molecules to end this "glial blockade". Every synapse in the brain is subject to this.

All of this takes us back to that discovery of a lymphatic system between the meninges and the dura. This was not visible to the eye, and was destroyed if the dura was separated during dissection. It became apparent when leukocytes in this region were found in lines or branching structures. Testing these surfaces revealed the laminins characteristic of endothelial tissues in lymphatic ducts.

Tracing these ducts to a destination showed that leukocytes leaving the brain are channeled to deep cervical lymph nodes (in the neck). Going in the other direction the network becomes more complicated, and I'm sure more discoveries will take place there.

Several immediate implications of this discovery spring to mind. For example, why the classic sign of acute bacterial meningitis is a stiff neck. Another is the mysterious delay in bizarre symptoms caused by a subdural hematoma, which puzzled medical researchers long ago. Had we been talking about a blocked lymphatic duct in the liver there would have been no puzzle. Here's an old paper which explicitly says that this required a special explanation because the brain was "known" to have no lymphatic system:

Two more implications have since struck me: 1) episodes of localized hypoperfusion in parts of the brain causing migraines or TIAs could be caused by problems in previously unknown lymphatic ducts adjacent to blood vessels in meninges; 2) endocrine organs within the brain can also be subject to damage due to invasion by leukocytes if these cells are not removed promptly. I am particularly interested in the mysterious example of pituitary damage like hypophysitis, for which estimates of incidence range from about 1 in 10,000,000 to 1 in 6, indicating we don't really know much. (I'm guessing rates for non-traumatic pituitary damage by immune cells run at about 1 in 40.)

(I feel the need to warn people that there is a difference between most endocrinologists and those specializing in pituitary problems. You have to choose the subspecialty of your expert fairly carefully when you have such a problem.)

While I have previously mentioned the role of serotonin receptors outside the brain in the autonomic nervous system, and the peculiar fact that fluoxetine strongly inhibits replication of the enterovirus Coxsackie B, something which seems to extend to other SSRIs, I'd now like to mention that large classes of immune cells have serotonin and dopamine receptors. These tend to be ignored by neurologists. Together with some other data, which are harder to interpret, I'd suggest that many kinds of psychotropic drugs function primarily as immunomodulators.

Anyone who recalls the origins of antidepressant drugs should not be surprised. Clinical trials of isoniazid on TB patients led to the unexpected discovery that some experienced much better affect, amounting to euphoria, even though their infection remained unchanged. This ultimately led to the introduction of MAO inhibitors like phenelzine. Isoniazid is still effective against many strains of mycobacterium tuberculosis, though it is usually combined with something like rifampicin.

A second class of antidepressants, tricyclics, was derived from antihistamines. So was the antipsychotic chlorpromazine. I hope I don't have to tell anyone that both antibiotics and antihistamines are related to immune responses. You should also have no trouble finding accounts in medical literature of psychotic episodes during anaphylactic reactions. Off-label uses of chlorpromazine include treatment of severe migraine, which takes on new significance with the discovery of a lymphatic system in meninges. (Haloperidol, a related antipsychotic, is also used in emergency medicine to rapidly lower blood pressure; it is not just for psychosis. That said, you probably do not want to give such drugs to patients already experiencing orthostatic hypotension, something many doctors may do. In an institutional setting it may be considered an advantage for the patient to be confined to bed most of the time.)

One of the ironies in this history is that isoniazid was first synthesized in 1912, at the height of the battle against TB. It remained on the shelf until other antibiotics were discovered many years later. You can trace the history of other drugs which might have played a role in the treatment of TB, but did not, back to about 1870 -- before mycobacterium tuberculosis was identified as the pathogen causing tuberculosis.

As for antipsychotic drugs, I've long suspected the warnings about seriously depleting classes of immune cells for older antipsychotic drugs implied powerful changes in immune response. In this regard I will also mention that in a few cases minocycline has reversed symptoms of schizophrenia -- if given for other indications right at the time of onset. Waiting for a year or more gives possible pathogens a chance to establish themselves. The distinction between antibiotics and antipsychotics is still not sharp.

One particular pathogen is the parasite toxoplasma gondii. In acute toxoplasmosis this has been known to produce symptoms of schizophrenia. We also know that the vast majority of those infected do not display signs of acute infection. Minocycline can be used to treat this, but is probably not the treatment of choice. T. gondii is also known to form cysts, when under attack by drugs or immune response, which are very difficult to eradicate. Immune response to the parasite may also cause the illness via inflammation.

Now, consider a natural question concerning mental illness and problems with immune response, did many of those early depressed or psychotic patients have an undetected organic disease? This is not a trivial problem.

At one time about 10% of those in mental hospitals had syphilis, a single infectious disease caused by the spirochete treponema pallidum. Depression, mania and schizophrenia serious enough to satisfy any psychiatrist can all result from neurosyphilis.

(True dementia with gross changes in the brain also often results from long-term infection by spirochetes. Controversy about finding spirochetes in brains of dementia patients at autopsy, and which are responsible, could be resolved if the disease were redefined as an immunological failure.)

Fatigue and depression are well-known problems in management of TB patients. Koch's work on m. tuberculosis was done in the context of a battle against doctors who flatly rejected germ theory. His postulates were designed to eliminate ambiguous cases, as were the diagnostic criteria for TB the medical profession finally settled on. If the disease was progressive, with rapid reproduction of pathogens, and the outcome was likely to be lethal there could be no question that patients were suffering from organic disease which could be measured with objective tests. Some of these tests might be done at autopsy, but that was no problem for professionals, only for patients.

Today we know that some 90% of those infected with m. tuberculosis do not exhibit signs of acute disease. Those who exhibit acute disease immediately after the time of infection amount to only 1% to 5% of those infected. Koch's available tests were not sensitive enough to detect most cases of latent infection. This means that 95% to 99% of those infected have immune systems capable of holding acute infectious disease at bay for some period of time. Had there been tests of modern sensitivity producing a yes/no answer about infection, those fighting against germ theory could easily have argued that the presence of m. tuberculosis was a consequence of disease rather than a cause, because essentially everyone in urban environments at that time was exposed to active cases of TB.

Thresholds for diagnosis were largely set by the presence of conspicuous signs or by visible bacteria in convenient samples. Most clinical tests were adjusted to match diagnosis by the best available experts. Doctors generally did not want to know about infections that were not causing acute disease. Historical contingency became enshrined in standard practice.

(This happenstance is hardly unique. A similar adjustment of clinical tests to match diagnosis via clinical signs took place in tests for autoantibodies when some tests came back positive in cases where doctors had not diagnosed autoimmune disease.)

The result is that we simply do not know what percentage of depressed patients in early trials also had infectious diseases which did not produce the clinical signs of acute, progressive disease. With the limited rates of responders in trials of modern antidepressants we cannot say that any of these completely eliminate either depression or the possibility of accidentally treating undetected organic disease. In addition we now know later "rationally designed" antidepressants effective in patients may also treat such things as enterovirus infections, a possibility frankly dismissed in that "rational design" aimed at changing affect alone.

( Note: when patients are psychotic the problems in conducting trials are worse. Consider the handwritten notation on a urinalysis describing one sample: "ginger ale".)

At this point I want to draw attention to a report of severe treatment-resistant schizophrenia following stem-cell therapy.

The patient needed stem cells because of cancer treatment. His brother was physically healthy, but schizophrenic. After cells from bone marrow were transferred, the recipient also developed schizophrenia that did not respond to treatment.

The easy inference would be that his brother had an inherited genetic defect which caused schizophrenia. This is not quite as simple as it looks. Ideally, healthy stem cells from bone marrow would be the only thing transferred during treatment. Unfortunately, we know of a range of infections which can enter cells in bone marrow, given enough time. That brother had been schizophrenic for many years. We are left with a choice between an inherited defect in immune cells in bone marrow leading directly to schizophrenia, or an immune defect in those stem cells making them susceptible to infection by an unknown infectious agent, or an autoimmune/autoinflammatory response damaging the brain. None of these options, all taking place outside neurons, looms large in contemporary psychiatry.

At this point many readers will have pigeonholed this post as a diatribe against psychopharmacology. They might well have forgotten that I was also talking about infectious diseases not normally considered psycho-anything. What about diseases not generally regarded as infectious?

Several examples of lymphomas show improvement when treated with rituximab. This is a monoclonal antibody (hence the -mab) which selectively depletes CD20+ B-cells. This does not necessarily explain why it offers improvement in autoimmune diseases like rheumatoid arthritis (RA), multiple sclerosis (MS) or systemic lupus erythmatosus (SLE). The list does not end there, and most readers here will be aware that some people treated with rituximab early in the course of ME/CFS have recovered substantially. The best hypothesis for why it works is that it is depleting defective B-cells which are then replaced by undamaged ones from bone marrow. If the B-cells in peripheral blood are damaged or infected, and those in bone marrow are not, this makes some sense. If the defect limits production of the peptide found in the research above on recruitment of cytotoxic T-cells to inflamed tissues this would again fit. Stay tuned for more research.

A variety of leukemias/lymphomas have been treated with adoptive immune therapy. In this case immune cells are extracted from a patient's blood, sorted to a particular desired type, stimulated to divide, and cloned in vitro. When enough are available these are reintroduced to the patient's body, and attack very specific target cells. When this target is chosen carefully the results are like magic. Literally "pounds of cancer cells simply melt away". Toxicity is low in those cases -- in contrast to traditional cancer chemotherapy.

Past problems with immunotherapy for cancer came from attempts to attack well-established tumors and cells which were results rather than causes of disease. It seems to me that there has been a blind spot in oncology toward the immune system, with most treatments of cancer damaging many parts of immune systems indiscriminately. The idea that the problems stemmed from a tiny proportion of cells which were misleading others because of errors in signalling was too abstract.

What researchers seem to have been missing was the extent to which people subject to environmental insults did not get cancer. You could hardly come up with a nastier insult than a pack-a-day cigarette smoking habit regularly putting carcinogens directly into the lungs. Even in this outrageous case the resulting lung cancers typically appear 30 years later. That is also a period in life when immune senescence begins.

We don't have any good measure of how effectively immune response is working, unless you have an infectious disease or a very serious immune defect. What we can deduce indirectly about the rate at which immune systems age fits remarkably well with statistics of cancer incidence. Other degenerative diseases follow the same pattern.

We have also lived through a period when AIDS has illuminated the role immune systems play in many diseases. An unquestionable acquired immune defect leads to an explosion in incidence of both infectious diseases and cancers. I can't even list all the conditions made worse by HIV infection. Nature is giving us very strong hints.

New research came in literally while I was writing this post. Another foundation stone of immunology appears wobbly. New research has just discovered that dendritic cells in the gut can communicate with monocyte precursors in bone marrow to start "programming" them for the particular activity they will need to engage in once they reach peripheral blood. Toxoplasmosis is one disease which triggers this.

This goes some distance toward explaining that mysterious case of acquired schizophrenia mentioned above. Our problem has been that we have been studying immune systems as if they were simply a collection of components without much understanding of the system they form by interacting.

I also hope that I have made clear above just how arbitrary our divisions between medical specializations are, and how much they are the result of historical contingency.

(Just counted three infectious disease specializations alone: bacteriology, virology, parasitology. Other specializations: immunology, endocrinology, hematology, rheumatology, oncology, neurology, gastroenterology, psychology, psychiatry and pharmacology. Somehow avoided directly mentioning cardiology, pulmonology, dermatology and hepatology.)


More questions about endothelial dysfunction, and why I think it important, cause me to restate something touched on above. Every organ with substantial vascularization is vulnerable to endothelial dysfunction and localized diffuse inflammation, but we seldom notice until the problem becomes more serious. In addition to the brain, stomach and gut, mentioned above, this includes the heart, lungs, liver and kidneys. It would be hard to find a physiological problem less suitable for current gerrymandering by organ systems. The problem with ME/CFS is not that it is marginal or trivial, but that a powerful selection effect has already removed all the easily identified examples of conspicuous damage to specific organs, and all the patients with convenient clinical signs, before you reach any doctor specializing in ME/CFS.

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